The combination of a certain genetic variation, along with inflammatory factors and smoking, significantly increases the risk of the vision disorder age-related macular degeneration, according to a study in the July 19 issue of JAMA.
Age-related macular degeneration (AMD) is the most important cause of irreversible visual loss in the elderly of the Western world, according to background information in the article. It has long been recognized that hereditary factors play a role in AMD and there is increasing evidence that inflammation is an important disease mechanism. Recent case-control studies demonstrated an association between the complement factor H (CFH) gene, a regulator of the complement pathway, and AMD.
Dominiek D. G. Despriet, M.D., of the Erasmus Medical Center, Rotterdam, the Netherlands, and colleagues hypothesized that the effect of this regulator gene may be particularly hazardous in persons in whom the complement cascade is activated. They assessed the association between the CFH gene and AMD and investigated the modifying effect of smoking, serum inflammatory markers, and genetic variation of C-reactive protein (CRP). The population-based study included 5,681 individuals age 55 years or older who were assessed for the gene mutation CFH Y402H. Information on smoking, serum inflammatory markers and CRP gene variation were assessed at baseline.
The frequency of CFH Y402H was 36.2 percent. At baseline, there were 2,062 persons (36.3 percent) with any type of AMD (prevalent cases), including 78 (1.4 percent) with late AMD. During an average follow-up of 8 years, 1,649 (35.5 percent) of 4,642 participants progressed to a higher stage of AMD (new cases), including 93 (5.6 percent) who developed late AMD.
The researchers found that the CFH gene was a major risk factor for AMD in the general population. The gene was implicated in all stages of AMD from early hallmarks such as drusen (material that builds up in the retina of the eye) to vision-disabling late AMD. The risks increased with each successive AMD stage, and homozygous individuals (i.e., with two identical gene copies of the CFH Y402H mutation at the corresponding site on a chromosome), had an 11 times higher risk to develop late AMD compared to noncarriers. Homozygous persons had a 48 percent cumulative risk of developing late AMD by age 95 years while this risk did not exceed 22 percent for noncarriers.
Factors that are known to activate the complement cascade modified the association between CFH and AMD: smoking further increased the risk of late AMD 34-fold; elevated serum CRP levels increased the risk 28-fold; and elevated sedimentation rates increased the risk 20-fold. The researchers also found a positive interaction between the CFH and the CRP gene for AMD, in particular with those forms of the gene predisposing for high serum CRP levels.
"These data suggest that CFH Y402H may be a causal factor in more than 50 percent of all AMD cases in the general population."
"Genetic predisposition to a malfunctioning CFH can only be of importance when the complement system is switched on," the authors write. "This is demonstrated by the significant interaction between chronic as well as acute inflammation and CFH Y402H."
"The effect of CFH is significantly influenced by environmental and genetic factors that determine the inflammatory response and activate the complement pathway." (JAMA. 2006;296:301-309. Available pre-embargo to the media at www.jamamedia.org)
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