Variants of the Arachidonate 5-Lipoxygenase-Activating Protein (ALOX5AP) Gene and Risk of Stroke: A HuGE Gene-Disease Association Review and Meta-Analysis

Abstract

Variants of the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene have been implicated as a risk factor for stroke. However, genetic association studies that have examined the association between ALOX5AP gene variants (HapA haplotype, HapB haplotype, and SG polymorphisms) and stroke have produced conflicting results. Therefore, the authors performed a meta-analysis of all studies with ALOX5AP genotyping (5,194 stroke cases and 4,566 controls). The meta-analysis showed significant heterogeneity among studies (P(Q) = 0.03, I(2) = 63%) and a nonsignificant association between the HapA haplotype (SG13S25G-SG13S114T-SG13S89G-SG13S32A) and stroke risk (random-effects (RE) odds ratio (OR) = 1.13, 95% confidence interval (CI): 0.88, 1.45). Regarding the HapB haplotype (SG13S377A-SG13S114A-SG13S41A-SG13S35G), there was no association with stroke risk (RE OR = 1.03, 95% CI: 0.77, 1.37). The SG13S114, SG13S89, SG13S25, SG13S32, SG13S35, and SG13S42 polymorphisms were not associated with stroke. The SG13S106 and SG13S377 polymorphisms revealed evidence of marginal association (RE OR = 1.23 (95% CI: 1.03, 1.46) and RE OR = 1.25 (95% CI: 1.04, 1.50), respectively). However, cumulative meta-analysis for the HapA haplotype showed a downward trend of odds ratios over time, and recursive cumulative meta-analysis indicated insufficient evidence for claiming or denying an association. Tests for bias revealed no evidence of biases. Rigorous genetic association studies investigating gene-gene-environment interactions may generate more conclusive claims about the genetics of stroke.

Association of a Genetic Variant in the <i>ALOX5AP</i> with Higher Risk of Ischemic Stroke: A Case-Control, Meta-Analysis and Functional Study

“…Concerning the ALOX5AP gene, 4 studies in European populations confirmed later the association with stroke [6,7,8,9], whereas 4 studies and a meta-analysis did not [10,11,12,13,14]. Concerning the PDE4D gene, 14 studies have been published as follow-up in European populations, 11 of which claimed replication of the findings [10,11,12,13,15,16,17,18,19,20,21] and 3 did not [7,22,23].…”

Association of ALOX5, LTA4H and LTC4S gene polymorphisms with ischemic stroke risk in a cohort of Chinese in east China

“…Stroke was defined by the presence of a new focal neurological defi cit, with an acute onset and with symptoms and signs persisting for more than 24 hours. [11] IS was confirmed in all patients by computed tomography and/or magnetic resonance imaging. The control group consisted of 690 unrelated individuals who were recruited simultaneously from the same geographical area as the patients.…”

“…[21] Thus, the potent LTs-induced immunostimulatory actions indicate a key role in the development of atheroma. Besides, some studies [10,11] have indicated a role for the LTs pathway in plaque rupture, causing thrombosis and vessel occlusion. The plaque rupture induces ischemia in distal organs (such as the brain), and the contribution of LTs in stroke has also been studied in models of ischemia and reperfusion.…”

Potential role of the lipoxygenase derived lipid mediators in atherosclerosis: leukotrienes, lipoxins and resolvins

“…In con-trast, a recent meta-analysis that included 9760 samples found that neither the A or B haplotype of FLAP are associated with increased risk for stroke. However, two independent polymorphisms that are part of these haplotypes were shown to moderately increase the risk for stroke (109). It should be emphasized that the mechanism of how haplotype B could alter LTB4 production and promote atherosclerosis is currently unknown.…”