Comprehensive analysis of CRP, CFH Y402H and environmental risk factors on risk of neovascular age-related macular degeneration.
OBJECTIVE
To examine if the gene encoding C-reactive protein (CRP), a biomarker of inflammation, confers risk for neovascular age-related macular degeneration (AMD) in the presence of other modifiers of inflammation, including body mass index (BMI), diabetes, smoking, and complement factor H (CFH) Y402 genotype. Additionally we examined the degree to which CRP common variation was in linkage disequilibrium (LD) within our cohort.


METHODS
We ascertained 244 individuals from 104 families where at least one member had neovascular AMD, and a sibling had normal maculae and was past the age of the index patient's diagnosis of neovascular AMD. We employed a direct sequencing approach to analyze the 5'-promoter region as well as the entire coding region and the 3'-untranslated region of the CRP gene. CFH Y402 genotype data was available for all participants. Lifestyle and medical factors were obtained via administration of a standardized questionnaire. The family-based association test, haplotype analysis, McNemar's test, and conditional logistic regression were used to determine significant associations and interactions. Haploview was used to calculate the degree of LD (r2) between all CRP variants identified.


RESULTS
Six single nucleotide polymorphisms (SNPs; rs3091244, rs1417938, rs1800947, rs1130864, rs1205, and rs3093068) comprised one haplotype block of which only rs1130864 and rs1417938 were in high LD (r2=0.94). SNP rs3093068 was in LD but less so with rs3093059 (r2=0.83), which is not part of the haplotype block. Six SNPs made up six different haplotypes with > or = 5% frequency, none of which were significantly associated with AMD risk. No statistically significant association was detected between any of the nine common variants in CRP and neovascular AMD when considering disease status alone or when controlling for smoking exposure, BMI, diabetes, or CFH genotype. Significant interactions were not found between CRP genotypes and any of the risk factors studied. No novel CRP variation was identified.


CONCLUSIONS
We provide evidence that if elevated serum/plasma levels of CRP are associated with neovascular AMD, it is likely not due to genetic variation within CRP, but likely due to variations in some other genetic as well as epidemiological factors.
Kim
Ivana K
IK
Department of Ophthalmology, Harvard Medical School, Massachusetts Eye and Ear Infirmary, Boston, MA 02114, USA.
Ji
Fei
F
Morrison
Margaux A
MA
Adams
Scott
S
Zhang
Qingrun
Q
Lane
Anne Marie
AM
Capone
Antonio
A
Dryja
Thaddeus P
TP
Ott
Jurg
J
Miller
Joan W
JW
DeAngelis
Margaret M
MM
D020413:3' Untranslated Regions / Q000235:genetics; D000368:Aged; D000369:Aged, 80 and over; D002097:C-Reactive Protein / Q000235:genetics*; D020256:Choroidal Neovascularization / Q000150:complications* / Q000235:genetics*; D017242:Complement Factor H / Q000235:genetics*; D003710:Demography; D004777:Environment; D005091:Exons / Q000235:genetics; D005787:Gene Frequency; D006239:Haplotypes; D006639:Histidine / Q000235:genetics; D006801:Humans; D015810:Linkage Disequilibrium / Q000235:genetics; D008268:Macular Degeneration / Q000150:complications / Q000235:genetics*; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics; D012044:Regression Analysis; D012307:Risk Factors; D014443:Tyrosine / Q000235:genetics
D020413:3' Untranslated Regions; D014443:Tyrosine; D006639:Histidine; D017242:Complement Factor H; D002097:C-Reactive Protein