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Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

ABSTRACT: The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The meta-analysis of 27 studies on Caucasian adults (n = 66,213) combining the different study designs did not support overall association of the CC-genotype with obesity, yielding an odds ratio (OR) of 1.05 (p-value = 0.27). The I(2) measure of 41% (p-value = 0.015) indicated between-study heterogeneity. Restricting to GP studies resulted in a declined I(2) measure of 11% (p-value = 0.33) and an OR of 1.10 (p-value = 0.015). Regarding the five hypotheses, our data showed (a) some difference between GP and HP studies (p-value = 0.012) and (b) an association in extreme comparisons (BMI> or =32.5, 35.0, 37.5, 40.0 kg/m(2) versus BMI<25 kg/m(2)) yielding ORs of 1.16, 1.18, 1.22, or 1.27 (p-values 0.001 to 0.003), which was also underscored by significantly increased CC-genotype frequencies across BMI categories (10.4% to 12.5%, p-value for trend = 0.0002). We did not find evidence for differential ORs (c) among studies with higher than average obesity prevalence compared to lower, (d) among studies with BMI assessment after the year 2000 compared to those before, or (e) among studies from older populations compared to younger. Analysis of non-Caucasian adults (n = 4889) or children (n = 3243) yielded ORs of 1.01 (p-value = 0.94) or 1.15 (p-value = 0.22), respectively. There was no evidence for overall association of the rs7566605 polymorphism with obesity. Our data suggested an association with extreme degrees of obesity, and consequently heterogeneous effects from different study designs may mask an underlying association when unaccounted for. The importance of study design might be under-recognized in gene discovery and association replication so far.

SUBMITTER: Heid IM

PROVIDER: S-EPMC2757909 | biostudies-literature | 2009 Oct

REPOSITORIES: biostudies-literature

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Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

Heid Iris M IM Huth Cornelia C Loos Ruth J F RJ Kronenberg Florian F Adamkova Vera V Anand Sonia S SS Ardlie Kristin K Biebermann Heike H Bjerregaard Peter P Boeing Heiner H Bouchard Claude C Ciullo Marina M Cooper Jackie A JA Corella Dolores D Dina Christian C Engert James C JC Fisher Eva E Francès Francesc F Froguel Philippe P Hebebrand Johannes J Hegele Robert A RA Hinney Anke A Hoehe Margret R MR Hu Frank B FB Hubacek Jaroslav A JA Humphries Steve E SE Hunt Steven C SC Illig Thomas T Järvelin Marjo-Riita MR Kaakinen Marika M Kollerits Barbara B Krude Heiko H Kumar Jitender J Lange Leslie A LA Langer Birgit B Li Shengxu S Luchner Andreas A Lyon Helen N HN Meyre David D Mohlke Karen L KL Mooser Vincent V Nebel Almut A Nguyen Thuy Trang TT Paulweber Bernhard B Perusse Louis L Qi Lu L Rankinen Tuomo T Rosskopf Dieter D Schreiber Stefan S Sengupta Shantanu S Sorice Rossella R Suk Anita A Thorleifsson Gudmar G Thorsteinsdottir Unnur U Völzke Henry H Vimaleswaran Karani S KS Wareham Nicholas J NJ Waterworth Dawn D Yusuf Salim S Lindgren Cecilia C McCarthy Mark I MI Lange Christoph C Hirschhorn Joel N JN Laird Nan N Wichmann H-Erich HE

PLoS genetics 20091023 10

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI> or =30 kg/m(2)) in one of the first genome-wide association studies, but replications were inconsistent. We collected statistics from 34 studies (n = 74,345), including general population (GP) studies, population-based studies with subjects selected for conditions related to a better health status ('healthy population', HP), and obesity studies (OB). We tested five hypotheses to explore potential sources of heterogeneity. The met ...[more]

PMID: 19851442

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Project description:In a genome-wide association study performed in the Framingham Offspring Cohort, individuals homozygous for the rs7566605 C allele located upstream of insulin-induced gene 2 (INSIG2) were reported to incur an increased risk of obesity. This finding was later replicated in four out of five populations examined. The goal of the study reported here was to assess the role of the INSIG2 single nucleotide polymorphism (SNP) in susceptibility to obesity in the prospective longitudinal Atherosclerosis Risk in Communities (ARIC) study (n = 14,566) and in three other cohorts: the Coronary Artery Risk Development in Young Adults (CARDIA) study (n = 3,888), the Genetic Epidemiology Network of Arteriopathy (GENOA) study (n = 4,766), and extremely obese and lean individuals ascertained at the University of Ottawa (n = 1,502). The combined study sample is comprised of 24,722 white, African-American, and Mexican-American participants.Differences in mean body mass index (BMI) and other anthropometric measures including weight, waist circumference, and waist-to-hip ratio were assessed by a general linear model in individuals categorized by INSIG2 rs7566605 genotype. Multivariable logistic regression was used to predict the risk of obesity (BMI >or= 30 kg/m2).There was no discernable variation in the frequencies of the three INSIG2 SNP genotypes observed between white, Hispanic, and African-American obese individuals and non-obese study subjects. When the relationship between rs7566605 and BMI considered either as a categorical variable or a continuous variable was examined, no significant association with obesity was found for participants in any of the four study populations or in a combined analysis (p = 0.38) under a recessive genetic model. There was also no association between the INSIG2 polymorphism and the obesity-related quantitative traits except for a reduced waist-to-hip ratio in white ARIC study participants homozygous for the C allele, and an increased waist-to-hip ratio in African-Americans in the ARIC cohort with the same genotype (p = 0.04 and p = 0.01, respectively). An association with waist-to-hip ratio was not seen when the combined study sample was analyzed (p = 0.74).These results suggest that the INSIG2 rs7566605 variant does not play a major role in determining obesity risk in a racially and ethnically diverse sample of 24,722 individuals from four cohorts.

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Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

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Meta-analysis of the INSIG2 association with obesity including 74,345 individuals: does heterogeneity of estimates relate to study design?

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