Journal Article

Genome scan for adiposity in Dutch dyslipidemic families reveals novel quantitative trait loci for leptin, body mass index and soluble tumor necrosis factor receptor superfamily 1A

Cantor, R.M, Greevenbroek, M.M.J. van, Aouizerat, B.E, Geurts, J.M.W, Bouwman, F.G, Allayee, H, Buurman, W.A, Kallen, C.J.H. van der, Lusis, A.J, Rotter, J.I

2000

Overview

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesity, hyperlipidemia and insulin resistance, using a 10cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamily members 1A and 1B (sTNFRSF1A and STNFRSF1B, also known as sTNFR1 and sTNFR2) were analyzed as unadjusted and adjusted quantitative phenotypes of adiposity, in addition to body mass index (BMI), in multipoint and single-point analyses. In the second stage of analysis, an important chromosome 1 positional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (FCH) (n = 198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (log of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1S3728 and D1S1665, flanking the leptin receptor {LEPR) gene by approximately 9 and 3 cM, respectively. The LOD score decreased to 1.8 with age- and gender-adjusted leptin levels. Notably, BMI also mapped to this region with an LOD score of 1.2 (adjusted BMI: LOD 0.5). Two polymorphic DNA markers in LEPR and their haplotypes revealed linkage to unadjusted and adjusted BMI and leptin, and an association with leptin levels was found as well. In addition, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma concentrations of soluble TNFRSF1A. BMI gave a LOD score of 0.6. Moreover, a chromosome 10 q-ter locus, AFM198ZB, showed linkage with adjusted BMI (LOD 3.3). CONCLUSION: These data provide evidence that a human chromosome 1 locus, harboring the LEPR gene, contributes to plasma leptin concentrations, adiposity and body weight in humans affected with this insulin resistant dyslipidemic syndrome. Novel loci on chromosome 8 and 10 qter need further study.

• Publisher: Nature Publishing,Nature Publishing Group
• Subject: adiposity / Adult / Antigens, CD / Biological and medical sciences / blood / Body mass index / Body weight / Carrier Proteins / Chromosome Mapping / Chromosomes / Chromosomes, Human, Pair 1 / Chromosomes, Human, Pair 10 / Chromosomes, Human, Pair 8 / Disorders of blood lipids. Hyperlipoproteinemia / Female / Gene mapping / genes / Genetic Linkage / genetic markers / genetics / Genome, Human / Genotype / Haplotypes / humans / hyperlipidemia / Hyperlipidemias / Insulin resistance / leptin / leptin receptors / loci / Lod Score / Male / Medical sciences / Metabolic diseases / Microsatellite Repeats / Middle Aged / Netherlands / Obesity / pedigree / phenotype / quantitative trait loci / Receptors, Cell Surface / Receptors, Leptin / Receptors, Tumor Necrosis Factor / Receptors, Tumor Necrosis Factor, Type I / Regression Analysis / sequence analysis / Tumor necrosis factor-TNF / tumor necrosis factors