LINKAGE STUDIES OF NIDDM WITH 23 CHROMOSOME-11 MARKERS IN A SAMPLE OFWHITES OF NORTHERN EUROPEAN DESCENT

Considerable data support a genetic basis to susceptibility for NIDDM, but previous analysis of candidate genes has failed to identify a maj or susceptibility locus. Among regions with multiple potential candida tes is chromosome 11, which includes the apolipoprotein C3 cluster, mu scle glycogen phosphorylase, two insulin-dependent diabetes loci, the sulfonylurea receptor, and ataxia telangiectasia. To test linkage, we initially typed 19 markers at 10- to 15-cM intervals along chromosome 11. Analyses carried out under parametric models in members of 16-19 f amilies of northern European ancestry detected possible linkage of NID DM to D11S916. Nonparametric methods detected possible linkage to NIDD M at D11S901, which was 5-10 cM distant, and at D11S935, which was sim ilar to 30 cM distant. Both D11S916 and D11S901 were near the IDDM4 lo cus. To further test Linkage, we typed five additional markers within 5 cM of D11S916 in the initial 19 families. We also tested markers fro m the Linked region in a second set of recently sampled additional fam ilies. Two additional markers (D11S527 and D11S534) showed possible Li nkage in the initial 19 families, but none of the markers were linked to NIDDM in a separate set of families from the same ethnic background . The best evidence for Linkage in the combined data set of the initia l 19 families and 26 additional families was at D11S534 under parametr ic analysis (Z = 1.20) and at D11S935 under nonparametric analysis (af fected pedigree member, P = 0.0013). Our findings suggest marginal evi dence for a diabetes susceptibility locus in the region between D11S90 1 and D11S935, with the best evidence for a locus at or near D11S935. Replication of these findings in other populations will be necessary t o distinguish false-positive linkage from a true NIDDM susceptibility locus.