A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27

Francke, Stephan; Manraj, Meera; Lacquemant, Corinne; Lecœur, Cécile; Leprêtre, Frédéric; Passa, P; Hébé, A; Corset, Laetitia; Yan, Solange Lee Kwai; Lahmidi, Saida; Jankee, Sarojini; Gunness, Teman K.; Ramjuttun, U. S.; Balgobin, Vinod; Dina, Christian; Froguel, Philippe

doi:10.1093/hmg/10.24.2751

Cited by 232 publications

(120 citation statements)

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“…Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect [7][8][9] . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 .…”

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The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

et al. 2004

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NATURE GENETICS VOLUME 36 | NUMBER 3 | MARCH 2004 233Cardiovascular diseases (CVD) are the leading causes of death and disability in the developed world 1 , with an increasing prevalence due to the aging of the population and the obesity epidemic. More than 1 million deaths in the US alone were caused by myocardial infarction and stroke in 2003 (ref. 2). Some of the processes underlying myocardial infarction are now understood: it is generally attributed to atherosclerosis with arterial wall inflammation that ultimately leads to plaque rupture, fissure or erosion 3,4 . This process is known to involve diapedesis of monocytes across the endothelial barrier; activation of neutrophils, macrophage cells and platelets; and release of a variety of cytokines and chemokines 5,6 , but the genetic basis of the process has not yet been deciphered. Two different approaches have been used to search for genes associated with myocardial infarction. SNPs in candidate genes have been tested for association and have, in general, not been replicated or confer only a modest risk of myocardial infarction. Case-control association studies have identified several proinflammatory genes with variants that are associated with either an increased risk of myocardial infarction or a protective effect 7-9 . Four genome-wide scans in families with myocardial infarction have yielded several loci with formidable linkage peaks, but the gene(s) underlying these loci have not yet been identified [10][11][12][13][14] . In addition, one large pedigree study identified a deletion mutation of a transcription factor gene, MEF2A, with autosomal dominant transmission 14 . This is an interesting cause of myocardial infarction, but the prevalence of this or other mutations in MEF2A outside this family remains to be determined.Here we report a genome-wide scan of 296 multiplex Icelandic families including 713 individuals with myocardial infarction. Through suggestive linkage to a locus on chromosome 13q12-13, we identified the gene (ALOX5AP) encoding FLAP and found that a four-SNP haplotype in the gene confers a nearly two times greater risk of myocardial infarction and stroke. FLAP is a regulator 15 of a crucial pathway in the genesis of leukotriene inflammatory mediators, which are implicated in atherosclerosis both in a mouse model 16 and in human studies 17,18 . Males had the strongest association to the at-risk haplotype, and male carriers of the at-risk haplotype also had significantly greater production of leukotriene-B4 (LTB4), supporting the idea that proinflammatory activity has a role in the pathogenesis of myocardial infarction. We confirmed the association of ALOX5AP with myocardial infarction in an independent cohort of British individuals with another haplotype. These results indicate that ALOX5AP is the first specific gene isolated that confers substantial population-attributable risk (PAR) of the complex traits of both myocardial infarction and stroke. We mapped a gene predisposing to myocardial infarction to a locus on chromosome 13q12-13....

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The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

et al. 2004

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“…More promising results were obtained using OSA with body mass index as covariate in a study of type II diabetes mellitus in Mauritius. 5 Studying the same disorder in families of Ashkenazi Jews, Permutt et al 6 found nominal significant LOD scores on chromosome 4 when they ranked the families by Body Mass Index (in increasing order). Studying the genetics of alcoholism, Watanabe et al 7 identified 40 families with low monoamine oxidase activity who provided evidence for linkage on chromosome 13.…”

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Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

Martins¹,

Hallmayer²

2004

Pharmacogenomics J

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“…Based on previous studies [18], we focused our studies on six traits (body mass index (BMI), waist circumference (WAIST), hip circumference (HIP), weight (WEIGHT), insulin (INSULIN) and insulin/glucose (I/G)) and on chromosome 3 from 182-227 cM (173.4-198.8 Mb), which contains potential pleiotropic QTL [18,19]. The most recent measures were used for all subjects.…”

Section: Methodsmentioning

confidence: 99%

“…The results indicated possible pleiotropic effects. Francke replicated this result, finding the same locus on 3q27 through a genome-wide linkage scan of 99 families of northeastern Indian origin [19]. Here, we attempted to identify markers on 3q27 that are associated with the six traits above by using PCBMR to analyze data from the Bogalusa Heart Study [20].…”

Section: Introductionmentioning

confidence: 98%

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

et al. 2010

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BackgroundQuantitative traits often underlie risk for complex diseases. For example, weight and body mass index (BMI) underlie the human abdominal obesity-metabolic syndrome. Many attempts have been made to identify quantitative trait loci (QTL) over the past decade, including association studies. However, a single QTL is often capable of affecting multiple traits, a quality known as gene pleiotropy. Gene pleiotropy may therefore cause a loss of power in association studies focused only on a single trait, whether based on single or multiple markers.ResultsWe propose using principal-component-based multivariate regression (PCBMR) to test for gene pleiotropy with comprehensive evaluation. This method generates one or more independent canonical variables based on the principal components of original traits and conducts a multivariate regression to test for association with these new variables. Systematic simulation studies have shown that PCBMR has great power. PCBMR-based pleiotropic association studies of abdominal obesity-metabolic syndrome and its possible linkage to chromosomal band 3q27 identified 11 susceptibility genes with significant associations. Whereas some of these genes had been previously reported to be associated with metabolic traits, others had never been identified as metabolism-associated genes.ConclusionsPCBMR is a computationally efficient and powerful test for gene pleiotropy. Application of PCBMR to abdominal obesity-metabolic syndrome indicated the existence of gene pleiotropy affecting this syndrome.

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A genome-wide scan for coronary heart disease suggests in Indo-Mauritians a susceptibility locus on chromosome 16p13 and replicates linkage with the metabolic syndrome on 3q27

Cited by 232 publications

References 74 publications

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

The gene encoding 5-lipoxygenase activating protein confers risk of myocardial infarction and stroke

Age at onset: important marker of genetic heterogeneity in Alzheimer's disease

Principal-component-based multivariate regression for genetic association studies of metabolic syndrome components

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