RT Journal Article
SR Electronic
T1 Analysis of anti-RNA polymerase III antibody positive systemic sclerosis suggests altered GPATCH2L and CTNND2 expression in scleroderma renal crisis
JF The Journal of Rheumatology
JO J Rheumatol
FD The Journal of Rheumatology
SP jrheum.190945
DO 10.3899/jrheum.190945
A1 Edward P.  Stern
A1 Sandra G.  Guerra
A1 Harry Chinque
A1 Vanessa Acquaah
A1 David González-Serna
A1 Markella Ponticos
A1 Javier Martin
A1 Voon H.  Ong
A1 Korsa Khan
A1 Svetlana I.  Nihtyanova
A1 Mark Harber
A1 Aine Burns
A1 Maureen D  Mayes
A1 Shervin Assassi
A1 Carmen Fonseca
A1 Christopher P.  Denton
YR 2020
UL http://www.jrheum.org/content/early/2020/03/09/jrheum.190945.abstract
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 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