Association between PPAR-γ2 Pro12Ala genotype and insulin resistance is modified by circulating lipids in Mexican children

Abstract

The Pro12Ala (rs1801282) polymorphism in peroxisome proliferator-activated receptor-γ2 (PPAR-γ2) has been convincingly associated with insulin resistance (IR) and type 2 diabetes (T2D) among Europeans, in interaction with a high-fat diet. Mexico is disproportionally affected by obesity and T2D however, whether the Pro12Ala polymorphism is associated with early metabolic complications in this population is unknown. We assessed the association of PPAR-γ2 Pro12Ala with metabolic traits in 1457 Mexican children using linear regression models. Interactions between PPAR-γ2 Pro12Ala and circulating lipids on metabolic traits were determined by adding an interaction term to regression models. We observed a high prevalence of overweight/obesity (49.2%), dyslipidemia (34.9%) and IR (11.1%). We detected nominally significant/significant interactions between lipids (total cholesterol, HDL-cholesterol, LDL-cholesterol), the PPAR-γ2 Pro12Ala genotype and waist-to-hip ratio, fasting insulin, HOMA-IR and IR (9.30 × 10−4 ≤ Pinteraction ≤ 0.04). Post-hoc subgroup analyses evidenced that the association between the PPAR-γ2 Pro12Ala genotype and fasting insulin, HOMA-IR and IR was restricted to children with total cholesterol or LDL-cholesterol values higher than the median (0.02 ≤ P ≤ 0.03). Our data support an association of the Pro12Ala polymorphism with IR in Mexican children and suggest that this relationship is modified by dyslipidemia.

Pro12Ala PPAR-γ2 and +294T/C PPAR-δ Polymorphisms and Association with Metabolic Traits in Teenagers from Northern Mexico

“…The Pro12Ala PPAR-γ2 G minor allele frequency in the literature ranges from 9% to 25% [9,[15][16][17]57,58]. In this study, the frequency in the total studied population was 17%, while other studies in Mexican population report 10-21% [11,17]. Similarly, the +294T/C PPAR-δ C minor allele frequencies vary from 12% to 31% among different populations [22,24,25,[27][28][29][30]35,[59][60][61].…”

“…A few studies in Mexican teenagers have shown association with Pro12Ala PPAR-γ2 polymorphism with obesity-related traits. Stryjecki et al reported an association between this polymorphism with insulin resistance in Mexican children [11]. No studies about +294T/C PPAR δ polymorphism and metabolic traits in Mexican children were found.…”

“…The PPAR-γ1 isoform is expressed in most tissues; the γ3 is seen in macrophages, colon epithelium, and adipose tissue [9]. However, the γ2 is specific for adipose tissue and it can be activated by fatty acids including prostanoids, thiazolidinediones, and other insulin-sensitizing antidiabetic agents [10,11]. The Pro12Ala polymorphism is a missense coding variant (CCA to GCA) in γ2, which results in a proline (major allele) to alanine (minor allele) substitution (rs1801282) [12].…”

Peroxisome Proliferator-Activated Receptors and Caloric Restriction—Common Pathways Affecting Metabolism, Health, and Longevity

“…Most of the data concerning Pparγ polymorphisms focus on the Pro(12)Ala substitution. Based on a report of a population of children in Mexico, Pro(12)Pro homozygosity is the more represented, followed by Pro(12)Ala heterozygosity, and more rarely Ala(12)Ala homozygosity (73.9%:24.5%:1.6%) [ 705 ]. The (12)Ala PPARγ protein shows a decreased binding affinity for PPRE and consequently is a weaker stimulator of target gene expression [ 441 , 706 ].…”

Identification of novel alleles associated with insulin resistance in childhood obesity using pooled-DNA genome-wide association study approach

“…Recently, a candidate gene approach study demonstrated that the Pro12Ala polymorphism in PPARG was associated with IR in Mexican children and suggested that this relationship was modified by dyslipidaemia. 19 Therefore, genetic studies of T2D in adults and epidemiological, as well as non-genetic (such as nutritional and physical activity), studies of IR and T2D in children are numerous, whereas genetic studies specifically aiming to identify novel genes predisposing to IR in children and adolescents are lacking.…”