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Abstract Number: 1957

Aggregation of Functional Variants in NOTCH4 Gene Increases SSc Risk

Pravitt Gourh1, Sarah Safran 2, Theresa Alexander 3, Steven Boyden 4, Ami Shah 5, Maureen Mayes 6, Ayo Doumatey 7, Amy Bentley 7, Daniel Shriner 7, Robyn Domsic 8, Thomas Medsger Jr 9, Paula Ramos 10, Richard Silver 11, Virginia Steen 12, John Varga 13, Vivien Hsu 14, Lesley Saketkoo 15, Elena Schiopu 16, Dinesh Khanna 17, Jessica Gordon 18, Brynn Kron 19, Lindsey Criswell 20, Heather Gladue 21, Chris Derk 22, Elana Bernstein 23, S Louis Bridges 24, Victoria Shanmugam 25, Kathleen Kolstad 26, Lorinda Chung 27, Suzanne Kafaja 28, Reem Jan 29, Marcin Trojanowski 30, Avram Goldberg 31, Benjamin Korman 32, Peter Steinbach 33, Settara Chandrasekharappa 7, James Mullikin 7, Adebowale Adeyemo 7, Charles Rotimi 7, Frederick Wigley 34, Daniel Kastner 35, Francesco Boin 36 and Elaine Remmers 7, 1National Institutes of Rheumatology, Bethesda, 2National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), Bethesda, MD, 3University of Maryland, College Park, MD, 4University of Utah, SALT LAKE CITY, UT, 5Johns Hopkins Hospital, Baltimore, MD, 6Division of Rheumatology and Clinical Immunogenetics, University of Texas McGovern Medical School, Houston, Texas, USA, Houston, TX, 7National Human Genome Research Institute (NHGRI), Bethesda, MD, 8University of Pittsburgh, Pittsburgh, PA, 9University of Pittsburg School of Medicine, Pittsburg, PA, 10Medical University of South Carolina, Charleston, 11Division of Rheumatology, Medical University of South Carolina, Charleston, SC, 12Georgetown University, Washington, D.C., USA, Georgetown, 13Northwestern University, Chicago,, IL, 14Rutgers- RWJ Medical School, SOUTH PLAINFIELD, NJ, 15New Orleans Scleroderma and Sarcoidosis Patient Care and Research Center, New Orleans; Tulane University School of Medicine, University Medical Center – Comprehensive Pulmonary Hypertension Center, USA, New Orleans, 16Department of Rheumatology, University of Michigan, Ann Arbor, 17Department of Medicine, University of Michigan, Ann Arbor, Michigan, USA, Ann Arbor, 18Hospital for Special Surgery, New York, NY, 19University of California San Francisco, San Francisco, CA, 20University of California, San Francisco, San Francisco, 21Arthritis & Osteoporosis Consultants Of The Carolinas, Charlotte, NC, 22University of Pennsylvania, Philadelphia, PA, 23Division of Rheumatology, Columbia University, New York, NY, 24University of Alabama at Birmingham, Birmingham, 25George Washington University, Georgetown, DC, 26Division of Immunology and Rheumatology, Department of Medicine, Stanford University, Stanford, CA, 27Stanford University, Palo Alto, CA, 28Department of Medicine. Rheumatology Division. UCLA, Los Angeles, CA, 29University of Chicago Pritzker School of Medicine, Chicago, IL, 30Boston University Medical Center, Boston, MA, 31New York University Langone Medical Center, New York, NY, 32University of Rochester Medical Center, Rochester, NY, 33Center for Molecular Modeling, Center for Information Technology, National Institutes of Health, Bethesda, MD, 34Johns Hopkins University, Division of Rheumatology, Baltimore, 35National Institutes of Health, Bethesda, MD, 36UCSF, San Francisco, CA

Meeting: 2019 ACR/ARP Annual Meeting

Keywords: NOTCH4 and sequencing, Scleroderma

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Session Information

Date: Tuesday, November 12, 2019

Title: Genetics, Genomics & Proteomics Poster

Session Type: Poster Session (Tuesday)

Session Time: 9:00AM-11:00AM

Background/Purpose: Genetic studies of common variants in scleroderma (systemic sclerosis, SSc) have identified several susceptibility loci increasing SSc risk. Most of these common variants are in the non-coding region and thus have a relatively minor effect size and are not able to fully account for the heritability of SSc. The risk accorded by rare and functional variants is presumed to be higher and could be part of the missing heritability.

Methods: We selected all SSc-associated loci at p-value< 0.00001 from the GWAS catalog, an NHGRI-EBI catalog of published genome-wide association studies and genes identified in candidate gene studies that were independently replicated. 26 genes were selected and sequenced using next generation sequencing technology in 379 SSc patients and 411 unaffected controls of Africa. Variants were selected for testing if they were missense, splice site or InDels and based on CADD score < 15 for synonymous and UTR variants. Association testing was performed using sequence kernel association test (SKAT). Significance threshold for p-value (P) was set at P< 0.002 after Bonferroni’s multiple testing correction.

Results: After multiple testing correction only NOTCH4 (Neurogenic Locus Notch Homolog Protein 4) gene was statistically significantly associated with SSc (P=0.00099, Pcorr=0.03) with an increased burden of functional variants (Table1). We used CMC test to confirm the NOTCH4 association and the P remained significant (CMC P=0.01, 100000 permutations). Majority of the variants were present on the extracellular domain of NOTCH4 (Figure 1). On comparing the phenotypic subsets of SSc, the NOTCH4 association was strongest in the diffuse skin subset (P=0.001) and interstitial lung disease subset of SSc (P=0.0003).

Conclusion: Aggregation of functional variants in genes previously implicated with SSc provides new approaches to understand SSc pathogenesis. Understanding the functional role of these NOTCH4 functional variants will increase our understanding of SSc and SSc-associated interstitial lung disease.


Disclosure: P. Gourh, None; S. Safran, None; T. Alexander, None; S. Boyden, None; A. Shah, Bristol Meyer Squibb, 5, Bristol-Myers Squibb, 5; M. Mayes, Boehringer Ingelheim, 5, 8, 9, Corbus, 9, Corbus Pharma, 9, Eicos, 9, Eicos Sciences, 9, Galapagos, 5, 9, GlaxoSmithKline, 9, Mitsubishi Tanabe Pharma, 5, Mitsubishi-Tanabe, 5, Reata Pharma, 9, Reata Pharmaceuticals, 9, Sanofi, 9; A. Doumatey, None; A. Bentley, None; D. Shriner, None; R. Domsic, Boehringer Ingelheim, 5, Boehringer-Ingelheim, 5, Eicos, 5, EICOS Sciences Inc, 5; T. Medsger Jr, None; P. Ramos, None; R. Silver, None; V. Steen, Boehringer Ingelheim, 5, Corbus, 5, 9, CSL, 5, 9, CSL Behring, 2, 5, DSMB, 5, 9, Galapagos, 5, 9; J. Varga, None; V. Hsu, None; L. Saketkoo, None; E. Schiopu, None; D. Khanna, Acceleron, 5, 8, Acceleron Pharma, 5, Actelion, 5, 8, Actelion Pharmaceuticals, 5, Astra Zeneca, 5, Bayer, 2, 5, 8, Behring, 5, Blade, 5, Blade Therapeutics, 5, 8, Blade therapeutics, 5, BMS, 2, 5, 8, Boehringer Ingelham, 5, Boehringer Ingelheim, 5, 8, Boehringer-Ingelheim, 5, Bristol Myers Squibb, 2, 5, Bristol-Myers Squibb, 2, 5, Celegene, 5, Celgene, 5, 8, ChemomAB, 5, ChemomAb, 5, CiviBioPharma, Inc., 3, Corbus, 5, Corobus, 5, Corpus, 5, CSL Behring, 5, 8, Curizon, 5, Curzion, 5, Cytori, 5, 8, Eicos, 4, Eicos Sciences, 4, Eicos Sciences, Inc, 4, Eicos Sciences, Inc/ CiviBioPharma, Inc, 1, 4, Eicos Sciences, Inc/ CiviBioPharma, Inc., 1, Eicos, Inc, 4, Eicos, Inc., 5, 8, Eicos, INC., 4, Galapagos, 5, Genentech, 5, Genentech/Roche, 5, GlaxoSmithKline, 5, GSK, 5, Horizon, 2, 5, Mitsubishi Tanabe Pharma, 5, Mitsubishi Tanabe Pharma Dev America, 5, Mitsubishi Tanabe Pharma Development America, 5, Mitsubishi Tanabi, 5, NIH K24 and R01, 2, NIH / NIAMS K24 AR-063120, 2, NIH/NIAMS R01& K24, 2, Pfizer, 2, 5, Sanofi, 5, Sanofi Aventis, 5, Sanofi-Aventis, 5, 8, Sanofi-Aventis/Genzyme, 5, UCB, 5, UCB Pharma, 5; J. Gordon, Corbus, 2, Corbus Pharmaceuticals, 2, Cumberland, 2, Cumberland Pharmaceuticals, 2, Elcos, 2; B. Kron, None; L. Criswell, None; H. Gladue, None; C. Derk, None; E. Bernstein, None; S. Bridges, None; V. Shanmugam, AbbVie, 2; K. Kolstad, None; L. Chung, BMS, 6, 9, Boehrenger-Ingelheim, 5, Boehringer Ingelheim, 5, Boehringer-Ingelheim, 5, Bristol-Myers Squib, 5, Eicos, 5, 6, 9, Eicos Steering Committee, 5, Mitsubishi Tanabe, 5, Reata, 5, 6, Reata DSMB, 5, Reatta, 5; S. Kafaja, None; R. Jan, None; M. Trojanowski, None; A. Goldberg, None; B. Korman, None; P. Steinbach, None; S. Chandrasekharappa, None; J. Mullikin, None; A. Adeyemo, None; C. Rotimi, None; F. Wigley, None; D. Kastner, None; F. Boin, None; E. Remmers, None.

To cite this abstract in AMA style:

Gourh P, Safran S, Alexander T, Boyden S, Shah A, Mayes M, Doumatey A, Bentley A, Shriner D, Domsic R, Medsger Jr T, Ramos P, Silver R, Steen V, Varga J, Hsu V, Saketkoo L, Schiopu E, Khanna D, Gordon J, Kron B, Criswell L, Gladue H, Derk C, Bernstein E, Bridges S, Shanmugam V, Kolstad K, Chung L, Kafaja S, Jan R, Trojanowski M, Goldberg A, Korman B, Steinbach P, Chandrasekharappa S, Mullikin J, Adeyemo A, Rotimi C, Wigley F, Kastner D, Boin F, Remmers E. Aggregation of Functional Variants in NOTCH4 Gene Increases SSc Risk [abstract]. Arthritis Rheumatol. 2019; 71 (suppl 10). https://acrabstracts.org/abstract/aggregation-of-functional-variants-in-notch4-gene-increases-ssc-risk/. Accessed .
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