Identification of a Glutamic Acid Repeat Polymorphism of ALMS1 as a Novel Genetic Risk Marker for Early-Onset Myocardial Infarction by Genome-Wide Linkage Analysis

Abstract

Two major approaches to the identification of susceptibility genes for CAD or MI have been adopted: genome-wide population-based case-control studies and genome-wide linkage studies (GWLSs), with the latter representing a comprehensive Background-Myocardial infarction (MI) is a leading cause of death worldwide. Given that a family history is an independent risk factor for coronary artery disease, genetic variants are thought to contribute directly to the development of this condition. The identification of susceptibility genes for coronary artery disease or MI may thus help to identify high-risk individuals and offer the opportunity for disease prevention. Methods and Results-We designed a 5-step protocol, consisting of a genome-wide linkage study followed by association analysis, to identify novel genetic variants that confer susceptibility to coronary artery disease or MI. A genome-wide affected sib-pair linkage study with 221 Japanese families with coronary artery disease yielded a statistically significant logarithm of the odds score of 3.44 for chromosome 2p13 and MI. Further association analysis implicated Alström syndrome 1 gene (ALMS1) as a candidate gene within the linkage region. Validation association analysis revealed that representative single-nucleotide polymorphisms of the ALMS1 promoter region were significantly associated with earlyonset MI in both Japanese and Korean populations. Moreover, direct sequencing of the ALMS1 coding region identified a glutamic acid repeat polymorphism in exon 1, which was subsequently found to be associated with early-onset MI. Conclusions-The

Genome-Wide Linkage Approach Yields Novel Early Onset Myocardial Infarction Locus in East Asians

“…If these results can be independently validated, the presence of hyperinsulinemia and type 2 diabetes mellitus in Alström syndrome merits further exploration as a potential mechanism of ALMS1 in early onset MI. The present study by Ichihara et al 15 highlights several issues pertinent to genetic discovery in the modern era. First is the importance of multistage replication and an integrative genomic approach to gene discovery, which is particularly crucial in this study given the checkered history of linkage analysis in complex human cardiovascular disease.…”

“…In this issue of Circulation: Cardiovascular Genetics, Ichihara et al 15 use a multimodal approach using both linkage and GWAS analysis techniques in an East Asian population to identify a novel gene, ALMS1, as a putative risk factor for early onset MI. In their discovery phase, the authors performed linkage analysis in 455 individuals from 221 families with CAD, using both single-nucleotide polymorphisms and microsatellites, and identified an MI-linked region on chromosome 2p13.…”

“…Ichihara et al 15 conclude that ALMS1 represents a novel risk locus for early onset MI in the East Asian population and postulate that ethnic population-specific effects combined with methodological differences between linkage analysis and GWAS account for the fact that this locus has not yet been identified in published GWAS efforts of early onset MI. Certainly, ALMS1 is an interesting gene, best known for its association with the autosomal recessive Alström syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes mellitus, cardiomyopathy, and renal and hepatocellular dysfunction.…”

“…Certainly, ALMS1 is an interesting gene, best known for its association with the autosomal recessive Alström syndrome, which is characterized by obesity, insulin resistance, type 2 diabetes mellitus, cardiomyopathy, and renal and hepatocellular dysfunction. 15,16 Although ALMS1 is widely expressed in multiple human tissue types, its exact function is unknown.…”

“…Further efforts to explore this locus in existing CAD and MI cohorts of multiple ethnicities should be considered to determine whether trending associations below the genome-wide significance threshold exist in other populations and whether the common variants identified by Ichihara et al 15 exhibit substantial stratification by ethnicity. If the effect of ALMS1 on early onset MI cannot be explained by population specificity, then explanations for why large-scale GWASs have not yet revealed risk associations at ALMS1 must be sought.…”