Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population

Yukihide Momozawa, Masato Akiyama, Yoichiro Kamatani, Satoshi Arakawa, Miho Yasuda, Shigeo Yoshida, Yuji Oshima, Ryusaburo Mori, Koji Tanaka, Keisuke Mori, Satoshi Inoue, Hiroko Terasaki, Tetsuhiro Yasuma, Shigeru Honda, Akiko Miki, Maiko Inoue, Kimihiko Fujisawa, Kanji Takahashi, Tsutomu Yasukawa, Yasuo YanagiKazuaki Kadonosono, Koh Hei Sonoda, Tatsuro Ishibashi, Atsushi Takahashi, Michiaki Kubo

研究成果: ジャーナルへの寄稿記事

14 引用 (Scopus)

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Age-related macular degeneration (AMD) is a major cause of blindness in the elderly. Previous sequencing studies of AMD susceptibility genes have revealed the association of rare coding variants in CFH, CFI, C3 and C9 in European population; however, the impact of rare or low-frequency coding variants on AMD susceptibility in other populations is largely unknown. To identify the role of low-frequency coding variants on exudative AMD susceptibility in a Japanese population, we analysed the association of coding variants of 34 AMD candidate genes in the two-stage design by a multiplex PCR-based target sequencing method. We used a total of 2,886 (1st: 827, 2nd: 2,059) exudative AMD cases including typical AMD, polypoidal choroidal vasculopathy, and retinal angiomatous proliferation and 9,337 (1st: 3,247 2nd: 6,090) controls. Gene-based analysis found a significant association of low-frequency variants (minor allele frequency (MAF)< 0.05) in CETP, C2 and CFB. The association of CETP remained after conditioned with all known genome-wide association study (GWAS) associated variants. In addition, when we included only disruptive variants, enrichment of rare variants (MAF < 0.01) was also observed after conditioned with all GWAS associated variants (P=1.03×10-6, odds ratio (OR)=2.48). Haplotype and conditional analysis of the C2-CFB-SKIV2L locus showed a low-frequency variant (R74H) in CFB would be individually associated with AMD susceptibility independent of the GWAS associated SNP. These findings highlight the importance of target sequencing to reveal the impact of rare or low-frequency coding variants on disease susceptibility in different ethnic populations.

元の言語英語
ページ(範囲)5027-5034
ページ数8
ジャーナルHuman Molecular Genetics
25
発行部数22
DOI
出版物ステータス出版済み - 11 15 2016

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All Science Journal Classification (ASJC) codes

  • Molecular Biology
  • Genetics
  • Genetics(clinical)

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