A sib-pair analysis study of 15 candidate genes in French families with morbid obesity - Indication for linkage with islet 1 locus on chromosome 5q

As part of an ongoing search for susceptibility genes in obese families, we performed linkage analyses in 101 French families between qualitative and quantitative traits related to morbid obesity and polymorphisms located in or near 15 candidate genes whose products are involved in body weight regul ation. These included cholecystokinin A and B receptors (CCK-AR and CCK-BR) , glucagon-like peptide 1 receptor (GLP-1R), the LIM/homeodomain islet-l ge ne (Isl-l), the caudal-type homeodomain 3 (CDX-3), the uncoupling protein 1 (UCP-1), the beta(3)-adrenoceptor (beta(3)-AR), the fatty acid-binding pro tein 2 (FABP-2), the hormone-sensitive Lipase (HSL), the lipoprotein lipase (LPL), the apoprotein-C2 (apo-C2), the insulin receptor substrate-1 (IRS-1 ) the peroxisome proliferator-activated receptor-gamma (PPAR-gamma), tumor necrosis factor-alpha (TNF-alpha), and the liver carnitine palmitoyltransfe rase-1 (CPT-1). Phenotypes related to obesity such as EMI, adult life body weight gain, fasting leptin, insulin, fasting glycerol, and free fatty acid s were used for nonparametric sib-pair analyses. A weak indication for link age was obtained between the Isl-l locus and obesity status defined by a z score over one SD of BMI (n = 226 sib pairs, pi = 0.54 +/- 0.02, P = 0.03). Moreover, a suggestive indication for linkage was found between the Isl-l locus and BMI and leptin values (P = 0.001 and 0.0003, respectively) and le ptin adjusted for BMI (P = 0.0001), Multipoint analyses for leptin trait wi th Isl-1 and two flanking markers (D5S418 and D5S407) showed that the logar ithm of odds (LOD) score is 1.73, coinciding with the Isl-l locus. Although marginally positive indications for linkage in subgroups of families were found with IRS-I, CPT-I, and HSL loci, our data suggested that these genes are not major contributors to obesity. Whether an obesity susceptibility ge ne (Isl-l itself or another nearby gene) lies on chromosome 5q should be de termined by further analyses.