Open AccessSystematic Validation of RNF 213 Coding Variants in Japanese Patients With Moyamoya Disease
Author(s) -
Moteki Yosuke,
Onda Hideaki,
Kasuya Hidetoshi,
Yoneyama Taku,
Okada Yoshikazu,
Hirota Kengo,
Mukawa Maki,
Nariai Tadashi,
Mitani Shohei,
Akagawa Hiroyuki
Publication year - 2015
Publication title -
journal of the american heart association
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.494
H-Index - 85
ISSN - 2047-9980
DOI - 10.1161/jaha.115.001862
Subject(s) - minor allele frequency , medicine , missense mutation , genetics , single nucleotide polymorphism , moyamoya disease , genetic association , allele , coding region , genotype , allele frequency , gene , biology , mutation
Background A founder variant of RNF 213 , p.R4810K (c.14429G>A, rs112735431), was recently identified as a major genetic risk factor for moyamoya disease ( MMD ) in Japan. Although the association of p.R4810K was reported to be highly significant and reproducible, the disease susceptibility of other RNF 213 variants remains largely unknown. In the present study, we systematically evaluated the coding variants detected in Japanese patients and controls for associations with MMD . Methods and Results To detect variants of RNF 213 , all coding exons were sequenced in 27 Japanese MMD patients without p.R4810K. We also validated all previously reported variants in our case–control samples and tested for associations in combination with previous Japanese study cohorts, including the 1000 Genomes Project data set, as population‐based controls. Forty‐six missense variants other than p.R4810K were identified among 370 combined patients and 279 combined controls in Japan. Sixteen of 46 variants were polymorphisms with minor allele frequency >1%, and, after conditioning on the p.R4810K genotype, were not associated with MMD . We conducted a variable threshold test using Combined Annotation‐Dependent Depletion on the remaining 30 rare variants (minor allele frequency <1%), and the results showed that the frequency of potentially functional variants was significantly higher in patients than in controls (permutation, minimum P =0.045). Conclusions Not only p.4810K but also other functional missense variants of RNF 213 conferred susceptibility to MMD . Our analysis also revealed that ≈20% of Japanese MMD patients did not harbor susceptibility variants of RNF 213 , indicating the presence of other susceptibility genes for MMD .