The mean baseline age of the 1,791 participants was 63.9 years, 42.8% were men, and 12.5% were current smokers at baseline. Late AMD developed in 47 of 1,791 persons (2.6%), and early AMD developed in 185 of 1,705 persons (10.9%) over the 10-year period. The CFH CC genotype was found in 13.6% (n = 244), the CT genotype in 46.7% (n = 836), and the TT genotype in 39.7% (n = 711). shows that persons with either incident early or late AMD were older, more likely to have the CFH CC genotype, and less likely to have the TT genotype. The CC genotype was found in 12.6% of subjects who did not have incident early or late AMD. The proportion of persons who consumed fish at least weekly was significantly lower among the 47 persons who developed incident late AMD (45%) than among the 1,520 persons who did not develop either early or late AMD (61%) during the follow-up period of our study ().
After adjustment for age and sex, each additional C allele was associated with a 60% greater risk for early AMD (relative risk (RR) = 1.6, 95% confidence interval (CI): 1.2, 1.9) and more than double the risk for late AMD (RR = 2.3, 95% CI: 1.5, 3.6) (). Although point estimates for these relative risks show a dose gradient pattern, the confidence intervals were wide and overlapping, likely because of the small numbers.
displays the combined exposures of CFH risk genotypes with the chosen study factors on the risk of late and early AMD. After adjustment for age, sex, white cell count, and regular fish consumption, there was no significant interaction (P = 0.96), but a joint effect of CFH risk genotypes with current smoking on the risk of late AMD was observed. Among noncurrent smokers, the relative risk was 2.2 (95% CI: 0.9, 5.5) for the CC/CT genotypes (for the CT genotype: RR = 1.7, 95% CI: 0.6, 4.6; for the CC genotype: RR = 4.2, 95% CI: 1.4, 12.6); among current smokers, the corresponding relative risk was 10.7 (95% CI: 3.4, 33.9) for the CC/CT genotypes () (for the CT genotype: RR = 10.9, 95% CI: 3.1, 38.1; for the CC genotype: RR = 9.7, 95% CI: 1.7, 54.8). The synergy index for late AMD between CFH genotypes and smoking was not obtainable as no participants in the smoking-alone group developed late AMD. A joint effect of CFH risk genotypes and current smoking on the risk of early AMD was not apparent ().
Similar joint effects of CFH Y402H with white cell count or plasma fibrinogen on incident late AMD were suggested (). The synergy indices for the risk of late AMD were 1.10 for combined exposure to both high white cell count and CFH risk genotypes and 1.48 for combined exposure to both high fibrinogen and CFH risk genotypes. The joint effects of this gene variant with both inflammatory markers appeared weaker for early than for late AMD ().
There was a significant interaction between the CFH risk allele and fish consumption on late AMD risk (P = 0.03). After adjustment for age, sex, smoking, and white cell count, the risk of developing late AMD doubled among subjects with either CT or CC genotypes who consumed less than 1 serving of fish per week (RR = 3.6, 95% CI: 1.2, 11.2), compared with genotypically similar subjects who consumed at least 1 serving of fish per week (RR = 1.7, 95% CI: 0.5, 5.5) (). This joint effect on the incidence of AMD persisted after further adjustment for vitamin C intake and higher occupational prestige (late AMD: RR = 3.4, 95% CI: 1.1, 10.7; early AMD: RR = 1.9, 95% CI: 1.1, 3.2). The synergy index for the risk of late AMD was 6.4, and for early AMD it was 0.95, from combined exposure to infrequent fish consumption and CFH genotypes.
In subgroup analysis stratified into the ages of less than 70 years and 70 years or more, the joint effects on late AMD from infrequent fish consumption and CFH CC/CT genotypes were similar for the 2 age subgroups (RR = 4.0, 95% CI: 0.8, 19.5 and RR = 3.4, 95% CI: 0.7, 17.0, respectively). However, the joint effect on early AMD appeared to be stronger in the older (RR = 3.8, 95% CI: 1.4, 9.8) than in the younger (RR = 1.3, 95% CI: 0.7, 2.6) age group.
In subgroup analysis stratified by CFH genotype, at least weekly fish consumption was associated with a reduced risk of late AMD in persons with only the CC genotype (RR = 0.15, 95% CI: 0.03, 0.8) but not the CT genotype (RR = 0.74, 95% CI: 0.3, 2.0) or the TT genotype (RR = 1.3, 95% CI: 0.2, 7.1) (). After further adjustment for vitamin C intake and higher occupational prestige, the protective association from weekly consumption of fish among persons with the CC genotype persisted (RR = 0.15, 95% CI: 0.03, 0.9). No similar effect was evident for early AMD ().
We also repeated analyses to include only the oldest family member of participants for whom first-degree family members were also study participants, and we found no difference from that when the youngest family member was included.