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

Abstract

Genetic association study; Quantitative trait; Systemic sclerosis

Estudi d'associació genètica; Tret quantitatiu; Esclerosi sistèmica

Estudio de asociación genética; Rasgo cuantitativo; Esclerosis sistémica

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.

This work was supported by grant RTI2018101332-B-100 funded by MCIN/AEI/10.13039/501100011033 by “ERDF A way of making Europe”, Red de Investigación en Inflamación y Enfermedades Reumáticas (RIER) from Instituto de Salud Carlos III (RD16/0012/0013). This work has received funding from the Innovative Medicines Initiative 1 & 2 Joint Undertaking (JU) under grant agreements No 115565 (PRECISESADS) and No 831434 (3TR). The JU receives support from the European Union’s FP7 and Horizon 2020 research and innovation programs and EFPIA. MAH was supported by the Juan de la Cierva Incorporacion program, grant IJC2018-035131-I funded by MCIN/AEI/10.13039/501100011033. This work is dedicated to the memory of Annette Kerick (1945-2020).