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Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease.

ABSTRACT: Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study. A nominally significant association was detected between a promoter SNP in ALOX5 (rs12762303) and CAD in our subset of white/European subjects (adjusted odds ratio per minor allele, log-additive model, 1.32; P = 0.002). In this race/ethnic group, rs12762303 has a minor allele frequency of 15% and is tightly linked to variation at the SP1 variable tandem repeat promoter polymorphism. However, the association between CAD and rs12762303 could not be reproduced in the atherosclerosis risk in communities study (hazard rate ratio per minor allele; 1.08, P = 0.1). Assuming a recessive mode of inheritance, the association was not significant in either population study but our power to detect modest effects was limited. No significant associations were observed between all other SNPs and the risk of CAD. Overall, our findings do not support a link between common allelic variation in or near ALOX5 or ALOX5AP and the risk of CAD. However, additional studies are needed to exclude modest effects of promoter variation in ALOX5 on the risk of CAD assuming a recessive mode of inheritance.

SUBMITTER: Assimes TL

PROVIDER: S-EPMC4023692 | biostudies-literature | 2008 May

REPOSITORIES: biostudies-literature

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Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease.

Assimes Themistocles L TL Knowles Joshua W JW Priest James R JR Basu Analabha A Volcik Kelly A KA Southwick Audrey A Tabor Holly K HK Hartiala Jaana J Allayee Hooman H Grove Megan L ML Tabibiazar Raymond R Sidney Stephen S Fortmann Stephen P SP Go Alan A Hlatky Mark M Iribarren Carlos C Boerwinkle Eric E Myers Richard R Risch Neil N Quertermous Thomas T

Human genetics 20080328 4

Recent human genetic studies suggest that allelic variants of leukotriene pathway genes influence the risk of clinical and subclinical atherosclerosis. We sequenced the promoter, exonic, and splice site regions of ALOX5 and ALOX5AP and then genotyped 7 SNPs in ALOX5 and 6 SNPs in ALOX5AP in 1,552 cases with clinically significant coronary artery disease (CAD) and 1,583 controls from Kaiser Permanente including a subset of participants of the coronary artery risk development in young adults study ...[more]

PMID: 18369664

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Project description:BackgroundStudies on the susceptibility of vitamin D receptor (VDR) polymorphisms to coronary artery disease (CAD) reached controversial results. We performed this study for a more accurate evaluation between the VDR polymorphisms and CAD susceptibility.MethodsPubMed, Embase, CNKI, Wan Fang, and VIP databases were searched. The odds ratios (ORs) and 95% confidence intervals (95% CIs) were used to evaluate the associations. Trial sequential analysis (TSA) was introduced to estimate the positive associations. The potential functions of the VDR polymorphisms were analyzed based on the SNPinfo and ENSEMBL databases.ResultsThirteen studies were finally included. In the overall analysis, increased CAD risks were observed in the VDR rs1544410 polymorphism and verified by the TSA; for the rs2228570 and rs731236 polymorphisms, significant associations with high heterogeneity were detected; decreased risk was remarkably observed for the rs7975232 polymorphism. In the subgroup analysis, wide associations with reduced heterogeneity were observed in the rs2228570, rs1544410, and rs731236 polymorphisms. The RNAfold analysis indicated the mutant G allele of the rs1544410 polymorphism was easier to disperse from the DNA double helix structure and may have a potential crucial role in the VDR transcription process.ConclusionsOur analysis supports the role of the rs1544410 polymorphism in the VDR gene as a risk factor for CAD. The VDR rs2228570 and rs731236 polymorphisms were associated with increased CAD risks in the White population. Restrict decreased CAD risk was firstly discovered in the rs7975232 polymorphism.LimitationsFirstly, the language was restricted to English and Chinese, which will cause the limited number of studies included; secondly, other unknown polymorphisms in VDR polymorphisms could also be associated the CAD susceptibility, and more case-control studies with comprehensive clinical outcomes and GWAS studies were required; thirdly, the rs1544410, rs7975232 and rs731236 polymorphism are in strong LD, haploid factors with CAD risk need to be considered; fourthly, the mechanisms of the VDR polymorphism on the VDR gene or RNA or protein were not discussed enough, further mechanistic studies are required; at last, genetic factor was the one side for CAD susceptibility, the interaction between environmental risk factors should be considered.

Dataset Information

Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease.

Publications

Common polymorphisms of ALOX5 and ALOX5AP and risk of coronary artery disease.

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