rs1800206

n-3 Long-chain PUFA (LCPUFA) can improve cardiometabolic blood markers, but studies in children are limited. SNP in the FADS genes, which encode fatty acid desaturases, influence endogenous LCPUFA production. Moreover, SNP in genes that encode PPAR and apoE may modulate the effects of n-3 LCPUFA. We explored whether FADS polymorphisms were associated with blood cholesterol and TAG, insulin and glucose and whether polymorphisms in PPAR and APOE modified associations between FADS or n-3 LCPUFA status and the cardiometabolic blood markers. We measured fasting cholesterol and TAG, insulin, glucose and n-3 LCPUFA in 757 Danish 8-11-year-old children and genotyped SNP in FADS (rs1535 and rs174448), PPARG2 (rs1801282), PPARA (rs1800206) and APOE (rs7412+rs429358). Carriage of two FADS rs174448 major alleles was associated with lower TAG (P = 0.027) and higher HDL-cholesterol (P = 0.047). Blood n-3 LCPUFA was inversely associated with TAG and insulin in PPARG2 minor allele carriers and positively with LDL-cholesterol in major allele homozygotes (Pn-3 LCPUFA x rs180182 < 0.01). Associations between n-3 LCPUFA and cardiometabolic markers were not modified by APOE genotype (Pn-3 LCPUFA x APOE > 0.11), but interaction between FADS rs1535 and APOE showed that rs1535 major allele homozygotes who also carried APOE2 had higher HDL-cholesterol than all other genotype combinations (Prs1535 x APOE = 0.019, pairwise-P < 0.05). This indicates that FADS genotypes, which increase endogenous LCPUFA production, may beneficially affect children’s cardiometabolic profile in a partly APOE-dependent manner. Also, the degree to which children benefit from higher n-3 LCPUFA intake may depend on their PPARG2 genotype.
PMID: 32713352

BACKGROUND: PPARalpha is a transcriptional factor that controls the expression of genes involved in fatty acid metabolism, including fatty acid transport, uptake by the cells, intracellular binding, and activation, as well as catabolism (particularly mitochondrial fatty acid oxidation) or storage. PPARA gene polymorphisms may be crucial for maintaining lipid homeostasis and in this way, being responsible for developing specific training-induced physiological reactions. Therefore, we have decided to check if post-training changes of body mass measurements as well as chosen biochemical parameters are modulation by the PPARA genotypes. METHODS: We have examined the genotype and alleles’ frequencies (described in PPARA rs1800206 and rs4253778 polymorphic sites) in 168 female participants engaged in a 12-week training program. Body composition and biochemical parameters were measured before and after the completion of a whole training program. RESULTS: Statistical analyses revealed that PPARA intron 7 rs4253778 CC genotype modulate training response by increasing low-density lipoproteins (LDL) and glucose concentration, while PPARA Leu162Val rs1800206 CG genotype polymorphism interacts in a decrease in high-density lipoproteins (HDL) concentration. CONCLUSIONS: Carriers of PPARA intron 7 rs4253778 CC genotype and Leu162Val rs1800206 CG genotype might have potential negative training-induced cholesterol and glucose changes after aerobic exercise.
PMID: 31319591

BACKGROUND: Peroxisome proliferator-activated receptors (PPARs) include the nuclear receptor superfamily of ligand-activated transcription factors involved in several metabolic processes, including carbohydrate and lipid metabolism. MATERIAL AND METHODS: In this study we examined PPARA: rs4253778, rs1800206, PPARD: rs2267668, rs2016520, rs1053049, PPARG rs1801282 and PPARGC1A rs8192678 polymorphisms in patients with unstable angina. This study included 246 patients with unstable angina confirmed by coronary angiography (defined by >70% stenosis in at least one major coronary artery) and 189 healthy controls. RESULTS: We observed statistically significant difference in distribution of PPARG rs1801282 genotypes and alleles between patients and control group. Among patients there was the increased frequency of CG and GG genotypes and G alleles. The association between PPARG rs1801282 G allele and unstable angina was confirmed in multivariate regression analysis. There were no statistically significant differences in the distributions of other studied polymorphisms between patients with unstable angina and the control group. CONCLUSIONS: The results of our study suggest the association between PPARG rs1801282 G allele and unstable angina in Polish population.
PMID: 31252163

Pre diabetes mellitus (pre-DM) is considered an early-reversible condition that can progress to Type 2 diabetes mellitus (T2DM) which is the main cause of death for adult Mexican population. Gene variants influencing fasting glucose levels may constitute helpful tool for prevention purposes in pre-DM condition. Physically active Mexican-Mestizo adults (n=565) were genotyped for 6 single nucleotide polymorphisms (SNPs) (ADIPOQ rs2241766, ACSL1 rs9997745, LIPC rs1800588, PPARA rs1800206, PPARG rs1801282 and PPARGC1A rs8192678) related to lipid and carbohydrate metabolism. Fasting glucose was measured and values classified as pre-DM (>/=100mg/dL) or normal fasting glucose. Logistic models were used to test associations between pre-DM condition and SNPs, and interaction with Body Mass Index (BMI) and physical fitness components. The A allele of ASCL1 rs9997745 conferred increased risk (OR=3.39, p=0.001) of pre-DM which is modulated by BMI. The A allele of the PPARGC1A rs8192678 showed significant SNP*BMI (OR=1.10, p=0.008) interaction effect for pre-DM risk, meaning that obese subjects showed higher pre-DM risk but normal weight subjects showed lower risk. The effect increased with age and was attenuated by higher cardiorespiratory values. We found that both ACSL1 rs9997745 and PPARGC1A rs8192678 are associated with pre-DM, and that BMI significantly modified their association.
PMID: 30041843

BACKGROUND/OBJECTIVE: Obesity is a complex and multifactorial disease resulting from the interactions among genetics, metabolic, behavioral, sociocultural and environmental factors. In this sense, the aim of the present study was to identify phenotype and genotype variables that could be relevant determinants of body mass index (BMI) variability. SUBJECTS/METHODS: In the present study, a total of 1050 subjects (798 females; 76%) were included. Least angle regression (LARS) analysis was used as regression model selection technique, where the dependent variable was BMI and the independent variables were age, sex, energy intake, physical activity level, and 16 polymorphisms previously related to obesity and lipid metabolism. RESULTS: The LARS analysis obtained the following formula for BMI explanation: (64.7 + 0.10 x age [years] + 0.42 x gender [0, men; 1, women] + -40.6 x physical activity [physical activity level] + 0.004 x energy intake [kcal] + 0.74 x rs9939609 [0 or 1-2 risk alleles] + -0.72 x rs1800206 [0 or 1-2 risk alleles] + -0.86 x rs1801282 [0 or 1-2 risk alleles] + 0.87 x rs429358 [0 or 1-2 risk alleles]. The multivariable regression model accounted for 21% of the phenotypic variance in BMI. The regression model was internally validated by the bootstrap method (r(2) original data set = 0.208, mean r(2) bootstrap data sets = 0.210). CONCLUSION: In conclusion, age, physical activity, energy intake and polymorphisms in FTO, APOE, PPARG and PPARA genes are significant predictors of the BMI trait.
PMID: 29795275

BACKGROUND: Several studies have been conducted to investigate the association of the peroxisome proliferator-activated receptor (PPAR) alpha (PPAR A) and PPAR gamma (PPAR G) polymorphism and breast cancer (BC) risk, but the results were inconsistent, and, until now, no study focused on the impact of gene-gene interactions between PPAR A and PPAR G on BC risk; thus, the aim of this study was to investigate the impact of interaction between PPAR A and PPAR G on BC risk in the Chinese Han population. METHODS: A total of 862 participants with a mean age of 63.0 +/- 15.7 years were selected, including 432 patients with BC and 430 controls. A logistic regression model was used to examine the association between single-nucleotide polymorphisms and BC risk. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were calculated. Generalized multifactor dimensionality reduction was employed to analyze the gene-gene interaction. RESULTS: Logistic regression analysis showed that BC risk was significantly higher in carriers of G allele of rs1800206 polymorphism than those with CC (CG + GG vs. CC) (adjusted OR, 1.50; 95% CI, 1.20-1.93). In addition, we found that BC risk was also significantly higher in carriers of the G allele of the rs1805192 polymorphism than those with the CC genotype (CG + GG vs. CC) (adjusted OR, 1.78; 95% CI, 1.34-2.26). There was a significant gene-gene interaction between rs1805192 and rs1800206. Overall, the 2-locus models had a cross-validation consistency of 10 of 10, and had a testing accuracy of 60.11%. Patients with CG or GG of rs1805192 and CG or GG of rs1800206 genotype have the highest BC risk, compared with patients with CC of rs1805192 and CC of rs1800206 genotype (OR, 2.59; 95% CI, 1.70-3.48, after covariates adjustment for gender, age, age at menarche, number of children, body mass index, and waist circumference). CONCLUSIONS: The minor allele of rs1800206 and rs1805192 and its interaction were associated with increased BC risk.
PMID: 28669518

We analyzed commonly reported European and Asian obesity-related gene variants in a Mexican-Mestizo population through each single nucleotide polymorphism (SNP) and a genetic risk score (GRS) based on 23 selected SNPs. Study subjects were physically active Mexican-Mestizo adults (n = 608) with body mass index (BMI) values from 18 to 55 kg/m(2) . For each SNP and for the GRS, logistic models were performed to test for simple SNP associations with BMI, fat mass percentage (FMP), waist circumference (WC), and the interaction with VO2max and muscular endurance (ME). To further understand the SNP or GRS*physical fitness components, generalized linear models were performed. Obesity risk was significantly associated to 6 SNPs (ADRB2 rs1042713, APOB rs512535, PPARA rs1800206, TNFA rs361525, TRHR rs7832552 and rs16892496) after adjustment by gender, age, ancestry, VO2max , and ME. ME attenuated the influence of APOB rs512535 and TNFA rs361525 on obesity risk in FMP. WC was significantly associated to GRS. Both ME and VO2max attenuated GRS effect on WC. We report associations for 6 out of 23 SNPs and for the GRS, which confer obesity risk, a novel finding for Mexican-Mestizo physically active population. Also, the importance of including physical fitness components variables in obesity genetic risk studies is highlighted, with special regard to intervention purposes.
PMID: 28294290

OBJECTIVE: Patients with schizophrenia are more likely to be smokers than the general population, which makes them an interesting group with which to study the etiology of nicotine dependency. We studied the prevalence of a gene variant of peroxisome proliferator-activated receptor alpha (PPARalpha) in schizophrenia, together with nicotine dependency, to investigate whether the PPARalpha-L162V polymorphism (rs1800206) influences nicotine dependency in schizophrenia. Given evidence suggesting that smoking influences the severity of schizophrenia, together with our recent data linking the PPARalpha-L162V polymorphism to clinical manifestations of schizophrenia (in the Croatian population), we hypothesized that interactions between the two (smoking and the PPARalpha-L162V polymorphism) might contribute to disease onset and scores for the Positive and Negative Syndrome Scale. To the best of our knowledge, this is the first study to investigate the possible associations between the PPARalpha gene and nicotine dependency. PATIENTS AND METHODS: Genotyping was performed for 267 chronically ill schizophrenia patients (males/females: 140/127) by polymerase chain reaction. RESULTS: A significant excess of PPARalpha-L162V genotypes and PPARalpha-162V alleles were detected among female smokers in comparison to female nonsmokers (18.2% vs. 2.0%, and 9.1% vs. 1.0%, p<0.01, respectively). We also revealed a significant PPARalpha genotype-smoking interaction that predicted positive symptom severity among male patients (F=4.43, p<0.05). These data indicated that the PPARalpha-L162V heterozygous genotype, depending on smoking status, might be of relevance as either protective, or a risk factor, for the severity of positive symptoms. No interaction between the PPARalpha-L162V polymorphism and smoking for the time of onset of schizophrenia was detected (p>0.05, respectively). CONCLUSION: We demonstrated two significant yet weak effects. The first showed an effect of the PPARalpha-L162V polymorphism on the risk of nicotine dependency. The second linked the PPARalpha genotype-smoking interaction to positive symptoms severity among schizophrenia patients; both effects manifested in a gender-specific fashion.
PMID: 27624431

AIMS: To investigate the impact of peroxisome proliferator-activated receptor alpha (PPAR alpha) SNPs and gene-obesity interaction on diabetic retinopathy (DR) susceptibility in a Chinese Han population. METHODS: A total of 812 patients (373men, 439 women) with type 2 diabetes mellitus (T2DM), with a mean age of 53.3+/-14.0 years old, were selected, including 402 diabetic retinopathy patients and 410 controls. Three single nucleotide polymorphisms (SNPs) were selected for genotyping in the case-control study: rs4253778, rs135539 and rs1800206. Generalised multifactor dimensionality reduction (GMDR) and logistic regression model was used to examine the association and interaction between SNP and obesity on DR, odds ratio (OR) and 95% confident interval (95%CI) were calculated. RESULTS: The carriers of homozygous mutant of rs1800206 SNP revealed decreased DR risk than those with wild-type homozygotes, OR (95%CI) was 0.78 (0.66-0.94). GMDR analysis indicated a significant two-locus model (p=0.0107) involving rs1800206 and abdominal obesity, indicating a potential interaction among rs1800206 and abdominal obesity. Overall, the two-locus models had a cross-validation consistency of 10 of 10, and had the testing accuracy of 60.72%. We also found that subjects with abdominal obesity and LV or VV genotype have lowest DR risk, compared to subjects with normal WC and LL genotype, OR (95%CI) was 0.39 (0.30-0.74), after covariates adjustment. CONCLUSIONS: Our results support an important association between rs1800206 minor allele of PPAR alpha and DR, and the interaction analysis also shown a combined effect of Leu162 allele-abdominal obesity interaction on DR.
PMID: 26671228

BACKGROUND: The aim was to examine the association between 6 single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors alpha (PPAR alpha) poly morphisms and C-reactive protein (CRP) level, as well as additional gene-gene interaction among the 6 SNPs. METHODS: A total of 1260 subjects (583 men, 677 women), with a mean age of 41.3 +/- 14.6 years old, were selected. Six SNPs of PPAR alpha were selected for genotyping in the study including: rs135539, rs135551, rs135549, rs1800206, rs1800243 and rs4253623. Linear regression analysis was performed to verify the polymorphism association between SNP with CRP levels. Generalized MDR (GMDR) was employed to analysis the interaction among six SNPs. RESULTS: Linear regression results indicated a significant negative correlation between mutation of rs1800206 and CRP level. The carriers of the V allele (LV + VV) of rs1800206 were associated with a significant decreased level of CRP (regression coefficients was -0.533, standard error was 0.148 (P < 0.001)). However, the other 5 SNPs in PPAR alpha were not significantly associated with CRP level before or after covariate adjustment. GMDR model indicated that there was a significant two-locus model (P = 0.0107) involving rs1800206 and rs135539, indicating a potential gene-gene interaction between rs1800206 and rs135539. Overall, the two- locus models had a cross-validation consistency of 10 of 10, respectively, and had the testing accuracy of 55.9%, respectively. CONCLUSIONS: Our results support an important association between rs1800206 minor allele (V) of PPAR alpha and lower CRP level. The interaction analysis showed a combined effect between rs1800206 and rs135539 on the lower CRP level.
PMID: 26497374

OBJECTIVE: To examine the main effect of 10 Peroxisome proliferators-activated receptor (PPAR) SNP in contribution to non-HDL-C and study whether there is an interaction in the 10 SNPs. METHODS: Participants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort-population-survey, which was initiated from April 1999 to June 2004, and 5-year follow-up data from total 4 582 subjects were obtained between March 2006 and October 2007. A total of 4 083 participants received follow-up examination. After excluding subjects who had experienced stroke or exhibited cardiovascular disease, type 2 diabetes or a BMI <18.5 kg/m(2), a total of 820 unrelated individual subjects were selected from 3 731 subjects on October of 2009. Blood samples which were collected at the baseline were subjected to PPARalpha, PPARdelta and PPARgamma 10 SNPs genotype analysis. Logistic regression model was used to examine the association between 10 SNPs in the PPARs and non-HDL-C. Interactions within the 10 SNP were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: A total of 820 participants (mean age was 50.05+/-9.41) were included in the study and 270 were males and 550 were females. Single-locus analysis showed that after adjusting gender, age, smoking, alcohol consumption, physical activity, high-fat diet and low-fiber diet factors, rs1800206-V and rs3856806-T were significantly associated with higher non-HDL-C levels. V allele (LV + VV genotype) carriers of rs1800206 have a average non-HDL-C levels on (3.15 +/- 0.89)mg/L (F = 15.01, P = 0.002); T allele (CT+TT genotype) carriers of rs3856806 have a average non-HDL-C levels on (3.03+/-1.01) mg/L (F = 9.87, P = 0.005). GMDR model analysis showed that after adjusting the same factors, two-locus model, five-locus model, six-locus model and seven-order interaction models were all statistically significant (P<0.05), and the seven-locus model (rs1800206, rs3856806, rs135539, rs4253778, rs2016520, rs1805192, rs709158) was the best model (P = 0.001), the cross-validation consistency was 10/10 and testing accuracy was 0.656. CONCLUSION: Rs1800206 and rs3856806 were significantly associated with non-HDL-C. And there was an gene-gene interaction among rs1800206, rs3856806, rs1800206, rs135539, rs4253778, rs2016520, rs1805192, rs3856806 and rs709158 which could influence the non-HDL-C levels.
PMID: 26268872

BACKGROUND: The peroxisome proliferator-activated receptors (PPARs) -alpha, -delta/beta and -gamma are the ligand-activated transcription factors involved in the regulation of fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation and atherosclerosis, etc. We investigated the associations of 10 single-nucleotide polymorphisms (SNPs) in PPARs with apolipoprotein (apo) A-I/apoB ratio in Chinese Han population. METHODS: Overall, 630 subjects (212 males, 418 females) were randomly selected from the Prevention of Metabolic Syndrome and Multiple Metabolic Disorders in Jiangsu Province of China Study Cohort. Population analyzed was as the general population which involved healthy people and individuals with disorders of apoA-I or apoB. 10 SNPs (rs1800206, rs135539, rs4253778, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were genotyped. Mean difference (Difference) and 95% confident interval (95%CI) were calculated. RESULTS: After covariates adjustment, rs1800206-V allele (LV+VV) and rs3856806-T allele (CT+TT) were significantly associated with a decreased apoA-I/apoB ratio than those wild type carriers, Difference (95%CI) were -1.29 (-1.96-0.62) and -0.8 (-1.42~-0.17), respectively. Rs4253778-C allele was significantly associated with an increased apoA-I/apoB ratio compared to the wild type carriers (GG), Difference (95%CI) was 0.76 (0.04-1.48). Generalized multifactor dimensionality reduction analysis showed that three-to-eight-locus models were significant with apoA-I/apoB ratio (P<0.05). We chose the seven-locus model (P=0.0010) as the best GMDR model (cross-validation consistency was 7/10 and testing accuracy was 62.97%). CONCLUSION: Our data provided the evidence that PPARs polymorphisms might be involved in regulation of apoA-I/apoB ratio in independently and/or in an interactive manner.
PMID: 26110145

AIMS: Elevated low-density lipoprotein-cholesterol (LDL-C) is regarded as one of major risks of cardiovascular diseases and atherosclerotic events. It has been previously reported that peroxisome proliferator-activated receptors (PPARs) play an important role in the regulation of lipid metabolism. In this study, we aimed to investigate the influence of PPARalpha/delta/gamma gene polymorphisms on LDL-C level. Eight hundred twenty unrelated participants were recruited. Ten single-nucleotide polymorphisms (SNPs) were genotyped to analyze the gene-gene interactions among these polymorphisms using the generalized multifactor dimensionality reduction (GMDR) method. RESULTS: The results of single-locus analyses indicated that the genotypes with minor allele variants at the rs1800206, rs9794, rs1805192, rs709158, and rs3856806 loci are associated with higher LDL-C levels (p<0.05) after adjusting for covariates. In contrast, individuals that were homozygous for the major allele (CC) of rs10865710 had significantly higher LDL-C than those with either one or more minor type alleles (CG+GG, mean difference: -0.21 mM; 95% confidence interval [CI]: -0.37 to -0.04 mM; p=0.013). Significant gene-gene interactions among PPAR gene polymorphisms on LDL-C were identified by a generalized multifactor dimensionality reduction (GMDR) approach in 2- to 8-locus models (p<0.05). CONCLUSION: Our results provide evidence that multiple PPARalpha/delta/gamma gene polymorphisms are individually associated with increased LDL-C, and that interactions, among these alleles result in additional increased risk suggesting that PPAR genes may contribute substantially to the risk of cardiovascular diseases and atherosclerosis.
PMID: 26098621

OBJECTIVE: To investigate the association between ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARalpha, beta, gamma) with apolipoprotein A I/apolipoprotein B100 (ApoA I/ApoB100) ratio and the additional role of a gene-gene interactions among the 10 SNPs. METHODS: Participants were recruited under the framework of the Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province (PMMJS) cohort population survey in the urban community of Jiangsu province of China.A total of 630 subjects were randomly selected and no individual was related.Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were selected from the HapMap database,which covered PPARalpha, PPARbeta and PPARgamma. A linear regression model was used to analyze the relations between ten SNPs in the PPARs and ApoA I/ApoB100 ratio level. Mean difference and 95% CI were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: After adjusting for age, gender, smoking status, alcohol consumption, occupational physical activity, high-fat diet as well as low-fiber diet, both rs1800206 and rs3856806 were significantly associated with a decreased level of ApoA I/ApoB100 ratio, mean difference (95% CI) values were -1.19 (-1.88 to -0.50) and -0.77 (-1.40 to -0.14). Whereas rs4253778 was significantly associated with an increased level of ApoA I/ApoB100 ratio, Mean difference (95% CI) values was 0.80 (0.08 to 1.52). GMDR analysis showed a significant gene-gene interaction among rs4253778, rs1800206 of PPARalpha, rs9794, rs2016520 of PPARbeta and rs10865710, rs3856806, rs709158, rs1805192 of PPARgamma for eight-dimension models (P = 0.01), in which prediction accuracy was 0.624 and cross-validation consistency was 7/10. CONCLUSIONS: The rs1800206 of PPARalpha and rs3856806 of PPARgamma are significantly associated with a decreased level of ApoA I/ApoB100 ratio while rs4253778 of PPARalpha is associated with an increased level of ApoA I/ApoB100 ratio. There is a gene-gene interaction between multiple SNPs.
PMID: 26082365

OBJECTIVE: The aim of this study was to investigate the association between three single-nucleotide polymorphisms (SNP) of in the peroxisome proliferator-activated receptor (PPAR) alpha gene and the level of lipoprotein (a) [Lp(a)]. METHODS: Participants were recruited under the framework of a cohort populations survey from the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) which was conducted in the urban community of Jiangsu province from 1999 to 2007. 644 subjects (234 males, 410 females) were randomly selected and genotyped for three polymorphisms which were used as genetic marker for PPARalpha gene (rs1800206, rs4253778 and rs135539). Data related to individual polymorphism and haplotype were available for analysis. chi(2) test was used to determine if the whole population was in Hardy-Weinberg genetic equilibrium. Linear regression models were used to analyze the association between SNPs in PPARalpha gene and the level of Lp(a). Associations between PPARalpha haplotypes and serum Lp(a) levels were analyzed by the SNPstats software. RESULTS: In the dominant model, after factors as sex, age, smoking, alcohol and BMI were adjusted, the presence of the V162 allele of L162V appeared associated with a high level of Lp(a) (mean difference was 57.70 mg/L (95% CI: 32.03-83.37 mg/L), P < 0.001. Data from the haplotype analysis revealed that A-G-V and C-G-V haplotype (established by 1A > C, 7G > C L162V) were significantly associated with a higher level of Lp(a) (P = 0.012 0 and 0.009 7). CONCLUSION: Results from our study might help to clarify the role of PPARalpha gene in regulation of Lp(a) and the evaluation of its polymorphisms and haplotypes which were characterized as genetic factors for Lp(a).
PMID: 25294067

Lipoprotein(a) [Lp(a)], a low-density lipoprotein-like particle, is recognized as an independent risk factor for atherosclerosis, cardiovascular diseases, and diabetic vascular diseases. Our recent studies revealed that the single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptors (PPARalpha/delta/gamma) gene are involved in the regulation of lipid storage and metabolism. In order to investigate the relationships between the SNPs of PPARalpha/gamma gene and plasma levels of Lp(a), 644 participants were randomly selected from Chinese Han population in the present study. As the results shown, Lp(a) was significantly associated with L162V (rs1800206) in PPARalpha. Compared with those subjects with widetype (LL), significantly higher Lp(a) concentration was determined in the individuals with mutant (LV + VV) (mean difference: 49.07 mg/l, 95% CI 23.32-74.82 mg/l, p = 0.0002). Moreover, with generalized multifactor dimensionality reduction analysis, our present results indicated that there was a significant association between plasma Lp(a) level and gene-gene interaction among the polymorphisms rs1800206, rs135539 in PPARalpha and rs10865710, rs1805192, and rs4684847 in PPARgamma. Therefore, our presented study indicated that PPARalpha/gamma polymorphisms should be involved in the regulation of plasma Lp(a) in independently and/or in an interactive manner, suggesting that PPARalpha/gamma gene may influence the risk of hypertension, cardiovascular diseases, and dyslipidemia by regulating Lp(a) level.
PMID: 24880474

The peroxisome proliferator-activated receptors (PPARs)-alpha, -beta/delta, and -gamma are the ligand-activated transcription factors that function as the master regulators of glucose, fatty acid and lipoprotein metabolism, inflammation, and atherosclerosis. Our aim was to test the association between ten single nucleotide polymorphisms of PPARs and CRP level, as well as their interaction with overweight/obesity. A sample population of 643 subjects was recruited from the prevention of MetS and multi-metabolic disorders in Jiangsu Province of China Study. The selected SNPs in PPAR alpha (rs135539, rs4253778, rs1800206), PPAR beta/delta (rs2016520 and rs9794), and PPAR gamma (rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped. After adjustment for smoking, alcohol consumption, SBP, DBP, TG, and HDL-C, rs1800206, rs709158, rs1805192, and rs4684847 polymorphisms were significantly associated with CRP level in normal weight subjects (P < 0.05). In the overweight/obese subjects, rs1800206 was also significant associated with CRP level (P<0.01). In addition, the rs709158, rs1805192, and rs4684847 polymorphisms were shown interactions with overweight/obesity to influence CRP level (P<0.05). PPARs polymorphisms are independently associated with CRP levels in Chinese Han population. Further, PPARs polymorphisms interact with overweight/obesity to set CRP levels.
PMID: 24599720

OBJECTIVE: To investigate the association of ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARalpha, delta, gamma) with lipid accumulation product (LAP) and the additional role of a gene-gene interactions among the 10 SNPs. METHODS: Participants were recruited under the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu province) cohort populations survey in the urban community of Jiangsu province of China. A total of 820 subjects were randomly selected and no individual was related. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806 and rs4684847) were selected from the HapMap database, which covered PPARalpha, PPARdelta and PPARgamma. A linear regression model was used to analyze the relations between ten SNPs in the PPARs and LAP. Mean difference (Difference) and 95% confident interval (95%CI)were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: After adjusting the factors as age, gender, smoking status, occupational physical activity, educational level, high-fat diet as well as low-fiber diet, both rs1800206, s1805192 and rs3856806 were significantly associated with the increased level of LAP. Difference (95% CI) values were 32.47 (22.62-42.31), 12.97 (4.61-21.33) and 12.49 (4.24-20.75). Whereas rs2016520 was significantly associated with the decreased level of LAP. Difference (95%CI) values was -14.67 ( -22.97–6.55). GMDR analysis showed a significant gene-gene interaction among rs135539, rs1800206 of PPARalpha, rs2016520 of PPARdelta and rs10865710, rs3856806, rs709158, rs1805192, rs4684847 of PPARgamma for eight-dimension models (P < 0.05), in which prediction accuracy was 0.5902 and cross-validation consistency was 10/10. CONCLUSION: The rs1800206 of PPARalpha and rs1805192, rs3856806 of PPARgamma were significantly associated with the increased level of LAP; rs2016520 of PPARdelta was associated with the decreased level of LAP. There was a gene-gene interaction between multiple SNPs.
PMID: 24517936

BACKGROUND: The PPAR alpha and PPAR gamma are the key messengers responsible for the translation of nutritional stimuli into changes for the expression of genes, particularly genes involved in lipid metabolism. However, the associations between PPAR alpha/gamma polymorphisms and lipid serum levels in the general population were rarely studied, and the conclusions were conflicting. The objective was to investigate the associations of the PPAR alpha and PPAR gamma polymorphisms with dyslipidemia. METHODS: 820 subjects were randomly selected from the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort populations. The logistic regression model was used to examine the association between these polymorphisms and dyslipidemia. SNPstats was used to explore the haplotype association analyses. RESULTS: In the codominant and log-additive models, rs1800206, rs1805192 and rs3856806 were all associated with dyslipidemia (P < 0.005). When the most common haplotype L-G (established by rs1800206, rs4253778) was treated as the reference group, the V-G haplotype was associated with dyslipidemia (P < 0.001), higher TC and TG levels (P < 0.01). Moreover, when compared to Pro-C haplotype (established by rs1805192, rs3856806), the Pro-T, Ala-C, Ala-T haplotypes were associated with dyslipidemia (p < 0.001). A-T haplotype was associated with higher TC levels, (p < 0.01), and the P-T, A-C, A-T haplotypes were associated with higher TG levels (p < 0.01). CONCLUSIONS: PPAR alpha and PPAR gamma polymorphisms and haplotypes may be the genetic risk factors for dyslipidemia.
PMID: 24460649

OBJECTIVE: To explore the roles of peroxisome proliferator-activated receptors (PPARs) on the levels of serum C-reactive protein(CRP)and the interactions of PPARs haplotypes with abnormal body weight. METHODS: Subjects(n = 644)were randomly selected from the cohort ‘Prevention of Multiple metabolic disorders and Metabolic syndrome in Jiangsu province(PMMJS)’ Variance test, t test and lineal regression were used to analyze the associations between PPARs polymorphisms and the levels of CRP. The association between PPARs haplotypes and serum CRP levels as well as the interaction of PPARs haplotypes with abnormal body weight were analyzed, under the SNPStats software. RESULTS: After adjusting for sex, age, blood pressure, cigarette smoking, alcohol drinking and so on, data showed that both rs1800206 and rs9794 were associated with the changes along with the levels of CRP (P < 0.05). After adjusting for the same factors, haplotypes of AVG and CVG in PPARalpha, CG in PPARd appeared to be associated with the increase (P < 0.05)while haplotypes of CC in PPARdelta, CPCAC in PPARgamma were associated with the decrease of CRP levels (P < 0.05). Results from the Interaction analysis also noted that the interactions did exist between abnormal body weight and both AVG, CVG in PPARalpha, and CG in PPARdelta. CONCLUSION: PPARs polymorphisms and haplotypes were associated with CRP. Interaction between PPAR a/d and abnormal body weight might contribute to the levels of CRP.
PMID: 24378001

OBJECTIVE: The aim of the present study was investigate the association between six genetic variants in the nuclear receptor genes PPARA, RXRA, NR1I2 and NR1I3 and the lipid-lowering efficacy and safety of statin therapy. SUBJECTS AND METHODS: The study was carried out on 240 Brazilian hypercholesterolemic patients on simvastatin and atorvastatin therapy. The polymorphisms were analyzed by PCR-based methods. RESULTS: The NR1I3 rs2307424 genotype distribution was different between subjects with and without adverse drug reactions. Among subjects in the ADR group, no T/T homozygotes were observed for this polymorphism, while in the non-ADR group the frequency of this genotype was 19.4% (P = 0.007, after multiple testing corrections P = 0.042). CONCLUSION: The polymorphisms investigated in PPARA (rs1800206), RXRA (rs11381416), and NR1I2 (rs1523130) did not influence the lipid-lowering efficacy and safety of statin. Our results show the possible influence of NR1I3 genetic variant on the safety of statin.
PMID: 24232815

OBJECTIVE: To explore the impact of the gene-gene interaction among the single nucleotide polymorphisms (SNPs) of peroxisome proliferator-activated receptor alpha/delta/gamma on essential hypertension (EH). METHODS: Participants were recruited based on the previous work of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province) cohort study in Jiangsu province of China. A total number of 820 subjects were randomly selected from the cohort and received gene polymorphism detection covered ten SNPs:PPARalpha/delta/gamma (PPARalpha: rs135539, rs1800206 and rs4253778; PPARdelta: rs2016520 and rs9794; PPARgamma: rs10865710, rs1805192, rs4684847, rs709158 and rs3856806). Generalized Multifactor Dimensionality Reduction (GMDR) model was used to evaluate the association between gene-gene interaction among the ten SNPs and EH. RESULTS: After adjusting factors as gender, age, BMI, FPG, TG, HDL-C, high fat diet, low fiber diet and physical activity, results from the GMDR analysis showed that the best qualitative trait models were 7/9-dimensional model (EH: cross-validation consistency were 9/10 and 10/10, prediction accuracy were 0.5862 and 0.5885), 5/9-dimensional model (SBP:cross-validation consistency were 10/10 and 8/10, prediction accuracy were 0.6055 and 0.6011), and 8/9-dimensional model (DBP: cross-validation consistency both were 10/10, prediction accuracy were 0.5926 and 0.5972), while the best quantitative trait models were 4/5-dimensional model (SBP: cross-validation consistency were 10/10 and 8/10, prediction accuracy were 0.6111 and 0.6072), and 5-dimensional model (DBP: cross-validation consistency were 9/10, prediction accuracy were 0.5753). CONCLUSION: Interactions among ten SNPs of PPARs seemed to have existed and with significant impact on the levels of blood pressure.
PMID: 23937834

BACKGROUND: Dyslipidemia is one of several known risk factors for coronary heart disease, a leading cause of death in Lithuania. Blood lipid levels are influenced by multiple genetic and environmental factors. Epidemiological studies demonstrated the impact of nutrition on lipid levels within the Lithuanian population although the role of genetic factors for dyslipidemias has not yet been studied. The objective of this study was to assess the distribution of the APOE, SCARB1, PPARalpha genotypes in the Lithuanian adult population and to determine the relationship of these genotypes with dyslipidemia. METHODS: A cross-sectional health survey was carried out in a representative random sample of the Lithuanian population aged 25-64 (n=1030). A variety of single-nucleotide polymorphisms (SNPs) of the APOE (rs429358 and rs7412), SCARB1 (rs5888) and PPARalpha (rs1800206) genes were assessed using real-time polymerase chain reaction. Serum lipids were determined using enzymatic methods. RESULTS/PRINCIPAL FINDINGS: Men and women with the APOE2 genotype had the lowest level of total and low-density lipoprotein cholesterol (LDL-C). Men with the APOE2 genotype had significantly higher levels of triglycerides (TG) than those with the APOE3 genotype. In men, the carriers of the APOE4 genotype had higher odds ratios (OR) of reduced (<1.0 mmol/L) high density lipoprotein cholesterol (HDL-C) levels versus APOE3 carriers (OR=1.98; 95% CI=1.05-3.74). The odds of having elevated (>1.7 mmol/L) TG levels was significantly lower in SCARB1 genotype CT carriers compared to men with the SCARB1 genotype CC (OR=0.50; 95% CI=0.31-0.79). In men, carriers of the PPARalpha genotype CG had higher OR of elevated TG levels versus carriers of PPARalpha genotype CC (OR=2.67; 95% CI=1.15-6.16). The odds of having high LDL-C levels were lower in women with the APOE2 genotype as compared to APOE3 genotype carriers (OR=0.35; 95% CI=0.22-0.57). CONCLUSIONS/SIGNIFICANCE: Our data suggest a gender difference in the associations between APOE, SCARB1, PPARalpha genotypes and lipid levels. In men, the APOE4 genotype and PPARalpha genotype CG were correlated with an atherogenic lipid profile while the SCARB1 genotype CT had an atheroprotective effect. In women, APOE2 carriers had the lowest odds of high LDL-C.
PMID: 23919842

BACKGROUND: We investigated the association of 10 single-nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (PPARs) with obesity and the additional role of gene-gene interaction. METHODS: Participants were recruited within the framework of the Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province cohort population survey of an urban community in China. In total, 820 subjects (513 nonobese adults, 307 obese adults) were randomly selected, and no individuals were consanguineous. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806, and rs4684847) were genotyped and analyzed. RESULTS: After covariate adjustment, minor alleles of rs2016520 in PPARdelta and rs10865170 in PPARgamma were associated with lower BMI (P < 0.01 for all). Generalized multifactor dimensionality reduction analysis showed significant gene-gene interaction among rs2016520, rs9794, and rs10865170 in 3-dimensional models (P = 0.0010); prediction accuracy was 0.6011 and cross-validation consistency was 9/10. It also showed significant gene-gene interaction between rs2016520 and rs10865170 in all 2-dimensional models (P = 0.0010); prediction accuracy was 0.6072 and cross-validation consistency was 9/10. CONCLUSIONS: rs2016520 and rs10865170 were associated with lower obesity risk. In addition, interaction was identified among rs2016520, rs9794, and rs10865170 in obesity.
PMID: 23545576

OBJECTIVE: To investigate the association of ten SNP at peroxisome proliferator-activated receptors (PPARalpha, delta, gamma) with hypertriglyceridemia and the gene-gene interaction. METHODS: Participants were recruited from the Prevention of MetS and Multi-metabolic Disorders in Jiangsu province of China Study (PMMJS). A total of 820 subjects were selected from the 4083 participants who had received follow-up examination, by using simple random sampling. Participants in baseline and follow-up study surveys were both collected blood samples 11 ml in the morning after at least 8 hours of fasting. Blood samples which collected at the baseline were subjected to PPARalpha, PPARdelta and PPARgamma genotype analyses. Blood samples which collected at the follow-up were used to measure serum triglyceride levels. The logistic regression model was used to analyze the association between different SNP and hypertriglyceridemia, and the generalized multifactor dimensionality reduction (GMDR) was applied to explore the gene-gene interaction. RESULTS: The samples included 474 in the non-hypertriglyceridemia group and 346 in the hypertriglyceridemia group. The genotype frequencies of rs1800206 in the hypertriglyceridemia group were 211 (61.0%) for LL, 132 (38.2%) for LV and 3 (0.9%) for VV, and in the non-hypertriglyceridemia group were 411 (86.7%) for LL, 59 (12.4%) for LV and 4(0.8%) for VV (chi(2) = 74.18, P < 0.01). V allele frequencies of rs1800206 in the hypertriglyceridemia group was 138(19.9%), and in the non-hypertriglyceridemia group was 67 (7.1%) (chi(2) = 60.62, P < 0.01). The genotype frequencies of rs2016520 in the hypertriglyceridemia group were 177 (51.2%) for TT, 154 (44.5%) for TC and 15 (4.3%) for CC, and in the non-hypertriglyceridemia group were 211 (44.5%) for TT, 212 (44.7%) for TC and 51 (10.8%) for CC(chi(2) = 15.93, P < 0.01). C allele frequencies of rs2016520 in the hypertriglyceridemia group was 184(26.6%), and in the non-hypertriglyceridemia group was 314 (33.1%) (chi(2) = 8.07, P < 0.01). The genotype frequencies of rs3856806 in the hypertriglyceridemia group were 149 (43.1%) for CC, 156 (45.1%) for CT and 41 (11.8%) for TT, and in the non-hypertriglyceridemia group were 269 (56.8%) for CC, 170 (35.9%) for CT and 35 (7.4%) for TT (chi(2) = 15.93, P < 0.01). T allele frequencies of rs3856806 in the hypertriglyceridemia group was 238(34.4%), and was 240 (25.3%) in the non-hypertriglyceridemia group (chi(2) = 15.96, P < 0.01). The genotype frequencies of rs1805192 in the hypertriglyceridemia group were 145 (41.9%) for PP, 158(45.7%) for PA and 43(12.4%) for AA, and in the non-hypertriglyceridemia group were 314 (66.2%) for PP, 137(28.9%) for PA and 23(4.9%) for AA (chi(2) = 50.92, P < 0.01). A allele frequencies of rs1805192 in the hypertriglyceridemia group was 244(35.2%), and was 183 (19.3%) in the non-hypertriglyceridemia group(chi(2) = 52.89, P < 0.01). After adjusting age, gender, smoking, alcohol consumption, high-fat diet, low -fiber diet and occupational physical activity factors, rs1800206, rs2016520, rs3856806 and rs1805192 were significantly associated with hypertriglyceride, while the OR (95%CI) was 3.88 (2.69 – 5.60), 0.71 (0.52 – 0.96), 1.40 (1.03 – 1.90) and 2.56 (1.88 – 3.49), respectively (P < 0.05). GMDR model analysis showed that the second-order model (rs1800206 and rs1805192) was the best model when quality traits of triglyceride was chosen as outcome (P < 0.01); while third-order model (rs1800206, rs1805192 and rs2016520) was the best model when quantitative traits of triglyceride was chosen as outcome (P < 0.01). CONCLUSION: The rs1800206, rs2016520, rs3856806 and rs1805192 were significantly associated with hypertriglyceridemia. There was a gene-gene interaction between multiple SNP.
PMID: 23363867

OBJECTIVE: To investigate the association of ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptors (alpha, delta, gamma) with low high-density lipoprotein-cholesterol (HDL-C) hyperlipidemia and the additional role of a gene-gene interactions among the 10 SNPs. METHODS: Participants were recruited under the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) cohort populations survey, in the urban community of Jiangsu province, China. 820 subjects (579 normal HDL-C, 241 low HDL-C) were randomly selected, with one of them related to each other. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806, rs4684847) were selected from the HapMap database, which covered PPARalpha, PPARdelta and PPARgamma. Logistic regression model was used to examine the association between ten SNPs in the PPARs and low HDL-C. Odds ratios (OR) and 95% confident interval (95%CI) were calculated. Interactions were explored by using the method of Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: After adjusting the factors as age, sex, smoking status, occupational physical activity, high-fat diet as well as low-fiber diet, both rs135539 and rs1800206 were significantly associated with the incidence of low HDL-C, with the OR (95% CI) values as 1.46 (1.07 – 1.99) and 0.62 (0.42 – 0.90). No statistically significant difference was found between other SNPs and the occurrence of low HDL-C. Data from GMDR analysis showed significant gene-gene interaction among rs135539, rs4253778 of PPARalpha and rs10865710, rs3856806, rs709158 and rs4684847 of PPAR gamma (P = 0.0107). CONCLUSION: PPARalpha rs135539 was associated with the occurrence of low HDL-C, and had interacted with rs4253778, rs10865710, rs3856806, rs709158 and rs4684847.
PMID: 23336188

The peroxisome proliferator-activated receptors (PPARs)-alpha,-beta/delta and -gamma are the ligand-activated transcription factors that function as the master regulators of glucose, fatty acid and lipoprotein metabolism, energy balance, cell proliferation and differentiation, inflammation and atherosclerosis. This study examined the main effects of both single-locus and multilocus interactions among genetic variants in Chinese Han individuals to test the hypothesis that PPAR-alpha/delta/gamma polymorphisms may contribute to the etiology of hypertriglyceridemia independently and/or through such complex interactions. We genotyped 9 single nucleotide polymorphisms for PPAR-alpha/delta/gamma. Participants were recruited from the Prevention of MetS and Multi-metabolic Disorders in Jiangsu Province of China Study. 820 subjects (474 non-hypertriglyceridemia subjects, 346 hypertriglyceridemia subjects) were randomly selected. Single-locus analyses showed that after adjusted for age, sex, smoking, alcohol consumption, body mass index, waist circumference and fasting glucose, rs1800206, rs9794, rs3856806 and rs1805192 were significantly associated with hypertriglyceridemia, the OR (95% CI) were 4.43(3.08-6.37), 1.49(1.10-2.02), 1.56(1.16-2.08), 2.43(1.80-3.29), respectively. Further, generalized multifactor dimensionality reduction method analysis showed that two-to-six-locus and eight-locus models were significant (p<0.05), which indicated a potential gene-gene interaction among PPAR-alpha/delta/gamma polymorphisms. The results suggest that PPAR-alpha/delta/gamma polymorphisms may contribute to the risk of hypertriglyceridemia independently and/or in an interactive manner.
PMID: 23262340

OBJECTIVE: PPARalpha, which is expressed in the liver, heart, skeletal muscle, and kidney, regulates lipid and lipoprotein metabolism. The aim of this study was to investigate the association between the PPARalpha gene and essential hypertension (EH) using a haplotype-based cohort study in a Chinese-Han population. METHODS: 820 subjects (270 males, 550 females) were genotyped for the three single-nucleotide polymorphisms used as genetic marker for the PPARalpha gene (rs1800206, rs4253778 and rs135539). Individual polymorphism and haplotype data were available for analyses. RESULTS: In the dominant model, the presence of the G allele of rs1800206 and the C allele of rs135539 were at a decreased risk of EH (OR = 0.48, 95%CI 0.40 – 0.64, P < 0.01; OR = 0.75, 95%CI 0.62 – 0.93, P < 0.01, respectively). A 3.16-fold increase (95%CI 1.86 – 6.94, P = 0.002) in the risk of the development of EH was observed in homozygous genotype (CC) of rs4253778 compared to carriers of GG genotype (co-dominant model). The A-G-V and C-G-V haplotype (established by rs135539, rs4253778, rs1800206) was associated with a statistically significant decreased risk of EH (OR = 0.56, 95%CI 0.33 – 0.83, P = 0.027; OR = 0.53, 95%CI 0.30 – 0.84, P = 0.033, respectively). CONCLUSION: These results may help to clarify the role of PPARalpha gene in EH and the evaluation of its polymorphisms and haplotypes as being characterized as genetic decreased risk factors for EH.
PMID: 23158661

OBJECTIVE: To investigate the association of ten single nucleotide polymorphisms (SNPs) in the peroxisome proliferator-activated receptor (alpha, delta, gamma) with obesity and the additional role of a gene-gene interaction among 10 SNPs. METHODS: Participants were recruited within the framework of the PMMJS (Prevention of Multiple Metabolic Disorders and Metabolic Syndrome in Jiangsu Province)-cohort-population-survey in the urban community of Jiangsu province, China. 820 subjects (513 non obese subjects, 307 obese subjects) were randomly selected and no individuals were related to each other. Ten SNPs (rs135539, rs4253778, rs1800206, rs2016520, rs9794, rs10865710, rs1805192, rs709158, rs3856806, rs4684847) were selected from the HapMap database, which covered PPARalpha, PPARdelta and PPARgamma. Logistic regression model was used to examine the association between ten SNPs in the PPARs and obesity. Odds ratios (OR) and 95% confident interval (95%CI) were calculated. Interactions were explored by using the Generalized Multifactor Dimensionality Reduction (GMDR). RESULTS: A group of 820 participants (mean age was 50.05+/- 9.41) was involved. The frequency of the mutant alleles of rs2016520 in obese populations was less than that in non-obese populations (26% vs. 33%, P < 0.01). The frequency of the mutant alleles of rs10865710 in obese populations was more than that in non-obese populations (37% vs. 31%, P = 0.01). C allele carriers had a significantly lower obesity occurrence than TT homozygotes [OR (95%CI) = 0.63 (0.47 – 0.84)] for rs2016520 but no significant association was observed between other SNP and incident obesity. GMDR analysis showed a significant gene-gene interaction among rs2016520, rs9794 and rs10865170 for the three-dimension models (P = 0.0010), in which prediction accuracy was 0.5834 and cross-validation consistency was 9/10. It also showed a significant gene-gene interactions between rs2016520 and rs10865170 in all the two-dimensional models (P = 0.0010), in which predictive accuracy was 0.5746 and cross-validation consistency was 9/10. CONCLUSION: Our data showed that rs2016520 was associated with lower obesity risk, as well as interactions among rs2016520, rs9794 and rs10865170 on incident obesity.
PMID: 22968028

Schizophrenia (SZ) is a complex psychiatric disorder with a large genetic burden and an estimated hereditability of 80%. A large number of neuroanatomical and psychopharmacological studies suggest a central role of the endocannabinoid (eCB) system in the susceptibility of the disease. To further investigate this hypothesis, we performed an association study with genes codifying for key elements of the eCB system in a sample of 170 schizophrenic patients and 350 healthy controls of Italian ancestry. A total of 57 Tag SNPs (tSNPs) were selected using HapMap CEU population SNP database spanning the following genes: cannabinoid receptor 1 (CNR1), peroxisome proliferator activator receptor-alpha (PPARA), fatty acid amide hydrolase (FAAH) and N-acyl phosphatidylethanolamine phospholipase D (NAPE-PLD). Seven out of the 32 tSNPs within PPARA (rs4253765, rs4263776, rs6007662, rs1800206, rs4253763, rs6008197 and rs4253655) and 3 out of 12 tSNPs within CNR1 (rs1049353, rs7766029 and rs806366) were nominally associated with SZ (uncorrected p<0.05). The same pattern of association was observed in the genotype analysis, with rs4253765 showing the highest level of significance (uncorrected p=2×10(-3)). None of these associations survived after permutation test. Our findings suggest a potential role for PPARA in the susceptibility to SZ, but further studies on larger independent samples are warranted in order to clarify the involvement of this gene in the pathophysiology of SZ.
PMID: 22920733

OBJECTIVE: To investigate the association between ten single nucleotide polymorphism (SNP) in the peroxisome proliferator-activated receptor (PPAR) alpha/delta/gamma and essential hypertension (EH). METHODS: Participants were recruited within the framework of a cohort populations survey from the PMMJS (Prevention of Multiple Metabolic Disorders and MS in Jiangsu Province) which was conducted in the urban community of Jiangsu province from 1999 to 2007. Eight hundred and twenty subjects (551 non-hypertensive subjects, 269 hypertensive subjects) were randomly selected but were not related to each other. Ten SNP (rs135539, rs1800206, rs4253778 of PPARalpha; rs2016520, rs9794 of PPARdelta; rs10865710, rs1805192, rs4684847, rs709158 and rs3856806 of PPARgamma) were selected from the HapMap database. chi(2) test was used to determine whether the whole population was in H-W genetic equilibrium. SHEsis software was used to examine the relations of SNP and linkage equilibrium. Logistic regression model was used to examine the association between ten SNP in the PPAR and EH. RESULTS: Difference on the distribution of four SNP genotypes including rs1800206, rs9794, rs10865710 and rs4684847 between high blood pressure and non-high blood pressure group, high systolic blood pressure (SBP) and normal SBP group, high diastolic blood pressure (DBP) and normal DBP group was significant (P < 0.05). After adjusting factors as age, sex, body mass index, fasting plasma glucose, high density lipoprotein cholesterol-C, high-fat diet and compared with wild-type gene carriers, the OR (95%CI) of objects with rs1800206 V allele appeared in high blood pressure, high SBP and high DBP were 0.60 (0.41 – 0.89), 0.57 (0.37 – 0.88) and 0.61 (0.39 – 0.96), respectively. The OR (95%CI) of objects with G allele of rs9794 were 0.63 (0.46 – 0.87), 0.51 (0.36 – 0.73) and 0.68 (0.47 – 1.01). The OR (95%CI) of objects with G allele of rs10865710 were 1.62 (1.19 – 2.20), 1.59 (1.14 – 2.22) and 1.53 (1.07 – 2.18), respectively. While the OR (95%CI) of objects with rs4684847 T allele were 1.42 (1.04 – 1.94), 1.38 (1.03 – 1.92) and 1.37 (1.00 – 1.88), respectively. CONCLUSION: The four SNPs including rs1800206 of PPARalpha, rs9794 of PPARdelta and rs4684847, rs10865710 of PPARgamma influenced high blood pressure, high SBP and high DBP to different degrees.
PMID: 22883268

BACKGROUND/AIMS: The peroxisome proliferator-activated receptors (PPARs) are transcriptional regulators of lipid metabolism, activated by unsaturated fatty acids. We investigated independent and interactive effects of PPARgamma2 gene PPARG Pro12Ala (rs1801282) andPPARalphagene PPARA Leu162Val (rs1800206) genotypes with dietary intake of fatty acids on concentrations of plasma lipids in subjects of whom 47.5% had metabolic syndrome. METHODS: The RISCK study is a parallel design, randomised controlled trial. Plasma lipids were quantified at baseline after a 4-week high saturated fatty acids diet and after three parallel 24-week interventions with reference (high saturated fatty acids), high monounsaturated fatty acids and low-fat diets. Single nucleotide polymorphisms were genotyped in 466 subjects. RESULTS: At baseline, the PPARG Ala12allele was associated with increased plasma total cholesterol (n = 378; p = 0.04), LDL cholesterol (p = 0.05) and apoB (p =0.05) after adjustment for age, gender and ethnicity. At baseline, PPARA Leu162Val x PPARG Pro12Ala genotype interaction did not significantly influence plasma lipid concentrations. After dietary intervention, gene-gene interaction significantly influenced LDL cholesterol (p =0.0002) and small dense LDL as a proportion of LDL (p = 0.005) after adjustments. CONCLUSIONS: Interaction between PPARG Pro12Ala and PPARA Leu162Val genotypes may influence plasma LDL cholesterol concentration and the proportion as small dense LDL after a high monounsaturated fatty acids diet.
PMID: 22378291

UNLABELLED: The risk of cardiovascular diseases (CVDs) is modulated by gene-diet interactions. The objective of this study was to examine whether gene-diet interactions affect peak particle diameters (PPD) of low-density lipoprotein (LDL). METHODS: The study included 674 participants. A food frequency questionnaire was administered to obtain dietary information. LDL-PPD was determined by non-denaturing 2-16% polyacrylamide gradient gel electrophoresis. Peroxisome proliferator-activated receptor (PPAR) gene polymorphisms PPARalpha L162V (rs1800206), PPARgamma P12A (rs1801282) and PPARdelta -87T–>C (rs2016520) were determined by PCR-RFLP. RESULTS: Among carriers of thePPARalpha L162V polymorphism, gene-diet interaction effects on LDL-PPD were observed with saturated fat (p=0.0005) and total dietary fat (p=0.006). Among PPARalpha V162 carriers, subjects with higher saturated fat intakes had smaller LDL-PPD than those with lower intakes (254.23+/-2.74 vs. 256.21+/-2.61 A, respectively, p=0.007). Among subjects homozygous for the PPARalpha L162 allele, those with higher saturated fat intakes had larger LDL-PPD than those with lower saturated fat intakes (255.86+/-2.66 vs. 255.05+/-2.65 A, respectively, p=0.01). Gene-diet interactions were also found for PPARgamma P12A polymorphism with saturated fat intake (p=0.04) and for PPARdelta -87T–>C with the polyunsaturated/saturated fat ratio (p=0.0013). CONCLUSIONS: These results stress that dietary factors should be included in studies determining the effect of different polymorphisms on CVD risk factors.
PMID: 21487230

OBJECTIVE: To analyze whether genetic variants of PPARA are associated with the development of stage C heart failure. METHODS: We analyzed the distribution of the rs1800206, rs4253778 and rs135551 polymorphisms in genomic DNA extracted from peripheral blood cells of 534 patients in different heart failure stages and 63 healthy individuals. The mRNA expression of the peroxisome proliferator-activated receptor (PPAR)alpha target genes long-chain 3-hydroxyacyl-CoA dehydrogenase (LCHAD) and medium-chain acyl-CoA dehydrogenase (MCAD) was measured in myocardial biopsies of a subgroup of stage B and C patients. Functional studies were performed in HL-1 cardiomyocytes. RESULTS: The V162 allele of the rs1800206 polymorphism was more frequent in stage C patients than in stage A and B patients and healthy individuals. Patients with the V162 allele exhibited decreased myocardial LCHAD and MCAD mRNA expression as compared to L162 homozygote patients. In addition, stage C patients exhibited lower myocardial LCHAD and MCAD mRNA expression than stage B patients. Cardiomyocytes transfected with the V162 allele presented decreased PPARalpha transcriptional activity, LCHAD mRNA expression and ATP production compared to cardiomyocytes transfected with the L162 variant. CONCLUSIONS: These findings suggest that the V162 allele of the human PPARA gene can be a new risk factor in the development of stage C heart failure, likely via depressed cardiac PPARalpha activity.
PMID: 21430558

BACKGROUND: The disposition index represents insulin secretion related to the degree of insulin sensitivity, being constant for given degree of glucose tolerance. The aim of this study is to discern genetic determinants influencing the value of disposition index, e.g. predisposition to glucose intolerance. METHODS AND RESULTS: Two hundred and four non-diabetic subjects with varied glucose tolerance were divided into groups according to the values of disposition index. Glucose and lipid metabolism, anthropometric parameters and family history of type 2 diabetes mellitus (DM2) were examined. The genotype frequency of candidate genes was compared between the groups of individuals within the lowest (Q1) and the highest (Q4) quartiles of the disposition index values. Those groups were not different concerning age and female to male ratio. Fasting and stimulated parameters of glucose metabolism and lipid profile were worse in group Q1 compared to group Q4. Group Q1 is characterized with higher number of individuals with metabolic syndrome and family history of DM2. The examination of candidate genes revealed the differences in genotype frequency of B2AR (rs1042714), PPARA (rs1800206), KCNJ11 (rs5219), and SLC30A8 (rs13266634) between groups Q1 and Q4. CONCLUSIONS: Low value of disposition index is related to the deterioration of glucose tolerance and other signs of metabolic syndrome. It is associated with genes affecting insulin secretion and genes related to energy metabolism and obesity.
PMID: 21391351

Recently, a single nucleotide polymorphism (SNP, rs1800206) in the peroxisome proliferator-activated receptor alpha (PPAR-alpha) gene has been proposed to be associated with Alzheimer’s disease (AD). To verify this finding, we analyzed the PPAR-alpha SNP in 461 patients with AD and 1395 controls. In subgroups, PPAR-alpha gene data could be investigated in relation to biochemical and neuropathological markers for AD. We found no significant differences in genotype or allele distributions between AD patients and controls. None of the PPAR-alpha gene variants influenced markers for AD.
PMID: 17850927

Peroxisome proliferator-activated receptor (PPAR) alpha, a transcription factor of the nuclear receptor superfamily, regulates fatty acid oxidation. We evaluated the association of single nucleotide polymorphisms (SNPs) of the PPAR-alpha gene (PPARA) with the conversion from impaired glucose tolerance to type 2 diabetes in 767 subjects of the STOP-NIDDM trial in order to investigate the effect of acarbose in comparison with placebo on the prevention of diabetes. In the placebo group, the G (162V) allele of rs1800206 increased the risk for diabetes by 1.9-fold (95% CI 1.05-3.58) and was associated with elevated levels of plasma glucose and insulin. The effect of this allele on the risk of diabetes in the placebo group was enhanced by the simultaneous presence of the risk alleles of the PPAR-gamma2, PPAR-gamma coactivator 1alpha, and hepatic nuclear factor 4alpha genes (odds ratios 2.2, 2.5, and 3.4, respectively). In the acarbose group, subjects carrying the minor G allele of rs4253776 and the CC genotype of rs4253778 of PPARA had a 1.7- and 2.7-fold increased risk for diabetes. Our data indicate that SNPs of PPARA increase the risk of type 2 diabetes alone and in combination with the SNPs of other genes acting closely with PPAR-alpha.
PMID: 17317762