Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects

PLoS Genet. 2012 Sep;8(9):e1002916. doi: 10.1371/journal.pgen.1002916. Epub 2012 Sep 13.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Complement C3 / genetics*
  • Complement C3 / metabolism
  • Complement C4 / genetics*
  • Complement C4 / metabolism
  • Genes, MHC Class II
  • Genome-Wide Association Study
  • HLA-A Antigens / genetics
  • HLA-B Antigens / genetics
  • HLA-C Antigens / genetics
  • HLA-DQ beta-Chains / genetics
  • HLA-DR alpha-Chains / genetics
  • Hepatitis B Surface Antigens / genetics
  • Hepatitis B Surface Antigens / metabolism
  • Humans
  • Male
  • Middle Aged
  • Polymorphism, Single Nucleotide / genetics
  • Serum / metabolism*

Substances

  • Complement C3
  • Complement C4
  • HLA-A Antigens
  • HLA-B Antigens
  • HLA-C Antigens
  • HLA-DQ beta-Chains
  • HLA-DQbeta antigen
  • HLA-DR alpha-Chains
  • Hepatitis B Surface Antigens

Grant support

This study was partially supported by grants from the National Natural Science Foundation of China (81060234, 30945204, 30360124, 30260110), Key Program and University Talents Highland Innovation Team of Guangxi (2012012D003, GJR201147-09), Chairman Science and Technology Fund and Tackle Program of Guangxi (1116-03, GKG1298003-07-01), Guangxi Science Fund for Distinguished Young Scholars (2012GXNSFFA060009), Guangxi Provincial Department of Finance and Education (2009GJCJ150), intramural funding from Fudan-VARI Center for Genetic Epidemiology, and intramural funding from Fudan University Institute of Urology. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.