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.
Highlights
The complement has been recognized as one pivotal part of innate and adaptive immune system, and it had three well-known physiologic activities, including host defense against infection, bridging interface between innate and adaptive immunity, and disposal of waste immune complexes or apoptotic cells [1,2].There are approximately 30 serum complement proteins, which can be activated by classical, alternative, and lectin pathways [3]
C3 and C4 participate in almost all physiological activities and activated pathways as key complement members and host defense proteins
We performed a two-stage genome-wide association study (GWAS) in a large cohort from the Chinese male population to examine the roles of common genetic variants on serum C3 and C4 levels
Summary
The complement has been recognized as one pivotal part of innate and adaptive immune system, and it had three well-known physiologic activities, including host defense against infection, bridging interface between innate and adaptive immunity, and disposal of waste immune complexes or apoptotic cells [1,2]. There are approximately 30 serum complement proteins, which can be activated by classical, alternative, and lectin pathways [3] Among these complement members, C3 and C4 are almost involved in all physiological activities and activated pathways, and exert their powerful roles as host defense proteins [4]. C3 and C4 are almost involved in all physiological activities and activated pathways, and exert their powerful roles as host defense proteins [4] Their abnormal expression, especially, complement deficiency and dysfunction, is associated with the pathogenesis of numerous
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