Lifestyle Affects Genetic Propensity for Age-Related Eye Disorder

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BOSTON -- The interplay of genetic predisposition and modifiable risk factors, such as obesity and smoking, increases the risk for age-related macular degeneration, researchers reported.

BOSTON, Jan. 8 -- The interplay of a genetic predisposition and modifiable risk factors, such as obesity and smoking, increases the risk for age-related macular degeneration, researchers here reported.

A mutation in the gene for complement factor H (CFH Y402H) is associated with age-related macular degeneration, as is a mutation in the gene LOC387715 A69S, according to earlier studies.

The high prevalence of these mutations in the white population, not all of whom will develop the eye disease, suggested that modifiable lifestyle risk factors may alter the underlying genetic risk, said Debra Schaumberg, Sc.D., D.O., of Brigham and Women's Hospital, and Harvard colleagues.

In a comparison of 457 men and women with age-related macular degeneration and 1,071 age- and sex-matched controls in a prospective nested case-control study, those homozygous for both risk alleles at both loci were 50 times more likely to develop age-related macular degeneration (50.48, 95% CI, 10.8-236.6),), although the 95% CI was wide, the researchers reported in the January issue of the Archives of Ophthalmology.

Cigarette smoking and obesity (BMI 30 or greater) multiplied the risk associated with these variants, they reported.

Study participants, ages 30 to 55 in 1976, were part of the Nurses' Health Study and also the Health Professional Follow-up study, which included male health-care professionals ages 40 to 75 in 1986. Participants were examined upon enrollment. Blood samples were taken for genetic analysis, and subjects completed a follow-up questionnaire every two years. The average age at age-related macular degeneration diagnosis was 68.7 years.

Non-obese individuals with two mutant alleles of the CFH gene were almost four times as likely to develop age-related macular degeneration as non-obese individuals with two normal alleles (incident rate ratio 3.92, CI, 2.69-5.76). Those with only one copy of the gene had almost twice the risk (IRR 1.98. CI, 1.64-2.40).

The LOC387715 A69S allele is also common, with 33.5% of controls having at least one risk allele, but little is known about the function of this variant, they added. For those with one copy and two copies of LOC387715 A69S, the risks were 2.38 (1.92-2.96) and 5.66 (3.69-8.76), respectively.

In estimates of the effect of modifiable risk factors on these two susceptibility genes, the researchers found that subjects homozygous for the CFH variant had a 12-fold increased risk (12.28 CI 4.88-30.90) if they were also obese and a nearly nine-fold higher increased risk (8.69, CI 3.86-19.57) if they smoked cigarettes, compared with persons exposed to neither the genetic variant nor the modifiable risk factor.

In addition, the investigators said, cigarette smoking appeared to multiply the risk conferred by the LOC387715 variant, showing a 22.47-fold higher risk (CI 4.70-107.54) among smokers homozygous for the variant compared with nonsmokers without genetic variants.

For homozygous obese patients with LOC387715, the risk was 8.94 times higher (CI, 2.65-30.15), than nonobese noncarriers, the researchers reported.

In the present study, most of the cases (62.8%) in these two large cohorts involved one or both of these variants (CI 58% to 68%). The role of CFH in innate immunity implies an ability to influence a variety of biological systems and conditions in addition to its effect on the risk of AMD, the investigators said.

The genetic risks were not affected by other lifestyle risk factors associated with AMD, including regular aspirin use, fruit intake, fatty acid ratios, or alcohol consumption.

The researchers noted, however, that compared with those with no LOC387715 alleles who used aspirin regularly, the AMD risk was seven-fold greater among those homozygous for LOC387715 who did not use aspirin regularly, but just twofold among similar individuals who used aspirin regularly. These data, they said, suggest that regular aspirin use may reduce the risk conferred by homozygosity for LOC387715, and the possibility may be worth investigating in larger studies.

One potential limitation of the study, the researchers wrote, related to the way the age-related macular degeneration cases were obtained. It was not possible to perform standardized clinical assessments of participants in this large and geographically dispersed cohort.

Furthermore, the investigators said, although some participants selected as controls may at a later point develop age-related macular degeneration, this was not a limitation but rather a predictable characteristic of the sampling method and does not introduce bias.

Finally, they noted that some of the exposures, such as cigarette smoking, are less common in the cohorts of health professionals than in the general population, suggesting the need for further study of these interactions in prospective studies with larger samples.

The high prevalence of the CFH Y402H and LOC397715 A69S and their strong association with age-related macular degeneration raised the question of the value of population-based genetic testing, Dr. Schaumberg's team wrote.

"The existence of interactions with modifiable lifestyle factors may provide further impetus for screening individuals who are at potentially greater risk, for example, cigarette smokers or the obese," they said. "Knowledge of the substantial risk of age-related macular degeneration among individuals homozygous for either or both of these major age-related macular degeneration-associated variants might help motivate these individuals to stop smoking, lose weight, modify other risk factors, and have regular eye examinations."

On the other hand, they added, the high prevalence of these variants relative to the proportion of individuals who develop visually significant age-related macular degeneration implies a relatively low positive predictive value for genetic testing.

Ongoing research suggests that joint consideration of other loci within these or other genes may improve the predictive value of genetic testing in the future, they said. The study findings, they concluded, "support the need for renewed attention to risk modification strategies to reduce the public health impact of this leading cause of blindness and visual impairment."