Defining the genetic determinants of NIDDM requires evidence from several complementary approaches, including both linkage and association analyses using both discrete phenotypes and intermediate quantitative traits. We tested for association between common genomic variation in three genes that map to chromosome 7q21-q22 and quantitative traits related to NIDDM in a sample of Oji-Cree. We found that a common genomic variation in codon 148 (alanine or glycine) of the paraoxonase-2 gene (PON2) demonstrated a significant association with a variation in fasting plasma glucose (P , 0.0001). Furthermore, we found a significant association between a variation in fasting plasma glucose and the interaction term comprised of a PON2 codon 148 genetic variation and the presence of noninsulin- dependent diabetes mellitus (NIDDM; P , 0.0001). We then analyzed subjects according to PON2 genotype and NIDDM status. In subjects with NIDDM, the PON2 codon 148 G/G homozygotes had significantly higher mean fasting plasma glucose than subjects with the other two genotypes (P , 0.0001). However, in non-NIDDM subjects, there was no difference in mean fasting plasma glucose among any of the ge- notypes. There was no association of the PON2 genotype with NIDDM itself, with impaired glucose tolerance, or with other quantitative traits related to NIDDM in this sample. These findings suggest that 1) the PON2 G148 gene variant worsens glycemia in subjects with NIDDM; 2) defining the physiological role of the PON2 gene product would be worthwhile; and 3) genetic factors can modify the severity of clinical phenotypes in subjects with NIDDM. (J Clin Endocrinol Metab 82: 3373-3377, 1997)