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Identification of susceptibility gene associated with female primary Sjögren’s syndrome in Han Chinese by genome-wide association study

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Abstract

Primary Sjögren’s syndrome (PSS) is an autoimmune disease targeting exocrine glands. It ten times more dominantly affects women than men with an onset peak at menopause. The genetic factor predisposing women to PSS remains unclear. Therefore, we aimed to identify susceptibility loci for PSS in women. We performed genome-wide association study (GWAS) using 242 female PSS patients and 1444 female control in Han Chinese population residing in Taiwan. Replication was conducted in an independent cohort of 178 female PSS and 14,432 control subjects. We identified rs117026326 on GTF2I with GWAS significance (P = 1.10 × 10−15) and rs13079920 on RBMS3 with suggestive significance (P = 2.90 × 10−5) associating with PSS in women. The association of RBMS3 was further evidenced by imputation in which rs13072846 (P = 4.89 × 10−5) was identified and confirmed as female PSS associating SNP within the same LD with rs13079920. PSS pathogenesis involves both immune (effector) and exocrine (target) system. We suggested that while GTF2I is a previously reported associating gene which may function in immune system, RBMS3 is a novel susceptibility gene that predisposes women to PSS potentially through modulating acinar apoptosis and TGF-β signaling in target exocrine system.

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References

  • Burbelo PD, Ambatipudi K, Alevizos I (2014) Genome-wide association studies in Sjogren’s syndrome: what do the genes tell us about disease pathogenesis? Autoimmun Rev 13:756–761. doi:10.1016/j.autrev.2014.02.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Callaghan R, Prabu A, Allan RB, Clarke AE, Sutcliffe N, Pierre YS, Gordon C, Bowman SJ, Group UKSsI (2007) Direct healthcare costs and predictors of costs in patients with primary Sjogren’s syndrome. Rheumatology (Oxford) 46:105–111. doi:10.1093/rheumatology/kel155

    Article  CAS  Google Scholar 

  • Chen J, Kwong DL, Zhu CL, Chen LL, Dong SS, Zhang LY, Tian J, Qi CB, Cao TT, Wong AM, Kong KL, Li Y, Liu M, Fu L, Guan XY (2012) RBMS3 at 3p24 inhibits nasopharyngeal carcinoma development via inhibiting cell proliferation, angiogenesis, and inducing apoptosis. PLoS ONE 7:e44636. doi:10.1371/journal.pone.0044636

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen CH, Chen HC, Chang CC, Peng YJ, Lee CH, Shieh YS, Hung YJ, Lin YF (2015) Growth arrest-specific 6 protein in patients with Sjogren syndrome: determination of the plasma level and expression in the labial salivary gland. PLoS ONE 10:e0139955. doi:10.1371/journal.pone.0139955

    Article  PubMed  PubMed Central  Google Scholar 

  • Chisholm DM, Mason DK (1968) Labial salivary gland biopsy in Sjogren’s disease. J Clin Pathol 21:656–660

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Forsblad-d’Elia H, Carlsten H, Labrie F, Konttinen YT, Ohlsson C (2009) Low serum levels of sex steroids are associated with disease characteristics in primary Sjogren’s syndrome; supplementation with dehydroepiandrosterone restores the concentrations. J Clin Endocrinol Metab 94:2044–2051. doi:10.1210/jc.2009-0106

    Article  PubMed  Google Scholar 

  • Fox RI (2005) Sjogren’s syndrome. Lancet 366:321–331. doi:10.1016/S0140-6736(05)66990-5

    Article  CAS  PubMed  Google Scholar 

  • Hartkamp A, Geenen R, Godaert GL, Bootsma H, Kruize AA, Bijlsma JW, Derksen RH (2008) Effect of dehydroepiandrosterone administration on fatigue, well-being, and functioning in women with primary Sjogren syndrome: a randomised controlled trial. Ann Rheum Dis 67:91–97. doi:10.1136/ard.2007.071563

    Article  CAS  PubMed  Google Scholar 

  • Helmick CG, Felson DT, Lawrence RC, Gabriel S, Hirsch R, Kwoh CK, Liang MH, Kremers HM, Mayes MD, Merkel PA, Pillemer SR, Reveille JD, Stone JH, National Arthritis Data W (2008) Estimates of the prevalence of arthritis and other rheumatic conditions in the United States. Part I. Arthritis Rheum 58:15–25. doi:10.1002/art.23177

    Article  PubMed  Google Scholar 

  • Howie BN, Donnelly P, Marchini J (2009) A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS Genet 5:e1000529. doi:10.1371/journal.pgen.1000529

    Article  PubMed  PubMed Central  Google Scholar 

  • Howie B, Marchini J, Stephens M (2011) Genotype imputation with thousands of genomes. G3 (Bethesda) 1:457–470. doi:10.1534/g3.111.001198

    Article  Google Scholar 

  • Howie B, Fuchsberger C, Stephens M, Marchini J, Abecasis GR (2012) Fast and accurate genotype imputation in genome-wide association studies through pre-phasing. Nat Genet 44:955–959. doi:10.1038/ng.2354

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ice JA, Li H, Adrianto I, Lin PC, Kelly JA, Montgomery CG, Lessard CJ, Moser KL (2012) Genetics of Sjogren’s syndrome in the genome-wide association era. J Autoimmun 39:57–63. doi:10.1016/j.jaut.2012.01.008

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishimaru N, Arakaki R, Watanabe M, Kobayashi M, Miyazaki K, Hayashi Y (2003) Development of autoimmune exocrinopathy resembling Sjogren’s syndrome in estrogen-deficient mice of healthy background. Am J Pathol 163:1481–1490. doi:10.1016/S0002-9440(10)63505-5

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ishimaru N, Arakaki R, Yoshida S, Yamada A, Noji S, Hayashi Y (2008) Expression of the retinoblastoma protein RbAp48 in exocrine glands leads to Sjogren’s syndrome-like autoimmune exocrinopathy. J Exp Med 205:2915–2927. doi:10.1084/jem.20080174

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Jayasena CS, Bronner ME (2012) Rbms3 functions in craniofacial development by posttranscriptionally modulating TGF-beta signaling. J Cell Biol 199:453–466. doi:10.1083/jcb.201204138

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kong L, Ogawa N, Nakabayashi T, Liu GT, D’Souza E, McGuff HS, Guerrero D, Talal N, Dang H (1997) Fas and Fas ligand expression in the salivary glands of patients with primary Sjogren’s syndrome. Arthritis Rheum 40:87–97

    Article  CAS  PubMed  Google Scholar 

  • Kong L, Robinson CP, Peck AB, Vela-Roch N, Sakata KM, Dang H, Talal N, Humphreys-Beher MG (1998) Inappropriate apoptosis of salivary and lacrimal gland epithelium of immunodeficient NOD-scid mice. Clin Exp Rheumatol 16:675–681

    CAS  PubMed  Google Scholar 

  • Konttinen YT, Fuellen G, Bing Y, Porola P, Stegaev V, Trokovic N, Falk SS, Liu Y, Szodoray P, Takakubo Y (2012) Sex steroids in Sjogren’s syndrome. J Autoimmun 39:49–56. doi:10.1016/j.jaut.2012.01.004

    Article  CAS  PubMed  Google Scholar 

  • Kuo C-F, Grainge MJ, Yu K-H, See L-C, Luo S-F, Valdes AM, Chou IJ (2012) Sibling relative risk and heritability of Sjgren’s syndrome: a nationwide population study in Taiwan. Arthritis Rheum 64:2673

    Google Scholar 

  • Labrie F (2010) DHEA, important source of sex steroids in men and even more in women. Prog Brain Res 182:97–148. doi:10.1016/S0079-6123(10)82004-7

    Article  CAS  PubMed  Google Scholar 

  • Labrie F (2015) All sex steroids are made intracellularly in peripheral tissues by the mechanisms of intracrinology after menopause. J Steroid Biochem Mol Biol 145:133–138. doi:10.1016/j.jsbmb.2014.06.001

    Article  CAS  PubMed  Google Scholar 

  • Li Y, Zhang K, Chen H, Sun F, Xu J, Wu Z, Li P, Zhang L, Du Y, Luan H, Li X, Wu L, Li H, Wu H, Li X, Li X, Zhang X, Gong L, Dai L, Sun L, Zuo X, Xu J, Gong H, Li Z, Tong S, Wu M, Li X, Xiao W, Wang G, Zhu P, Shen M, Liu S, Zhao D, Liu W, Wang Y, Huang C, Jiang Q, Liu G, Liu B, Hu S, Zhang W, Zhang Z, You X, Li M, Hao W, Zhao C, Leng X, Bi L, Wang Y, Zhang F, Shi Q, Qi W, Zhang X, Jia Y, Su J, Li Q, Hou Y, Wu Q, Xu D, Zheng W, Zhang M, Wang Q, Fei Y, Zhang X, Li J, Jiang Y, Tian X, Zhao L, Wang L, Zhou B, Li Y, Zhao Y, Zeng X, Ott J, Wang J, Zhang F (2013) A genome-wide association study in Han Chinese identifies a susceptibility locus for primary Sjogren’s syndrome at 7q11.23. Nat Genet 45:1361–1365. doi:10.1038/ng.2779

    Article  CAS  PubMed  Google Scholar 

  • Manoussakis MN, Tsinti M, Kapsogeorgou EK, Moutsopoulos HM (2012) The salivary gland epithelial cells of patients with primary Sjogren’s syndrome manifest significantly reduced responsiveness to 17beta-estradiol. J Autoimmun 39:64–68. doi:10.1016/j.jaut.2012.01.005

    Article  CAS  PubMed  Google Scholar 

  • Marchini J, Howie B, Myers S, McVean G, Donnelly P (2007) A new multipoint method for genome-wide association studies by imputation of genotypes. Nat Genet 39:906–913. doi:10.1038/ng2088

    Article  CAS  PubMed  Google Scholar 

  • McCartney-Francis NL, Mizel DE, Redman RS, Frazier-Jessen M, Panek RB, Kulkarni AB, Ward JM, McCarthy JB, Wahl SM (1996) Autoimmune Sjogren’s-like lesions in salivary glands of TGF-beta1-deficient mice are inhibited by adhesion-blocking peptides. J Immunol 157:1306–1312

    CAS  PubMed  Google Scholar 

  • Pan WH, Fann CS, Wu JY, Hung YT, Ho MS, Tai TH, Chen YJ, Liao CJ, Yang ML, Cheng AT, Chen YT (2006) Han Chinese cell and genome bank in Taiwan: purpose, design and ethical considerations. Hum Hered 61:27–30. doi:10.1159/000091834

    Article  PubMed  Google Scholar 

  • Ponten F, Jirstrom K, Uhlen M (2008) The Human Protein Atlas–a tool for pathology. J Pathol 216:387–393. doi:10.1002/path.2440

    Article  CAS  PubMed  Google Scholar 

  • Porola P, Virkki L, Przybyla BD, Laine M, Patterson TA, Pihakari A, Konttinen YT (2008) Androgen deficiency and defective intracrine processing of dehydroepiandrosterone in salivary glands in Sjogren’s syndrome. J Rheumatol 35:2229–2235

    Article  CAS  PubMed  Google Scholar 

  • Rahimi Darabad R, Suzuki T, Richards SM, Jakobiec FA, Zakka FR, Barabino S, Sullivan DA (2014) Does estrogen deficiency cause lacrimal gland inflammation and aqueous-deficient dry eye in mice? Exp Eye Res 127:153–160. doi:10.1016/j.exer.2014.07.017

    Article  CAS  PubMed  Google Scholar 

  • Rajaiya J, Nixon JC, Ayers N, Desgranges ZP, Roy AL, Webb CF (2006) Induction of immunoglobulin heavy-chain transcription through the transcription factor Bright requires TFII-I. Mol Cell Biol 26:4758–4768. doi:10.1128/MCB.02009-05

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Robinson CP, Yamachika S, Alford CE, Cooper C, Pichardo EL, Shah N, Peck AB, Humphreys-Beher MG (1997) Elevated levels of cysteine protease activity in saliva and salivary glands of the nonobese diabetic (NOD) mouse model for Sjogren syndrome. Proc Natl Acad Sci USA 94:5767–5771

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schot LP, Verheul HA, Schuurs AH (1984) Effect of nandrolone decanoate on Sjogren’s syndrome like disorders in NZB/NZW mice. Clin Exp Immunol 57:571–574

    CAS  PubMed  PubMed Central  Google Scholar 

  • Shim GJ, Warner M, Kim HJ, Andersson S, Liu L, Ekman J, Imamov O, Jones ME, Simpson ER, Gustafsson JA (2004) Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjogren’s syndrome. Proc Natl Acad Sci USA 101:12628–12633. doi:10.1073/pnas.0405099101

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Spaan M, Porola P, Laine M, Rozman B, Azuma M, Konttinen YT (2009) Healthy human salivary glands contain a DHEA-sulphate processing intracrine machinery, which is deranged in primary Sjogren’s syndrome. J Cell Mol Med 13:1261–1270. doi:10.1111/j.1582-4934.2009.00727.x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sullivan RM, Cermak JM, Papas AS, Dana MR, Sullivan DA (2002) Economic and quality of life impact of dry eye symptoms in women with Sjogren’s syndrome. Adv Exp Med Biol 506:1183–1188

    Article  CAS  PubMed  Google Scholar 

  • Sullivan DA, Belanger A, Cermak JM, Berube R, Papas AS, Sullivan RM, Yamagami H, Dana MR, Labrie F (2003) Are women with Sjogren’s syndrome androgen-deficient? J Rheumatol 30:2413–2419

    PubMed  Google Scholar 

  • Taiym S, Haghighat N, Al-Hashimi I (2004) A comparison of the hormone levels in patients with Sjogren’s syndrome and healthy controls. Oral Surg Oral Med Oral Pathol Oral Radiol Endod 97:579–583. doi:10.1016/S107921040400068X

    Article  CAS  PubMed  Google Scholar 

  • Valtysdottir ST, Wide L, Hallgren R (2001) Low serum dehydroepiandrosterone sulfate in women with primary Sjogren’s syndrome as an isolated sign of impaired HPA axis function. J Rheumatol 28:1259–1265

    CAS  PubMed  Google Scholar 

  • Virkki LM, Porola P, Forsblad-d’Elia H, Valtysdottir S, Solovieva SA, Konttinen YT (2010) Dehydroepiandrosterone (DHEA) substitution treatment for severe fatigue in DHEA-deficient patients with primary Sjogren’s syndrome. Arthritis Care Res (Hoboken) 62:118–124. doi:10.1002/acr.20022

    Article  CAS  Google Scholar 

  • Vitali C, Bombardieri S, Jonsson R, Moutsopoulos HM, Alexander EL, Carsons SE, Daniels TE, Fox PC, Fox RI, Kassan SS, Pillemer SR, Talal N, Weisman MH, European Study Group on Classification Criteria for Sjogren’s S (2002) Classification criteria for Sjogren’s syndrome: a revised version of the European criteria proposed by the American-European Consensus Group. Ann Rheum Dis 61:554–558

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Zheng J, Huang R, Huang Q, Deng F, Chen Y, Yin J, Chen J, Wang Y, Shi G, Gao X, Liu Z, Petersen F, Yu X (2015) The GTF2I rs117026326 polymorphism is associated with anti-SSA-positive primary Sjogren’s syndrome. Rheumatology (Oxford) 54:562–564. doi:10.1093/rheumatology/keu466

    Article  Google Scholar 

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Acknowledgments

We thank the Academia Sinica Genomic Medicine Multicenter Study (40-05-GMM) and the National Center for Genome Medicine at Academia Sinica, Taiwan, for technical/bioinformatics support. This Center was supported by grants from the National Core Facility Program for Biotechnology of National Science Council, Taiwan (NSC102-2319-B-001-001). We thank the Translational Resource Center for Genomic Medicine (TRC, NSC102-2325-B-001-040) of National Research Program for Biopharmaceuticals (NRPB) for the support in sample management. We thank the Taiwan Biobank for providing the allele frequency and NGS data of controls for our replication.

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    Authors and Affiliations

    1. National Center for Genome Medicine, Institute of Biomedical Sciences, Academia Sinica, 128 Sec. 2, Academia Rd. Nankang, Taipei, 11529, Taiwan

      I-Wen Song, Jenn-Hwai Yang, Ming-Ta Michael Lee, Yi-Chun Chou, Chien-Hsiun Chen, Yuan-Tsong Chen & Jer-Yuarn Wu

    2. Rheumatology, Immunology and Allergy Division, Tri-Service General Hospital, National Defense Medical Center, Taipei, 11490, Taiwan

      Hsiang-Cheng Chen

    3. Graduate Institute of Clinical Medicine, College of Medicine, Taipei Medical University, Taipei, 11031, Taiwan

      Yuh-Feng Lin

    4. Division of Nephrology, Department of Internal Medicine, Shuang Ho Hospital, New Taipei, 23561, Taiwan

      Yuh-Feng Lin

    5. Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Taipei Medical University Hospital, Taipei, 11031, Taiwan

      Chi-Ching Chang

    6. Division of Allergy-Immunology-Rheumatology, Veterans General Hospital, Taipei, 11217, Taiwan

      Chung-Tei Chou

    7. Genomic Medicine Institute, Geisinger Health System, Danville, PA, 17822, USA

      Ming-Ta Michael Lee

    8. Graduate Institute of Chinese Medical Science, China Medical University, Taichung, 40447, Taiwan

      Chien-Hsiun Chen & Jer-Yuarn Wu

    9. Department of Pediatrics, Duke University Medical Center, Durham, NC, 27710, USA

      Yuan-Tsong Chen

    10. Division of Rheumatology, Immunology and Allergy, Department of Internal Medicine, Taipei Tzu Chi Hospital, No.289, Jianguo Rd., Xindian Dist., New Taipei City, 23142, Taiwan

      Chen-Hung Chen

    11. Buddhist Tzu Chi Medical Foundation, School of Medicine, Tzu Chi University, Hualien, 97002, Taiwan

      Chen-Hung Chen

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    1. I-Wen Song
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    I.-W. Song and H.-C. Chen contribute equally to this work.

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    Song, IW., Chen, HC., Lin, YF. et al. Identification of susceptibility gene associated with female primary Sjögren’s syndrome in Han Chinese by genome-wide association study. Hum Genet 135, 1287–1294 (2016). https://doi.org/10.1007/s00439-016-1716-0

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