TY - JOUR
T1 - Common variants in the 5′ region of the leptin gene are associated with body mass index in men from the National Heart, Lung, and Blood Institute Family Heart Study
AU - Jiang, Yuxin
AU - Wilk, J. B.
AU - Borecki, I.
AU - Williamson, S.
AU - DeStefano, A. L.
AU - Xu, G.
AU - Liu, J.
AU - Ellison, R. C.
AU - Province, M.
AU - Myers, R. H.
N1 - Funding Information:
NHLBI grant HL68891-03 supported this project. This article is presented on behalf of the investigators of the NHLBI FHS.
PY - 2004/8
Y1 - 2004/8
N2 - Linkage of body mass index (BMI) to a broad region of chromosome 7q22-35 has been reported in multiple studies. We previously published a multipoint LOD score of 4.9 at D7S1804 for BMI from the National Heart, Lung, and Blood Institute Family Heart Study. Leptin (LEP), the human homolog of the mouse obesity (ob) gene, is positioned near the linkage peak and is the most prominent candidate gene in this region. Interest in LEP as a susceptibility gene for human obesity has led to numerous linkage and association studies, but the results of these studies are still controversial. In the present study, we employed family-based tests of association with both a quantitative measure of BMI adjusted for age and sex and a dichotomously defined obesity trait. We genotyped 29 single-nucleotide polymorphisms (SNPs) spanning 240 kb around the LEP gene in the 82 extended pedigrees with the strongest evidence for linkage. When the programs TRANSMIT and FBAT were used, a number of SNPs showed association in men but not women, for both the quantitative and qualitative trait definitions (P < .05). Five SNPs (H1328084, H1328083, H1328082, H1328081, and H1328080) positioned 2 kb beyond the previously defined promoter region showed strong association in single-marker and multiple-marker haplotype analysis. This five-marker haplotype (frequency 49% in this sample) is overtransmitted to obese offspring (P = .00005). All five of these SNPs are predicted to modify transcription-factor binding sites. This may indicate new functional variants in an extended promoter region of LEP.
AB - Linkage of body mass index (BMI) to a broad region of chromosome 7q22-35 has been reported in multiple studies. We previously published a multipoint LOD score of 4.9 at D7S1804 for BMI from the National Heart, Lung, and Blood Institute Family Heart Study. Leptin (LEP), the human homolog of the mouse obesity (ob) gene, is positioned near the linkage peak and is the most prominent candidate gene in this region. Interest in LEP as a susceptibility gene for human obesity has led to numerous linkage and association studies, but the results of these studies are still controversial. In the present study, we employed family-based tests of association with both a quantitative measure of BMI adjusted for age and sex and a dichotomously defined obesity trait. We genotyped 29 single-nucleotide polymorphisms (SNPs) spanning 240 kb around the LEP gene in the 82 extended pedigrees with the strongest evidence for linkage. When the programs TRANSMIT and FBAT were used, a number of SNPs showed association in men but not women, for both the quantitative and qualitative trait definitions (P < .05). Five SNPs (H1328084, H1328083, H1328082, H1328081, and H1328080) positioned 2 kb beyond the previously defined promoter region showed strong association in single-marker and multiple-marker haplotype analysis. This five-marker haplotype (frequency 49% in this sample) is overtransmitted to obese offspring (P = .00005). All five of these SNPs are predicted to modify transcription-factor binding sites. This may indicate new functional variants in an extended promoter region of LEP.
UR - http://www.scopus.com/inward/record.url?scp=3242725813&partnerID=8YFLogxK
U2 - 10.1086/422699
DO - 10.1086/422699
M3 - Article
C2 - 15197684
AN - SCOPUS:3242725813
SN - 0002-9297
VL - 75
SP - 220
EP - 230
JO - American journal of human genetics
JF - American journal of human genetics
IS - 2
ER -