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Genetic polymorphism in C3 is associated with progression in chronic kidney disease (CKD) patients with IgA nephropathy but not in other causes of CKD

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  • Sara T Ibrahim
  • Rajkumar Chinnadurai
  • Ibrahim Ali
  • Debbie Payne
  • Gillian I Rice
  • William G Newman
  • Eman Algohary
  • Ahmed G Adam
  • Philip A Kalra

Abstract

Objectives: The R102G variant in complement 3 (C3) results in two allotypic variants: C3 fast (C3F) and C3 slow (C3S). C3F presents at increased frequency in patients with chronic kidney disease (CKD), our aim is to explore its role in CKD progression and mortality. Methods: Delta (Δ) eGFR for 2038 patients in the Salford Kidney Study (SKS) was calculated by linear regression; those with ≤-3ml/min/1.73m2/yr were defined as rapid progressors (RP) and those with ΔeGFR between -0.5 and +1ml/min/1.73m2/yr, labelled stable CKD patients (SP).A group of 454 volunteers was used as a control group. In addition, all biopsy-proven glomerulonephritis (GN) patients were studied regardless of their ΔeGFR. R102G was analysed by real-time PCR, and genotypic and allelic frequencies were compared between RP and SP along with the healthy control group. Results: There were 255 SP and 259 RP in the final cohort. Median ΔeGFR was 0.07 vs. -4.7 ml/min/1.73m2/yr in SP vs. RP. C3F allele frequency was found to be significantly higher in our CKD cohort (25.7%) compared with the healthy control group (20.6%); p = 0.008.However, there was no significant difference in C3F allele frequency between the RP and SP groups. In a subgroup analysis of 37 patients with IgA nephropathy in the CKD cohort (21 RP and 16 SP), there was a significantly higher frequency of C3F in RP 40.5% vs. 9.4% in SP; p = 0.003. In the GN group, Cox regression showed an association between C3F and progression only in those with IgA nephropathy (n = 114);HR = 1.9 (95% CI 1.1–3.1; p = 0.018) for individuals heterozygous for the C3F variant, increased further for individuals homozygous for the variant, HR = 2.8 (95% CI 1.2–6.2; p = 0.014). Conclusion: The C3 variant R102G is associated with progression of CKD in patients with IgA nephropathy.

Suggested Citation

  • Sara T Ibrahim & Rajkumar Chinnadurai & Ibrahim Ali & Debbie Payne & Gillian I Rice & William G Newman & Eman Algohary & Ahmed G Adam & Philip A Kalra, 2020. "Genetic polymorphism in C3 is associated with progression in chronic kidney disease (CKD) patients with IgA nephropathy but not in other causes of CKD," PLOS ONE, Public Library of Science, vol. 15(1), pages 1-16, January.
    • Handle: RePEc:plo:pone00:0228101
    DOI: 10.1371/journal.pone.0228101
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    1. Cristian Pattaro & Anna Köttgen & Alexander Teumer & Maija Garnaas & Carsten A Böger & Christian Fuchsberger & Matthias Olden & Ming-Huei Chen & Adrienne Tin & Daniel Taliun & Man Li & Xiaoyi Gao & Ma, 2012. "Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function," PLOS Genetics, Public Library of Science, vol. 8(3), pages 1-15, March.
    2. Bert J. C. Janssen & Agni Christodoulidou & Andrew McCarthy & John D. Lambris & Piet Gros, 2006. "Structure of C3b reveals conformational changes that underlie complement activity," Nature, Nature, vol. 444(7116), pages 213-216, November.
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