Comment on "A Common Genetic Variant Is Associated with Adult and Childhood Obesity"

Abstract

Contrary to the findings of Herbert et al. (Reports, 14 April 2006, p. 279), homozygous carriers of the C allele of the rs7566605 variant near the INSIG2 gene did not exhibit a significantly increased risk for obesity in a large population-based cross-sectional German study. A subgroup analysis, however, revealed that this allele significantly increased the risk for obesity in already overweight individuals.O besity is a leading health problem in many countries and results from a complex and dynamic interaction of social, environmental, and genetic factors. Herbert et al.(1) recently reported the association of the C allele in the rs7566605 polymorphism located near the INSIG2 gene with obesity in four different human samples. In a fifth sample, however, a large cohort of the Nurses Health Study (NHS), no such association was detectable (1). Therefore, we examined this association in the Study of Health in Pomerania (SHIP), a crosssectional population-based health survey from the northeastern area of Germany comprising 4310 unrelated German individuals, collected in 12 five-year age strata from 20 to 79 years (2-4). SHIP was designed to address general health and community medicine issues, with obesity as a main focus. In SHIP, 66.1% of all participants were overweight [body mass index (BMI) ≥ 25 kg/m 2 ] and 25.4% were obese (BMI ≥ 30 kg/m 2 ). Genotyping of the rs7566605 polymorphism was successful in 4089 of 4304 individuals (in six subjects, data sets were incomplete). Excluded individuals and the entire study sample did not differ with respect to age, gender, and BMI. Genotype frequencies (45.5% GG, 44.4% GC, 10.1% CC) were compatible with a HardyWeinberg equilibrium (P = 0.6769) and similar to the Caucasian samples reported in (1). Logistic regression analyses (dependent variable, obesity) and linear models (dependent variable, BMI) were performed on adjustments for age and gender. Table 1 details BMI stratified by genotype, gender, and the genotype distribution in predefined BMI strata.Mean adjusted BMI for the whole sample amounted to 27.38 ± 0.22 kg/m 2 (means ± SE; linear model), 27.16 ± 0.11 kg/m 2 , and 27.18 ± 0.10 kg/m 2 for CC, GC, and GG genotypes, respectively, and rs7566605 genotypes were not associated with BMI [P = 0.6531; 2 degrees of freedom (df)]. Odds ratios (ORs) for obesity were 1.13 (95% CI 0.97 to 1.31) and 1.20 (95% CI 0.94 to 1.54) for carriers of the GC and CC genotypes compared with GG genotypes, and thus were not significantly different (P = 0.1782, 2 df, logistic regression). This observation for obesity did not change in a recessive model (CC versus GC + GG), as pursued by Herbert et al.(1), with OR of 1.13 (95% CI 0.90 to 1.43; P = 0.2916). Likewise, the age-and gender-adjusted mean BMI of CC carriers did not differ significantly (difference from GC + GG carriers, 0.21 ± 0.23 kg/m 2 ; mean ± SE; P = 0.3593). Taken together, our data indicate that the rs7566605 variant is not associated with the overall risk for obesity in SHIP.The current scenario suggests that the rs7566605 v...

Converging evidence for a pseudoautosomal cytokine receptor gene locus in schizophrenia

“…Notably, rs4129148 showed zero errors in the reproducibility analysis, and had a high minor allele frequency resulting in apparently robust calling of both heterozygotes and homozygotes. Still, it is important to note that even multiply replicated findings can be subject to subsequent failures to replicate, [41][42][43][44] presumably owing to the multiple sources of heterogeneity underlying the pathophysiology of complex disease.…”

Association analysis of positional obesity candidate genes based on integrated data from transcriptomics and linkage analysis

“…3,4 The association with INSIG2 has not been confirmed in all subsequent studies. [5][6][7] In obesity, imbalance between intake of food, regulated primarily by the brain, and energy utilization in metabolically active peripheral tissues such as adipose tissue, skeletal muscle and liver result in accumulation of fat. The literature reporting association between functional candidate genes in these organs and common obesity is immense, but has established few new obesity genes and is less likely to introduce new pathways in obesity.…”

Association of FTO With Obesity-Related Traits in the Cebu Longitudinal Health and Nutrition Survey (CLHNS) Cohort

“…Single nucleotide polymorphism (SNP) rs7566605, near insulin-induced gene 2 (INSIG2) and found to be associated with BMI (2), has not been consistently replicated (3)(4)(5)(6)(7). Several variants in the fat mass-and obesity-associated (FTO) gene identified through two independent GWA studies (8,9) and a third study (10) were associated with BMI and risk of being overweight in children and adults in cohorts of Europeans, European Americans, and Hispanic Americans, but not in African Americans.…”