Low-frequency coding variants in CETP and CFB are associated with susceptibility of exudative age-related macular degeneration in the Japanese population.
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.
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Yukihide
Y
Momozawa
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.|Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.|Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Masato
M
Akiyama
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Yoichiro
Y
Kamatani
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.|Japan Community Health care Organization, Kyushu Hospital, Fukuoka, Japan.
Satoshi
S
Arakawa
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Miho
M
Yasuda
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Shigeo
S
Yoshida
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Yuji
Y
Oshima
Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, Nihon University Hospital, Tokyo, Japan.
Ryusaburo
R
Mori
Division of Ophthalmology, Department of Visual Sciences, Nihon University School of Medicine, Nihon University Hospital, Tokyo, Japan.
Koji
K
Tanaka
Department of Ophthalmology, Saitama Medical University, Saitama, Japan.|Department of Ophthalmology, International University of Health and Welfare Hospital, Tochigi, Japan.
Keisuke
K
Mori
Division of Gene Regulation and Signal Transduction, Research Center for Genomic Medicine, Saitama Medical University, Saitama, Japan.
Satoshi
S
Inoue
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Aichi, Japan.
Hiroko
H
Terasaki
Department of Ophthalmology, Nagoya University Graduate School of Medicine, Aichi, Japan.
Tetsuhiro
T
Yasuma
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Shigeru
S
Honda
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Akiko
A
Miki
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Maiko
M
Inoue
Japan Community Health care Organization, Kyushu Hospital, Fukuoka, Japan.
Kimihiko
K
Fujisawa
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Kanji
K
Takahashi
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Hyogo, Japan.
Tsutomu
T
Yasukawa
Department of Ophthalmology and Visual Science, Nagoya City University Graduate School of Medical Sciences, Nagoya, Japan.
Yasuo
Y
Yanagi
Department of Pediatric Surgery, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Kazuaki
K
Kadonosono
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Koh-Hei
KH
Sonoda
Department of Ophthalmology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Tatsuro
T
Ishibashi
Laboratory for Statistical Analysis, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Atsushi
A
Takahashi
Laboratory for Genotyping Development, RIKEN Center for Integrative Medical Sciences, Kanagawa, Japan.
Michiaki
M
Kubo
D000368:Aged; D001483:Base Sequence; D016022:Case-Control Studies; D053480:Cholesterol Ester Transfer Proteins / Q000235:genetics* / Q000378:metabolism; D003175:Complement C2 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics* / Q000378:metabolism; D017242:Complement Factor H / Q000235:genetics; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D055106:Genome-Wide Association Study / Q000379:methods; D005838:Genotype; D006239:Haplotypes; D006801:Humans; D007564:Japan; D008268:Macular Degeneration / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008297:Male; D020641:Polymorphism, Single Nucleotide
C506642:CETP protein, human; D053480:Cholesterol Ester Transfer Proteins; D003175:Complement C2; D017242:Complement Factor H; D011415:Complement Factor B