The 31-cM Region of Chromosome 11 Including the Obesity Gene Tubby and ATP-Sensitive Potassium Channel Genes, SUR1 and Kir6.2, Does Not Contain a Major Susceptibility Locus for NIDDM in 127 Non-Hispanic White Affected Sibships

Late-onset NIDDM is apolygenic disorder with both genes and environmental factors contributing to susceptibility (1). Various genetic strategies are being used to identify NIDDM susceptibility genes, including linkage studies using large groups of affected sib pairs and association studies with well-matched groups of affected and unaffected subjects. Risch and Merikangas (2) have recently reviewed the merits of these two approaches and they note that affected-sib pair linkage analysis has good power to find genes with major effects but only limited power to detect genes of modest effect. The ATP-sensitive K channel plays a central role in the regulation of insulin secretion by coupling metabolism to membrane potential. This channel is a heteromeric complex of the type 1 sulfonylurea receptor (SUR1) and the inwardly rectifying K channel (Kir6.2) (3). The genes encoding these two proteins are located adjacent to one another in human chromosome band Ilpl4.1, and mutations in both SUR1 and Kir6.2 are associated with familial hyperinsulinism, a rare recessive disorder characterized by excessive insulin secretion in the presence of severe hypoglycemia (4). hi addition, association studies have identified two variants in SUR1 that are associated with NIDDM in two non-Hispanic white populations from Utah and the U.K. and a twoto threefold increase in relative risk of NIDDM (5). Based on their results, the authors suggested that defects at SUR1 may be a major genetic factor contributing to NIDDM in whites of northern European origin. In contrast, linkage studies in MexicanAmerican and Japanese affected sib pairs found no evidence