title: 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.
abstract: 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.
  
  
  METHODS
  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.
  
  
  METHODS
  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).
  
  
  CONCLUSIONS
  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.
authors: Department of Medicine, Academic Hospital Maastricht and Cardiovascular Research Institute Maastricht, University of Maastricht, The Netherlands.
authors: C J
authors: CJ
authors: van der Kallen
authors: R M
authors: RM
authors: Cantor
authors: M M
authors: MM
authors: van Greevenbroek
authors: J M
authors: JM
authors: Geurts
authors: F G
authors: FG
authors: Bouwman
authors: B E
authors: BE
authors: Aouizerat
authors: H
authors: H
authors: Allayee
authors: W A
authors: WA
authors: Buurman
authors: A J
authors: AJ
authors: Lusis
authors: J I
authors: JI
authors: Rotter
authors: T W
authors: TW
authors: de Bruin
mesh_terms: D000328:Adult; D015703:Antigens, CD / Q000097:blood / Q000235:genetics*; D015992:Body Mass Index; D002352:Carrier Proteins / Q000235:genetics; D002874:Chromosome Mapping; D002878:Chromosomes, Human, Pair 1; D002879:Chromosomes, Human, Pair 10; D002898:Chromosomes, Human, Pair 8; D005260:Female; D008040:Genetic Linkage; D015894:Genome, Human; D005838:Genotype; D006801:Humans; D006949:Hyperlipidemias / Q000235:genetics*; D007333:Insulin Resistance / Q000235:genetics*; D020738:Leptin / Q000097:blood / Q000235:genetics*; D008126:Lod Score; D008297:Male; D018895:Microsatellite Repeats; D008875:Middle Aged; D009426:Netherlands; D009765:Obesity / Q000235:genetics*; D010641:Phenotype; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D018124:Receptors, Tumor Necrosis Factor / Q000097:blood / Q000235:genetics*; D047888:Receptors, Tumor Necrosis Factor, Type I; D012044:Regression Analysis
chemical_list: D015703:Antigens, CD; D002352:Carrier Proteins; C515448:LEPR protein, human; D020738:Leptin; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin; D018124:Receptors, Tumor Necrosis Factor; D047888:Receptors, Tumor Necrosis Factor, Type I