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Diabetes 54:2477-2481, 2005
© 2005 by the American Diabetes Association, Inc.

Brief Genetics Reports

A Synonymous Coding Polymorphism in the {alpha}2-Heremans-Schmid Glycoprotein Gene Is Associated With Type 2 Diabetes in French Caucasians

Afshan Siddiq1, Frederic Lepretre1,2, Serge Hercberg3, Philippe Froguel1,2, and Fernando Gibson1

1 Section of Genomic Medicine, Imperial College, Hammersmith Campus, London, United Kingdom
2 Institut de Biologie de Lille, Institut Pasteur, CHU, Lille, France
3 U557 INSERM and Unite de Surveillance et d’Epidemiologie Nutritionnelle, InVS/CNAM, Institut Scientifique et Technique de la Nutrition et de l’Alimentation/CNAM, Paris, France

{alpha}2-Heremans-Schmid glycoprotein (AHSG) is an abundant plasma protein synthesized predominantly in the liver. The AHSG gene, consisting of seven exons and spanning 8.2 kb of genomic DNA, is located at chromosome 3q27, a susceptibility locus for type 2 diabetes and the metabolic syndrome. AHSG is a natural inhibitor of the insulin receptor tyrosine kinase, and AHSG-null mice exhibit significantly enhanced insulin sensitivity. These observations suggested that the AHSG gene is a strong positional and biological candidate for type 2 diabetes susceptibility. Direct sequencing of the AHSG promoter region and exons identified nine common single nucleotide polymorphisms (SNPs) with a minor allele frequency ≥5%. We carried out a detailed genetic association study of the contribution of these common AHSG SNPs to genetic susceptibility of type 2 diabetes in French Caucasians. The major allele of a synonymous coding SNP in exon 7 (rs1071592) presented significant evidence of association with type 2 diabetes (P = 0.008, odds ratio 1.27 [95% CI 1.06–1.52]). Two other SNPs (rs2248690 and rs4918) in strong linkage disequilibrium with rs1071592 showed evidence approaching significance. A haplotype carrying the minor allele of SNP rs1071592 was protective against type 2 diabetes (P = 0.014). However, our analyses indicated that rs1071592 is not associated with the evidence for linkage of type 2 diabetes to 3q27.

Address correspondence and reprint requests to Fernando Gibson, Section of Genomic Medicine, 2nd Floor, 233 L Block, Imperial College, Hammersmith Campus, Du Cane Rd., London, W12 0NN U.K. E-mail: fernando.gibson{at}imperial.ac.uk

Abbreviations: AHSG, {alpha}2-Heremans-Schmid glycoprotein; ASP, affected sibpair; IBD, identical by descent; SNP, single nucleotide polymorphism; UTR, untranslated region


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