Stern, EP;
Guerra, SG;
Chinque, H;
Acquaah, V;
González-Serna, D;
Ponticos, M;
Martin, J;
... Denton, CP; + view all
(2020)
Analysis of anti-RNA polymerase III antibody positive systemic sclerosis suggests altered GPATCH2L and CTNND2 expression in scleroderma renal crisis.
The Journal of Rheumatology
, 47
(3)
, Article 190945. 10.3899/jrheum.190945.
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Abstract
OBJECTIVE: Scleroderma renal crisis (SRC) is a life-threatening complication of systemic sclerosis (SSc) strongly associated with anti RNA polymerase III antibody (ARA) autoantibodies. We explore genetic susceptibility and altered protein expression in renal biopsy specimens in ARA positive SRC. METHODS: ARA-positive patients (n=99) with at least 5 years' follow-up (49% with a history of SRC) were selected from a well-characterised SSc cohort (n=2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, nine SNPs were chosen for validation in a separate cohort of 256 ARA+ patients (40 with SRC). Immunostaining of tissue sections from SRC or control kidney was used to quantify expression of candidate proteins based upon genetic analysis of the discovery cohort. RESULTS: Analysis of 641,489 SNPs suggested association of POU2F1 (rs2093658; 1.98x10-5), CTNND2 (rs1859082; p=7.14 x 10-5), HECW2 (rs16849716; p=1.2 x 10-4) and GPATCH2L (rs935332; p=4.92 x 10-5) with SRC. Furthermore, the validation cohort showed an association between rs935332 within the GPATCH2L region, with SRC (p=0.025). Immunostaining of renal biopsy sections showed increased tubular expression of GPATCH2L (p=0.026), and glomerular expression of CTNND2 (p=0.026) in SRC samples (n=8) compared with normal human kidney controls (n=8), despite absence of any genetic replication for the associated SNP. CONCLUSION: Increased expression of two candidate proteins GPATCH2L and CTNND2 in SRC compared with control kidney suggests a potential role in pathogenesis of SRC. For GPATCH2L this may reflect genetic susceptibility in ARA positive SSc based upon 2 independent cohorts.
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