A Deep Phenotype Association Study Reveals Specific Phenotype Associations with Genetic Variants in Age-related Macular Degeneration: Age-Related Eye Disease Study 2 (AREDS2) Report No. 14.

PURPOSE: Age-related macular degeneration (AMD), a multifactorial disease with variable phenotypic presentation, was associated with 52 single nucleotide polymorphisms (SNPs) at 34 loci in a genome-wide association study (GWAS). These genetic variants could modulate different biological pathways involved in AMD, contributing to phenotypic variability. To better understand the effects of these SNPs, we performed a deep phenotype association study (DeePAS) in the Age-Related Eye Disease Study 2 (AREDS2), followed by replication using AREDS participants, to identify genotype associations with AMD and non-AMD ocular and systemic phenotypes. DESIGN: Cohort study. PARTICIPANTS: AREDS and AREDS2 participants. METHODS: AREDS2 participants (discovery cohort) had detailed phenotyping for AMD; other eye conditions; cardiovascular, neurologic, gastrointestinal, and endocrine disease; cognitive function; serum nutrient levels; and others (total of 139 AMD and non-AMD phenotypes). Genotypes of the 52 GWAS SNPs were obtained. The DeePAS was performed by correlating the 52 SNPs to all phenotypes using logistic and linear regression models. Associations that reached Bonferroni-corrected statistical significance were replicated in AREDS. MAIN OUTCOME MEASURES: Genotype-phenotype associations. RESULTS: A total of 1776 AREDS2 participants had 5 years follow-up; 1435 AREDS participants had 10 years. The DeePAS revealed a significant association of the rs3750846 SNP at the ARMS2/HTRA1 locus with subretinal/sub-retinal pigment epithelial (RPE) hemorrhage related to neovascular AMD (odds ratio 1.55 [95% confidence interval 1.31-1.84], P = 2.67 × 10-7). This novel association remained significant after conditioning on participants with neovascular AMD (P = 2.42 × 10-4). Carriers of rs3750846 had poorer visual acuity during follow-up (P = 6.82 × 10-7) and were more likely to have a first-degree relative with AMD (P = 5.38 × 10-6). Two SNPs at the CFH locus, rs10922109 and rs570618, were associated with the drusen area in the Early Treatment Diabetic Retinopathy Study Report (ETDRS) grid (P = 2.29 × 10-11 and P = 3.20 × 10-9, respectively) and the center subfield (P = 1.24 × 10-9 and P = 6.68 × 10-8, respectively). SNP rs570618 was additionally associated with the presence of calcified drusen (P = 5.38 × 10-6). Except for positive family history of AMD with rs3750846, all genotype-phenotype associations were significantly replicated in AREDS. No pleiotropic associations were identified. CONCLUSIONS: The association of the SNP at the ARMS2/HTRA1 locus with subretinal/sub-RPE hemorrhage and poorer visual acuity and of SNPs at the CFH locus with drusen area may provide new insights in pathophysiological pathways underlying different stages of AMD.

C-reactive protein and CFH, ARMS2/HTRA1 gene variants are independently associated with risk of macular degeneration.

PURPOSE: Genetic variants CFH and ARMS2/HTRA1 gene regions as well as high-sensitivity C-reactive protein (CRP) levels are related to age-related macular degeneration (AMD). We evaluated their independent and combined effects on risk of AMD, as well as their interactions. DESIGN: Case-control study. PARTICIPANTS: Subjects with AMD (n = 244) or no or minimal maculopathy (n = 209) in the Age Related Eye Disease Ancillary Study. METHODS: Risk factors, genotypes, and biomarkers were assessed by questionnaire, direct measurement, and analyses of blood specimens. The independent and joint effects of serum CRP and CFH (rs1061170) and ARMS2/HTRA1 (rs10490924) genotypes were assessed using logistic regression analyses, adjusting for age, gender, education, smoking, body mass index, and vitamin/mineral supplementation. MAIN OUTCOME MEASURES: We defined AMD as large drusen, geographic atrophy, or neovascular disease. RESULTS: Higher CRP levels were associated with a higher risk of AMD, controlling for genotype and demographic and behavioral risk factors, with odds ratio 2.6 for levels of 3.0 mg/L and above versus below 1.0 mg/L (95% confidence interval, 1.01-6.7). Single nucleotide polymorphisms (SNPs) in both genes were also independently associated with risk of AMD, controlling for the level of CRP and other factors. Presence of both highest level of CRP together with risk genotypes for both SNPs, conferred the highest risk of AMD (OR 5.4, 95% CI 1.4-21.1). CONCLUSIONS: High-sensitivity CRP and polymorphisms in the CFH and ARMS2/HTRA1 genes are independently associated with risk of AMD. Higher CRP level tends to confer a higher risk of AMD within most genotype groups.