An interactive association of common sequence variants in the neuropeptide Y gene with susceptibility to ischemic stroke.
OBJECTIVE
Knowledge of the genetic architecture of ischemic stroke has been quite limited. Most significant associations of candidate genes with ischemic stroke have been difficult to replicate. This might be because the associations were not strong enough for results to be consistent, and testing a mixture of heterogeneous ischemic strokes might lead to confounded genetic associations.


METHODS
A preliminary association analysis with 28 sequence variants in 18 candidate genes (ACE, AGT, AGTR1, BDNF, CRP, F13B, LIF, MMP9, NPPA, NPY, PTGS2, SELP, SERPINE1, SREBF2, TFPI, THBD, VCAM1, and VEGF) revealed that NPY might be the most responsible for the susceptibility of ischemic stroke. Forty-five variants were discovered in the NPY gene by full sequencing, and 5 polymorphisms were selected based on their allele frequency and linkage disequilibrium estimates to conduct a thorough examination of their associations with ischemic stroke and its subtypes classified by TOAST. This study was conducted with 271 patients with ischemic stroke and 455 control subjects.


RESULTS
In contrast to a slight significance for an allelic association with ischemic stroke, remarkable discrepancies between haplotype frequencies of control subjects and patients were found. Especially, TA and CC of the haplotypes composed of C4112T and A6411C in the NPY gene were associated with increased risk (P=1.8 x 10(-21), P=2.0 x 10(-13)). The interchanged haplotypes, TC and CA, were protective against the diseases (P=9.3 x 10(-12), P=6.0 x 10(-17)). The associations were also shown in major subtypes of ischemic stroke.


CONCLUSIONS
This remarkable haplotypic association suggested that the interaction between the 2 common sequence polymorphisms in NPY contributed to a great amount of phenotypic variability of ischemic stroke.
Lee
Chaeyoung
C
Ilsong Institute of Life Science, Hallym University, 1605-4 Gwanyang-dong, Dongan-gu, Anyang, Kyonggi-do 431-060, South Korea. clee@hallym.ac.kr
Kong
Minyoung
M
D000368:Aged; D002545:Brain Ischemia / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D008875:Middle Aged; D009478:Neuropeptide Y / Q000235:genetics*; D010641:Phenotype; D011110:Polymorphism, Genetic; D020521:Stroke / Q000235:genetics*
D009478:Neuropeptide Y