Genome-Wide Association Study for Serum Complement C3 and C4 Levels in Healthy Chinese Subjects
Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33×10−11 and P = 1.83×10−9, respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5′ and 3′ of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19×10−22 to 5.62×10−97. HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.
Vyšlo v časopise:
Genome-Wide Association Study for Serum Complement C3 and C4 Levels in Healthy Chinese Subjects. PLoS Genet 8(9): e32767. doi:10.1371/journal.pgen.1002916
Kategorie:
Research Article
prolekare.web.journal.doi_sk:
https://doi.org/10.1371/journal.pgen.1002916
Souhrn
Complement C3 and C4 play key roles in the main physiological activities of complement system, and their deficiencies or over-expression are associated with many clinical infectious or immunity diseases. A two-stage genome-wide association study (GWAS) was performed for serum levels of C3 and C4. The first stage was conducted in 1,999 healthy Chinese men, and the second stage was performed in an additional 1,496 subjects. We identified two SNPs, rs3753394 in CFH gene and rs3745567 in C3 gene, that are significantly associated with serum C3 levels at a genome-wide significance level (P = 7.33×10−11 and P = 1.83×10−9, respectively). For C4, one large genomic region on chromosome 6p21.3 is significantly associated with serum C4 levels. Two SNPs (rs1052693 and rs11575839) were located in the MHC class I area that include HLA-A, HLA-C, and HLA-B genes. Two SNPs (rs2075799 and rs2857009) were located 5′ and 3′ of C4 gene. The other four SNPs, rs2071278, rs3763317, rs9276606, and rs241428, were located in the MHC class II region that includes HLA-DRA, HLA-DRB, and HLA-DQB genes. The combined P-values for those eight SNPs ranged from 3.19×10−22 to 5.62×10−97. HBsAg-positive subjects have significantly lower C3 and C4 protein concentrations compared with HBsAg-negative subjects (P<0.05). Our study is the first GWAS report which shows genetic components influence the levels of complement C3 and C4. Our significant findings provide novel insights of their related autoimmune, infectious diseases, and molecular mechanisms.
Zdroje
1. WalportMJ (2001) Complement. First of two parts. The New England journal of medicine 344: 1058–1066.
2. WalportMJ (2001) Complement. Second of two parts. The New England journal of medicine 344: 1140–1144.
3. GadjevaM, ThielS, JenseniusJC (2001) The mannan-binding-lectin pathway of the innate immune response. Current opinion in immunology 13: 74–78.
4. InoueH, MashimoY, FunamizuM, ShimojoN, HasegawaK, et al. (2008) Association study of the C3 gene with adult and childhood asthma. Journal of human genetics 53: 728–738.
5. UnsworthDJ (2008) Complement deficiency and disease. Journal of clinical pathology 61: 1013–1017.
6. SeppanenM, LokkiML, TimonenT, LappalainenM, JarvaH, et al. (2001) Complement C4 deficiency and HLA homozygosity in patients with frequent intraoral herpes simplex virus type 1 infections. Clinical infectious diseases : an official publication of the Infectious Diseases Society of America 33: 1604–1607.
7. SotoK, WuYL, OrtizA, AparicioSR, YuCY (2010) Familial C4B deficiency and immune complex glomerulonephritis. Clinical immunology 137: 166–175.
8. WuYL, HauptmannG, ViguierM, YuCY (2009) Molecular basis of complete complement C4 deficiency in two North-African families with systemic lupus erythematosus. Genes and immunity 10: 433–445.
9. HunnangkulS, NitschD, RhodesB, ChadhaS, RobertonCA, et al. (2008) Familial clustering of non-nuclear autoantibodies and C3 and C4 complement components in systemic lupus erythematosus. Arthritis and rheumatism 58: 1116–1124.
10. RhodesB, HunnangkulS, MorrisDL, HsaioLC, GrahamDS, et al. (2009) The heritability and genetics of complement C3 expression in UK SLE families. Genes and immunity 10: 525–530.
11. TanA, GaoY, YangX, ZhangH, QinX, et al. (2011) Low serum osteocalcin level is a potential marker for metabolic syndrome: results from a Chinese male population survey. Metabolism 60: 1186–1192.
12. MarchiniJ, HowieB, MyersS, McVeanG, DonnellyP (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nature genetics 39: 906–913.
13. PurcellS, NealeB, Todd-BrownK, ThomasL, FerreiraMA, et al. (2007) PLINK: a tool set for whole-genome association and population-based linkage analyses. American journal of human genetics 81: 559–575.
14. PriceAL, PattersonNJ, PlengeRM, WeinblattME, ShadickNA, et al. (2006) Principal components analysis corrects for stratification in genome-wide association studies. Nat Genet 38: 904–909.
15. PangburnMK (2000) Host recognition and target differentiation by factor H, a regulator of the alternative pathway of complement. Immunopharmacology 49: 149–157.
16. Rodriguez de CordobaS, Esparza-GordilloJ, Goicoechea de JorgeE, Lopez-TrascasaM, Sanchez-CorralP (2004) The human complement factor H: functional roles, genetic variations and disease associations. Molecular immunology 41: 355–367.
17. JozsiM, ZipfelPF (2008) Factor H family proteins and human diseases. Trends Immunol 29: 380–387.
18. NicaAC, PartsL, GlassD, NisbetJ, BarrettA, et al. The architecture of gene regulatory variation across multiple human tissues: the MuTHER study. PLoS Genet 7: e1002003 doi:10.1371/journal.pgen.1002003.
19. MiyagawaH, YamaiM, SakaguchiD, KiyoharaC, TsukamotoH, et al. (2008) Association of polymorphisms in complement component C3 gene with susceptibility to systemic lupus erythematosus. Rheumatology 47: 158–164.
20. YangY, ChungEK, ZhouB, BlanchongCA, YuCY, et al. (2003) Diversity in intrinsic strengths of the human complement system: serum C4 protein concentrations correlate with C4 gene size and polygenic variations, hemolytic activities, and body mass index. J Immunol 171: 2734–2745.
21. SaxenaK, KitzmillerKJ, WuYL, ZhouB, EsackN, et al. (2009) Great genotypic and phenotypic diversities associated with copy-number variations of complement C4 and RP-C4-CYP21-TNX (RCCX) modules: a comparison of Asian-Indian and European American populations. Mol Immunol 46: 1289–1303.
22. de BakkerPI, McVeanG, SabetiPC, MirettiMM, GreenT, et al. (2006) A high-resolution HLA and SNP haplotype map for disease association studies in the extended human MHC. Nat Genet 38: 1166–1172.
23. RaychaudhuriS, SandorC, StahlEA, FreudenbergJ, LeeHS, et al. Five amino acids in three HLA proteins explain most of the association between MHC and seropositive rheumatoid arthritis. Nat Genet 44: 291–296.
Štítky
Genetika Reprodukčná medicínaČlánok vyšiel v časopise
PLOS Genetics
2012 Číslo 9
- Je „freeze-all“ pro všechny? Odborníci na fertilitu diskutovali na virtuálním summitu
- Gynekologové a odborníci na reprodukční medicínu se sejdou na prvním virtuálním summitu
Najčítanejšie v tomto čísle
- Enrichment of HP1a on Drosophila Chromosome 4 Genes Creates an Alternate Chromatin Structure Critical for Regulation in this Heterochromatic Domain
- Normal DNA Methylation Dynamics in DICER1-Deficient Mouse Embryonic Stem Cells
- The NDR Kinase Scaffold HYM1/MO25 Is Essential for MAK2 MAP Kinase Signaling in
- Functional Variants in and Involved in Activation of the NF-κB Pathway Are Associated with Rheumatoid Arthritis in Japanese