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

Circ Cardiovasc Genet. 2013 Dec;6(6):569-78. doi: 10.1161/CIRCGENETICS.111.000027. Epub 2013 Oct 11.

Abstract

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 early-onset 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 glutamic acid repeat polymorphism of ALMS1 identified in the present study may provide insight into the pathogenesis of early-onset MI.

Keywords: genetic association studies; genetics; genome-wide association study; linkage mapping; myocardial infarction; susceptibility, genetic.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Age of Onset
  • Asian People / genetics
  • Cell Cycle Proteins
  • Cell Line
  • Chromosome Mapping / methods
  • Chromosomes, Human, Pair 2 / genetics
  • Coronary Artery Disease / ethnology
  • Coronary Artery Disease / genetics
  • Family Health
  • Gene Frequency
  • Genetic Linkage
  • Genetic Predisposition to Disease / ethnology
  • Genetic Predisposition to Disease / genetics*
  • Genome-Wide Association Study / methods
  • Genotype
  • Glutamic Acid / genetics*
  • Humans
  • Japan / epidemiology
  • Myocardial Infarction / epidemiology
  • Myocardial Infarction / ethnology
  • Myocardial Infarction / genetics*
  • Odds Ratio
  • Polymorphism, Single Nucleotide*
  • Proteins / genetics*
  • Repetitive Sequences, Amino Acid / genetics*
  • Republic of Korea / epidemiology
  • Risk Factors

Substances

  • ALMS1 protein, human
  • Cell Cycle Proteins
  • Proteins
  • Glutamic Acid