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Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis

Kerick, M. ; Hesselstrand, R. LU and Martin, Javier (2022) In npj Genomic Medicine 7(1).
Abstract
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4... (More)
Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals. © 2022, The Author(s). (Less)
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keywords
complement component C4a, complement component C4b, HLA DPB1 antigen, HLA DRB1 antigen, adult, allele, Article, cohort analysis, controlled study, copy number variation, disease predisposition, female, gene expression, gene locus, genetic association, haplotype, human, human tissue, major clinical study, major histocompatibility complex, male, parity, protein expression, quantitative trait, RNA sequencing, sex difference, systemic sclerosis
in
npj Genomic Medicine
volume
7
issue
1
article number
57
publisher
Nature Publishing Group
external identifiers
  • scopus:85139419835
  • pmid:36198672
ISSN
2056-7944
DOI
10.1038/s41525-022-00327-8
language
English
LU publication?
yes
id
b683dfac-9214-4d0d-ac05-5c00e55e3402
date added to LUP
2022-12-20 10:18:14
date last changed
2022-12-22 03:00:20
@article{b683dfac-9214-4d0d-ac05-5c00e55e3402,
  abstract     = {{Copy number (CN) polymorphisms of complement C4 play distinct roles in many conditions, including immune-mediated diseases. We investigated the association of C4 CN with systemic sclerosis (SSc) risk. Imputed total C4, C4A, C4B, and HERV-K CN were analyzed in 26,633 individuals and validated in an independent cohort. Our results showed that higher C4 CN confers protection to SSc, and deviations from CN parity of C4A and C4B augmented risk. The protection contributed per copy of C4A and C4B differed by sex. Stronger protection was afforded by C4A in men and by C4B in women. C4 CN correlated well with its gene expression and serum protein levels, and less C4 was detected for both in SSc patients. Conditioned analysis suggests that C4 genetics strongly contributes to the SSc association within the major histocompatibility complex locus and highlights classical alleles and amino acid variants of HLA-DRB1 and HLA-DPB1 as C4-independent signals. © 2022, The Author(s).}},
  author       = {{Kerick, M. and Hesselstrand, R. and Martin, Javier}},
  issn         = {{2056-7944}},
  keywords     = {{complement component C4a; complement component C4b; HLA DPB1 antigen; HLA DRB1 antigen; adult; allele; Article; cohort analysis; controlled study; copy number variation; disease predisposition; female; gene expression; gene locus; genetic association; haplotype; human; human tissue; major clinical study; major histocompatibility complex; male; parity; protein expression; quantitative trait; RNA sequencing; sex difference; systemic sclerosis}},
  language     = {{eng}},
  number       = {{1}},
  publisher    = {{Nature Publishing Group}},
  series       = {{npj Genomic Medicine}},
  title        = {{Complement component C4 structural variation and quantitative traits contribute to sex-biased vulnerability in systemic sclerosis}},
  url          = {{http://dx.doi.org/10.1038/s41525-022-00327-8}},
  doi          = {{10.1038/s41525-022-00327-8}},
  volume       = {{7}},
  year         = {{2022}},
}