GENETICS OF NIDDM IN FRANCE - STUDIES WITH 19 CANDIDATE GENES IN AFFECTED SIB PAIRS

As part of an ongoing search for susceptibility loci for NIDDM, we tes ted 19 genes whose products are implicated in insulin secretion or act ion for linkage with NIDDM. Loci included the G-protein-coupled inward ly rectifying potassium channels expressed in beta-cells (KCNJ3 and KC NJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon- like peptide I receptor (GLP1R), LIM/homeodomain islet-1 (ISL1), cauda l-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecys tokinin B receptor (CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mi tochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscl e forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (F ABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine ph osphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR) . Additionally, we tested the histidine-rich calcium locus (HRC) on ch romosome 19q. An regions were tested for linkage with microsatellite m arkers in 751 individuals from 172 families with at least two patients with overt NIDDM (according to World Health Organization criteria) in the sibship, using nonparametric methods. These 172 families comprise 352 possible affected sib pairs with overt NIDDM or 621 possible affe cted sib pairs defined as having a fasting plasma glucose value of >6. 1 mmol/l or a glucose value of >7.8 mmol/l 2 h after oral glucose load . No evidence for linkage was found with any of the 19 candidate genes and NIDDM in our population by nonparametric methods, suggesting that those genes are not major contributors to the pathogenesis of NIDDM. However, some evidence for suggestive linkage was found between a more severe form of NIDDM, defined as overt NIDDM diagnosed before 45 year s of age, and the CCKBR locus (11p15.4; P = 0.004). Analyses of six ad ditional markers spanning 27 cM on chromosome 11p confirmed the sugges tive linkage in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further ana lyses.