Edward P Stern1, Sandra G Guerra2, Harry Chinque2, Vanessa Acquaah2, David González-Serna3, Markella Ponticos2, Javier Martin3, Voon H Ong2, Korsa Khan2, Svetlana I Nihtyanova2, Mark Harber4, Aine Burns4, Maureen D Mayes5, Shervin Assassi5, Carmen Fonseca2, Christopher P Denton6. 1. E.P. Stern, MRCP, University College London (UCL) Centre for Rheumatology and Connective Tissue Diseases, and UCL Centre for Nephrology, London. 2. S.G. Guerra, PhD, H. Chinque, BSc, V. Acquaah, BSc, M. Ponticos, V.H. Ong, PhD, FRCP, K. Khan, BSc, S.I. Nihtyanova, MD, C. Fonseca, MD, C.P. Denton, PhD, FRCP, Professor of Experimental Rheumatology, UCL Centre for Rheumatology and Connective Tissue Diseases, London, UK. 3. D. González-Serna, PhD, J. Martin, MD, Instituto de Parasitologia y Biomedicina Lopez-Neyra, Consejo Superior de Investigaciones Científicas (CSIC), Granada, Spain. 4. M. Harber, FRCP, A. Burns, MD, UCL Centre for Nephrology, London, UK. 5. M.D Mayes, MD, S. Assassi, MD, University of Texas Houston - McGovern Medical School, Houston, Texas, USA. 6. S.G. Guerra, PhD, H. Chinque, BSc, V. Acquaah, BSc, M. Ponticos, V.H. Ong, PhD, FRCP, K. Khan, BSc, S.I. Nihtyanova, MD, C. Fonseca, MD, C.P. Denton, PhD, FRCP, Professor of Experimental Rheumatology, UCL Centre for Rheumatology and Connective Tissue Diseases, London, UK; c.denton@ucl.ac.uk.
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 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.
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.
Authors: Edward P Stern; Lauren V Host; Ivy Wanjiku; K Jane Escott; Peter S Gilmour; Rachel Ochiel; Robert Unwin; Aine Burns; Voon H Ong; Helen Cadiou; Aidan G O'Keeffe; Christopher P Denton Journal: Arthritis Res Ther Date: 2022-06-01 Impact factor: 5.606
Authors: Anca Cardoneanu; Alexandra Maria Burlui; Luana Andreea Macovei; Ioana Bratoiu; Patricia Richter; Elena Rezus Journal: Biomedicines Date: 2022-01-29