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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, IM; Huth, C; Loos, RJF; Kronenberg, F; Adamkova, V; Anand, SS; Ardlie, K; ... Wichmann, HE; + view all (2009) Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design? PLOS GENET , 5 (10) , Article e1000694. 10.1371/journal.pgen.1000694. Green open access

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Abstract

The INSIG2 rs7566605 polymorphism was identified for obesity (BMI >= 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 >= 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.

Type: Article
Title: Meta-Analysis of the INSIG2 Association with Obesity Including 74,345 Individuals: Does Heterogeneity of Estimates Relate to Study Design?
Open access status: An open access version is available from UCL Discovery
DOI: 10.1371/journal.pgen.1000694
Publisher version: http://dx.doi.org/10.1371/journal.pgen.1000694
Language: English
Additional information: © 2009 Heid et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: This work was funded by the NIH subcontract from the Children's Hospital, Boston, Massachusetts, United States, (HEW, IMH, prime grant 1 R01 DK075787-01A1 to JNH), the German National Genome Research Net NGFN2 and NGFNplus (HEW 01GS0823, S. Schreiber, JH, AH), by the Munich Center of Health Sciences (HEW), the DFG excellence cluster “Inflammation at Interfaces” (S. Schreiber), the “Genomics of Lipid-associated Disorders” GOLD of the “Austrian Genome Research Programme GEN-AU” (FK), the Deutsche Forschungsgemeinschaft (HE1446/4-1,4-2, JH, AH), the European Union (FP6 LSHMCT-2003-503041, JH), the EU (Vasoplus-037254, MC) and MIUR (RBIN064YAT, MC), the British Heart Foundation (PG2005/015, SEH, JAC), the PIONEER WP2 (HB), by NIH (HL-045670) to the Heritage Family Study to CB and TR, by NIH grant DK078150 (KLM), Unilever Corporate Research, UK (SL), the Danish Medical Research Council (PB), the Commission for Scientific Research in Greenland (PB), the NHLBI grant 5R01HL087679-02 through the STAMPEED program (MRJ), the MRC of the UK (MRJ), ENGAGE project (MRJ, HEW), the grant agreement HEALTH-F4-2007-201413 (MRJ), the Academy of Finland (MRJ); Biocenter Oulu, University of Oulu, Finland (MRJ), the German Federal Ministry of Education and Research (BMBF, FKZ 0313438A, MRH) and the BioProfile-Program (MRH), and by project N.00023001 (IKEM, CR, JAH), 1M0510 (MSMT, CR, JAH), and grant PI061326 (DC). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing interests: Dawn Waterworth and Vincent Moser are employers of GSK. Gudmar Thorleifsson is employer and shareholder of deCODE.
Keywords: COMMON GENETIC VARIANT, METABOLIC SYNDROME, BODY-MASS, POLYMORPHISM, LIVER, POPULATION, EXPRESSION, UPSTREAM, INSULIN, PROTEIN
UCL classification: UCL
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Institute of Cardiovascular Science
URI: https://discovery.ucl.ac.uk/id/eprint/1385223
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