Genome-Wide Association Study for Serum Complement C3 and C4 Levels in Healthy Chinese Subjects

Yang, Xiaobo; Sun, Jielin; Gao, Yong; Tan, Aihua; Zhang, Haiying; Hu, Yanling; Feng, Junjie; Qin, Xue; Tao, Sha; Chen, Zhuo; Kim, Seong-Tae; Peng, Tao; Liao, Ming; Lin, Xiaoling; Zhang, Zengfeng; Tang, Minzhong; Li, Li; Mo, Linjian; Liang, Zhengjia; Shi, Deyi; Zhang, Huang; Huang, Xianghua; Liu, Ming; Liu, Qian; Zhang, Shijun; Trent, Jeffrey M.; Zheng, S. Lilly; Xu, Jianfeng; Mo, Zengnan

doi:10.1371/journal.pgen.1002916

Cited by 51 publications

(52 citation statements)

References 24 publications

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“…In accordance with our findings, Yang et al 34 reported that rs3753394 in CFH was associated with circulating C3 levels. Because rs3753394 and rs6677604 are in LD, the study by Yang et al 34 provides independent validation for our findings. Meanwhile, by showing that plasma CFH was positively correlated with circulating C3 levels and negatively correlated with mesangial C3 deposition, our results suggest that rs6677604 regulated systemic complement activation and the subsequent mesangial C3 deposition in IgAN through its influence on CFH.…”

Section: Discussionsupporting

confidence: 93%

“…33 Therefore, higher CFH levels, together with the absence of antagonist (CFHR1 protein), resulted in the robust complement inhibition, which is represented by the higher circulating C3 and lower C3a that we observed in patients with IgAN with the rs6677604-AA genotype and CFHR3-1D. In accordance with our findings, Yang et al 34 reported that rs3753394 in CFH was associated with circulating C3 levels. Because rs3753394 and rs6677604 are in LD, the study by Yang et al 34 provides independent validation for our findings.…”

Section: Discussionsupporting

confidence: 90%

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Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

125

105

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Complement activation is common in patients with IgA nephropathy (IgAN) and associated with disease severity. Our recent genome-wide association study of IgAN identified susceptibility loci on 1q32 containing the complement regulatory protein-encoding genes CFH and CFHR1-5, with rs6677604 in CFH as the top single-nucleotide polymorphism and CFHR3-1 deletion (CFHR3-1Δ) as the top signal for copy number variation. In this study, to explore the clinical effects of variation in CFH, CFHR3, and CFHR1 on IgAN susceptibility and progression, we enrolled two populations. Group 1 included 1178 subjects with IgAN and available genome-wide association study data. Group 2 included 365 subjects with IgAN and available clinical follow-up data. In group 1, rs6677604 was associated with mesangial C3 deposition by genotype-phenotype correlation analysis. In group 2, we detected a linkage between the rs6677604-A allele and CFHR3-1Δ and found that the rs6677604-A allele was associated with higher serum levels of CFH and lower levels of the complement activation split product C3a. Furthermore, CFH levels were positively associated with circulating C3 levels and negatively associated with mesangial C3 deposition. Moreover, serum levels of the pathogenic galactose-deficient glycoform of IgA1 were also associated with the degree of mesangial C3 deposition in patients with IgAN. Our findings suggest that genetic variants in CFH, CFHR3, and CFHR1 affect complement activation and thereby, predispose patients to develop IgAN.

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Section: Discussionsupporting

confidence: 93%

Section: Discussionsupporting

confidence: 90%

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Zhu

Zhai

Wang

et al. 2015

Journal of the American Society of Nephrology

125

105

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“…For example, we replicated an association between rs2187668 and coeliac disease ( p=1.9E-08, FDR=0.0072). 32 33 Rs3131296 and rs2071278, previously shown to be associated with schizophrenia 34 and levels of complement factors C3 and C4, 35 respectively, and in partial linkage disequilibrium (LD) with rs2187668 in the PMRP sample (r 2 =0.53 and 0.45, respectively), were also associated with coeliac disease. Similar scenarios of multiple SNPs in LD sharing common associations were observed for other phenotypes (table 1).…”

Section: Phewas For 'Gwas Significant' Snpsmentioning

confidence: 94%

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Liu

Mayer

et al. 2016

J Med Genet

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Background Over 160 disease phenotypes have been mapped to the major histocompatibility complex (MHC) region on chromosome 6 by genome-wide association study (GWAS), suggesting that the MHC region as a whole may be involved in the etiology of many phenotypes, including unstudied diseases. The phenome-wide association study (PheWAS), a powerful and complementary approach to GWAS, has demonstrated its ability to discover and rediscover genetic associations. The objective of this study is to comprehensively investigate the MHC region by PheWAS to identify new phenotypes mapped to this genetically important region. Methods In the current study, we systematically explored the MHC region using PheWAS to associate 2692 MHC-linked variants (minor allele frequency ≥ 0.01) with 6221 phenotypes in a cohort of 7481 subjects from the Marshfield Clinic Personalized Medicine Research Project. Results Findings showed that expected associations previously identified by GWAS could be identified by PheWAS (e.g. psoriasis, ankylosing spondylitis, type I diabetes, and celiac disease) with some having strong cross-phenotype associations potentially driven by pleiotropic effects. Importantly, novel associations with 8 diseases not previously assessed by GWAS (e.g., lichen planus) were also identified and replicated in an independent population. Many of these associated diseases appear to be immune-related disorders. Further assessment of these diseases in 16,484 Marshfield Clinic twins suggests that some of these diseases, including lichen planus, may have genetic etiologies. Conclusions These results demonstrate that the PheWAS approach is a powerful and novel method to discover SNP-disease associations, and is ideal when characterizing cross-phenotype associations, and further emphasizes the importance of the MHC region in human health and disease.

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“…The FAMHES is described elsewhere [17]. Briefly, it was designed to investigate the effects of environmental and genetic factors.…”

Section: Methodsmentioning

confidence: 99%

Genome-Wide Association Study Identifies Variants in PMS1 Associated with Serum Ferritin in a Chinese Population

et al. 2014

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Only a small proportion of genetic variation in serum ferritin has been explained by variant genetic studies, and genome-wide association study (GWAS) for serum ferritin has not been investigated widely in Chinese population. We aimed at exploring the novel genetic susceptibility to serum ferritin, and performed this two stage GWAS in a healthy Chinese population of 3,495 men aged 20–69 y, including 1,999 unrelated subjects in the first stage and 1,496 independent individuals in the second stage. Serum ferritin was measured with electrochemiluminescence immunoassay, and DNA samples were collected for genotyping. A total of 1,940,243 SNPs were tested by using multivariate linear regression analysis. After adjusting for population stratification, age and BMI, the rs5742933 located in the 5′UTR region of PMS1 gene on chromosome 2 was the most significantly associated with ferritin concentrations (P-combined = 2.329×10−10) (β = −0.11, 95% CI: −0.14, −0.07). Moreover, this marker was about 200kb away from the candidate gene SLC40A1 which is responsible for iron export. PMS1 gene was the novel genetic susceptibility to serum ferritin in Chinese males and its relation to SLC40A1 needs further study.

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Genome-Wide Association Study for Serum Complement C3 and C4 Levels in Healthy Chinese Subjects

Cited by 51 publications

References 24 publications

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Variants in Complement Factor H and Complement Factor H-Related Protein Genes, CFHR3 and CFHR1, Affect Complement Activation in IgA Nephropathy

Phenome-wide association study maps new diseases to the human major histocompatibility complex region

Genome-Wide Association Study Identifies Variants in PMS1 Associated with Serum Ferritin in a Chinese Population

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