CHROMOSOME-4Q LOCUS ASSOCIATED WITH INSULIN-RESISTANCE IN PIMA-INDIANS - STUDIES IN 3 EUROPEAN NIDDM POPULATIONS

Markers on chromosome 4q have recently been shown to be associated wit h insulin resistance in Pima Indians, a population in which insulin re sistance precedes and predicts the development of non-insulin-dependen t diabetes mellitus (NIDDM). To examine whether genes in this region c ould play a major role in susceptibility to NIDDM in other populations , we have examined the allele frequencies of a trinucleotide repeat ne ar the fatty acid-binding protein 2 (FABP2) gene on 4q28-31 in three E uropean populations: Finnish, U.K. Caucasian, and Welsh. The U.K. NIDD M population was selected for insulin resistance by studying patients whose obesity-corrected fasting plasma insulin before treatment was ab ove the 98th percentile. Seven alleles were detected. On cross-tabulat ion analysis, there were no significant associations between allele fr equencies and glucose intolerance in any of the populations. Log-linea r analysis of the results from all three populations suggested a moder ately significant interaction of glucose tolerance status (normal vers us diabetic) and the FABP2 allele (partial chi(2) = 24, df 6, P = 0.02 7). The parameter describing the interaction of allele A3 and glucose tolerance status was the only such parameter differing significantly f rom zero (z-score +2.003, P = 0.046). In both the Finnish and U.K. pop ulation, the A3 allele was found approximately twice as frequently in NIDDM: than in control subjects (Finnish control subjects, impaired gl ucose tolerance, and NIDDM: 12.2, 22.4, and 26.6%, respectively; U.K. control subjects and NIDDM: 7.8 and 14.6%, respectively). In the Finni sh populations, no associations were found between FABP2 alleles and p lasma insulin levels or with homeostatic model assessment (HOMA) estim ates of beta-cell function and insulin sensitivity. Specific compariso n of those subjects with and without the A3 allele revealed no differe nce in fasting (47.4 [36-61.8] vs. 47.4 [39-57] pM, geometric means an d 95% confidence interval, NS) and 2-h (288 [222.6-373.2] vs. 297 [252 .6-349.2] pM, NS) insulin or in insulin sensitivity as assessed by HOM A (47.6 [32.3-70.3] vs. 50.5 [39.8-64.2]%, NS). Similarly, in the U.K. NIDDM population, no differences in clinical or metabolic characteris tics were found between those with and those without the A3 allele. In summary, in three European Caucasian populations, there is no evidenc e for a major genetic influence of the FABP2 locus on the development of diabetes. The weak association of the A3 allele with diabetes does not appear to be because of an effect of this allele on insulin resist ance.