PT  - JOURNAL ARTICLE
AU  - Edward P. Stern
AU  - Sandra G. Guerra
AU  - Harry Chinque
AU  - Vanessa Acquaah
AU  - David González-Serna
AU  - Markella Ponticos
AU  - Javier Martin
AU  - Voon H. Ong
AU  - Korsa Khan
AU  - Svetlana I. Nihtyanova
AU  - Mark Harber
AU  - Aine Burns
AU  - Maureen D. Mayes
AU  - Shervin Assassi
AU  - Carmen Fonseca
AU  - Christopher P. Denton
TI  - Analysis of Anti-RNA Polymerase III Antibody-positive Systemic Sclerosis and Altered GPATCH2L and CTNND2 Expression in Scleroderma Renal Crisis
AID  - 10.3899/jrheum.190945
DP  - 2020 Nov 01
TA  - The Journal of Rheumatology
PG  - 1668--1677
VI  - 47
IP  - 11
4099  - http://www.jrheum.org/content/47/11/1668.short
4100  - http://www.jrheum.org/content/47/11/1668.full
SO  - J Rheumatol2020 Nov 01; 47
AB  - 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 investigated genetic susceptibility and altered protein expression in renal biopsy specimens in ARA-positive patients with 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 characterized SSc cohort (n = 2254). Cases were genotyped using the Illumina Human Omni-express chip. Based on initial regression analysis, 9 single-nucleotide polymorphisms (SNP) were chosen for validation in a separate cohort of 256 ARA-positive 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 SNP suggested association of POU2F1 (rs2093658; P = 1.98 × 10−5), CTNND2 (rs1859082; P = 5.58 × 10−5), HECW2 (rs16849716; P = 1.2 × 10−4), and GPATCH2L (rs935332; P = 4.92 × 10−5) with SRC. Further, 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 2 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 patients with SSc based upon 2 independent cohorts.