To identify chromosomal regions containing susceptibility genes for NIDDM, we have undertaken an autosomal genome-scan for DNA markers linked to pre-diabetic metabolic phenotypes in non-diabetic Pima Indians. Sib-pair linkage analysis identified 5 markers (D4S1627-D4S3242-D4S3241-D4S3255-D4S3248) within a 12 cm region on chromosome 4 which are potentially linked to the glucose response to a 75g oral glucose tolerance test (p<0.04), a mixed meal (p<0.003), or an intravenous glucose bolus (p<0.006) after adjusting for age, sex and obesity. We mapped the gene which encodes the vitamin D binding protein, VDBP, to this region. Since this locus has previously been associated with NIDDM in southwest Pacific Island populations, and has been associated with fasting plasma insulin and glucose levels in Dogrib Indians of the Northwest Territories, and fasting plasma glucose levels in a Hispanic-Anglo U.S. population, we analyzed VDBP as a candidate gene for our linkage findings in Pimas. We sequenced all 12 exons of VDBP and identified two polymorphisms. A GAG --< GAT polymorphism at codon 416 (frequencies = 0.41 and 0.59) results in Glu--
