Journal List > J Korean Soc Transplant > v.30(2) > 1034505

J Korean Soc Transplant. 2016 Jun;30(2):59-68. Korean.
Published online June 30, 2016.  https://doi.org/10.4285/jkstn.2016.30.2.59
Copyright © 2016 The Korean Society for Transplantation
Genetic Polymorphism in Proteins of the Complement System
Hyori Kim, Ph.D.,1 Dobeen Hwang, Ph.D.,2 Jungwon Han,3,4 Hwa Kyoung Lee,3,4 Won Jun Yang,3 Junyeong Jin,3,4 Ki-hyun Kim,3 Sang Il Kim,3 Duck-Kyun Yoo,3,4 Soohyun Kim,3 and Junho Chung, M.D.2,3,4,5
1Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul, Korea.
2Cancer Research Institute, Seoul National University College of Medicine, Seoul, Korea.
3Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, Seoul, Korea.
4Biomedical Science, Seoul National University College of Medicine, Seoul, Korea.
5Transplantation Research Institute, Medical Research Center, Seoul National University College of Medicine, Seoul, Korea.

Corresponding author: Junho Chung. Department of Biochemistry and Molecular Biology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 03080, Korea. Tel: 82-2-740-8242, Fax: 82-2-747-5769, Email: jjhchung@snu.ac.kr
Received June 14, 2016; Accepted June 15, 2016.

Abstract

The complement system is a part of the innate immune system that potentiates the ability of antibodies and phagocytic cells to clear microbes and damaged cells. The complement system consists of a number of proteins circulating as inactive precursors. It is stimulated mainly by three pathways: the classical pathway, the alternative pathway, and the lectin pathway. There are many genetic polymorphisms in this system, which can over-activate the immune system. In this study, we collected the polymorphisms reported to over-activate complement cascades that affect the immune system and induce autoimmune diseases.

Keywords: Complement system proteins; Genetic polymorphism; Autoimmune diseases

Figures


Fig. 1
Complement cascade pathways and complement proteins. Abbreviations: C, complement component; fB, factor B; fD, factor D; MBL, Mannose Binding Lectin; MAC, Membrane Attack Complex.
Click for larger image

References
1. Darbani B, Noeparvar S, Borg S. Deciphering Mineral Homeostasis in Barley Seed Transfer Cells at Transcriptional Level. PLoS One 2015;10:e0141398.
2. Budding K, van de Graaf EA, Kardol-Hoefnagel T, Broen JC1, Kwakkel-van Erp JM, Oudijk EJ, et al. A Promoter Polymorphism in the CD59 Complement Regulatory Protein Gene in Donor Lungs Correlates With a Higher Risk for Chronic Rejection After Lung Transplantation. Am J Transplant 2016;16:987–998.
3. Krych-Goldberg M, Atkinson JP. Structure-function relationships of complement receptor type 1. Immunol Rev 2001;180:112–122.
4. Racila DM, Sontheimer CJ, Sheffield A, Wisnieski JJ, Racila E, Sontheimer RD. Homozygous single nucleotide polymorphism of the complement C1QA gene is associated with decreased levels of C1q in patients with subacute cutaneous lupus erythematosus. Lupus 2003;12:124–132.
5. Slingsby JH, Norsworthy P, Pearce G, Vaishnaw AK, Issler H, Morley BJ, et al. Homozygous hereditary C1q deficiency and systemic lupus erythematosus. A new family and the molecular basis of C1q deficiency in three families. Arthritis Rheum 1996;39:663–670.
6. McAdam RA, Goundis D, Reid KB. A homozygous point mutation results in a stop codon in the C1q B-chain of a C1q-deficient individual. Immunogenetics 1988;27:259–264.
7. Topaloglu R, Bakkaloglu A, Slingsby JH, Mihatsch MJ, Pascual M, Norsworthy P, et al. Molecular basis of hereditary C1q deficiency associated with SLE and IgA nephropathy in a Turkish family. Kidney Int 1996;50:635–642.
8. Westra HJ, Peters MJ, Esko T, Yaghootkar H, Schurmann C, Kettunen J, et al. Systematic identification of trans eQTLs as putative drivers of known disease associations. Nat Genet 2013;45:1238–1243.
9. Bellemore SM, Nikoopour E, Schwartz JA, Krougly O, Lee-Chan E, Singh B. Preventative role of interleukin-17 producing regulatory T helper type 17 (Treg 17) cells in type 1 diabetes in non-obese diabetic mice. Clin Exp Immunol 2015;182:261–269.
10. Ma YB, Fu SY, Ma YH, Liu HL. Relationship between SERPING1 rs2511989 polymorphism and age-related macular degeneration risk: a meta-analysis. Mol Vis 2014;20:1434–1442.
11. Ennis S, Jomary C, Mullins R, Cree A, Chen X, Macleod A, et al. Association between the SERPING1 gene and age-related macular degeneration: a two-stage case-control study. Lancet 2008;372:1828–1834.
12. Xu YY, Zhi YX, Yin J, Wang LL, Wen LP, Gu JQ, et al. Mutational spectrum and geno-phenotype correlation in Chinese families with hereditary angioedema. Allergy 2012;67:1430–1436.
13. Ricklin D, Hajishengallis G, Yang K, Lambris JD. Complement: a key system for immune surveillance and homeostasis. Nat Immunol 2010;11:785–797.
14. Maller J, George S, Purcell S, Fagerness J, Altshuler D, Daly MJ, et al. Common variation in three genes, including a noncoding variant in CFH, strongly influences risk of age-related macular degeneration. Nat Genet 2006;38:1055–1059.
15. Sturfelt G, Truedsson L. Complement and its breakdown products in SLE. Rheumatology (Oxford) 2005;44:1227–1232.
16. Johnson CA, Densen P, Hurford RK Jr, Colten HR, Wetsel RA. Type I human complement C2 deficiency. A 28-base pair gene deletion causes skipping of exon 6 during RNA splicing. J Biol Chem 1992;267:9347–9353.
17. Wetsel RA, Kulics J, Lokki ML, Kiepiela P, Akama H, Johnson CA, et al. Type II human complement C2 deficiency. Allele-specific amino acid substitutions (Ser189 → Phe; Gly444 → Arg) cause impaired C2 secretion. J Biol Chem 1996;271:5824–5831.
18. Chen HH, Tsai LJ, Lee KR, Chen YM, Hung WT, Chen DY. Genetic association of complement component 2 polymorphism with systemic lupus erythematosus. Tissue Antigens 2015;86:122–133.
19. Chen X, Kang X, Zhao K, Zhao C. C2 rs547154 polymorphism and polypoidal choroidal vasculopathy susceptibility: a meta-analysis. Sci Rep 2015;5:8709.
20. Zhan X, Larson DE, Wang C, Koboldt DC, Sergeev YV, Fulton RS, et al. Identification of a rare coding variant in complement 3 associated with age-related macular degeneration. Nat Genet 2013;45:1375–1379.
21. Frémeaux-Bacchi V, Miller EC, Liszewski MK, Strain L, Blouin J, Brown AL, et al. Mutations in complement C3 predispose to development of atypical hemolytic uremic syndrome. Blood 2008;112:4948–4952.
22. Botto M, Fong KY, So AK, Koch C, Walport MJ. Molecular basis of polymorphism of human complement component C3. J Exp Med 1990;172:1011–1017.
23. Giles JL, Choy E, van den Berq C, Morgan BP, Harris CL. Functional analysis of a complement polymorphism (rs17611) associated with rheumatoid arthritis. J Immunol 2015;194:3029–3034.
24. Tremblay GM, Janelle MF, Bourbonnais Y. Anti-inflammatory activity of neutrophil elastase inhibitors. Curr Opin Investig Drugs 2003;4:556–565.
25. Xu D, Hou S, Jiang Y, Zhang J, Cao S, Zhang D, et al. Complement C5 Gene Confers Risk for Acute Anterior Uveitis. Invest Ophthalmol Vis Sci 2015;56:4954–4960.
26. Liu B, Wei L, Meyerle C, Tuo J, Sen HN, Li Z, et al. Complement component C5a promotes expression of IL-22 and IL-17 from human T cells and its implication in age-related macular degeneration. J Transl Med 2011;9:1–12.
27. DiScipio RG, Gehring MR, Pdack ER, Kan CC, Hugli TE, Fey GH. Nucleotide sequence of cDNA and derived amino acid sequence of human complement component C9. Proc Natl Acad Sci U S A 1984;81:7298–7302.
28. Wang Y, Xu S, Su Y, Ye B, Hua Z. Molecular characterization and expression analysis of complement component C9 gene in the whitespotted bambooshark, Chiloscyllium plagiosum. Fish Shellfish Immunol 2013;35:599–606.
29. Seddon JM, Yu Y, Miller EC, Reynolds R, Tan PL, Gowrisankar S, et al. Rare variants in CFI, C3 and C9 are associated with high risk of advanced age-related macular degeneration. Nat Genet 2013;45:1366–1370.
30. Nishiguchi KM, Yasuma TR, Tomida D, Nakamura M, Ishikawa K, Kikuchi M, et al. C9-R95X polymorphism in patients with neovascular age-related macular degeneration. Invest Ophthalmol Vis Sci 2012;53:508–512.
31. Miura T, Goto S, Iguchi S, Shimada H, Ueno M, Nishi S, et al. Membranoproliferative pattern of glomerular injury associated with complement component 9 deficiency due to Arg95Stop mutation. Clin Exp Nephrol 2011;15:86–91.
32. Gold B, Merriam JE, Zernant J, Hancox LS, Taiber AJ, Gehrs K, et al. Variation in factor B (BF) and complement component 2 (C2) genes is associated with age-related macular degeneration. Nat Genet 2006;38:458–462.
33. Goicoechea de Jorge E, Harris CL, Esparza-Gordillo J, Carreras L, Arranz EA, Garrido CA, et al. Gain-of-function mutations in complement factor B are associated with atypical hemolytic uremic syndrome. Proc Natl Acad Sci U S A 2007;104:240–245.
34. Alexander P, Gibson J, Cree AJ, Ennis S, Lotery AJ. Complement factor I and age-related macular degeneration. Mol Vis 2014;20:1253–1257.
35. Kavanagh D, Yu Y, Schramm EC, Triebwasser M, Wagner EK, Raychaudhuri S, et al. Rare genetic variants in the CFI gene are associated with advanced age-relate macular degeneration and commonly result in reduced serum factor I levels. Hum Mol Genet 2015;24:3861–3870.
36. van de Ven JP, Nilsson SC, Tan PL, Buitendijk GH, Ristau T, Mohlin FC, et al. A functional variant in the CFI gene confers a high risk of age-related macular degeneration. Nat Genet 2013;45:813–817.
37. Bienaime F, Dragon-Durey MA, Regnier CH, Nilsson SC, Kwan WH, Blouin J, et al. Mutations in components of complement influence the outcome of Factor I-associated atypical hemolytic uremic syndrome. Kidney Int 2010;77:339–349.
38. Hakobyan S, Harris CL, Tortajada A, Goicochea de Jorge E, García-Layana A, Fernández-Robredo P, et al. Measurement of factor H variants in plasma using variant-specific monoclonal antibodies: application to assessing risk of age-related macular degeneration. Invest Ophthalmol Vis Sci 2008;49:1983–1990.
39. Gros P. In self-defense. Nat Struct Mol Biol 2011;18:401–402.
40. Lauer N, Mihlan M, Hartmann A, Schlötzer-Schrehardt U, Keilhauer C, Scholl HP, et al. Complement regulation at necrotic cell lesions is impaired by the age-related macular degeneration-associated factor-H His402 risk variant. J Immunol 2011;187:4374–4383.
41. Schmidt BZ, Fowler NL, Hidvegi T, Perlmutter DH, Colten HR. Disruption of disulfide bond is responsible for impaired secretion in human complement factor H deficiency. J Biol Chem 1999;274:11782–11788.
42. Schmidt CQ, Slingsby FC, Richards A, Barlow PN. Production of biologically active complement factor H in therapeutically useful quantities. Protein Expr Purif 2011;76:254–263.
43. Rougier N, Kazatchkine MD, Rougier JP, Fremeaux-Bacchi V, Blouin J, Deschenes G, et al. Human complement factor H deficiency associated with hemolytic uremic syndrome. J Am Soc Nephrol 1998;9:2318–2326.
44. Manuelian T, Hellwage J, Meri S, Caprioli J, Noris M, Heinen S, et al. Mutations in factor H reduce binding affinity to C3b and heparin and surface attachment to endothelial cells in hemolytic uremic syndrome. J Clin Invest 2003;111:1181–1190.
45. Pérez-Caballero D, González-Rubio C, Gallardo ME, Vera M, López-Trascasa M, Rodríguez de Córdoba S, et al. Clustering of missense mutations in the C-terminal region of factor H in atypical hemolytic uremic syndrome. Am J Hum Genet 2001;68:478–484.
46. Venables JP, Strain L, Routledge D, Bourn D, Powell HM, Warwicker P, et al. Atypical haemolytic uremic syndrome associated with a hybrid complement gene. PLoS Med 2006;3:e431.
47. Malik TH, Lavin PJ, Goicoechea de Jorge E, Vernon KA, Rose KL, Patel MP, et al. A hybrid CFHR3-1 gene causes familial C3 glomerulopathy. J Am Soc Nephrol 2012;23:1155–1160.
48. Mihlan M, Hebecker M, Dahse HM, Hälbich S, Huber-Lang M, Dahse R, et al. Human complement factor H-related protein 4 binds and recruits native pentameric C-reactive protein to necrotic cells. Mol Immunol 2009;46:335–344.
49. Hebecker M, Józsi M. Factor H-related protein 4 activates complement by serving as a platform for the assembly of alternative pathway C3 convertase via its interaction with C3b protein. J Biol Chem 2012;287:19528–19536.
50. Zhao J, Wu H, Khosravi M, Cui H, Qian X, Kelly JA, et al. Association of genetic variants in complement factor H and factor H-related genes with systemic lupus erythematosus susceptibility. PLoS Genet 2011;7:e1002079.
51. Liszewski MK, Atkinson JP. Complement regulator CD46: genetic variants and disease associations. Hum Genomics 2015;9:7.
52. Lee HK, Na HK, Lee JY, Chang JW, Yang WS, Kim SB, et al. A case of familial atypical hemolytic uremic syndrome associated with complement factor H mutation in adults. Korean J Nephrol 2009;28:259–264.
53. Caprioli J, Noris M, Brioschi S, Pianetti G, Castelletti F, Bettinaglio P, et al. Genetics of HUS: the implact of MCP, CFH, and IF mutations on clinical presentation, response to treatment, and outcome. Blood 2006;108:1267–1279.
54. Richards A, Kemp EJ, Liszewski MK, Goodship JA, Lampe AK, Decorte R, et al. Mutations in human complement regulator, membrane cofactor protein (CD46), predispose to development of familial hemolytic uremic syndrome. Proc Natl Acad Sci U S A 2003;100:12966–12971.
55. Heckmann JM, Uwimpuhwe H, Ballo R, Kaur M, Bajic VB, Prince S. A functional SNP in the regulatory region of the decay-accelerating factor gene associates with extraocular muscle pareses in myasthenia gravis. Genes Immun 2010;11:1–10.
56. Nevo Y, Ben-Zeev B, Tabib A, Straussberg R, Anikster Y, Shorer Z, et al. CD59 deficiency is associated with chronic hemolysis and childhood relapsing immune-mediated polyneuropathy. Blood 2013;121:129–135.
57. Jackson DG. Immunological functions of hyaluronan and its receptors in the lymphatics. Immunol Rev 2009;230:216–231.
58. Zhang H, Zhou G, Zhi L, Yang H, Zhai Y, Dong X, et al. Association between mannose-binding lectin gene polymorphisms and susceptibility to severe acute respiratory syndrome coronavirus infection. J Infect Dis 2005:1355–1361.
59. Pradhan V, Surve P, Rajadhyaksha A, Rajendran V, Patwardhan M, Umare V, et al. Mannose binding lectin (MBL) 2 gene polymorphism & its association with clinical manifestations in systemic lupus erythematosus (SLE) patients from western India. Indian J Med Res 2015;141:199–204.
60. Lee YH, Witte T, Momot T, Schmidt RE, Kaufman KM, Harley JB, et al. The mannose-binding lectin gene polymorphisms and systemic lupus erythematosus: two case-control studies and a meta-analysis. Arthritis and Rheumatism 2005;52:3966–3974.
61. Kaur S, Gupta VK, Shah A, Thiel S, Sarma PU, Madan T. Elevated levels of mannan-binding lectin [corrected] (MBL) and eosinophilia in patients of bronchial asthma with allergic rhinitis and allergic bronchopulmonary aspergillosis associate with a novel intronic polymorphism in MBL. Clin Exp Immunol 2006;143:414–419.
62. Zhao L, Zhang Z, Lin J, Cao L, He B, Han S, et al. Complement receptor 1 genetic variants contribute to the susceptibility to gastric cancer in Chinese population. J Cancer 2015;6:525–530.
63. Lambert JC, Heath S, Even G, Campion D, Sleegers K, Hiltunen M, et al. Genome-wide association study identifies variants at CLU and CR1 associated with Alzheimer's disease. Nat Genet 2009;41:1094–1099.
64. Rezzonico R, Imbert V, Chicheportiche R, Dayer JM. Ligation of CD11b and CD11c beta(2) integrins by antibodies or soluble CD23 induces macrophage inflammatory protein 1alpha (MIP-1alpha) and MIP-1beta production in primary human monocytes through a pathway dependent on nuclear factor-kappaB. Blood 2001;97:2932–2940.
65. Park SR, Park KS, Park YJ, Band D, Lee ES. CD11a, CD11c, and CD18 gene polymorphisms and susceptibility to Behcet's disease in Koreans. Tissue Antigens 2014;84:398–404.
66. Degn SE, Hansen AG, Steffensen R, Jacobsen C, Jensenius JC, Thiel S. MAp44, a human protein associated with pattern recognition molecules of the complement system and regulating the lectin pathway of complement activation. J Immunol 2009;183:7371–7378.
67. Endo Y, Matsushita M, Fujita T. The role of ficolins in the lectin pathway of innate immunity. Int J Biochem Cell Biol 2011;43:705–712.
68. Riley LB, Anderson DW. Cancer epigenetics. In: Tollefsbol T, editor. Handbook of Epigenetics. Amsterdam: Boston: Elsevier/Academic Press; 2011. pp. 521-534.
69. Liu X, Chi X, Gong Q, Gao L, Niu Y, Chi X, et al. Association of serum level of growth differentiation factor 15 with liver cirrhosis and hepatocellular carcinoma. PLoS One 2015;10:e0127518.
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