Further assessment of the complement component 2 and factor B region associated with age-related macular degeneration.
OBJECTIVE
Polymorphic variation in genes involved in regulation of the complement system has been implicated as a major cause of genetic risk, in addition to the LOC387715/HTRA1 locus and other environmental influences. Previous studies have identified polymorphisms in the complement component 2 (CC2) and factor B (CFB) genes, as potential functional variants associated with AMD, in particular CFB R32Q and CC2 rs547154, both of which share strong linkage disequilibrium (LD).


METHODS
Data derived from the HapMap Project were used to select 18 haplotype-tagging SNPs across the extended CC2/CFB region for genotyping, to measure the strength of LD in 318 patients with neovascular AMD and 243 age-matched control subjects to identify additional potential functional variants in addition to those originally reported.


RESULTS
Strong LD was measured across this region as far as the superkiller viralicidic activity 2-like gene (SKIV2L). Nine SNPs were identified to be significantly associated with the genetic effect observed at this locus. Of these, a nonsynonymous coding variant SKIV2L R151Q (rs438999; OR, 0.48; 95% confidence interval [CI], 0.31-0.74; P<0.001), was in strong LD with CFB R32Q, rs641153 (r(2)=0.95) and may exert a functional effect. When assessed within a logistic regression model measuring the effects of genetic variation at the CFH and LOC387715/HTRA1 loci and smoking, the effect remained significant (OR, 0.38; 95% CI, 0.22-0.65; P<0.001). Additional variation identified within this region may also confer a weaker but independent effect and implicate additional genes within the pathogenesis of AMD.


CONCLUSIONS
Because of the high level of LD within the extended CC2/CFB region, variation within SKIV2L may exert a functional effect in AMD.
McKay
Gareth J
GJ
Centre for Vision Sciences, Queen's University of Belfast, Belfast, Northern Ireland, United Kingdom. g.j.mckay@qub.ac.uk
Silvestri
Giuliana
G
Patterson
Christopher C
CC
Hogg
Ruth E
RE
Chakravarthy
Usha
U
Hughes
Anne E
AE
D000368:Aged; D003175:Complement C2 / Q000235:genetics*; D011415:Complement Factor B / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics; D004265:DNA Helicases / Q000235:genetics; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D015810:Linkage Disequilibrium; D016015:Logistic Models; D008268:Macular Degeneration / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D011506:Proteins / Q000235:genetics
C514392:ARMS2 protein, human; C493495:CFH protein, human; D003175:Complement C2; D011506:Proteins; D017242:Complement Factor H; D011415:Complement Factor B; D004265:DNA Helicases; C114718:SKIV2L protein, human