Lack of association between variations of PDE4D and ischemic stroke in the Japanese population.
OBJECTIVE
After the first genomewide association study of ischemic stroke identified PDE4D as a susceptible gene, many replication studies have been conducted. However, the validity of the association has remained controversial because of the heterogeneity of both genetic markers and phenotypes.


METHODS
We investigated the association between variations of PDE4D and ischemic stroke by 3 methods: single-marker, haplotype, and tag-single nucleotide polymorphism (SNP) analyses. In the single-marker analysis, we evaluated the association using 2 large case-control samples (1112 cases and 1112 control subjects in a sample obtained from Kyushu, Japan, and 1711 cases and 1786 control subjects in BioBank Japan) and a prospective cohort with 14 years of follow-up. These samples were analyzed both separately and pooled. Haplotype and tag-SNP analyses were performed using the 2 case-control samples together.


RESULTS
In single-marker association tests, we found no significant association in the same direction among the 6 SNP reported in the initial study and ischemic stroke subtypes. Haplotype analysis revealed no significant association between the region around the 5'-end of the gene and combined atherothrombotic and cardioembolic infarction. Rs7730070, a SNP located around the 3'-end of PDE4D, showed the lowest nominal probability value by tag-SNP analysis but was not significant after adjustment for multiple testing (adjusted probability value =0.36).


CONCLUSIONS
These results suggest that variations in PDE4D are not associated with ischemic stroke risk in the Japanese population.
Matsushita
Tomonaga
T
Laboratory for Genotyping Development, Center for Genomic Medicine, RIKEN, Yokohama, Kanagawa, Japan.
Kubo
Michiaki
M
Yonemoto
Koji
K
Ninomiya
Toshiharu
T
Ashikawa
Kyota
K
Liang
Bailing
B
Hata
Jun
J
Doi
Yasufumi
Y
Kitazono
Takanari
T
Ibayashi
Setsuro
S
Iida
Mitsuo
M
Kiyohara
Yutaka
Y
Nakamura
Yusuke
Y
D000368:Aged; D000369:Aged, 80 and over; D044466:Asian People / Q000235:genetics / Q000706:statistics & numerical data; D002545:Brain Ischemia / Q000208:ethnology* / Q000235:genetics*; D016022:Case-Control Studies; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3 / Q000235:genetics*; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; D005260:Female; D005819:Genetic Markers; D020022:Genetic Predisposition to Disease / Q000208:ethnology; D006239:Haplotypes; D006801:Humans; D006973:Hypertension / Q000208:ethnology / Q000235:genetics; D007564:Japan / Q000453:epidemiology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D020521:Stroke / Q000208:ethnology* / Q000235:genetics*
D005819:Genetic Markers; D054684:Cyclic Nucleotide Phosphodiesterases, Type 3; D054703:Cyclic Nucleotide Phosphodiesterases, Type 4; C517376:PDE4D protein, human