A Promoter Polymorphism (rs17222919, −1316T/G) of ALOX5AP Gene Is Associated with Decreased Risk of Ischemic Stroke in Two Independent Chinese Populations

Abstract

No coding sequence variants of the gene encoding 5-lipoxygenase-activating protein (ALOX5AP) leading to amino acid substitutions have been identified. Therefore, variants in the ALOX5AP promoter region have received attention recently. The purpose of this study was to explore whether the promoter polymorphism rs17222919 is involved in the etiology of ischemic stroke (IS) in the Chinese Han population. We investigated the rs17222919 polymorphism by TaqMan genotyping in two independent Chinese Han samples: the first comprised 910 IS patients and 925 healthy inhabitants from the northern Henan Province, while the second included 1003 IS patients and 889 healthy controls from the southern Henan Province. Functional characterization of rs17222919 was performed by an in vitro luciferase assay. After adjusting for conventional risk factors, the G allele frequencies in the IS groups were significantly lower than that in the control groups of the two independent Chinese cohorts (19.0% vs. 22.9%, P = 0.004, odds ratio (OR) = 0.792, 95% confidence interval (CI) = 0.675–0.929; 18.8% vs. 22.9%, P = 0.002, OR = 0.782, 95% CI = 0.668–0.915, respectively). This was also observed in the large-artery atherosclerosis (LAA) and stroke of other undetermined etiology (SUE) subtypes (P = 0.019, OR = 0.815, 95% CI = 0.687–0.967; P = 0.021, OR = 0.815, 95% CI = 0.685–0.970, respectively). Additionally, the TG genotype and G allele frequencies were significantly lower in the IS compared with the control group in two female cohorts (P<0.05). Finally, the in vitro luciferase assay demonstrated that the G allele has a significantly lower transcription activity than the T allele (P = 0.031). Our study provides evidence that the promoter single nucleotide polymorphism (SNP) rs17222919 is a potential genetic protective factor for IS in the Chinese Han population.

<p>Lack of association between <em>ALOX5AP</em> genetic polymorphisms and risk of ischemic stroke: evidence from meta-analyses</p>

“…Four Asian studies in three publications investigated the role of the ALOX5AP rs17222919 polymorphism 24,27,33. Random-effects meta-analysis indicated no association of the SNP with IS (OR=0.89 for G allele vs T allele; 95% CI: 0.75–1.06; P =0.175) (Table 2).…”

Association between the polymorphism (rs17222919, −1316T/G) of 5-lipoxygenase-activating protein gene (ALOX5AP) and the risk of stroke

“…Then in the remaining 27 documents, 22 were excluded, including 7 reviews, 6 cases reports, 4 studies with repeated crowd, and 5 studies with unacquirable data. Finally, 5 documents [ 22 – 26 ] were included in this meta-analysis.…”

“…As reported in the original study, ALOX5AP mRNA levels were not compared between cases and controls, [ 22 , 25 ] which might also be a limitation of this study. Other limitations are listed as follows.…”

Genetic Variants in the Transcriptional Regulatory Region of the ALOX5AP gene and Susceptibility to Ischemic Stroke in Chinese Populations

“…Our previous i n vitro promoter assay revealed that the G allele had a lower transcriptional activity than the T allele, suggesting that the −1316T/G variation reduces ALOX5AP promoter activity and consequently down-regulates gene expression. The decreased ALOX5AP transcription results in increased inactivation of the 5-LO pathway and reduces leukotriene biosynthesis, which in turn protects from IS 18 . The rs9579646 polymorphism showed no significant differences between groups and was not associated with IS in our second Chinese cohort.…”