Role of RDBP and SKIV2L variants in the major histocompatibility complex class III region in polypoidal choroidal vasculopathy etiology.
OBJECTIVE
To investigate whether polymorphisms in 4 tightly linked genes of the major histocompatibility complex class III--complement component 2 (C2), complement factor B (CFB), RD RNA-binding protein (RDBP), and superkiller viralicidic activity 2-like (SKIV2L)--are associated with polypoidal choroidal vasculopathy (PCV).


METHODS
Cross-sectional study.


METHODS
A case-control group of 136 PCV subjects and 183 unrelated controls.


METHODS
We performed an association analysis between PCV and polymorphisms across the C2-CFB-RDBP-SKIV2L region in a Japanese population, genotyping 13 single nucleotide polymorphisms (SNPs) spanning this region, including rs9332739 (E318D), rs547154, rs4151667 (L9H), and rs641153 (R32Q) that are known to be associated with age-related macular degeneration (AMD). Genotyping was conducted using TaqMan technology (Applied Biosystems, Foster City, CA). We also examined population stratification in our study cohort.


METHODS
Allele and haplotype frequencies of the variants across the C2-CFB-RDBP-SKIV2L region.


RESULTS
We initially scanned the C2-CFB locus using 11 SNPs that capture the majority of common variations in this locus. We found a significant omnibus haplotype association and a single disease-protective haplotype, but individually, none of the 11 SNPs were associated with PCV. Further studies led to the identification of 2 untested allelic variants in RDBP (rs3880457) and SKIV2L (rs2075702) that were located on the protective haplotype. We also analyzed these 2 SNPs, detecting a significant association with a decreased risk of developing PCV (for both SNPs, allelic P = 0.0038 and per allele odds ratio = 0.31 [95% confidence interval, 0.13-0.71]). The 2 SNPs were correlated (r(2) = 1) in our dataset. Haplotype analysis and conditional testing demonstrated that either rs3880457 or rs2075702 could fully account for the omnibus haplotype association detected across the C2-CFB-RDBP-SKIV2L region. Population stratification analyses excluded stratification artifacts in our study cohort.


CONCLUSIONS
Our results do not support any major role of the 4 AMD-associated variants in the risk of developing PCV, but favor a predominant association with the RDBP-SKIV2L variants, which has some potential implications for pathobiological differences between PCV and neovascular AMD. Further genetic characterization of this locus will provide additional insights into the genetic basis of PCV susceptibility.
Kondo
Naoshi
N
Department of Surgery, Division of Ophthalmology, Kobe University Graduate School of Medicine, Kobe, Japan.
Honda
Shigeru
S
Kuno
Shin-ichi
S
Negi
Akira
A
D000368:Aged; D000369:Aged, 80 and over; D000483:Alleles; D016022:Case-Control Studies; D002829:Choroid / Q000098:blood supply*; D015862:Choroid Diseases / Q000235:genetics*; D003175:Complement C2 / Q000235:genetics; D011415:Complement Factor B / Q000235:genetics; D003430:Cross-Sectional Studies; D004265:DNA Helicases / Q000235:genetics*; D005260:Female; D006239:Haplotypes; D006801:Humans; D008268:Macular Degeneration / Q000235:genetics; D008285:Major Histocompatibility Complex / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D016491:Peripheral Vascular Diseases / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D016601:RNA-Binding Proteins / Q000235:genetics; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors / Q000235:genetics*
D003175:Complement C2; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; D014157:Transcription Factors; D035602:Transcriptional Elongation Factors; C118437:negative elongation factor; D011415:Complement Factor B; D004265:DNA Helicases; C114718:SKIV2L protein, human