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

OBJECTIVE: To search for novel genes contributing to adiposity in familial combined hyperlipidemia (FCH), a disorder characterized by abdominal obesit y, hyperlipidemia and insulin resistance, using a 10 cM genome-wide scan. DESIGN: Plasma leptin and soluble tumor necrosis factor receptor superfamil y members 1A and 1B (sTNFRSF1A and sTNFRSF1B, also known as sTNFR1 and sTNF R2) were analyzed as unadjusted and adjusted quantitative phenotypes of adi posity, in addition to body mass index (BMI), in multipoint and single-poin t analyses. In the second stage of analysis, an important chromosome 1 posi tional candidate gene, the leptin receptor (LEPR), was studied. SUBJECTS: Eighteen Dutch pedigrees with familial combined hyperlipidemia (F CH) (n=198) were analyzed to search for chromosomal regions harboring genes contributing to adiposity. RESULTS: Multipoint analysis of the genome scan data identified linkage (lo g of odds, LOD, 3.4) of leptin levels to a chromosomal region defined by D1 S3728 and D1S1665, flanking the leptin receptor (LEPR) gene by approximatel y 9 and 3 cM, respectively, The LOD score decreased to 1.8 with age- and ge nder-adjusted leptin levels. Notably, BMI also mapped to this region with a n 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 a nd leptin, and an association with leptin levels was found as well. In addi tion, the marker D8S1110 showed linkage (LOD 2.8) with unadjusted plasma co ncentrations 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, ha rboring the LEPR gene, contributes to plasma leptin concentrations, adiposi ty and body weight in humans affected with this insulin resistant dyslipide mic syndrome, Navel loci on chromosome 8 and 10 qter need further study.