促炎基因ALOX5AP基因多态性与脑卒中的相关性研究

白三烯是作用较强的促炎症因子,在动脉粥样硬化的发生发展中发挥着重要作用。5-脂氧合酶激活蛋白是白三烯合成的关键调控因素,通过全基因组扫描的连锁分析和关联分析发现编码5-脂氧合酶激活蛋白的基因ALOX5AP在白种人中与心肌梗塞和脑卒中的患病风险相关。然而,目前尚无关于该基因与亚洲人脑卒中患病风险的遗传学资料。本研究探讨了ALOX5AP基因多态与脑卒中及其亚型易感性的关系。采用PCR—RFLP方法,对来自7个临床中心的1713名对照和1773名脑卒中患者检测了ALOX5AP基因的4个SNPs：SG13S25、SG13S114、SG13S89和SG13S32。多元logistic回归方法校正传统危险因素后分析基因多态与脑卒中患病风险的独立相关性。结果表明,人群未发现SG13S25和SG13S32具有多态性;ALOX5AP基因多态SG13S114A等位基因频率在男性脑梗塞组显著高于对照组（33．6％VS29．2％;P=0．014）,SG13S114AA基因型增加男性脑梗塞1．62倍的发病风险（95％CI：1．1-2．35：P=0．012）。多态SG13S89G／A与脑梗塞的易感性不相关。单体型分析表明单体型频率在脑卒中患者和对照组间无显著的统计学差异。因此,本研究结果提示ALOX5AP基因多态的等位基因和基因型频率在东、西方人群存在种族差异,SG13S114AA基因型增加中国人群男性脑梗塞的易感性。     

Genetic polymorphisms of <Emphasis Type="Italic">T-1131C APOA5</Emphasis> and <Emphasis Type="Italic">ALOX5AP SG13S114</Emphasis> with the susceptibility of ischaemic stroke in Morocco

Ischaemic stroke is a multifactorial disease. Genetic polymorphisms involved in lipid, inflammatory and thrombotic metabolisms play an important role in the development of ischaemic stroke. The present study aimed to assess the relationship between T1131C APOA5 and SG13S114 ALOX5AP polymorphisms and the risk of ischemic stroke in 175 cases and 201 controls. Genotyping was performed by high resolution melting and polymerase chain reaction restriction fragment length polymorphism methods. In the case of T-1131C APOA5, a modest risk of ischaemic stroke was noticed with CC (OR: 2.86; 95% CI = 1.24–6.58; Pc = 0.039) and C allele (OR: 1.54; 95% CI = 1.01–2.33; Pc = 0.014). For SG13S114ALOX5AP, a significant association was observed among subjects with TT (OR: 2.57; 95% CI =1.49–4.83; Pc = 0.009) and T allele (OR: 1.59; 95% CI = 1.16–2.19; Pc = 0.008). According to the risk factors of ischaemic stroke, a positive correlation was observed only between SG13S114 variant of ALOX5AP gene and hypertension (Pc = 0.026). Despite lower sample size, T-1131C APOA5 and SG13S114 variants could be considered an independent genetic risk factor of ischaemic stroke in Moroccan population.     

Correlation Between Cerebral Infarction and ALOX5AP Gene Expression

Linkage/linkage-disequilibrium analysis studies, based on positional information and gene function, indicated that ALOX5AP gene was an independent risk factor of cerebral infarction in humans; however, this needs to be verified among different populations. Herein, we verified whether ALOX5AP was a risk factor of cerebral infarction in the Chinese Han population. For this purpose, 547 cerebral infarction patients were enrolled as the case group; the control group comprised 794 healthy, age-matched individuals unrelated to case group and had no history of cerebral infarction/transient ischemic attack. Regarding single-nucleotide polymorphism (SNP) selection and ALOX5AP genotyping, we selected four SNP loci (SG13S25, SG13S114, SG13S89, and SG13S32) and determined allelic frequencies. Genotyping of SG13S114 and SG13S32 adopted a method of combining real-time quantitative PCR and allele-specific PCR. A linkage-disequilibrium analysis of ALOX5AP was also performed. We found that the allelic frequencies of SG13S25 and SG13S89 were below 5 % and those of SG13S114 and SG13S32 were above 5 %. We did not find any differences between the case and control groups regarding allele, allele types, and haplotype gene frequencies of two SNP loci. The results indicate that the two genetic polymorphisms of ALOX5AP, SG13S114 and SG13S32, are not associated with cerebral infarction in Chinese Han population.     

The arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism and ischemic stroke in Chinese population: A meta-analysis

Previous studies have indicated that the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene SG13S114 polymorphism is associated with risk of ischemic stroke (IS), but the results remain inconclusive even in Chinese population. A meta-analysis of 10 case-control studies was conducted on the relationship between ALOX5AP SG13S114 polymorphism and susceptibility to IS in Chinese population published domestically and abroad from September 2007 to December 2012. Data were extracted by two authors and pooled odds ratios (ORs) and 95% confidence intervals (CIs) were calculated. Meta-analysis results showed that the significant association between SG13S114 variant and IS was found under the allelic (OR = 0.87, 95% CI: 0.80–0.96, P = 0.004), dominant (OR = 0.75, 95% CI: 0.62–0.92, P = 0.005), and recessive (OR = 0.89, 95% CI: 0.82–0.97, P = 0.005) genetic models in Chinese population. In subgroup meta-analysis, SG13S114 variant and atherothrombotic stroke, rather than lacunar stroke, showed the significant association under the allelic (OR = 0.86, 95% CI: 0.80–0.92, P < 0.0001), dominant (OR = 0.72, 95% CI: 0.57–0.91, P = 0.006), and recessive (OR = 0.86, 95% CI: 0.78–0.95, P = 0.002) models. ALOX5AP SG13S114 polymorphism is associated with susceptibility to IS in Chinese population.     

Polymorphic variants of ALOX5AP gene and the risk of acute stroke development in the Russian population

A protein capable of activating 5-lipoxygenase (ALOX5AP) is considered a presumable risk factor of acute stroke development. Polymorphic variants of the ALOX5AP gene were examined. Two ALOX5AP gene polymorphisms (SG13S114 (rs10507391) and SG13S32 (rs9551963)), which previously had shown association with the risk of ischemic stroke in other populations, were studied. These single nucleotide polymorphisms were analyzed using a sample of acute stroke patients (N = 1320) and a control sample (N = 467). No statistically significant associations were found between acute stroke and the ALOX5AP gene polymorphisms examined.     

Polymorphic variants of <Emphasis Type="Italic">ALOX</Emphasis>5<Emphasis Type="Italic">AP</Emphasis> gene and the risk of acute stroke development in the Russian population

The role of variants of the gene encoding arachidonate 5-lipoxygenase-activating protein (ALOX5AP) as possible susceptibility factors for acute stroke were examinated. Two ALOX5AP gene polymorphisms (SG13S114 (rs10507391) and SG13S32 (rs9551963)), which previously had shown association with the risk of ischemic stroke in other populations, were studied. These single nucleotide polymorphisms were analyzed using a sample of acute stroke patients (N = 1320) and a control sample (N = 467). No statistically significant associations were found between acute stroke and the ALOX5AP gene polymorphisms examined.     

Are ALOX5AP gene SNPs a risk or protective factor for stroke?

ALOX5AP (5-lipoxygenase) has been recognized as a susceptibility gene for stroke. Using a case–control design, the whole coding and adjoining intronic regions of ALOX5AP were sequenced to study the role of SNPs and their interplay with other risk factors in Greek patients with stroke. Patients (n = 213) were classified by the Trial of Org 10172 in Acute Stroke Treatment (TOAST). Their mean age of was 58.9 ± 14.64, comprising 145 males. The control group consisted of 210 subjects, ethnicity, sex and age matched, with no stroke history. Risk factors (hyperlipidemia, hypertension, atrial fibrillation, migraine, CAD, diabetes, smoking and alcohol consumption) were assessed as confounding factors and comparisons were done using logistic regression analysis. SNPs rs4769055, rs202068154 and rs3803277 located in intronic regions of the gene and according to in silico programs EX_SKIP and HSF possibly affecting splicing of exons 1 and 2 of ALOX5AP, showed significantly different frequencies between patients and controls. The genotype frequencies of rs4769055: AA, of rs202068154: AC and of rs3803277: CA were significantly higher (p < 0.001, 0.058) in controls than in patients. The results were indicative of a protective role of the three SNPs either in homozygosity or heterozygosity for MAF and more specifically rs3803277: CA/AA genotypes were protective against SVO stroke subtype.     

A tagging SNP in <Emphasis Type="Italic">ALOX5AP</Emphasis> and risk of stroke: a haplotype-based analysis among eastern Chinese Han population

A genome-wide approach found significant association of two at-risk haplotypes (HapA, HapB) in the ALOX5AP gene with myocardial infarction and stroke. To date, it is still controversial whether ALOX5AP gene polymorphisms are risk factors for stroke. The aim of the present study is to investigate the association between the ALOX5AP gene polymorphism and the risk for stroke in Eastern Chinese Han population with a haplotype-based analysis. We conducted a comprehensive association study of 507 stroke patients and 510 healthy controls to assess the association between the ALOX5AP tagging single-nucleotide polymorphisms (tSNPs) and stroke risk. Genotyping was performed using the PCR–RFLP assay. In the single-locus analysis, we found that the rs9579646 AG genotype was associated with a marginally decreased risk for stroke (adjusted odds ratio, 0.65; 95% confidence interval, 0.45–0.96), compared with the AA genotype. Haplotype-based association analysis of block 2 involving rs10507391 and rs12429692 revealed that the decreased risk of stroke was significantly associated with haplotype AA (OR, 0.66; 95% CI, 0.46–0.95). These results suggested that the genetic variants in ALOX5AP might modulate the risk of stroke in Eastern Chinese Han population. The frequencies of single-marker alleles and haplotypes showed remarkable differences from those in other populations.     

Association of three-gene interaction among MTHFR, ALOX5AP and NOTCH3 with thrombotic stroke: a multicenter case–control study

Stroke is a common complex trait and does not follow Mendelian pattern of inheritance. Gene–gene or gene–environment interactions may be responsible for the complex trait. How the interactions contribute to stroke is still under research. This study aimed to explore the association between gene–gene interactions and stroke in Chinese in a large case–control study. Nearly 4,000 participants were recruited from seven clinical centers. Eight variants in five candidate genes were examined for stroke risk. Gene–gene interactions were explored by using Generalized Multifactor Dimensionality Reduction (GMDR). A significant gene–gene interaction was found by GMDR. The best model including MTHFR C677T, ALOX5AP T2354A and NOTCH3 C381T scored 10 for Cross-Validation Consistency and 9 for Sign Test (P = 0.0107). The individuals with combination of MTHFR 677TT, ALOX5AP 2354AA and NOTCH3 381TT/TC had a significantly higher risk of thrombotic stroke (OR 3.165, 95% CI 1.461–6.858, P = 0.003). Our results show that combination of these alleles conferred higher risk for stroke than single risk allele. The gene–gene interaction may serve as a novel area for stroke research. The three-locus combination may change the susceptibility of particular subjects to the disease.     

Association of ALOX5AP with ischemic stroke: a population-based case-control study

Arachidonate 5-lipoxygenase activating protein (ALOX5AP) has been reported to demonstrate linkage and association with ischemic stroke and myocardial infarction. However, replication studies have been conflicting and to date, a significant proportion of blacks have not been studied. We prospectively recruited cases of ischemic stroke from all 16 hospitals in the Greater Cincinnati/Northern Kentucky region and demographically matched them to stroke-free population-based controls. Single nucleotide polymorphisms (SNPs) were selected based on association with ischemic stroke in prior studies. Allelic, genotypic and haplotypic association testing was performed using HAPLOVIEW. Multiple logistic regression was used to control for the presence of traditional risk factors including hypertension, diabetes, hypercholesterolemia and smoking. A total of 357 cases and 482 controls were genotyped. The SNPs, rs9579646 and rs4769874 were found to be significantly associated at both allelic (P = 0.019 and P < 10⁻⁴, respectively) and genotypic level with ischemic stroke among whites after correction for multiple testing. Haplotype association was identified with ischemic stroke as well as ischemic stroke subtypes among whites. Although an overall haplotype association with ischemic stroke was identified among blacks no evidence of association among individual haplotypes, alleles or genotypes were observed. Allele frequencies for the SNPs examined were markedly different among whites and blacks. In conclusion, we report significant association of variants of ALOX5AP with ischemic stroke and ischemic stroke subtypes among whites. No significant association was identified among blacks.     

Genetic variation in members of the leukotrienes biosynthesis pathway confers risk of ischemic stroke in Eastern Han Chinese

This study was aimed to explore the association of genetic variation in members of the leukotrienes biosynthesis pathway as potential mediators with ischemic stroke (IS) risk in Eastern Han Chinese. A case-control study of was conducted with five selected single nucleotide polymorphisms (SNPs). In the single-locus analysis, carriers of C allele of rs730012 in LTC4S were more susceptible to IS (OR, 1.28; 95% CI, 1.02–1.60; P=0.033). Under the recessive genetic model, ALOX5 rs2029253 variant reduced IS risk (adjusted OR, 0.78; 95% CI, 0.60–1.00; P=0.048) while LTA4H rs6538697 and LTC4S rs730012 variants increased (adjusted OR, 1.66; 95% CI, 1.04–2.64; P=0.032 and adjusted OR, 3.63; 95% CI, 1.01–13.05; P=0.048, respectively). However, there was no evidence of association between all five SNPs and IS risk after correction for multiple testing. In combined analysis of multiple genes and loci, individuals with ALOX5AP rs12429692 T allele, ALOX5 rs2029253 A allele, and LTA4H rs6538697 C allele suggested a significantly increased susceptibility to IS (adjusted OR, 1.70; 95% CI, 1.07–2.69; P=0.024). The present study suggested gene–gene interactions in leukotrienes pathway could exert influences on the risk of IS.     

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

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. Themistocles L. Assimes and Joshua W. Knowles contributed equally to this work.     

Promoter methylation and functional variants in arachidonate 5-lipoxygenase and forkhead box protein O1 genes associated with coronary artery disease

Coronary artery disease (CAD) is a multifactorial chronic inflammatory disease, which is the most common form of heart disease. This is one of the main causes of death in the United States. Inflammation is one of the key drivers of atherosclerotic plaque development. Forkhead box protein O1 (FOXO1s) family and 5-lipoxygenase make an important contribution to atherosclerosis. The aim of this study was to investigate the methylation pattern and polymorphism analysis of FOXO1 and arachidonate 5-lipoxygenase (ALOX5) promoter genes. We studied 50 patients with CAD and 50 age- and sex-matched healthy controls by high resolution melt technique. Overall, we found significant differences between patients and controls in terms of the promoter methylation of ALOX5 (P > 0.05). But there was no significant difference in FOXO1 promoter methylation between patient and controls. Single nucleotide polymorphisms genotyping of rs12762303 and rs2297627, in ALOX5 and FOXO1 genes were demonstrated a significant correlation between mutant allele and the risk of CAD, respectively. Furthermore, there were significant associations between CT + CC genotype and ALOX5 expression. Our findings demonstrated functional effects of single nucleotide polymorphisms (SNPs) and DNA methylation in ALOX5 on mentioned genes expression and they resulted in CAD progression.     

Interrelationships between ALOX5AP Polymorphisms,Serum Leukotriene B4 Level and Risk of Acute Coronary Syndrome

Background

We investigated the relationships between the ALOX5AP gene rs10507391 and rs4769874 polymorphisms, serum levels of leukotriene (LT) B4, and risk of acute coronary syndrome (ACS).

Methods

A total of 709 participants, comprising 508 ACS patients (ACS group) and 201 noncoronary artery disease patients with chest pain (control group) were recruited from the Han population of the Changwu region in China. Two polymorphic loci were genotyped using polymerase chain reaction and restriction fragment length polymorphism analysis. Serum LTB4 level was determined by enzyme-linked immunosorbent assay.

Results

Serum LTB4 levels were significantly higher (P<0.001) in the ACS group (median/interquartile range, 470.27/316.32 pg/ml) than in the control group (233.05/226.82 pg/ml). No statistical differences were observed between genotype, allele and haplotype frequencies for the tested loci in either the ACS group or the control group, even after adjustments were made for conventional risk factors by multivariate logistic regression. This suggests there is no association between the ALOX5AP rs10507391 and rs4769874 polymorphisms and ACS risk. Elevated serum LTB4 level was closely linked to ACS risk, and may be independent of traditional risk factors as a risk factor for ACS (P<0.001). There was no significant association between serum LTB4 levels and the two variants in either the ACS group or the control group.

Conclusions

Rs10507391, rs4769874 and its haplotypes in ALOX5AP are unrelated to ACS risk in the Chinese Han population of Changwu, but elevated serum LTB4 level is strongly associated with ACS risk. Serum LTB4 level is not subject to the influence of either the rs10507391, rs4769874 or the haplotype.     

Genetic effects in the leukotriene biosynthesis pathway and association with atherosclerosis

Leukotrienes are arachidonic acid derivatives long known for their inflammatory properties and their involvement with a number of human diseases, most particularly asthma. Recently, leukotriene-based inflammation has also been shown to play an important role in atherosclerosis: ALOX5AP and LTA4H, both genes in the leukotriene biosynthesis pathway, have individually been shown to be associated with various cardiovascular disease (CVD) phenotypes. To assess the role of the leukotriene pathway in CVD pathogenesis, we performed genetic association studies of ALOX5AP and LTA4H in a family based study of early onset coronary artery disease (EOCAD) (GENECARD, 1,101 families) and in a non-familial dataset of EOCAD (CATHGEN, 656 cases and 405 controls). We found weak to moderate association between single nucleotide polymorphisms (SNPs) in ALOX5AP and LTA4H with EOCAD. The previously reported four-SNP haplotype (HapA) in ALOX5AP showed association with EOCAD in CATHGEN (P = 0.02), while controlling for age, race and CVD risk factors. HapK, the previously reported ten-SNP haplotype in LTA4H was associated with EOCAD in CATHGEN (P = 0.04). Another previously reported four-SNP haplotype in ALOX5AP (HapB) was not significant in our sample (P = 0.39). The overall lack of (or weak) association of single SNPs as compared with the haplotype results demonstrates the need for analyzing multiple SNPs within each gene in such studies. Interestingly, we detected an association of SNPs in ALOX5 (P < 0.05), the target of ALOX5AP, with CVD. Using a pathway-based approach, we also detected statistical evidence for interactions among ALOX5, ALOX5AP and LTA4H using RNA expression data from a collection of freshly harvested human aortas with varying degrees of atherosclerosis. The GENECARD families did not demonstrate evidence for linkage or association with ALOX5, ALOX5AP or LTA4H. Our results support a modest role for the leukotriene pathway in atherosclerosis pathogenesis, reveal important genomic interactions within the pathway, and suggest the importance of using pathway-based modeling for evaluating the genomics of atherosclerosis susceptibility. Electronic supplementary material  The online version of this article (doi:) contains supplementary material, which is available to authorized users.     

Functional variants of the human 5-lipoxygenase gene and their genetic diagnosis

Variants in the 5-lipoxygenase (ALOX5) gene are first-line candidate causes for interindividual differences in diseases where leukotrienes play a key role, e.g., inflammatory and immune diseases, atherosclerosis, asthma or the acute respiratory distress syndrome (ARDS). We developed and validated Pyrosequencing™ screening assays for single nucleotide polymorphism (dbSNP-IDs rs4986832, rs4987105, rs2115819, rs3740107, rs1565096, rs2291427, rs10571382, rs2242334, rs2229136, rs3802548), and a capillary electrophoresis assay for the ALOX5 Sp1/Egr1 promoter tandem repeat polymorphism. This selection spans the whole ALOX5 gene range and includes all variants with reported functional associations. A gene structure analysis in DNAs from 187 healthy unrelated Caucasians revealed two haploblocks, one in the promoter and one spanning six SNPs from rs3740107G>A in intron 6 to rs2229136A>G in exon 13. The five-repeat genotype was the most frequent Sp1/Egr1 promoter tandem repeat variant (allelic frequency 84%). These assays and analyses provide a solid basis for future assessments of the genetic modulation of leukotriene production.     

Apolipoprotein A5 polymorphisms in Turkish population: association with serum lipid profile and risk of ischemic stroke

Atherosclerosis, a major cause of ischemic stroke, may be associated with variability of triglyceride (TG) levels. Apolipoprotein A5 (APOA5) genetic polymorphisms are associated with altered TG levels. The objective of this study was to investigate the coding region polymorphisms S19W (rs3135506) and G185C (rs2075291) and the promoter region polymorphism ?1131T>C (rs662799) of the APOA5 gene as risk factors for ischemic stroke in Turkish population. Study group consisted of 272 ischemic stroke patients and 123 controls. Genotypes were determined by real-time polymerase chain reaction (PCR) for S19W and PCR-restriction fragment length polymorphism analysis (PCR–RFLP) for ?1131T>C and G185C. 19W allele frequency was 0.090 in stroke patients and 0.062 in controls (P = 0.191). Minor allele frequencies of ?1131T>C and G185C in patients were 0.106 and 0.004, respectively, and were nearly the same in controls. Total cholesterol and LDL-cholesterol levels were significantly higher for stroke patients having at least one 19W allele compared to non-carriers. A significant difference was also found for LDL-cholesterol levels of stroke patients; higher in ?1131C allele carriers compared to wild type patients. There was a trend for higher frequency of ischemic stroke among ?1131C allele carrier hypertensive, diabetic or obese subjects compared to non-carriers. However, APOA5 genotypes were not associated with the risk of ischemic stroke by logistic regression analysis. The present study demonstrated that carrying rare alleles of APOA5 S19W, ?1131T>C and G185C alone do not constitute a risk for ischemic stroke in the studied Turkish subjects.     

Association between the gene encoding 5-lipoxygenase-activating protein and stroke replicated in a Scottish population

Cardiovascular diseases, including myocardial infarction (MI) and stroke, most often occur on the background of atherosclerosis, a condition attributed to the interactions between multiple genetic and environmental risk factors. We recently reported a linkage and association study of MI and stroke that yielded a genetic variant, HapA, in the gene encoding 5-lipoxygenase-activating protein (ALOX5AP), that associates with both diseases in Iceland. We also described another ALOX5AP variant, HapB, that associates with MI in England. To further assess the contribution of the ALOX5AP variants to cardiovascular diseases in a population outside Iceland, we genotyped seven single-nucleotide polymorphisms that define both HapA and HapB from 450 patients with ischemic stroke and 710 controls from Aberdeenshire, Scotland. The Icelandic at-risk haplotype, HapA, had significantly greater frequency in Scottish patients than in controls. The carrier frequency in patients and controls was 33.4% and 26.4%, respectively, which resulted in a relative risk of 1.36, under the assumption of a multiplicative model (P=.007). We did not detect association between HapB and ischemic stroke in the Scottish cohort. However, we observed that HapB was overrepresented in male patients. This replication of haplotype association with stroke in a population outside Iceland further supports a role for ALOX5AP in cardiovascular diseases.     

ALOX5 gene variants affect eicosanoid production and response to fish oil supplementation

The objective of this study was to determine whether 5-lipoxygenase (ALOX5) gene variants associated with cardiovascular disease affect eicosanoid production by monocytes. The study was a randomized, double-masked, parallel intervention trial with fish oil (5.0 g of fish oil daily, containing 2.0 g of eicosapentaenoic acid [EPA] and 1.0 g of docosahexaenoic acid [DHA]) or placebo oil (5.0 g of corn/soy mixture). A total of 116 subjects (68% female, 20-59 years old) of African American ancestry enrolled, and 98 subjects completed the study. Neither ALOX5 protein nor arachidonic acid-derived LTB4, LTD4, and LTE4 varied by genotype, but 5-hydroxyeicosatetraenoate (5-HETE), 6-trans-LTB4, 5-oxo-ETE, 15-HETE, and 5,15-diHETE levels were higher in subjects homozygous for the ALOX5 promoter allele containing five Sp1 element tandem repeats ("55" genotype) than in subjects with one deletion (d) (three or four repeats) and one common ("d5" genotype) allele or with two deletion ("dd") alleles. The EPA-derived metabolites 5-HEPE and 15-HEPE and the DHA-derived metabolite 17-HDoHE had similar associations with genotype and increased with supplementation; 5-HEPE and 15-HEPE increased, and 5-oxo-ETE decreased to a greater degree in the 55 than in the other genotypes. This differential eicosanoid response is consistent with the previously observed interaction of these variants with dietary intake of omega-3 fatty acids in predicting cardiovascular disease risk.