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

https://doi.org/10.1016/j.numecd.2013.05.001Get rights and content

Abstract

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.

Section snippets

Study design

We genotyped the SH2B1 tag SNP rs4788102 in 6978 participants from six independent samples of white adults (≥18 years of age) of European ancestry, from an expanded version of the GENIUS T2D consortium.

Among these, four samples (namely San Giovanni Rotondo (SGR, Italy), Catanzaro (Italy), Boston (USA) and Dallas (USA) were case-control studies for T2D from the original GENIUS T2D consortium [26]. In these samples, cases were unrelated patients with T2D defined according to the 2003 American

GENIUS T2D consortium

The SH2B1 tag SNP rs4488102 (G > A) was genotyped in the six samples belonging to the GENIUS T2D consortium including 3796 cases and 3182 controls for AGH. Clinical characteristics of both cases and controls are shown in Table 1.

Genotype distributions did not show deviations from HWE (P > 0.01) in both cases and controls from the whole study sample. No association between the A allele at rs4788102 (i.e., the risk allele for obesity) and AGH was observed in any individual sample (Table 1).

Discussion

We investigated whether genetic variability at the SH2B1 obesity locus is associated with abnormalities in glucose homeostasis in several samples from the GENIUS T2D and the DIAGRAM+ consortia and then carried out a Bayesian meta-analysis by adding also so-far-published studies. Overall, data from a total of 93,543 individuals of European ancestry showed no association between SH2B1 genetic variability and glucose homeostasis. The validity of this conclusion is strengthened by the large study

Conflict of interest

The authors declare no conflict of interest.

Acknowledgments

This work was partly supported by the Italian Ministry of Health (Ricerca Corrente 2011 and 2012 to S.P., F.P. and V.T.) and by the European Union (FP6 EUGENE2 n° LSHM-CT-2004-512013 to G.S.).

References (43)

  • D. Altshuler et al.

    The common PPARgamma Pro12Ala polymorphism is associated with decreased risk of type 2 diabetes

    Nat Genet

    (2000)
  • D. Meyre et al.

    Variants of ENPP1 are associated with childhood and adult obesity and increase the risk of glucose intolerance and type 2 diabetes

    Nat Genet

    (2005)
  • J. Rung et al.

    Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia

    Nat Genet

    (2009)
  • E.K. Speliotes et al.

    Association analyses of 249,796 individuals reveal 18 new loci associated with body mass index

    Nat Genet

    (2010)
  • D. Ren et al.

    Neuronal SH2B1 is essential for controlling energy and glucose homeostasis

    J Clin Invest

    (2007)
  • G. Thorleifsson et al.

    Genome-wide association yields new sequence variants at seven loci that associate with measures of obesity

    Nat Genet

    (2009)
  • C.J. Willer et al.

    Six new loci associated with body mass index highlight a neuronal influence on body weight regulation

    Nat Genet

    (2009)
  • F. Renstrom et al.

    Replication and extension of genome-wide association study results for obesity in 4923 adults from northern Sweden

    Hum Mol Genet

    (2009)
  • E.G. Bochukova et al.

    Large, rare chromosomal deletions associated with severe early-onset obesity

    Nature

    (2010)
  • M.E. Doche et al.

    Human SH2B1 mutations are associated with maladaptive behaviors and obesity

    J Clin Invest

    (2012)
  • M. Nishi et al.

    Kinase activation through dimerization by human SH2-B

    Mol Cell Biol

    (2005)

    • Cited by (0)

    1

    A complete list of the DIAGRAM Consortium members can be found in the Supplementary Information.

    View full text
    Copyright © 2013 Elsevier B.V. All rights reserved.