Open AccessSynergic effect of polymorphisms inERCC65′ flanking region andcomplement factor Hon age-related macular degeneration predisposition
Author(s) -
Jingsheng Tuo,
Baitang Ning,
C.M. Bojanowski,
Zhongning Lin,
Robert Ross,
George F. Reed,
Defen Shen,
Xiaodong Jiao,
Min Zhou,
Emily Y. Chew,
Fred F. Kadlubar,
Chi–Chao Chan
Publication year - 2006
Publication title -
proceedings of the national academy of sciences of the united states of america
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 5.011
H-Index - 771
eISSN - 1091-6490
pISSN - 0027-8424
DOI - 10.1073/pnas.0603485103
Subject(s) - biology , single nucleotide polymorphism , genetics , macular degeneration , allele , genotype , medicine , gene , ophthalmology
This study investigates age-related macular degeneration (AMD) genetic risk factors through identification of a functional single-nucleotide polymorphism (SNP) and its disease association. We choseERCC6 because of its roles in the aging process, DNA repair, and ocular degeneration from the gene disruption. Bioinformatics indicated a putative binding-element alteration on the sequence containing C−6530>G SNP in the 5′ flanking region ofERCC6 from Sp1 on the C allele to SP1, GATA-1, and OCT-1 on the G allele. Electrophoretic mobility shift assays displayed distinctive C and G allele-binding patterns to nuclear proteins. Luciferase expression was higher in the vector construct containing the G allele than that containing the C allele. A cohort of 460 advanced AMD cases and 269 age-matched controls was examined along with pathologically diagnosed 57 AMD and 18 age-matched non-AMD archived cases.ERCC6 C−6530>G was associated with AMD susceptibility, both independently and through interaction with an SNP (rs380390) in the complement factor H (CFH) intron reported to be highly associated with AMD. A disease odds ratio of 23 was conferred by homozygozity for risk alleles at bothERCC6 andCFH compared with homozygozity for nonrisk alleles. Enhanced ERCC6 expression was observed in lymphocytes from healthy donors bearing ERCC6 C−6530>G alleles. Intense immunostaining of ERCC6 was also found in AMD eyes fromERCC6 C−6530>G carriers. The strong AMD predisposition conferred by theERCC6 andCFH SNPs may result from biological epistasis, because ERCC6 functions in universal transcription as a component of RNA pol I transcription complex.