Dataset Information

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.

ABSTRACT: 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.

SUBMITTER: Jiang Y

PROVIDER: S-EPMC1216056 | biostudies-literature | 2004 Aug

REPOSITORIES: biostudies-literature

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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.

Jiang Y Y Wilk J B JB Borecki I I Williamson S S DeStefano A L AL Xu G G Liu J J Ellison R C RC Province M M Myers R H RH

American journal of human genetics 20040611 2

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 ...[more]

PMID: 15197684

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Project description:A combined analysis of genome scans for obesity was undertaken using the interim results from the National Heart, Lung, and Blood Institute Family Blood Pressure Program. In this research project, four multicenter networks of investigators conducted eight individual studies. Data were available on 6,849 individuals from four ethnic groups (white, black, Mexican American, and Asian). The sample represents the largest single collection of genomewide scan data that has been analyzed for obesity and provides a test of the reproducibility of linkage analysis for a complex phenotype. Body mass index (BMI) was used as the measure of adiposity. Genomewide linkage analyses were first performed separately in each of the eight ethnic groups in the four networks, through use of the variance-component method. Only one region in the analyses of the individual studies showed significant linkage with BMI: 3q22.1 (LOD 3.45, for the GENOA network black sample). Six additional regions were found with an associated LOD >2, including 3p24.1, 7p15.2, 7q22.3, 14q24.3, 16q12.2, and 17p11.2. Among these findings, the linkage at 7p15.2, 7q22.3, and 17p11.2 has been reported elsewhere. A modified Fisher's omnibus procedure was then used to combine the P values from each of the eight genome scans. A complimentary approach to the meta-analysis was undertaken, combining the average allele-sharing identity by descent (pi) for whites, blacks, and Mexican Americans. Using this approach, we found strong linkage evidence for a quantitative-trait locus at 3q27 (marker D3S2427; LOD 3.40, P=.03). The same location has been shown to be linked with obesity-related traits and diabetes in at least two other studies. These results (1) confirm the previously reported obesity-susceptibility locus on chromosomes 3, 7, and 17 and (2) demonstrate that combining samples from different studies can increase the power to detect common genes with a small-to-moderate effect, so long as the same gene has an effect in all samples considered.

Project description:AimsThere are limited data examining whether body mass index (BMI) influences the association between cardiovascular biomarkers and incident heart failure (HF).Methods and resultsThirteen biomarkers representing key HF domains were measured: N-terminal pro-B-type natriuretic peptide (NT-proBNP), mid-regional pro-A-type natriuretic peptide (MR-proANP), cardiac troponin T (cTnT), C-reactive protein, procalcitonin, galectin-3, C-terminal pro-endothelin-1 (CT-proET-1), mid-regional pro-adrenomedullin, plasminogen activator inhibitor-1, copeptin, renin, aldosterone, and cystatin-C. Associations of biomarkers with BMI were examined using linear regression models, and with incident HF using Cox regression models. We selected biomarkers significantly associated with incident HF, and evaluated whether BMI modified these associations. Among 8202 individuals, 41% were overweight (BMI 25-30 kg/m2 ), and 16% were obese (BMI ≥30 kg/m2 ). Mean age of the cohort was 49 years (range 28-75), and 50% were women. All biomarkers except renin were associated with BMI: inverse associations were observed with NT-proBNP, MR-proANP, CT-proET-1 and aldosterone whereas positive associations were observed with the remaining biomarkers (all P ≤ 0.001). During 11.3 ± 3.1 years of follow-up, 357 HF events were recorded. Only NT-proBNP, MR-proANP and cTnT remained associated with incident HF (P < 0.001), and a significant biomarker*BMI interaction was not observed (interaction P > 0.1). Combined NT-proBNP and cTnT measurements modestly improved performance metrics of the clinical HF model in overweight (ΔC-statistic = 0.024; likelihood ratio χ2 = 38; P < 0.001) and obese (ΔC-statistic = 0.020; likelihood ratio χ2 = 32; P < 0.001) individuals.ConclusionsPlasma concentrations of several cardiovascular biomarkers are influenced by obesity. Only NT-proBNP, MR-proANP and cTnT were associated with incident HF, and BMI did not modify these associations. A combination of NT-proBNP and cTnT improves HF risk prediction in overweight and obese individuals.

Dataset Information

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.

Publications

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.

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