No evidence for linkage at candidate type 2 diabetes susceptibility loci on chromosomes 12 and 20 in United Kingdom Caucasians

Several studies have identified evidence for linkage between type 2 diabete s and the regions on chromosomes 12 and 20 containing the maturity-onset di abetes of the young (MODY) genes, hepatocyte nuclear factor-1 alpha (HNF-1 alpha) and HNF-4 alpha. Two studies examining the HNF-1 alpha region have d emonstrated evidence for Linkage at genome-wide levels of significance, whe reas four studies examining the HNF-4 alpha locus have resulted in evidence for linkage at more suggestive levels of significance. The demonstration o f Linkage to these regions in additional patient series will strengthen the evidence that susceptibility alleles exist at these loci. We therefore ass essed the evidence for linkage to these regions using a large cohort of Uni ted Kingdom Caucasian type 2 diabetes-affected sibling pairs. A maximum total of 315 affected full sibling pairs were typed far microsate llite markers across the MODY regions and, in a subset of families, for mar kers spanning the whole of chromosome 20. Evidence for linkage was assessed using a multipoint, mode of inheritance-free method. Linkage analysis did not reveal any significant evidence far excess allele sharing at any of the regions studied. Loci contributing sibling recurrence risks, relative to t he general population risk, of 1.75 and 1.25 could be excluded far the HNF- 1 alpha and HNF-4 alpha regions, respectively. We have not confirmed in United Kingdom Caucasians the evidence for linkage previously reported on 12q and 20q. Our results highlight further the prob lems of replicating previous positive linkage results across different ethn ic groups.