Abstract
Age-related macular degeneration (ARMD) is the leading cause of blindness in the elderly population not only Western but also Asian industrial countries. In Caucasian, a polymorphism of the complement factor H gene (CFH), the C allele of rs1061170 (Y402H), was established as the first strong genetic factor for excursively exudative type of ARMD. In this study, we performed an extensive sequencing of the 22 exons in the CFH gene by recruiting 146 exudative ARMD patients and 105 normal controls of Japanese origin and identified 61 polymorphisms. We found that the frequency of the C allele of rs1061170 (Y402H) is much lower (0.04) in Japanese controls than in Caucasians (0.45). No case disease susceptibility to exudative ARMD was noted for rs1061170 (Y402H) (χ 2 = 3.19, P corr = 0.423), or other 12 single nucleotide polymorphisms (SNPs) whose frequency is greater than 0.05. When haplotypes were inferred for 13 SNPs (these 12 SNPs with a frequency greater than 0.05 and rs1061170), three haplotypes whose pattern was similar to those in Caucasians were identified but with substantial difference in frequency. Again we failed to identify genetic association between Japanese exudative ARMD and any of the haplotypes including the J1 haplotype which was shown to be susceptible to ARMD in Caucasians (χ 2 = 3.92, P corr = 0.157). CFH does not appear to be a primary hereditary contributor to ARMD in Japanese. The absence of CFH contribution to ARMD in Japanese may correlate with the findings in ethnic differences of ARMD phenotypes.
Similar content being viewed by others
References
Allikmets R (2000) Further evidence for an association of ABCR alleles with age-related macular degeneration. The International ABCR Screening Consortium. Am J Hum Genet 67:487–491
Barrett JC, Fry B, Maller J, Daly MJ (2005) Haploview: analysis and visualization of LD and haplotype maps. Bioinformatics 21:263–265
Bird AC (2003) The Bowman lecture: towards an understanding of age-related macular disease. Eye 17:457–466
Bottini N, Musumeci L, Alonso A, Rahmouni S, Nika K, Rostamkhani M, MacMurray J, Meloni GF, Lucarelli P, Pellecchia M, Eisenbarth GS, Comings D, Mustelin T (2004) A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes. Nat Genet 36:337–338
Conley YP, Thalamuthu A, Jakobsdottir J, Weeks DE, Mah T, Ferrell RE, Gorin MB (2005) Candidate gene analysis suggests a role for fatty acid biosynthesis and regulation of the complement system in the etiology of age-related maculopathy. Hum Mol Genet 14:1991–2002
Edwards AO, Ritter R III, Abel KJ, Manning A, Panhuysen C, Farrer LA (2005) Complement factor H polymorphism and age-related macular degeneration. Science 308:421–424
Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, Cramer K, Neel J, Bergeron J, Barile GR, Smith RT, Hageman GS, Dean M, Allikmets R, Chang S, Yannuzzi LA, Merriam JC, Barbazetto I, Lerner LE, Russell S, Hoballah J, Hageman J, Stockman H (2006) Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 38:458–462
Hageman GS, Luthert PJ, Victor Chong NH, Johnson LV, Anderson DH, Mullins RF (2001) An integrated hypothesis that considers drusen as biomarkers of immune-mediated processes at the RPE-Bruch’s membrane interface in aging and age-related macular degeneration. Prog Retin Eye Res 20:705–732
Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, et al (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci USA 102:7227–7232
Haines JL, Hauser MA, Schmidt S, Scott WK, Olson LM, Gallins P, Spencer KL, Kwan SY, Noureddine M, Gilbert JR, Schnetz-Boutaud N, Agarwal A, Postel EA, Pericak-Vance MA (2005) Complement factor H variant increases the risk of age-related macular degeneration. Science 308:419–421
Horikawa Y, Oda N, Cox NJ, Li X, Orho-Melander M, Hara M, Hinokio Y, et al. (2000) Genetic variation in the gene encoding calpain-10 is associated with type 2 diabetes mellitus. Nat Genet 26:163–175
Japanese Age-Related Macular Degeneration Tial (JAT) Study Group (2003) Japanese age-related macular degeneration trial: 1-year results of photodynamic therapy with verteporfin in Japanese patients with subfoveal CNV secondary to age-related macular degeneration. Am J Ophthalmol 136:1049–1061
Klaver CC, Kliffen M, van Duijn CM, Hofman A, Cruts M, Grobbee DE, van Broeckhoven C, de Jong PT (1998) Genetic association of apolipoprotein E with age-related macular degeneration. Am J Hum Genet 63:200–206
Klein RJ, Zeiss C, Chew EY, Tsai JY, Sackler RS, Haynes C, Henning AK, SanGiovanni JP, Mane SM, Mayne ST, Bracken MB, Ferris FL, Ott J, Barnstable C, Hoh J (2005) Complement factor H polymorphism in age-related macular degeneration. Science 308:385–389
Lesage S, Zouali H, Cezard JP, Colombel JF, Belaiche J, Almer S, Tysk C, O’Morain C, Gassull M, Binder V, Finkel Y, Modigliani R, Gower-Rousseau C, Macry J, Merlin F, Chamaillard M, Jannot AS, Thomas G, Hugot JP (2002) CARD15/NOD2 mutational analysis and genotype–phenotype correlation in 612 patients with inflammatory bowel disease. Am J Hum Genet 70:845–857
Meyers SM, Greene T, Gutman FA (1995) A twin study of age-related macular degeneration. Am J Ophthalmol 120:757–766
Mori M, Yamada R, Kobayashi K, Kawaida R, Yamamoto K (2005) Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J Hum Genet 50:264–266
Okamoto H, Umeda S, Obazawa M, Minami M, Noda T, Mizota A, Honda M, Tanaka M, Koyama R, Takagi I, Sakamoto Y, Saito Y, Miyake Y, Iwata T (2006) Complement factor H polymorphisms in Japanese population with age-related macular degeneration. Mol Vis 12: 156–158
Oshima Y, Ishibashi T, Murata T, Tahara Y, Kiyohara Y, Kubota T (2001) Prevalence of age related maculopathy in a representative Japanese population: the Hisayama study. Br J Ophthalmol 85:1153–1157
Perez-Caballero D, Gonzalez-Rubio C, Gallardo ME, Vera M, Lopez-Trascasa M, Rodriguez de Cordoba S, Sanchez-Corral P (2001) Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 68:478–484
Rivera A, Fisher SA, Fritsche LG, Keilhauer CN, Lichtner P, Meitinger T, Weber BH (2005) Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration contributing independently from complement factor H to disease risk. Hum Mol Genet 14:3227–3236
Rodriguez de Cordoba S, Esparza-Gordillo J, Goicoechea de Jorge E, Lopez-Trascasa M, Sanchez-Corral P (2004) The human complement factor H: functional roles, genetic variations and disease associations. Mol Immunol 41:355–367
Seddon JM, Cote J, Page WF, Aggen SH, Neale MC (2005) The US twin study of age-related macular degeneration: relative roles of genetic and environmental influences. Arch Ophthalmol 123:321–327
Souied EH, Leveziel N, Richard F, Dragon-Durey MA, Coscas G, Soubrane G, Benlian P, Fremeaux-Bacchi V (2005) Y402H complement factor H polymorphism associated with exudative age-related macular degeneration in the French population. Mol Vis 11:1135–1140
Tsai HJ, Sun G, Weeks DE, Kaushal R, Wolujewicz M, McGarvey ST, Tufa J, Viali S, Deka R (2001) Type 2 diabetes and three calpain-10 gene polymorphisms in Samoans: no evidence of association. Am J Hum Genet 69:1236–1244
Turnberg D, Botto M (2003) The regulation of the complement system: insights from genetically-engineered mice. Mol Immunol 40:145–153
Umeda (2005) Molecular composition of drusen and possible involvement of anti-retinal autoimmunity in two different forms of macular degeneration in cynomolgus monkey (Macaca fascicularis). FASEB J August:12
Weeks DE, Conley YP, Tsai HJ, Mah TS, Rosenfeld PJ, Paul TO, Eller AW, Morse LS, Dailey JP, Ferrell RE, Gorin MB (2001) Age-related maculopathy: an expanded genome-wide scan with evidence of susceptibility loci within the 1q31 and 17q25 regions. Am J Ophthalmol 132:682–692
Weeks DE, Conley YP, Tsai HJ, Mah TS, Schmidt S, Postel EA, Agarwal A, Haines JL, Pericak-Vance MA, Rosenfeld PJ, Paul TO, Eller AW, Morse LS, Dailey JP, Ferrell RE, Gorin MB (2004) Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions. Am J Hum Genet 75:174–189
Yamazaki K, Takazoe M, Tanaka T, Kazumori T, Nakamura Y (2002) Absence of mutation in the NOD2/CARD15 gene among 483 Japanese patients with Crohn’s disease. J Hum Genet 47:469–472
Zareparsi S, Branham KE, Li M, Shah S, Klein RJ, Ott J, Hoh J, Abecasis GR, Swaroop A (2005) Strong association of the Y402H variant in complement factor H at 1q32 with susceptibility to age-related macular degeneration. Am J Hum Genet 77:149–153
Author information
Authors and Affiliations
Corresponding author
Additional information
This work was accomplished by equal contribution of two groups organized by the last two authors.
Electronic supplementary material
Rights and permissions
About this article
Cite this article
Gotoh, N., Yamada, R., Hiratani, H. et al. No association between complement factor H gene polymorphism and exudative age-related macular degeneration in Japanese. Hum Genet 120, 139–143 (2006). https://doi.org/10.1007/s00439-006-0187-0
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00439-006-0187-0