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Human Molecular Genetics Advance Access originally published online on January 28, 2004
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Human Molecular Genetics, 2004, Vol. 13, No. 7 715-725
DOI: 10.1093/hmg/ddh070

Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits

Santiago Rodríguez1,*,{dagger}, Tom R. Gaunt1,{dagger}, Sandra D. O'Dell1,{ddagger}, Xiao-he Chen1, Dongfeng Gu1,§, Emma Hawe2, George J. Miller3, Stephen E. Humphries2 and Ian N.M. Day1

1Human Genetics Division, University of Southampton, School of Medicine, Duthie Building (MP 808), Southampton General Hospital, Tremona Road, Southampton SO16 6YD, UK, 2Centre for the Genetics of Cardiovascular Disease, British Heart Foundation Laboratories, The Rayne Building, Royal Free and University College London Medical School, University Street, London WC1E 6JJ, UK and 3Medical Research Council Cardiovascular Research Group, Wolfson Institute of Preventive Medicine, Barts and the London Queen Mary's School of Medicine and Dentistry, Charterhouse Square, London EC1M 6BQ, UK

Received November 20, 2003; Accepted January 23, 2004

The IGF2–INS–TH genomic region has been implicated in various common disorders including the metabolic syndrome, type 2 diabetes and coronary heart disease (CHD). Here we present detailed haplotype analysis of 2743 males 51–62 years old in relation to body weight and composition, blood pressure (BP) and plasma triglycerides (TG). Use of the total data set was complicated by the number of loci typed, missing data, multi-allelic markers and continuous trait phenotypes. Different algorithms and subsets of the data were analysed using the programmes haplotype trend regression, haplo.score, evolutionary-based haplotype analysis package and Phase, in conjunction with SPSS. Ten haplotypes designated in frequency order *1(20.0%) to *10(3.4%) represented 89% of all haplotypes. Haplotype *5 protected against obesity. Haplotype *4 carriers exhibited elevated BP and fat mass, haplotype *6 was associated with raised plasma TG levels. Haplotype *8 also showed similar magnitude effects as *4. These cohort trait analyses and detailed haplotypic analyses enable integration with published case data. Haplotypes *4, *6 and *8 are the only INS VNTR class III-bearing haplotypes, although differing in flanking haplotype, whereas *5 displays unique features in all three genes (with significant commonality with type 1 diabetes-predisposition haplotypes). We propose that long repeat insertion in the insulin gene promoter (‘class III’), reported to result in low insulin production, predisposes to the metabolic syndrome features of elevated BP, fat mass or TG level, therefore appearing more frequently in type 2 diabetic, polycystic ovary syndrome and CHD cases. The functional element(s) of *5 for weight-lowering could reside in any of the three genes.

* To whom correspondence should be addressed. Tel: +44 2380794141; Fax: +44 2380794264; Email: santi{at}soton.ac.uk


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