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A near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease.

TitleA near null variant of 12/15-LOX encoded by a novel SNP in ALOX15 and the risk of coronary artery disease.
Publication TypeJournal Article
Year of Publication2008
AuthorsAssimes TL, Knowles JW, Priest JR, Basu A, Borchert A, Volcik KA, Grove ML, Tabor HK, Southwick A, Tabibiazar R, Sidney S, Boerwinkle E, Go AS, Iribarren C, Hlatky MA, Fortmann SP, Myers RM, Kuhn H, Risch N, Quertermous T
JournalAtherosclerosis
Volume198
Issue1
Pagination136-44
Date Published2008 May
ISSN1879-1484
KeywordsAged, Arachidonate 12-Lipoxygenase, Arachidonate 15-Lipoxygenase, Cell Line, Tumor, Coronary Artery Disease, Female, Genetic Predisposition to Disease, Genetic Variation, Genotype, Humans, Kidney Neoplasms, Male, Middle Aged, Mutagenesis, Polymorphism, Single Nucleotide, Prevalence, Risk Factors
Abstract

OBJECTIVE: Murine genetic models suggest that function of the 12/15-LOX enzyme promotes atherosclerosis. We tested the hypothesis that exonic and/or promoter single nucleotide polymorphisms (SNPs) in the human 12/15-LOX gene (ALOX15) alter the risk of symptomatic coronary artery disease (CAD).

METHODS AND RESULTS: We resequenced ALOX15 and then genotyped a common promoter and a less common novel coding SNP (T560M) in 1809 subjects with CAD and 1734 controls from Kaiser Permanente including a subset of participants of the Coronary Artery Risk Development in Young Adults study. We found no association between the promoter SNP and the risk of CAD. However, heterozygote carriers of the 560M allele had an increased risk of CAD (adjusted OR, 1.62; P=0.02) compared to non-carriers. In vitro studies demonstrated a 20-fold reduction in the catalytic activity of 560M when compared to 560T. We then genotyped T560M in 12,974 participants of the Atherosclerosis Risk in Communities study and similarly found that heterozygote carriers had an increased risk of CAD compared to non-carriers (adjusted HR, 1.31; P=0.06). In both population studies, homozygote carriers were rare and associated with a non-significant decreased risk of CAD compared to non-carriers (adjusted OR, 0.55; P=0.63 and HR, 0.93; P=0.9).

CONCLUSIONS: A coding SNP in ALOX15 (T560M) results in a near null variant of human 12/15-LOX. Assuming a co-dominant mode of inheritance, this variant does not protect against CAD. Assuming a recessive mode of inheritance, the effect of this mutation remains unclear, but is unlikely to provide a protective effect to the degree suggested by mouse knockout studies.

DOI10.1016/j.atherosclerosis.2007.09.003
Alternate JournalAtherosclerosis
PubMed ID17959182
PubMed Central IDPMC2440699
Grant ListN01HC55018 / HL / NHLBI NIH HHS / United States
N01-HC-55022 / HC / NHLBI NIH HHS / United States
N01-HC-55016 / HC / NHLBI NIH HHS / United States
N01 HC055018 / HC / NHLBI NIH HHS / United States
N01HC55015 / HL / NHLBI NIH HHS / United States
N01-HC-48050 / HC / NHLBI NIH HHS / United States
N01 HC055019 / HC / NHLBI NIH HHS / United States
N01-HC-55019 / HC / NHLBI NIH HHS / United States
N01HC95095 / HL / NHLBI NIH HHS / United States
N01-HC-55015 / HC / NHLBI NIH HHS / United States
N01-HC-48049 / HC / NHLBI NIH HHS / United States
N01 HC055015 / HC / NHLBI NIH HHS / United States
N01 HC055021 / HC / NHLBI NIH HHS / United States
N01HC48047 / HL / NHLBI NIH HHS / United States
N01 HC055020 / HC / NHLBI NIH HHS / United States
N01 HC055016 / HC / NHLBI NIH HHS / United States
N01HC48048 / HL / NHLBI NIH HHS / United States
N01HC55020 / HL / NHLBI NIH HHS / United States
N01 HC055022 / HC / NHLBI NIH HHS / United States
N01-HC-48047 / HC / NHLBI NIH HHS / United States
N01HC48049 / HL / NHLBI NIH HHS / United States
N01-HC-95095 / HC / NHLBI NIH HHS / United States
N01HC55022 / HL / NHLBI NIH HHS / United States
N01-HC-55021 / HC / NHLBI NIH HHS / United States
N01-HC-55020 / HC / NHLBI NIH HHS / United States
N01HC55016 / HL / NHLBI NIH HHS / United States
N01HC48050 / HL / NHLBI NIH HHS / United States
N01HC55019 / HL / NHLBI NIH HHS / United States
N01-HC-48048 / HC / NHLBI NIH HHS / United States
N01-HC-55018 / HC / NHLBI NIH HHS / United States
N01HC55021 / HL / NHLBI NIH HHS / United States