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• W2147794854 abstract "The discovery of a major gene that predisposes an individual to age-related macular degeneration (AMD) is one of the principal targets of ophthalmic genetics research. Up to now, many genes have been analyzed in an effort to determine their involvement in the disease, but it was not until 2005 that the first evidence of the involvement of the variant Y402H (T/C) of the complement factor H gene (CFH) was reported as a susceptibility allele for AMD.1Klein R.J. Zeiss C. Chew E.Y. et al.Complement factor H polymorphism in age-related macular degeneration.Science. 2005; 308: 385-389Crossref PubMed Scopus (3515) Google Scholar In several studies, odds ratios (ORs) from 2.45 to 4.6 for the risk allele (402H) were described, and this common variant was suggested to explain 43% of AMD in adults. Most of these studies have been performed on United States populations, and it is necessary to extend such studies to different populations to confirm the 402H allele as a generalized risk allele for AMD. Some physiological studies have suggested that the 2 forms of AMD can arise from different physiological processes2Yoshida T. Ohno-Matsui K. Ichinose S. et al.The potential role of amyloid beta in the pathogenesis of age-related macular degeneration.J Clin Invest. 2005; 115: 2793-2800Crossref PubMed Scopus (185) Google Scholar; therefore, it also is important to investigate the possible different involvement of the risk allele when the stratification of AMD is made by late manifestation, either geographic atrophy or choroidal neovascularization. We performed the genotyping of the Y402H variation in the Spanish population in a sample of 140 exudative and 35 atrophic AMD individuals and 119 age-matched control individuals without AMD. A strong association was found between the 402H risk allele and atrophic AMD, showing ORs of 3.3 (95% confidence interval [CI], 1.74–5.20) and 5.2 (95% CI, 2.19–12.30) for the C allele and CC genotype, respectively. Nevertheless, exudative AMD, which showed less association with the CFH risk allele than atrophic AMD, demonstrated ORs of 2.03 (95% CI, 1.49–3.04) and 2.4 (95% CI, 1.23–4.64) for the risk allele and risk genotype, respectively (Table 1 [available at http://aaojournal.org]). Although departure from Hardy–Weinberg equilibrium was found in the atrophic sample, our findings were unlikely to be spurious, because the reanalyses using the chi-square test, giving the model of best fit for the observed genotypes, showed that this departure was consistent with a recessive association model. To explain the differences in risk allele frequency between atrophic and exudative AMDs, we independently analyzed smokers and nonsmokers from the exudative group, because smoking habit has been demonstrated to be a risk factor for AMD. Odds ratios of 1.95 (95% CI, 1.280–3.187) and 2.76 (95% CI, 1.236–7.111) for the C allele and CC genotype, respectively, have been found in the subset of nonsmokers, both the choroidal neovascularization–affected and controls. However, no significant differences in allele risk frequency (Fisher exact test) were found between smokers (choroidal neovascularization versus controls), which confirms the absence of association in this subset. This might explain the lower association value of the CFH risk allele and exudative AMD cases.Table 1Association between the Tyr402His Polymorphisms of CFH and Age-Related Macular DegenerationStatusTTCCTCCnFsP Value (Allele Association)P Value⁎The genotype association compares CC with CT and TT. (Genotype Association)OR (C) (95% CI)OR (CC) (95% CI)D′Control55 (0.46)15 (0.13)49 (0.41)0.3321190.07Atrophic8 (0.23)15 (0.43)12 (0.34)0.61350.280.000010.00013.03 (1.74–5.20)5.25 (2.19–12.30)0.3Neovascular32 (0.23)36 (0.26)72 (0.51)0.51140−0.030.00010.0052.03 (1.49–3.04)2.4 (1.23–4.64)0.2Smoker Affected13 (0.25)12 (0.23)28 (0.53)0.4953−0.06NSNS1.12 (0.62–2.00)1.59 (0.56–4.45)−0.07 Control15 (0.33)7 (0.16)23 (0.51)0.4245−0.05Nonsmoker Affected18 (0.21)23 (0.26)46 (0.53)0.5387−0.060.00220.01042.01 (1.28–3.18)2.96 (1.23–7.11)0.22 Control32 (0.43)8 (0.11)34 (0.46)0.3474−0.02C = risk allele; CC = risk genotype; D′ = linkage disequilibrium measure between risk allele and disease; NS = not significant; OR = odds ratio.The unified fixation index for alleles in the sample was computed as the ratio of the difference between the expected (hs) and observed (ho) heterozygosity, to the expected heterozygosity: Fs = (hs − ho)/hs. A significance test for F = 0 with k(k − 1)/2 degrees of freedom is given by the relation χ2 = Fs2 n (k − 1), where n is the sample size and k the number of alleles in affected and control sets. P value, Fisher exact test, which determines the presence of significant differences in C and CC frequencies between affected and control individuals. Odds ratios were calculated for C and CC. The genotype association compares CC with CT and TT. Open table in a new tab C = risk allele; CC = risk genotype; D′ = linkage disequilibrium measure between risk allele and disease; NS = not significant; OR = odds ratio. The unified fixation index for alleles in the sample was computed as the ratio of the difference between the expected (hs) and observed (ho) heterozygosity, to the expected heterozygosity: Fs = (hs − ho)/hs. A significance test for F = 0 with k(k − 1)/2 degrees of freedom is given by the relation χ2 = Fs2 n (k − 1), where n is the sample size and k the number of alleles in affected and control sets. P value, Fisher exact test, which determines the presence of significant differences in C and CC frequencies between affected and control individuals. Odds ratios were calculated for C and CC. It is well known that a decrease of plasma levels of CFH is caused by smoking3Esparza-Gordillo J. Soria J.M. Buil A. et al.Genetic and environmental factors influencing the human factor H plasma levels.Inmunogenetics. 2004; 56: 77-82Crossref PubMed Scopus (135) Google Scholar; therefore, it could be possible that low CFH plasma levels lead to the phenotypic characteristics of choroidal neovascularization eyes in exudative AMD patients. Or, the disease may be associated with another genetic variant; a possible candidate is the LOC387715 gene, because its A69S variation has been hypothesized as a genetic factor that could accentuate the effect of smoking habit on the risk of AMD.4Weeks D. Conley Y. Tsai H. et al.Age-related maculopathy: a genomewide scan with continued evidence of susceptibility loci within the 1q31, 10q26, and 17q25 regions.Am J Hum Genet. 2004; 75: 174-189Abstract Full Text Full Text PDF PubMed Scopus (156) Google Scholar, 5Rivera A. Fisher S.A. Fritsche L.G. et al.Hypothetical LOC387715 is a second major susceptibility gene for age-related macular degeneration, contributing independently of complement factor H to disease risk.Hum Mol Genet. 2005; 14: 3227-3236Crossref PubMed Scopus (661) Google Scholar This variation contributes to the disease independently of the presence of Y402H variation in the CFH, following an additive model. In summary, the current study suggests that the CFH risk allele could explain both 40% of atrophic AMD adults and the exudative form of AMD in nonsmoking individuals in Spain. Moreover, our study suggests that the previously reported associations between CFH risk allele and exudative AMD could be due to the high level of association presented by nonsmokers. In contrast, a variation in a gene different than CFH may be the major factor to predispose smokers to exudative AMD. More smoking-matched case–control studies are needed to confirm these results that must be taken into account when assessing risk loci." @default.
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• W2147794854 date "2007-01-01" @default.
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• W2147794854 title "Complement Factor H" @default.
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• W2147794854 doi "https://doi.org/10.1016/j.ophtha.2006.10.004" @default.
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