Analysis of Risk Alleles and Complement Activation Levels in Familial and Non-Familial Age-Related Macular Degeneration

Abstract

Aims: Age-related macular degeneration (AMD) is a multifactorial disease, in which complement-mediated inflammation plays a pivotal role. A positive family history is an important risk factor for developing AMD. Certain lifestyle factors are shown to be significantly associated with AMD in non-familial cases, but not in familial cases. This study aimed to investigate whether the contribution of common genetic variants and complement activation levels differs between familial and sporadic cases with AMD.

Methods and results: 1216 AMD patients (281 familial and 935 sporadic) and 1043 controls (143 unaffected members with a family history of AMD and 900 unrelated controls without a family history of AMD) were included in this study. Ophthalmic examinations were performed, and lifestyle and family history were documented with a questionnaire. Nine single nucleotide polymorphisms (SNPs) known to be associated with AMD were genotyped, and serum concentrations of complement components C3 and C3d were measured. Associations were assessed in familial and sporadic individuals. The association with risk alleles of the age-related maculopathy susceptibility 2 (ARMS2) gene was significantly stronger in sporadic AMD patients compared to familial cases (p = 0.017 for all AMD stages and p = 0.003 for advanced AMD, respectively). ARMS2 risk alleles had the largest effect in sporadic cases but were not significantly associated with AMD in densely affected families. The C3d/C3 ratio was a significant risk factor for AMD in sporadic cases and may also be associated with familial cases. In patients with a densely affected family this effect was particularly strong with ORs of 5.37 and 4.99 for all AMD and advanced AMD respectively.

Conclusion: This study suggests that in familial AMD patients, the common genetic risk variant in ARMS2 is less important compared to sporadic AMD. In contrast, factors leading to increased complement activation appear to play a larger role in patients with a positive family history compared to sporadic patients. A better understanding of the different contributions of risk factors in familial compared to non-familial AMD will aid the development of reliable prediction models for AMD, and may provide individuals with more accurate information regarding their individual risk for AMD. This information is especially important for individuals who have a positive family history for AMD.

Fig 1. Odds ratios for risk variants in ARMS2 and CFH and the C3d/C3 ratio for development of AMD split by family history.

The risk variant in ARMS2 confers a strong risk for AMD in the sporadic group. In the group with a dense family history there is no effect of this SNP. The CFH Y402H risk allele is associated with AMD in all subgroups, irrespective of family history. In case of a dense family history, the Log C3d/C3 ratio is associated with AMD development. In the subgroups with a mild family history, this effect was not observed. OR = odds ratio; AMD = age-related macular degeneration; Sporadic = negative family history for AMD; Familial = positive family history for AMD; Dense familial = a positive family history for AMD satisfying 1 out of 3 criteria: (1) both parents have (possible) AMD, or (2) one affected parent and at least 25% of number of the sibs are affected, or (3) at least 50% of the number of sibs is affected; Mild familial = a positive family history for AMD but in a lesser extent, not meeting one of the 3 criteria.