title: Analysis of parent-offspring trios provides evidence for linkage and association between the insulin gene and type 2 diabetes mediated exclusively through paternally transmitted class III variable number tandem repeat alleles.
abstract: Variation at the variable number tandem repeat (VNTR) minisatellite 5' of the insulin gene (INS) is associated with several phenotypes, including type 1 diabetes, polycystic ovary syndrome, and birth weight. Case-control studies have suggested that class III VNTR alleles are also associated with type 2 diabetes, but results have been inconsistent and may reflect population stratification. To explore further the role of the INS-VNTR in type 2 diabetes susceptibility, we used family-based association methods in 155 parent-offspring trios from the British Diabetic Association-Warren Trios repository, each ascertained via a Europid proband with type 2 diabetes. Overall, there was no significant association between diabetes and the INS-VNTR genotype, with 65 of 119 heterozygous parents (55%) transmitting class III and 54 class I (P = 0.16, one-sided). However, whereas maternal transmissions followed Mendelian expectation, there was a marked excess of class III transmission from the 49 heterozygous fathers (34 [69%] vs. 15, P = 0.003 vs. 50% expectation, P = 0.003 vs. maternal transmission). These results confirm that variation within the TH-INS-IGF2 locus, most plausibly at the VNTR itself, influences type 2 diabetes susceptibility. By demonstrating that this effect is mediated exclusively by the paternally derived allele, these findings implicate imprinted genes in the pathogenesis of type 2 diabetes.
authors.affiliation: Division of Medicine, Imperial College School of Medicine, St. Mary's Hospital, London, UK.
authors.forename: S J
authors.initials: SJ
authors.lastname: Huxtable
authors.forename: P J
authors.initials: PJ
authors.lastname: Saker
authors.forename: L
authors.initials: L
authors.lastname: Haddad
authors.forename: M
authors.initials: M
authors.lastname: Walker
authors.forename: T M
authors.initials: TM
authors.lastname: Frayling
authors.forename: J C
authors.initials: JC
authors.lastname: Levy
authors.forename: G A
authors.initials: GA
authors.lastname: Hitman
authors.forename: S
authors.initials: S
authors.lastname: O'Rahilly
authors.forename: A T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: M I
authors.initials: MI
authors.lastname: McCarthy
mesh_terms: D000328:Adult; D000483:Alleles; D003924:Diabetes Mellitus, Type 2 / Q000235:genetics*; D005220:Fathers; D005260:Female; D008040:Genetic Linkage / Q000235:genetics*; D018392:Genomic Imprinting; D005838:Genotype; D006579:Heterozygote; D006801:Humans; D007328:Insulin / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020080:Tandem Repeat Sequences
chemical_list: D007328:Insulin