AGE

, 36:9627

In-depth analyses unveil the association and possible functional involvement of novel RAD51B polymorphisms in age-related macular degeneration

  • Xi K. Chu
  • Catherine B. Meyerle
  • Xiaoling Liang
  • Emily Y. Chew
  • Chi-Chao Chan
  • Jingsheng Tuo
Article

Abstract

The contribution of DNA damage to the pathogenesis of age-related macular degeneration (AMD) has been reported. Recently, a genomewide association study detected the association of a single-nucleotide polymorphism (SNP) in RAD51B (rs8017304 A>G) with AMD. RAD51B is involved in recombinational repair of DNA double-strand breaks. We analyzed RAD51B influence on AMD using two cohorts from Caucasian and Han Chinese populations. The Caucasian set replicated the rs8017304 A>G association and revealed two novel AMD-associated SNPs in RAD51B, rs17105278 T>C and rs4902566 C>T. Under the dominant model, these two SNPs exhibit highly significant disease risk. SNP–SNP interaction analysis on rs17105278 T>C and rs4902566 C>T homozygous demonstrated a synergistic effect on AMD risk, reaching an odds ratio multifold higher than well-established AMD susceptibility loci in genes such as CFH, HTRA1, and ARMS2. Functional study revealed lower RAD51B mRNA expression in cultured primary human fetal retinal pigment epithelium (hfRPE) carrying rs17105278 T>C variants than in hfRPE carrying rs17105278 wild type. We concluded that the risk of developing AMD exhibits dose dependency as well as an epistatic combined effect in rs17105278 T>C and rs4902566 C>T carriers and that the elevated risk for rs17105278 T>C carriers may be due to decreased transcription of RAD51B. This study further confirms the role of DNA damage/DNA repair in AMD pathogenesis.

Keywords

Age-related macular degeneration RAD51B DNA repair Single-nucleotide polymorphism Functional genomicsl Gene expression 

References

  1. Age-Related Eye Disease Study Research G (2000) Risk factors associated with age-related macular degeneration. A case–control study in the age-related eye disease study: age-related eye disease study report number 3. Ophthalmology 107(12):2224–2232CrossRefGoogle Scholar
  2. Age-Related Eye Disease Study Research G (2001) A randomized, placebo-controlled, clinical trial of high-dose supplementation with vitamins C and E, beta carotene, and zinc for age-related macular degeneration and vision loss: AREDS report no. 8. Arch Ophthalmol 119(10):1417–1436CrossRefGoogle Scholar
  3. Ardeljan D, Meyerle CB, Agron E, Jin Wang J, Mitchell P, Chew EY, Zhao J, Maminishkis A, Chan CC, Tuo J (2013) Influence of TIMP3/SYN3 polymorphisms on the phenotypic presentation of age-related macular degeneration. Eur J Hum Gen: EJHG 21(10):1152–1157. doi:10.1038/ejhg.2013.14 CrossRefGoogle Scholar
  4. Beatty S, Koh H, Phil M, Henson D, Boulton M (2000) The role of oxidative stress in the pathogenesis of age-related macular degeneration. Surv Ophthalmol 45(2):115–134PubMedCrossRefGoogle Scholar
  5. Blasiak J, Glowacki S, Kauppinen A, Kaarniranta K (2013) Mitochondrial and nuclear DNA damage and repair in age-related macular degeneration. Int J Mol Sci 14(2):2996–3010. doi:10.3390/ijms14022996 PubMedCentralPubMedCrossRefGoogle Scholar
  6. Blasiak J, Synowiec E, Salminen A, Kaarniranta K (2012) Genetic variability in DNA repair proteins in age-related macular degeneration. Int J Mol Sci 13(10):13378–13397. doi:10.3390/ijms131013378 PubMedCentralPubMedCrossRefGoogle Scholar
  7. Chan CC, Shen D, Zhou M, Ross RJ, Ding X, Zhang K, Green WR, Tuo J (2007) Human HtrA1 in the archived eyes with age-related macular degeneration. TAm Ophthalm Soc 105:92–97, discussion 97–98Google Scholar
  8. Chen LJ, Liu DT, Tam PO, Chan WM, Liu K, Chong KK, Lam DS, Pang CP (2006) Association of complement factor H polymorphisms with exudative age-related macular degeneration. Mol Vis 12:1536–1542PubMedGoogle Scholar
  9. Chou CF, Frances Cotch M, Vitale S, Zhang X, Klein R, Friedman DS, Klein BE, Saaddine JB (2013) Age-related eye diseases and visual impairment among U.S. adults. Am J Prev Med 45(1):29–35. doi:10.1016/j.amepre.2013.02.018 PubMedCentralPubMedCrossRefGoogle Scholar
  10. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL 3rd, Age-Related Eye Disease Study Research G (2005a) Risk factors for the incidence of advanced age-related macular degeneration in the age-related eye disease study (AREDS) AREDS report no. 19. Ophthalmology 112(4):533–539. doi:10.1016/j.ophtha.2004.10.047 PubMedCrossRefGoogle Scholar
  11. Clemons TE, Milton RC, Klein R, Seddon JM, Ferris FL III (2005b) Risk factors for the incidence of advanced age-related macular degeneration in the age-related eye disease study (AREDS) AREDS report no. 19. Ophthalmology 112(4):533–539PubMedCrossRefGoogle Scholar
  12. Coleman HR, Chan CC, Ferris FL III, Chew EY (2008) Age-related macular degeneration. Lancet 372(9652):1835–1845PubMedCentralPubMedCrossRefGoogle Scholar
  13. Davis MD, Gangnon RE, Lee LY, Hubbard LD, Klein BE, Klein R, Ferris FL, Bressler SB, Milton RC (2005) The age-related eye disease study severity scale for age-related macular degeneration: AREDS report no. 17. Arch Ophthalmol 123(11):1484–1498PubMedCrossRefGoogle Scholar
  14. Dewan A, Liu M, Hartman S, Zhang SS, Liu DT, Zhao C, Tam PO, Chan WM, Lam DS, Snyder M, Barnstable C, Pang CP, Hoh J (2006) HTRA1 promoter polymorphism in wet age-related macular degeneration. Science 314(5801):989–992PubMedCrossRefGoogle Scholar
  15. Ding X, Patel M, Chan CC (2009) Molecular pathology of age-related macular degeneration. Prog Retin Eye Res 28(1):1–18. doi:10.1016/j.preteyeres.2008.10.001 PubMedCentralPubMedCrossRefGoogle Scholar
  16. Dudbridge F, Koeleman BP (2004) Efficient computation of significance levels for multiple associations in large studies of correlated data, including genomewide association studies. Am J Hum Genet 75(3):424–435. doi:10.1086/423738 PubMedCentralPubMedCrossRefGoogle Scholar
  17. Fritsche LG, Chen W, Schu M, Yaspan BL, Yu Y, Thorleifsson G, Zack DJ, Arakawa S, Cipriani V, Ripke S, Igo RP Jr, Buitendijk GH, Sim X, Weeks DE, Guymer RH, Merriam JE, Francis PJ, Hannum G, Agarwal A, Armbrecht AM, Audo I, Aung T, Barile GR, Benchaboune M, Bird AC, Bishop PN, Branham KE, Brooks M, Brucker AJ, Cade WH, Cain MS, Campochiaro PA, Chan CC, Cheng CY, Chew EY, Chin KA, Chowers I, Clayton DG, Cojocaru R, Conley YP, Cornes BK, Daly MJ, Dhillon B, Edwards AO, Evangelou E, Fagerness J, Ferreyra HA, Friedman JS, Geirsdottir A, George RJ, Gieger C, Gupta N, Hagstrom SA, Harding SP, Haritoglou C, Heckenlively JR, Holz FG, Hughes G, Ioannidis JP, Ishibashi T, Joseph P, Jun G, Kamatani Y, Katsanis N, NK C, Khan JC, Kim IK, Kiyohara Y, Klein BE, Klein R, Kovach JL, Kozak I, Lee CJ, Lee KE, Lichtner P, Lotery AJ, Meitinger T, Mitchell P, Mohand-Said S, Moore AT, Morgan DJ, Morrison MA, Myers CE, Naj AC, Nakamura Y, Okada Y, Orlin A, Ortube MC, Othman MI, Pappas C, Park KH, Pauer GJ, Peachey NS, Poch O, Priya RR, Reynolds R, Richardson AJ, Ripp R, Rudolph G, Ryu E, Sahel JA, Schaumberg DA, Scholl HP, Schwartz SG, Scott WK, Shahid H, Sigurdsson H, Silvestri G, Sivakumaran TA, Smith RT, Sobrin L, Souied EH, Stambolian DE, Stefansson H, Sturgill-Short GM, Takahashi A, Tosakulwong N, Truitt BJ, Tsironi EE, Uitterlinden AG, van Duijn CM, Vijaya L, Vingerling JR, Vithana EN, Webster AR, Wichmann HE, Winkler TW, Wong TY, Wright AF, Zelenika D, Zhang M, Zhao L, Zhang K, Klein ML, Hageman GS, Lathrop GM, Stefansson K, Allikmets R, Baird PN, Gorin MB, Wang JJ, Klaver CC, Seddon JM, Pericak-Vance MA, Iyengar SK, Yates JR, Swaroop A, Weber BH, Kubo M, Deangelis MM, Leveillard T, Thorsteinsdottir U, Haines JL, Farrer LA, Heid IM, Abecasis GR, Consortium AMDG (2013) Seven new loci associated with age-related macular degeneration. Nat Genet 45(4):433–439. doi:10.1038/ng.2578, e431–432PubMedCrossRefGoogle Scholar
  18. Hageman GS, Anderson DH, Johnson LV, Hancox LS, Taiber AJ, Hardisty LI, Hageman JL, Stockman HA, Borchardt JD, Gehrs KM, Smith RJ, Silvestri G, Russell SR, Klaver CC, Barbazetto I, Chang S, Yannuzzi LA, Barile GR, Merriam JC, Smith RT, Olsh AK, Bergeron J, Zernant J, Merriam JE, Gold B, Dean M, Allikmets R (2005) A common haplotype in the complement regulatory gene factor H (HF1/CFH) predisposes individuals to age-related macular degeneration. Proc Natl Acad Sci U S A 102(20):7227–7232PubMedCentralPubMedCrossRefGoogle Scholar
  19. Kanda A, Chen W, Othman M, Branham KE, Brooks M, Khanna R, He S, Lyons R, Abecasis GR, Swaroop A (2007) A variant of mitochondrial protein LOC387715/ARMS2, not HTRA1, is strongly associated with age-related macular degeneration. Proc Natl Acad Sci U S A 104(41):16227–16232PubMedCentralPubMedCrossRefGoogle Scholar
  20. Keller-Seitz MU, Certa U, Sengstag C, Wurgler FE, Sun M, Fasullo M (2004) Transcriptional response of yeast to aflatoxin B1: recombinational repair involving RAD51 and RAD1. Mol Biol Cell 15(9):4321–4336. doi:10.1091/mbc.E04-05-0375 PubMedCentralPubMedCrossRefGoogle Scholar
  21. Maminishkis A, Chen S, Jalickee S, Banzon T, Shi G, Wang FE, Ehalt T, Hammer JA, Miller SS (2006) Confluent monolayers of cultured human fetal retinal pigment epithelium exhibit morphology and physiology of native tissue. Invest Ophthalmol Vis Sci 47(8):3612–3624PubMedCentralPubMedCrossRefGoogle Scholar
  22. Ross RJ, Bojanowski CM, Wang JJ, Chew EY, Rochtchina E, Ferris FL III, Mitchell P, Chan CC, Tuo J (2007) The LOC387715 polymorphism and age-related macular degeneration: replication in three case–control samples. Invest Ophthalmol Vis Sci 48(3):1128–1132PubMedCentralPubMedCrossRefGoogle Scholar
  23. Singh DK, Ahn B, Bohr VA (2009) Roles of RECQ helicases in recombination based DNA repair, genomic stability and aging. Biogerontology 10(3):235–252. doi:10.1007/s10522-008-9205-z PubMedCentralPubMedCrossRefGoogle Scholar
  24. Strunnikova N, Hilmer S, Flippin J, Robinson M, Hoffman E, Csaky KG (2005) Differences in gene expression profiles in dermal fibroblasts from control and patients with age-related macular degeneration elicited by oxidative injury. Free Radic Biol Med 39(6):781–796. doi:10.1016/j.freeradbiomed.2005.04.029 PubMedCrossRefGoogle Scholar
  25. Suwaki N, Klare K, Tarsounas M (2011) RAD51 paralogs: roles in DNA damage signalling, recombinational repair and tumorigenesis. Semin Cell Dev Biol 22(8):898–905. doi:10.1016/j.semcdb.2011.07.019 PubMedCrossRefGoogle Scholar
  26. Szaflik JP, Janik-Papis K, Synowiec E, Ksiazek D, Zaras M, Wozniak K, Szaflik J, Blasiak J (2009) DNA damage and repair in age-related macular degeneration. Mutat Res 669(1–2):169–176. doi:10.1016/j.mrfmmm.2009.06.008 PubMedCrossRefGoogle Scholar
  27. Takata M, Sasaki MS, Sonoda E, Fukushima T, Morrison C, Albala JS, Swagemakers SM, Kanaar R, Thompson LH, Takeda S (2000) The Rad51 paralog Rad51B promotes homologous recombinational repair. Mol Cell Biol 20(17):6476–6482PubMedCentralPubMedCrossRefGoogle Scholar
  28. Tuo J, Ning B, Bojanowski CM, Lin ZN, Ross RJ, Reed GF, Shen D, Jiao X, Zhou M, Chew EY, Kadlubar FF, Chan CC (2006) Synergic effect of polymorphisms in ERCC6 5′ flanking region and complement factor H on age-related macular degeneration predisposition. Proc Natl Acad Sci U S A 103(24):9256–9261PubMedCentralPubMedCrossRefGoogle Scholar
  29. Tuo J, Ross RJ, Reed GF, Yan Q, Wang JJ, Bojanowski CM, Chew EY, Feng X, Olsen TW, Ferris FL 3rd, Mitchell P, Chan CC (2008) The HtrA1 promoter polymorphism, smoking, and age-related macular degeneration in multiple case-control samples. Ophthalmology 115(11):1891–1898. doi:10.1016/j.ophtha.2008.05.021 PubMedCentralPubMedCrossRefGoogle Scholar
  30. Wilson DM 3rd, Bohr VA (2007) The mechanics of base excision repair, and its relationship to aging and disease. DNA Repair 6(4):544–559. doi:10.1016/j.dnarep.2006.10.017 PubMedCrossRefGoogle Scholar
  31. Wozniak K, Szaflik JP, Zaras M, Sklodowska A, Janik-Papis K, Poplawski TR, Blasiak J, Szaflik J (2009) DNA damage/repair and polymorphism of the hOGG1 gene in lymphocytes of AMD patients. J Biomed Biotechnol 2009:827562PubMedCentralPubMedCrossRefGoogle Scholar
  32. Yang Z, Camp NJ, Sun H, Tong Z, Gibbs D, Cameron DJ, Chen H, Zhao Y, Pearson E, Li X, Chien J, DeWan A, Harmon J, Bernstein PS, Shridhar V, Zabriskie NA, Hoh J, Howes K, Zhang K (2006) A variant of the HTRA1 gene increases susceptibility to age-related macular degeneration. Science 314(5801):992–993PubMedCrossRefGoogle Scholar
  33. Yao Y, Bilichak A, Titov V, Golubov A, Kovalchuk I (2013) Genome Stability of Arabidopsis atm, ku80 and rad51b Mutants: Somatic and Transgenerational Responses to Stress. Plant Cell Physiol 54(6):982–989. doi:10.1093/pcp/pct051 PubMedCrossRefGoogle Scholar

Copyright information

© American Aging Association 2014

Authors and Affiliations

  • Xi K. Chu
    • 1
  • Catherine B. Meyerle
    • 2
  • Xiaoling Liang
    • 3
  • Emily Y. Chew
    • 2
  • Chi-Chao Chan
    • 1
  • Jingsheng Tuo
    • 1
  1. 1.Laboratory of Immunology, National Eye InstituteNational Institutes of HealthBethesdaUSA
  2. 2.Division of Epidemiology and Clinical Applications, National Eye InstituteNational Institutes of HealthBethesdaUSA
  3. 3.State Key Laboratory of OphthalmologyZhongshan Ophthalmic CenterGuangzhouChina

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