Our findings indicate that the A allele in rs4073259 is markedly increased in cerebral infarction patients in comparison to control subjects of Han ancestry in northern China. Genotype rs9579646 GG and rs9551963 AC were positively, while rs4073259 GG was negatively associated with cerebral infarction. Haplotypes rs9315050 & rs9551963 AAAC were positively associated with cerebral infarction. Furthermore, genotypes rs4147064 CT and rs9551963 AC were associated with cerebral infarction in patients with hypertension, while rs9579646 GG and rs4073259 GG were associated with cerebral infarction in patients with diabetes. The findings suggest that SNP rs4073259 of the ALOX5AP gene is associated with developing cerebral infarction in this cohort, although the possibility that it is a functional variant cannot be ruled out. Although we found no marked difference in the frequency of alleles of other ALOX5AP SNPs tested between the control and case groups studied, we found significant differences of genotype frequency of other ALOX5AP SNPs between the control and case subjects, suggesting that they might play a role in the pathogenesis of cerebral infarction in the Han population of northern China.
Microarray assays have revealed positive linkage domains associated with cardiovascular and cerebrovascular diseases which locate at 13p12-13 [1
]. The ALOX5AP gene is located at bands 2 and 3 of region 1 of the long arm of chromosome 13, and encodes 5-lipoxygenase activating protein (FLAP) which regulates the synthesis of leukotrienes [15
]. An increase in the production of leukotrienes and resulting inflammatory changes in local blood vessels may be associated with development of atherosclerosis [4
]. Whether the rs4073259 SNP alters FLAP warrants further study.
The association between the genetic polymorphism of ALOX5AP
and the occurrence of cerebral infarction has been previously reported, but discrepancies between studies carried out in different populations have been noted. For example, Kaushal et al.
] found that rs957646 and rs769874 were significantly associated with stroke in whites in the US, but no association was found in blacks. Another US study by Zee et al.
] found no association of HapA or Hap B with stroke. Meschia et al.
] found no association of ALOX5AP
variants and ischemic stroke in a US population, Zhang et al.
] reported the ALOX5AP
variant SG13S114T/A was associated with increased risk of stroke in Chinese males, and Linsel-Nitschke et al.
] found HapB was associated with an increased risk of myocardial infarction in a German population. Ji et al.
] in a recent study reported that the −581_582 Ins A polymorphism in ALOX5AP
might be a genetic risk factor for ischemic stroke in the Chinese Han population. The lack of consistency in available studies also suggests a limit of the analytical methodologies used in these studies, the population association test. A better refined methodology, such as the Family base association test (FBAT), may be needed to provide consistent results [22
Zintaras et al.
] performed a meta-analysis in 2009 including all studies of ALOX5AP
genotyping (5,194 stroke cases and 4,566 controls). The authors found significant heterogeneity among studies (PQ
63%), a non-significant association between the HapA and stroke risk (random-effects [RE] OR
1.13, 95% CI 0.88-1.45), and no association of HapB with stroke risk (RE OR
1.03, 95% CI 0.77-1.37). They also reported that the SG13S114, SG13S89, SG13S25, SG13S32, SG13S35, and SG13S42 polymorphisms were not associated with stroke. The authors concluded that to date, the cumulated evidence did not support an association of ALOX5AP
variants and risk of stroke, though they cautioned that the conclusion was based on a relatively small number of studies.
The primary limitation of this study is the relatively low case number, especially in stratification based on genotypes. Further study with a larger population is required to confirm the findings. In addition, we did not study SNPs from other susceptible genes, e.g.
, phosphodiesterase 4D (PDE4D
) in which some of the SNPs have been shown to be associated with the development of cerebral infarction [4