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The SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.

TitleThe SH2B1 obesity locus and abnormal glucose homeostasis: lack of evidence for association from a meta-analysis in individuals of European ancestry.
Publication TypeJournal Article
Year of Publication2013
AuthorsPrudente S, Copetti M, Morini E, Mendonca C, Andreozzi F, Chandalia M, Baratta R, Pellegrini F, Mercuri L, Bailetti D, Abate N, Frittitta L, Sesti G, Florez JC, Doria A
Secondary AuthorsTrischitta V
Corporate AuthorsDIAGRAM Consortium
JournalNutr Metab Cardiovasc Dis
Date Published2013 Nov
KeywordsAdaptor Proteins, Signal Transducing, Adult, European Continental Ancestry Group, Evidence-Based Medicine, Genetic Association Studies, Genetic Loci, Glucose Metabolism Disorders, Humans, Obesity, Polymorphism, Single Nucleotide

BACKGROUND/AIMS: The development of type 2 diabetes (T2D) is influenced both by environmental and by genetic determinants. Obesity is an important risk factor for T2D, mostly mediated by obesity-related insulin resistance. Obesity and insulin resistance are also modulated by the genetic milieu; thus, genes affecting risk of obesity and insulin resistance might also modulate risk of T2D. Recently, 32 loci have been associated with body mass index (BMI) by genome-wide studies, including one locus on chromosome 16p11 containing the SH2B1 gene. Animal studies have suggested that SH2B1 is a physiological enhancer of the insulin receptor and humans with rare deletions or mutations at SH2B1 are obese with a disproportionately high insulin resistance. Thus, the role of SH2B1 in both obesity and insulin resistance makes it a strong candidate for T2D. However, published data on the role of SH2B1 variability on the risk for T2D are conflicting, ranging from no effect at all to a robust association.

METHODS: The SH2B1 tag SNP rs4788102 (SNP, single nucleotide polymorphism) was genotyped in 6978 individuals from six studies for abnormal glucose homeostasis (AGH), including impaired fasting glucose, impaired glucose tolerance or T2D, from the GENetics of Type 2 Diabetes in Italy and the United States (GENIUS T2D) consortium. Data from these studies were then meta-analyzed, in a Bayesian fashion, with those from DIAGRAM+ (n = 47,117) and four other published studies (n = 39,448).

RESULTS: Variability at the SH2B1 obesity locus was not associated with AGH either in the GENIUS consortium (overall odds ratio (OR) = 0.96; 0.89-1.04) or in the meta-analysis (OR = 1.01; 0.98-1.05).

CONCLUSION: Our data exclude a role for the SH2B1 obesity locus in the modulation of AGH.

Alternate JournalNutr Metab Cardiovasc Dis
PubMed ID24103803
Grant List090532 / / Wellcome Trust / United Kingdom
P30 DK036836 / DK / NIDDK NIH HHS / United States
R01 HL073168 / HL / NHLBI NIH HHS / United States