Genome-wide association study for serum complement C3 and C4 levels in healthy Chinese subjects
Xiaobo Yang1, Jielin Sun, Yong Gao
1Department of Occupational Health and Environmental Health, School of Public Health, Guangxi Medical University, Nanning, Guangxi, China.
Insights
This genome-wide association study identified genetic factors influencing complement C3 and C4 levels. These findings offer new insights into autoimmune and infectious diseases linked to complement system variations.
Area of Science:
- Immunology
- Genetics
- Human Physiology
Background:
- Complement C3 and C4 are crucial for immune responses.
- Deficiencies or over-expression of C3 and C4 are linked to various infectious and autoimmune diseases.
- Understanding the genetic basis of C3 and C4 levels is essential for disease research.
Purpose of the Study:
- To identify genetic variants associated with serum levels of complement C3 and C4 using a two-stage genome-wide association study (GWAS).
- To explore the relationship between genetic factors and complement protein concentrations in a Chinese population.
Main Methods:
- A two-stage GWAS involving 1,999 and 1,496 healthy Chinese subjects.
- Statistical analysis to identify single nucleotide polymorphisms (SNPs) significantly associated with C3 and C4 serum levels.
- Comparison of C3 and C4 levels between HBsAg-positive and HBsAg-negative individuals.
Main Results:
- Identified two SNPs (rs3753394 in CFH and rs3745567 in C3) significantly associated with serum C3 levels.
- Located eight SNPs on chromosome 6p21.3, including regions within and near the C4 gene and MHC class I and II areas, associated with serum C4 levels.
- Observed significantly lower C3 and C4 protein concentrations in HBsAg-positive subjects compared to HBsAg-negative subjects.
Conclusions:
- This study is the first GWAS to demonstrate the influence of genetic components on complement C3 and C4 levels.
- The findings provide novel insights into the genetic architecture of complement C3 and C4.
- The results contribute to understanding the molecular mechanisms underlying autoimmune and infectious diseases related to the complement system.
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.
