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Risk alleles in CFH and ARMS2 and the long-term natural history of age-related macular degeneration: the Beaver Dam Eye Study.

ABSTRACT: To describe the relationships of risk alleles in complement factor H (CFH, rs1061170) and age-related maculopathy susceptibility 2 (ARMS2, rs10490924) to the incidence and progression of age-related macular degeneration (AMD) during a 20-year period.There were 4282 persons aged 43 to 86 years at the baseline examination in 1988-1990 enrolled in a population-based cohort study who participated in at least 1 examination spaced 5 years apart during a 20-year period and had gradable fundus photographs for AMD and genotype information on CFH and ARMS2. Low, intermediate, and high genetic risk for AMD was defined by the presence of 0 to 1, 2, or 3 to 4 risk alleles for CFH and ARMS2, respectively. Multistate models were used to estimate the progression of AMD throughout the entire age range.There were 2820 (66%), 1129 (26%), and 333 persons (8%) with low, intermediate, and high genetic risk for AMD, respectively. The 5-year incidences of early and late AMD were 9.1% and 1.6%, respectively, and increased with age but did not differ significantly by sex. Using the multistate model, of persons aged 45 years with no AMD in the low, intermediate, and high AMD genetic risk groups, 33.0%, 39.9%, and 46.5%, respectively, were estimated to develop early AMD, and 1.4%, 5.2%, and 15.3% were estimated to develop late AMD by age 80 years.These population-based data provide estimates of the long-term risk of the incidence and progression of AMD and its lesions by age and genetic risk alleles for CFH and ARMS2. They also show that when early AMD is present, knowing the phenotype contributes more to risk assessment than knowing the genetic risk based on these 2 AMD genes.

SUBMITTER: Klein R

PROVIDER: S-EPMC3602927 | biostudies-literature | 2013 Mar

REPOSITORIES: biostudies-literature

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Project description:ObjectiveTo examine the associations of cataract and cataract surgery with early and late age-related macular degeneration (AMD) over a 20-year interval.DesignLongitudinal population-based study of age-related eye diseases.ParticipantsBeaver Dam Eye Study participants.MethodsPersons aged 43 to 86 years participated in the baseline examination in 1988-1990. Participants were followed up at 5-year intervals after the baseline examination. Examinations consisted of ocular examination with lens and fundus photography, medical history, measurements of blood pressure, height, and weight. Values of risk variables were updated, and incidences of early and late AMD were calculated for each 5-year interval. Odds ratios were computed using discrete linear logistic regression modeling with generalized estimating equation methods to account for correlation between the eyes and multiple intervals.Main outcome measuresAge-related macular degeneration.ResultsAfter adjusting for age and sex, neither cataract nor cataract surgery was associated with increased odds for developing early AMD. Further adjusting for high-risk gene alleles (CFH and ARMS2) and other possible risk factors did not materially affect the odds ratio (OR). However, cataract surgery was associated with incidence of late AMD (OR 1.93; 95% confidence interval [CI], 1.28-2.90). This OR was not materially altered by further adjusting for high-risk alleles (CFH Y402H, ARMS2) or other risk factors. The OR for late AMD was higher for cataract surgery performed 5 or more years prior compared with less than 5 years prior.ConclusionsThese data strongly support the past findings of an association of cataract surgery with late AMD independent of other risk factors, including high-risk genetic status, and suggest the importance of considering these findings when counseling patients regarding cataract surgery. These findings should provide further impetus for the search for measures to prevent or delay the development of age-related cataract.

Project description:PurposeTo evaluate the contribution of genetic variants of complement factor H (CFH), complement component 2 and 3 (C2 and C3), complement factor B (CFB), and age-related maculopathy susceptibility 2 (ARMS2) to age-related macular degeneration (AMD) risk in the Mexican Mestizo population.MethodsAnalysis included 282 unrelated Mexican patients with advanced AMD, 205 healthy controls, and 280 population controls. Stereoscopic fundus images were graded on the Clinical Age-Related Maculopathy System (CARMS). We designed a resequencing strategy using primers with M13 adaptor for the 23 exons of the CFH gene in a subgroup of 96 individuals clinically evaluated: 48 AMD cases and 48 age- and sex-matched healthy controls. Single nucleotide polymorphisms (SNPs) in C3 (Arg80Gly and Pro292Leu), C2 (rs547154), CFB (Leu9His), and ARMS2 (Ala69Ser) were genotyped in all patients, healthy and population controls using TaqMan assay.ResultsAll evaluated individuals were Mexican Mestizos, and their genetic ancestry was validated using 224 ancestry informative markers and calculating F(st) values. The CFH resequencing revealed 19 SNPs and a common variant in the intron 2 splice acceptor site; three CFH haplotypes inferred from individual genotypes, showed significant differences between cases and controls. The risk alleles in C3 (rs1047286, odds ratio [OR]=2.48, 95% confidence interval [CI]=1.64-3.75, p=1.59E-05; rs2230199, OR=2.15, 95% CI=1.48-3.13, p=6.28E-05) and in ARMS2 (rs10490924, OR=3.09, 95% CI=2.48-3.86, p=5.42E-23) were strongly associated with risk of AMD. The protective effect of alleles in C2 (rs547154) and CFB (rs4151667) showed a trend but was not significantly associated after correction for multiple testing.ConclusionsOur results show that ARMS2 and C3 are major contributors to advanced AMD in Mexican patients, while the contributions of CFH, C2, and CFB are minor to those of other populations, reveling significant ethnic differences in minor allele frequencies. We provide evidence that two specific common haplotypes in the CFH gene predispose individuals to AMD, while another may confer reduced risk of disease in this admixed population.

Project description:ImportanceAge-related macular degeneration (AMD) is a common cause of irreversible vision loss among individuals older than 50 years. Although considerable advances have been made in our understanding of AMD genetics, the differential effects of major associated loci on disease manifestation and progression may not be well characterized.ObjectiveTo elucidate the specific associations of the 2 most common genetic risk loci for AMD, the CFH-CFHR5 locus on chromosome 1q32 (Chr1) and the ARMS2/HTRA1 locus on chromosome 10q26 (Chr10)-independent of one another and in combination-with time to conversion to late-stage disease and to visual acuity loss.Design, setting, and participantsThis case series study included 502 individuals who were homozygous for risk variants at both Chr1 and Chr10 (termed Chr1&10-risk) or at either Chr1 (Chr1-risk) or Chr10 (Chr10-risk) and who had enrolled in Genetic and Molecular Studies of Eye Diseases at the Sharon Eccles Steele Center for Translational Medicine between September 2009 and March 2020. Multimodal imaging data were reviewed for AMD staging, including grading of incomplete and complete retinal pigment epithelium and outer retinal atrophy.Main outcomes and measuresHazard ratios and survival times for conversion to any late-stage AMD, atrophic or neovascular, and associated vision loss of 2 or more lines.ResultsIn total, 317 participants in the Chr1-risk group (median [IQR] age at first visit, 75.6 [69.5-81.7] years; 193 women [60.9%]), 93 participants in the Chr10-risk group (median [IQR] age at first visit, 77.5 [72.2-84.2] years; 62 women [66.7%]), and 92 participants in the Chr1&10-risk group (median [IQR] age at first visit, 71.7 [68.0-76.3] years; 62 women [67.4%]) were included in the analyses. After adjusting for age and AMD grade at first visit, compared with 257 participants in the Chr1-risk group, 56 participants in the Chr1&10-risk group (factor of 3.3 [95% CI, 1.6-6.8]; P < .001) and 58 participants in the Chr10-risk group (factor of 2.6 [95% CI, 1.3-5.2]; P = .007) were more likely to convert to a late-stage phenotype during follow-up. This difference was mostly associated with conversion to macular neovascularization, which occurred earlier in participants with Chr1&10-risk and Chr10-risk. Eyes in the Chr1&10-risk group (median [IQR] survival, 5.7 [2.1-11.1] years) were 2.1 (95% CI, 1.1-3.9; P = .03) times as likely and eyes in the Chr10-risk group (median [IQR] survival, 6.3 [2.7-11.3] years) were 1.8 (95% CI, 1.0-3.1; P = .05) times as likely to experience a visual acuity loss of 2 or more lines compared with eyes of the Chr1-risk group (median [IQR] survival, 9.4 [4.1-* (asterisk indicates event rate did not reach 75%)] years).Conclusions and relevanceThese findings suggest differential associations of the 2 major AMD-related risk loci with structural and functional disease progression and suggest distinct underlying biological mechanisms associated with these 2 loci. These genotype-phenotype associations may warrant consideration when designing and interpreting AMD research studies and clinical trials.

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Risk alleles in CFH and ARMS2 and the long-term natural history of age-related macular degeneration: the Beaver Dam Eye Study.

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