Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs

• Published in: Diabetes (New York, N.Y.) Vol. 46; no. 6; pp. 1062 - 1068
• Main Authors: Vionnet, N., Hani, E. H., Lesage, S., Philippi, A., Hager, J., Varret, M., Stoffel, M., Tanizawa, Y., Chiu, K. C., Glaser, B., Permutt, M. A., Passa, P., Demenais, F., Froguel, P.
• Format: Journal Article
• Language: English
• Published: American Diabetes Association 01-06-1997
• ISSN: 0012-1797; 1939-327X; 0012-1797
• DOI: 10.2337/diabetes.46.6.1062

Genetics of NIDDM in France: studies with 19 candidate genes in affected sib pairs.
N Vionnet ,
E H Hani ,
S Lesage ,
A Philippi ,
J Hager ,
M Varret ,
M Stoffel ,
Y Tanizawa ,
K C Chiu ,
B Glaser ,
M A Permutt ,
P Passa ,
F Demenais and
P Froguel
Centre National Recherche Scientifique, Institut Pasteur de Lille, France. [e-mail]
Abstract
As part of an ongoing search for susceptibility loci for NIDDM, we tested 19 genes whose products are implicated in insulin
secretion or action for linkage with NIDDM. Loci included the G-protein-coupled inwardly rectifying potassium channels expressed
in beta-cells (KCNJ3 and KCNJ7), glucagon (GCG), glucokinase regulatory protein (GCKR), glucagon-like peptide I receptor (GLP1R),
LIM/homeodomain islet-1 (ISL1), caudal-type homeodomain 3 (CDX3), proprotein convertase 2 (PCSK2), cholecystokinin B receptor
(CCKBR), hexokinase 1 (HK1), hexokinase 2 (HK2), mitochondrial FAD-glycerophosphate dehydrogenase (GPD2), liver and muscle
forms of pyruvate kinase (PKL, PKM), fatty acid-binding protein 2 (FABP2), hepatic phosphofructokinase (PFKL), protein serine/threonine
phosphatase 1 beta (PPP1CB), and low-density lipoprotein receptor (LDLR). Additionally, we tested the histidine-rich calcium
locus (HRC) on chromosome 19q. All regions were tested for linkage with microsatellite markers 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 affected
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 years of age, and the CCKBR
locus (11p15.4; P = 0.004). Analyses of six additional markers spanning 27 cM on chromosome 11p confirmed the suggestive linkage
in this region. Whether an NIDDM susceptibility gene lies on chromosome 11p in our population must be determined by further
analyses.