Localization of a Gene for Peripheral Arterial Occlusive Disease to Chromosome 1p31

Guðmundsson, Guðmundur A.; Matthíasson, Stefán E.; Arason, Haukur; Jóhannsson, Halldór; Runarsson, Freyr; Bjarnason, Hjördis; Helgadottir, Katrin; Thorisdottir, Steinthora; Ingadottir, G.; Lindpaintner, Klaus; Sainz, Jesús; Gudnason, Vilmundur; Frigge, Michael L.; Kong, Augustine; Gulcher, Jeffrey R.; Stefánsson, Kāri

doi:10.1086/339251

Cited by 62 publications

(42 citation statements)

References 15 publications

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“…Putting aside theoretical arguments, the suitability of the Icelandic population for genemapping studies is now perhaps best judged by results; see, for example, Stefánsson et al (2003), Hicks et al (2002), Grétarsdóttir et al (2002) and Gudmundsson et al (2002).…”

Section: Discussionmentioning

confidence: 99%

A Reassessment of Genetic Diversity in Icelanders: Strong Evidence from Multiple Loci for Relative Homogeneity Caused by Genetic Drift

Helgason

Nicholson

Stefánsson

et al. 2003

Annals of Human Genetics

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SummaryThere has been some controversy in the literature concerning whether Icelanders are genetically homogenous or heterogeneous relative to other European populations. We reassess this question in the light of large data sets spanning 83 autosomal SNP loci, 14 serogenetic loci, 6622 Y-chromosomes and 3214 sequences from mtDNA hypervariable segments 1 and 2 (HVS1 and HVS2). Our results strongly support the hypothesis that genetic drift, with a consequent loss of variation, has had a greater impact on Icelanders than most other Europeans. We also analyse 7245 HVS1 sequences from 25 European populations. In line with other studies, we observe a deficit of rare HVS1 haplotypes and an excess of intermediate frequency haplotypes in Icelanders compared to most European populations, with some measures of genetic diversity indicating relative heterogeneity and others indicating relative homogeneity of Icelanders. Simulations indicate that genetic drift, and not admixture (as proposed byÁrnason , 2003) is the most likely cause of the atypical Icelandic HVS1 frequency spectrum. These simulations reveal that gene diversity (heterozygosity) and mean pairwise differences are largely insensitive to events in recent population history, while statistics based on the number of haplotypes or segregating sites are much more sensitive. Overall, our analyses strongly indicate that the Icelandic gene pool is less heterogeneous than those of most other European populations.

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Section: Discussionmentioning

confidence: 99%

A Reassessment of Genetic Diversity in Icelanders: Strong Evidence from Multiple Loci for Relative Homogeneity Caused by Genetic Drift

Helgason

Nicholson

Stefánsson

et al. 2003

Annals of Human Genetics

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“…The control group for the SNP association study was population-based and comprised of 624 unrelated males and females 20-90 years of age whose medical history was unknown. The stroke and PAOD cohorts used in this study have previously been described [32][33][34] . For the stroke linkage analysis, we used genotypes from 342 males with ischemic stroke or TIA that were linked to at least one other male within and including six meioses in 164 families.…”

Section: Study Populationmentioning

confidence: 99%

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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“…We are aware of only 1 study, a familybased linkage study that identified a genetic locus conferring susceptibility to PAD. 31 Gudmundsson et al 31 identified a locus mapping to human chromosome 1p31 termed PAOD1. One of the strengths of this study is that it took an unbiased approach, starting with the PAD phenotype, to identify novel genetic risk factors rather than starting with a potentially biased list of candidate genes.…”

Section: Days Post Surgerymentioning

confidence: 99%

A Quantitative Trait Locus (LSq-1) on Mouse Chromosome 7 Is Linked to the Absence of Tissue Loss After Surgical Hindlimb Ischemia

et al. 2008

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Background— Peripheral arterial disease (PAD) caused by occlusive atherosclerosis of the lower extremity has 2 major clinical manifestations. Critical limb ischemia is characterized by rest pain and/or tissue loss and has a ≥40% risk of death and major amputation. Intermittent claudication causes pain on walking, has no tissue loss, and has amputation plus mortality rates of 2% to 4% per year. Progression from claudication to limb ischemia is infrequent. Risk factors in most PAD patients overlap. Thus, we hypothesized that genetic variations may be linked to presence or absence of tissue loss in PAD. Methods and Results— Hindlimb ischemia (murine model of PAD) was induced in C57BL/6, BALB/c, C57BL/6×BALB/c (F1), F1×BALB/c (N2), A/J, and C57BL/6J-Chr7 A/J /NaJ chromosome substitution strains. Mice were monitored for perfusion recovery and tissue necrosis. Genome-wide scanning with polymorphic markers across the 19 murine autosomes was performed on the N2 mice. Greater tissue loss and poorer perfusion recovery occurred in BALB/c than in the C57BL/6 strain. Analysis of 105 N2 progeny identified a single quantitative trait locus on chromosome 7 that exhibited significant linkage to both tissue necrosis and extent of perfusion recovery. Using the appropriate chromosome substitution strain, we demonstrate that C57BL/6-derived chromosome 7 is required for tissue preservation. Conclusions— We have identified a quantitative trait locus on murine chromosome 7 (LSq-1) that is associated with the absence of tissue loss in a preclinical model of PAD and may be useful in identifying gene(s) that influence PAD in humans.

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Localization of a Gene for Peripheral Arterial Occlusive Disease to Chromosome 1p31

Cited by 62 publications

References 15 publications

A Reassessment of Genetic Diversity in Icelanders: Strong Evidence from Multiple Loci for Relative Homogeneity Caused by Genetic Drift

A Reassessment of Genetic Diversity in Icelanders: Strong Evidence from Multiple Loci for Relative Homogeneity Caused by Genetic Drift

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

A Quantitative Trait Locus (LSq-1) on Mouse Chromosome 7 Is Linked to the Absence of Tissue Loss After Surgical Hindlimb Ischemia

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