Variation in the peroxisome proliferator-activated receptor δ gene in relation to common metabolic traits in 7,495 middle-aged white people

Abstract

Aims/hypothesis Studies in animals reveal that peroxisome proliferator-activated receptor δ (PPARδ) regulates glucose metabolism and insulin sensitivity in both the liver and skeletal muscles. Moreover, PPARδ augments physical endurance and increases oxidative metabolism, thereby averting obesity. Thus, we hypothesised that common variation in the PPARD gene is associated with insulin resistance and metabolic traits. Materials and methods We studied variation in the exonic region of PPARD. Based upon the results of variant detection and information derived from the HapMap data resource, we selected common variants and tag singlenucleotide polymorphisms for genotyping in 7,495 white subjects, including 1,416 patients with type 2 diabetes. Results Fourteen nucleotide variants were identified and a total of 12 variants capturing the common variation of PPARD were genotyped. In the population-based Inter99 (ClinicalTrials.gov ID no: NCT00289237) sample we observed no robust association with homeostasis model assessment of insulin resistance (HOMA-IR), adiposity measures or fasting serum lipids. Similarly, no association with type 2 diabetes or the metabolic syndrome was found. Conclusions/interpretation Based on thorough investigation, we conclude that common variation in PPARD does not significantly affect the risk of metabolic disease in the population studied. Given the confidence intervals that were found for effect size estimates, we can effectively rule out an increase in HOMA-IR of any tag SNP above 7% per allele, assuming an additive model. Likewise, we can exclude an odds ratio of type 2 diabetes above 1.27 per allele.

Screening of Peroxisome Proliferator-activated Receptors (PPARs) α, γ and δ Gene Polymorphisms for Obesity and Metabolic Syndrome Association in the Multi-ethnic Malaysian Population

“…Similar with our study, several studies from other populations reported the lack of association of PPARδ T294C SNP with obesity, 38,47 Met-S and their related clinical variables. 47 Meanwhile, other studies found significant association with obesity, 46,[48][49][50] increased plasma LDL-C, 6,51 and decreased plasma HDL-C. 6,49 When participants with homozygous wild type for all the three SNPs were clustered together to compare with those with at least one mutant allele, no significant differences in the anthropometric and clinical measurements were observed. This finding suggests that polygenic obesity and Met-S have a multi-factorial etiology that involves complex interactions between many candidate genes, hormonal status, dietary habits, and other environmental factors.…”

Regulation of Skeletal Muscle Physiology and Metabolism by Peroxisome Proliferator-Activated Receptor δ

“…This risk was more pronounced in combination with SNPs of the PPARGC1A and PPARG2 genes (Andrulionyte et al, 2006). On the other hand, Grarup et al (2007) found no major effect of SNPs in PPARD on the risk for type 2 diabetes. Again, this is in line with the absence of finding the PPARD in GWAS for type 2 diabetes.…”

“…Because PPAR␦ is an important regulator of genes involved in lipid and glucose metabolism, one might expect polymorphisms in PPARD to be associated with the metabolic syndrome, type 2 diabetes, obesity, and/or cardiovascular disease. Several association studies on the role of PPARD polymorphisms in relation to metabolic dysfunction and risk for diabetes and cardiovascular disease have been published (Skogsberg et al, 2003a,b;Shin et al, 2004;Gouni-Berthold et al, 2005;Vä nttinen et al, 2005;Aberle et al, 2006a,b;Andrulionyte et al, 2006;Hu et al, 2006;Grarup et al, 2007;Hautala et al, 2007;Robitaille et al, 2007;Stefan et al, 2007;Lagou et al, 2008;Sá ez et al, 2008;Thamer et al, 2008). More than 16 SNPs in PPARD have been analyzed thus far, and the majority of these relatively large association studies have investigated a polymorphism in exon 4, rs2016520, located 87 base pairs upstream of the translational start site.…”

“…Furthermore, a common haplotype including the major alleles of rs2016520 in exon 4 and rs1053049 in exon 9 has been shown to be associated with higher BMI in 249 nondiabetic control subjects from Korea (Shin et al, 2004). However, when all of these SNPs were tested in a large study comprising three cohorts consisting of 7495 white subjects, including 1416 subjects with type 2 diabetes, no associations of tag SNPs with either lipid concentrations or BMI were found (Grarup et al, 2007). Furthermore, a recent study in 2102 Greek children aged 1 to 6 years failed to detect any associations between the rs2016520 in exon 4 and adiposity measures (Lagou et al, 2008).…”

Genes Associated with Increased Fasting Glucose in Patients with Schizophrenia Spectrum Disorders

“…Genetic variants of WFS1 (rs10010131) and EXT2 (rs11037909, rs1113132, rs37408788) were significantly associated with type 2 diabetes in several studies [15,22,23]. Genetic variants of MTTP (rs1800804) and PPARD (rs1053049, rs2016520, rs2076167, rs34474204, rs6902123) were selected since they have been shown to be involved in ischemic heart disease, glucose and lipid metabolism [24][25][26][27][28][29]. Likewise, genetic variants near HHEX (rs7923837, and rs1544210) were associated with type 2 diabetes in several linkage studies [15,19,30].…”