A Genomewide Scan for Loci Predisposing to Type 2 Diabetes in a U.K. Population (The Diabetes UK Warren 2 Repository): Analysis of 573 Pedigrees Provides Independent Replication of a Susceptibility Locus on Chromosome 1q

Abstract

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.

IA-2 antibody prevalence and risk assessment of early insulin requirement in subjects presenting with type 2 diabetes (UKPDS 71)

“…We recommend that all participants in future type 2 diabetes studies be screened for GADA and other autoantibodies. This may be especially important in genetic [22] as well as therapeutic studies.…”

Genetic variations in the gene encoding TFAP2B are associated with type 2 diabetes mellitus

“…Written informed consent was obtained from each patient, and DNA extraction was performed using a standard phenol-chloroform procedure. The UK samples comprised 590 cases with type 2 diabetes enriched for positive family history (probands from the Diabetes UK Warren 2 repository) (Wiltshire et al 2001) and 549 UK population controls (the ECACC-HRC collection) (Groves et al 2003).…”

Osteocalcin gene polymorphisms influence concentration of serum osteocalcin and enhance fracture identification

“…(7,10,11) Additionally, there also has been consistent evidence for linkage to type 2 diabetes in this region. (12)(13)(14) Ducy and colleagues have identified a causal role for osteocalcin in the regulation of BMD in mice. Targeted deletion of the osteocalcin gene results in a high BMD phenotype.…”