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

Abstract

AimsAge-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 Results1216 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.ConclusionThis 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.

The rareC9P167S risk variant for age-related macular degeneration increases polymerization of the terminal component of the complement cascade

“…Carriers of this mutation had a 2.2-fold increased risk of developing AMD ( 5 ). This association has been confirmed in subsequent studies ( 4 , 28 ). The risk variant C9 P167S also tended to increase the risk of progression from early and intermediate levels of AMD to AAMD in prospective studies ( 29–31 ), although it was not independently related after adjusting for all other behavioral and genetic factors.…”

Phenotype Characteristics of Patients With Age-Related Macular Degeneration Carrying a Rare Variant in the Complement Factor H Gene

“…However, the minor allele frequencies of these common variants in noncarriers are comparable with the general AMD population. 23 This may imply that carriers of rare CFH variants are less burdened by common AMD risk variants and that their AMD risk is rather attributable to the rare variants.…”

From compliment to insult: genetics of the complement system in physiology and disease in the human retina

“…Since that time, a number of complement-related genetic variants have been associated with AMD, including C2/ CFB, C3, C7, C9, CFI and SERPING1 ( (6,35,36)). Some of these appear to be associated with specific AMD phenotypes (7,8,(37)(38)(39)(40)) and certain rare, highly penetrant genetic variants in complement genes appear to be particularly important in familial AMD (9,10,(41)(42)(43). Furthermore, the CFH Y402H polymorphism may predict response to treatment with AREDS vitamin supplements, zinc and anti-VEGF therapy, although published results are conflicting (11,12,44).…”