A regulatory variant in the C1Q gene cluster is associated with tuberculosis susceptibility and C1qA plasma levels in a South African population

Abstract

Several genetic studies have implicated genes that encode for components of the innate immune response in tuberculosis (TB) susceptibility. The complement system is an early player in the innate immune response and provides the host with initial protection by promoting phagocytosis of apoptotic or necrotic cells. The C1q molecule is the first component of the classical pathway that leads to the activation of complement by binding to immune complexes and is encoded by the C1Q gene cluster. We investigated variants in this region to determine its association with TB susceptibility. Five single nucleotide polymorphisms (SNPs) (rs12033074, rs631090, rs172378, rs587585, and rs665691) were genotyped using TaqMan® SNP assays in 456 TB cases and 448 healthy controls and analysed by logistic regression models. The rs587585 variant showed a significant additive allelic association where the minor G allele was found more frequently in TB cases than in controls in both the discovery (p = 0.023; OR = 1.30; 95% CI, 1.04–1.64) and validation cohort (p = 0.038; OR = 1.31; 95% CI, 1.22–1.40). In addition, we detected increased C1qA expression when comparing cases and controls (p = 0.037) and linked this to a dosage effect of the G allele, which increased C1qA expression in TB cases. This is the first study to report the association of C1Q gene polymorphisms with progression to tuberculosis.

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Data availability

The summary statistics from the case-control cohort will be made available to researchers on request, while access to the raw data will only be available to researchers who meet the criteria for access to confidential data after application to the Health Research Ethics Committee of Stellenbosch University. Requests can be sent to Prof. Marlo Möller, E-mail: marlom@sun.ac.za.

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Acknowledgement

We thank the study participants.

Funding

This research was partially funded by the South African government through the South African Medical Research Council. The content is solely the responsibility of the authors and does not necessarily represent the official views of the South African Medical Research Council. This work was also supported by the National Research Foundation of South Africa.

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Correspondence to Marlo Möller or Nicolaas C. Gey van Pittius.

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All protocols were approved by the Health Research Ethics Committee of the Faculty of Medicine and Health Sciences, Stellenbosch University, before participant recruitment, and written informed consent was obtained from all study participants prior to blood collection (project numbers 95/072 and S17/01/013).

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Bruiners, N., Schurz, H., Daya, M. et al. A regulatory variant in the C1Q gene cluster is associated with tuberculosis susceptibility and C1qA plasma levels in a South African population. Immunogenetics 72, 305–314 (2020). https://doi.org/10.1007/s00251-020-01167-5

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Keywords

  • Tuberculosis
  • Susceptibility
  • C1q
  • Association
  • Dosage