A total of 547 eyes (255 right eyes and 292 left eyes) from 372 individuals (159 males and 213 females) were available for analysis, of which 167 eyes from 137 individuals progressed over the study period (72 to grade 4 and 95 to grade 5) with a mean progression time of 32.2 (±25.2) months (range, 1–138 months). Age at first grade 3 exam ranged from 53 to 95 years (mean age per eye = 76.3 ± 7.6). Individuals with two risk alleles at
CFH:rs10737680 progressed at a significantly faster rate than those with one allele (HR = 1.61, 95% CI = 1.08–2.40,
P = 0.02;
Table 2;
Fig. 1a), although this was not significant after Bonferroni correction for multiple tests (
n = 7). There was no significant difference in progression rate between individuals with no
CFH:rs10737680 risk alleles and either one or two risk alleles, but the sample size of individuals with no
CFH:rs10737680 risk alleles was small (
n = 31 eyes/20 individuals;
Tables 1,
2;
Supplementary Table S1). Concordance of the Cox proportional hazards model including
CFH, sex, and age was 0.65 (±SE 0.03). Time-dependent ROC curves estimated that the AUC at 3 years (mean follow-up time in our dataset) for a model including age, sex, and
CFH:rs10737680 was slightly higher (0.67; AUC range, 0.67–0.71 for 1–5 year follow-up time) compared to a model accounting for age and sex only (AUC = 0.64; range, 0.64–0.67;
Fig. 2). Since the
CFH:rs10737680 variant is correlated with two distinct protective haplotypes,
CFH:p.I62V that is tagged by
CFH:rs800292, and the CFHR1-3 deletion tagged by
CFH:rs6677604, we further evaluated the signal at this position by testing progression rate with respect to these two (uncorrelated) SNPs that were available in our imputed dataset. Individuals with two risk alleles (no protective alleles) at
CFH:rs6677604 (
n = 288) progressed significantly faster than those with fewer than two risk alleles (one or two protective alleles,
n = 81; HR = 1.81, 95% CI = 1.11–2.94,
P = 0.02;
Fig. 1b) where individuals with one or two protective alleles were pooled due to small sample size (
n = 5 and 76, respectively). There was no association between progression rate and genotype at the rs800292 SNP (HR = 0.95, 95% CI = 0.61–1.47,
P = 0.81).