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


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.


CONCLUSIONS
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.
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Nicole T M
NT
Saksens
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Yara T E
YT
Lechanteur
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Sanne K
SK
Verbakel
Department of Epidemiology, Biostatistics and Health Technology Assessment, Radboud University Medical Center, Nijmegen, the Netherlands.
Joannes M M
JM
Groenewoud
Department of Nephrology, Leiden University Nijmegen Medical Center, Leiden, the Netherlands.
Mohamed R
MR
Daha
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
Tina
T
Schick
Department of Ophthalmology, University Hospital of Cologne, Cologne, Germany.
Sascha
S
Fauser
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Ophthalmology, Leiden University Medical Center, Albinusdreef 2, Leiden, the Netherlands.
Camiel J F
CJ
Boon
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.
Carel B
CB
Hoyng
Department of Ophthalmology, Radboud University Medical Center, Nijmegen, the Netherlands.|Department of Human Genetics, Radboud University Medical Center, Nijmegen, the Netherlands.
Anneke I
AI
den Hollander
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D003167:Complement Activation; D003176:Complement C3 / Q000032:analysis*; D015933:Complement C3d / Q000032:analysis*; D016208:Databases, Factual; D005260:Female; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D008268:Macular Degeneration / Q000097:blood / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011506:Proteins / Q000235:genetics*; D012189:Retrospective Studies; D012307:Risk Factors
C514392:ARMS2 protein, human; D003176:Complement C3; D011506:Proteins; D015933:Complement C3d