title: Haplotypic analyses of the IGF2-INS-TH gene cluster in relation to cardiovascular risk traits.
abstract: 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.
authors.affiliation: Human Genetics Division, University of Southampton, School of Medicine, Southampton General Hospital, Southampton, UK. santi@soton.ac.uk
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodríguez
authors.forename: Tom R
authors.initials: TR
authors.lastname: Gaunt
authors.forename: Sandra D
authors.initials: SD
authors.lastname: O'Dell
authors.forename: Xiao-He
authors.initials: XH
authors.lastname: Chen
authors.forename: Dongfeng
authors.initials: D
authors.lastname: Gu
authors.forename: Emma
authors.initials: E
authors.lastname: Hawe
authors.forename: George J
authors.initials: GJ
authors.lastname: Miller
authors.forename: Stephen E
authors.initials: SE
authors.lastname: Humphries
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D000368:Aged; D000465:Algorithms; D000483:Alleles; D001794:Blood Pressure; D001823:Body Composition; D001835:Body Weight; D002318:Cardiovascular Diseases / Q000235:genetics*; D004247:DNA / Q000737:chemistry; D005091:Exons; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007328:Insulin / Q000235:genetics; D007335:Insulin-Like Growth Factor II / Q000235:genetics*; D008875:Middle Aged; D018598:Minisatellite Repeats; D008957:Models, Genetic; D015233:Models, Statistical; D005810:Multigene Family; D010641:Phenotype; D011110:Polymorphism, Genetic; D011401:Promoter Regions, Genetic; D012189:Retrospective Studies; D012306:Risk; D014280:Triglycerides / Q000097:blood
chemical_list: D007328:Insulin; D014280:Triglycerides; D007335:Insulin-Like Growth Factor II; D004247:DNA