Search

Genetic variation in the gene encoding complement factor H (CFH) on chromosome 1q31 has repeatedly been associated with an increased risk of age-related macular degeneration (AMD); however, previous studies have had inadequate numbers of participants across a sufficiently wide age range to determine whether the association varies by age. We conducted a genetic case-control study using data from 2294 cases and 2294 controls selected from the Melbourne Collaborative Cohort Study, matched on age, sex and region of origin. Four consistently replicated CFH single-nucleotide polymorphisms (SNPs) were genotyped: rs1061170 (Y402H), rs2274700, rs393955 and rs800292; their relationship with AMD prevalence was determined across the age range 48-86. A difference in genotype frequencies was seen across age groups, where the low-risk homozygote prevalence rose with each increasing age group. Associations with early AMD were strongly modified by age for three of the four SNPs (interaction P-value: 0.01-0.00003). An inverse association between the high-risk homozygote for each SNP and early AMD was observed in the younger age groups [odds ratios (OR) range 0.37-0.48 for age <55], reversing to a positive association with increasing age (OR 1.87-2.8 for age >75). The direction of associations for this gene change was from inverse to risk with increasing age. These findings have important implications for predictive models for AMD and potentially other age-related diseases which extrapolate risks from older cohorts, as they assume homogeneity of association by age, which might not exist.

Little evidence exists regarding associations between age-related macular degeneration (AMD) and moderate alcohol consumption, patterns of consumption, or different types of alcoholic beverage. The authors examined associations between AMD prevalence and alcohol intake using 20,963 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). Participants' alcohol consumption was determined from a structured interview at baseline. At follow-up from 2003 to 2007, digital macula photographs of both eyes were taken and evaluated for early and late AMD signs. Drinking more than 20 g of alcohol per day was associated with an approximate 20% increase in the odds of early AMD (odds ratio = 1.21, 95% confidence interval: 1.06, 1.38; P = 0.004) when compared with those who reported no alcohol intake at baseline, having adjusted for sex, age, smoking, country of birth, education, physical activity, and energy from food. This positive association was apparent for wine, beer, and spirits. The estimates were similar for both sexes. The odds ratio for those drinking more than 20 g of alcohol per day for late AMD was 1.44 (95% confidence interval: 0.85, 2.45; P = 0.17). These results show a modest association between alcohol consumption and increased AMD risk.

The apolipoprotein E gene (APOE) has been found to be associated with age-related macular degeneration (AMD). Reported associations have been questioned, as they are opposite those for Alzheimer's disease and cardiovascular disease. The authors examined associations between APOE genotype and AMD using a case-control study (2,287 cases and 2,287 controls individually matched on age, sex, and country of origin) nested within Melbourne Collaborative Cohort Study participants aged 48-86 years at AMD detection. The odds ratio for early AMD among participants with ε2-containing genotypes (ε2ε2/ε2ε3/ε2ε4) was 1.32 (95% confidence interval (CI): 1.11, 1.58; P = 0.002) versus persons with genotype ε3ε3. Associations with early AMD varied by smoking status; ε2-containing genotypes were positively associated with early AMD for never and previous smokers (never smokers: odds ratio (OR) = 1.40, 95% CI: 1.12, 1.76 (P = 0.003); previous smokers: OR = 1.39, 95% CI: 1.00, 1.93 (P = 0.05)) but not for current smokers (OR = 0.66, 95% CI: 0.34, 1.30 (P = 0.2; interaction P = 0.05). The ε4-containing genotype group (ε3ε4/ε4ε4) had an inverse association with early AMD among current smokers only (OR = 0.41, 95% CI: 0.22, 0.77 (P = 0.005)). These results highlight the importance of stratifying by smoking status in elderly populations. Smokers who survive to old age may be more likely to possess unknown genotypes which modify exposure-disease associations.

Evidence for an association between age-related macular degeneration (AMD) and obesity is inconsistent. The authors examined associations between adiposity and AMD prevalence using 21,287 participants from the Melbourne Collaborative Cohort Study aged 40-69 years at baseline (1990-1994). For men, each increase of 0.1 in waist/hip ratio (~1 standard deviation) was associated with a 13% increase in the odds of early AMD (odds ratio = 1.13, 95% confidence interval: 1.01, 1.26; P = 0.03) and a 75% increase in the odds of late AMD (odds ratio = 1.75, 95% confidence interval: 1.11, 2.76; P = 0.02). No other adiposity measure was associated with early AMD for men. Smoking status modified the relation between waist/hip ratio and early AMD (P = 0.05), with no association for former smokers. For women, there were inverse associations with early AMD for all adiposity measures (odds ratios = 0.89-0.93; P = 0.002-0.02), but no associations were observed for late AMD. This study confirms abdominal obesity as an AMD risk factor for men despite a survivorship effect from competing risks in morbidity and mortality. The inverse associations for women may reflect weaker true positive associations with AMD that are insufficient to overcome the survivorship effect. New data are provided on complex interactions between environmental exposures and AMD risk.