Obesity Epidemiology

GENETIC PREDICTORS OF OBESITY 447Peroxisome Proliferator Activated Receptor-γ Gene P12A PolymorphismPeroxisome proliferator activated receptor-γ (PPARG) is an attractive obesity candidategene because it regulates adipocyte differentiation, lipid metabolism, and insulinsensitivity. 81,82 The most frequently studied PPARG variant is the proline (P) to alanine(A) substitution at amino acid 12 which reduces PPARG activity and improves insulinsensitivity. 83,84 Masud et al. 85 carried out a meta-analysis using 40 datasets from 30 independentstudies to examine the effect of the P12A polymorphism on BMI. There was anegligible difference in mean BMI (0.07 kg/m 2 ) between the A allele carriers and noncarriers.However, stratified analysis revealed significant differences only among obesesubjects (mean difference of 0.11 kg/m 2 ). Recently, Paracchini et al. 86 summarized datafrom six case-control studies and reported a borderline significant increased risk of obesityassociated with the A allele (OR: 1.13, 95% CI: 0.98 to 1.29).LEPR Gene PolymorphismsIn addition to rare mutations in LEPR causing monogenic obesity, several common SNPson this gene may be relevant to the common form of obesity. Three SNPs resulting inamino acid substitutions, including Q223R, K109R, and K656N, have been extensivelyexamined with respect to obesity. The R223 and R109 variants occur more frequentlyamong Asians than other ethnic groups, while the N656 variant is more frequent amongCaucasians. 86 In an earlier meta-analysis, Heo et al. 87 summarized data from 9 studiesyielding a total of 3263 related and unrelated subjects from diverse ethnic background.They found no significant relationships between the three LEPR alleles and BMI or waistcircumference in the overall population or subgroups defined by age, sex, and ethnicity.A more recent meta-analysis of case-control studies yielded similar results. 86 The pooledORs for obesity were 1.13 (95% CI: 0.98 to 1.30) for Q223R (10 studies), 1.05 (95% CI:0.89 to 1.23) for K109R (7 studies), and 1.02 (95% CI: 0.86 to 1.21) for K656N (7 studies).Glucocorticoid Receptor Gene N365S PolymorphismIncreased cortisol production has been implicated in the development of visceral obesity(see Chapter 18). The glucocorticoid receptor belongs to a nuclear receptor subfamily and isinvolved in the regulation of the transcription of glucocorticoid-responsive genes. 88 The glucocorticoidreceptor gene (GRL) is located on chromosome 5q31.3 and contains a commonasparagine (N) to serine (S) substitution at codon 363 of exon 2. The S variant increases thetransactivating capacity and has been shown to be associated with an increased sensitivityto glucocorticoids. 89,90 This variant has been associated with increased BMI, but the resultshave been inconsistent. Marti et al. 91 conducted a meta-analysis to assess the associationbetween the N363S polymorphism and obesity risk. The analysis, including 5909 subjectsfrom 12 published and 3 unpublished studies, found that carriers of the S allele had a modestbut significantly higher BMI than noncarriers (mean difference of 0.18 kg/m 2 ). However,the association between this variant and obesity risk was not statistically significant.Tumor Necrosis Factor-α Gene –308G>A PolymorphismTumor necrosis factor-α (TNFA) is an inflammatory cytokine that stimulates production ofother cytokines and regulates glucose and lipid metabolism and insulin resistance. 92 Adiposetissue is a major source of endogenous TNFA production, and elevated levels of TNFA areassociated with increased adiposity and insulin resistance in humans. The G to A substitution