Abstract
Antiphospholipid syndrome (APS) is the most important treatable cause of recurrent pregnancy loss. The live birth rate is limited to only 70–80% in patients with APS undergoing established anticoagulant therapy. Lupus anticoagulant (LA), but not anticardiolipin antibody (aCL), was found to predict adverse pregnancy outcome. Recent genome-wide association studies (GWAS) of APS focusing on aCL have shown that several molecules may be involved. This is the first GWAS for obstetric APS focusing on LA. A GWAS was performed to compare 115 Japanese patients with obstetric APS, diagnosed according to criteria of the International Congress on APS, and 419 healthy individuals. Allele or genotype frequencies were compared in a total of 426 344 single-nucleotide polymorphisms (SNPs). Imputation analyses were also performed for the candidate regions detected by the GWAS. One SNP (rs2288493) located on the 3′-UTR of TSHR showed an experiment-wide significant APS association (P=7.85E-08, OR=6.18) under a recessive model after Bonferroni correction considering the number of analyzed SNPs. Another SNP (rs79154414) located around the C1D showed a genome-wide significant APS association (P=4.84E-08, OR=6.20) under an allelic model after applying the SNP imputation. Our findings demonstrate that a specific genotype of TSHR and C1D genes can be a risk factor for obstetric APS.
Similar content being viewed by others
Log in or create a free account to read this content
Gain free access to this article, as well as selected content from this journal and more on nature.com
or
References
Branch, D. W., Gibson, M. & Silver, R. M. Recurrent miscarriage. N. Engl. J. Med. 363, 1740–1747 (2010).
Farquharson, R. G., Pearson, J. F. & John, L. Lupus anticoagulant and pregnancy management. Lancet 28, 228–229 (1984).
Miyakis, S., Lockshin, M. D., Atsumi, T., Branch, D. W., Brey, R. L., Cervera, R. et al. International consensus statement of an update of the classification criteria for definite antiphospholipid syndrome. J. Thromb. Haemost. 4, 295–306 (2006).
Sugiura-Ogasawara, M., Ozaki, Y., Kitaori, T., Kumagai, K. & Suzuki, S. Midline uterine defect size correlated with miscarriage of euploid embryos in recurrent cases. Fertil. Steril. 93, 1983–1988 (2010).
Sugiura-Ogasawara, M., Ozaki, Y., Sato, T., Suzumori, N. & Suzumori, K. Poor prognosis of recurrent aborters with either maternal or paternal reciprocal translocation. Fertil. Steril. 81, 367–373 (2004).
Sugiura-Ogasawara, M., Ozaki, Y., Katano, K., Suzumori, N., Kitaori, T. & Mizutani, E. Abnormal embryonic karyotype is the most frequent cause of recurrent miscarriage. Hum. Reprod. 27, 2297–2303 (2012).
Ruiz-Irastorza, G., Growther, M., Branch, W. & Khamashta, M. Antiphospholipid syndrome. Lancet 376, 1498–1509 (2010).
Ito, I., Kawasaki, A., Ito, S., Hayashi, T., Goto, D., Matsumoto, I. et al. Replication of the association between the C8orf13-BLK region and systemic lupus erythematosus in a Japanese population. Arthritis. Rheum. 60, 553–558 (2009).
Shimane, K., Kochi, Y., Horita, T., Ikari, K., Amano, H., Hirakata, M. et al. The association of a nonsynonymous single-nucleotide polymorphism in TNFAIP3 with systemic lupus erythematosus and rheumatoid arthritis in the Japanese population. Arthritis. Rheum. 62, 574–579 (2010).
Okada, Y., Shimane, K., Kochi, Y., Tahira, T., Suzuki, A., Higasa, K. et al. A genome-wide association study identified AFF1 as a susceptibility locus for systemic lupus eyrthematosus in Japanese. PloS. Genet. 8, e1002455 (2012).
Shimane, K., Kochi, Y., Suzuki, A., Okada, Y., Ishii, T., Horita, T. et al. An association analysis of HLA-DRB1 with systemic lupus erythematosus and rheumatoid arthritis in a Japanese population: effects of *09:01 allele on disease phenotypes. Rheumatology 52, 1172–1182 (2013).
Horita, T., Atsumi, T., Yoshida, N., Nakagawa, H., Kataoka, H., Yasuda, S. et al. STAT4 single nucleotide polymorphism, rs7574865 G/T, as a risk for antiphospholipid syndrome. Ann. Rheum. Dis. 68, 1366–1367 (2009).
Yin, H., Borghi, M. O., Delgado-Vega, A. M., Tincani, A., Meroni, P. L. & Alarcón-Riquelme, M. E. Association of STAT4 and BLK, but not BANK1 or IRF5, with primary antiphospholipid syndrome. Arthritis. Rheum. 60, 2468–2471 (2009).
Kamboh, M. I., Wang, X., Kao, A. H., Barmada, M. M., Clarke, A., Ramsey-Goldman, R. et al. Genome-wide association study of antiphospholipid antibodies. Autoimmune. Dis. 2013, 761046 (2013).
Müller-Calleja, N., Rossmann, H., Müller, C., Wild, P., Blankenberg, S., Pfeiffer, N. et al. Antiphospholipid antibodies in a large population-based cohort: genome-wide associations and effects on monocyte gene expression. Thromb. Haemost. 116, 115–123 (2016).
Cowchock, F. S., Reece, E. A., Balaban, D., Branch, D. W. & Plouffe, L. Repeated fetal losses associated with antiphospholipid antibodies: a collaborative randomized trial comparing prednisone with low-dose heparin treatment. Am. J. Obstet. Gynecol. 166, 1318–1323 (1992).
Rai, R., Cohen, H., Dave, M. & Regan, L. Randomised controlled trial of aspirin and aspirin plus heparin in pregnant women with recurrent miscarriage associated with phospholipid antibodies (or antiphospholipid antibodies). BMJ 314, 253–257 (1997).
Lockshin, M. D., Kim, M., Laskin, C. A., Guerra, M., Branch, D. W., Merrill, J. et al. Prediction of adverse pregnancy outcome by the presence of lupus anticoagulant, but not anticardiolipin antibody, in patients with antiphospholipid antibodies. Arthritis Rheum. 64, 2311–2318 (2012).
Clark, C. A., Davidovits, J., Spitzer, K. A. & Laskin, C. A. The lupus anticoagulant: results from 2257 patients attending a high-risk pregnancy clinic. Blood 122, 341–347 (2013).
Lefkou, E., Mamopoulos, A., Dagklis, T., Vosnakis, C., Rousso, D. & Girardi, G. Pravastatin improves pregnancy outcomes in obstetric antiphospholipid syndrome refractory to antithrombotic therapy. J. Clin. Invest. 126, 2933–2940 (2016).
Sciascia, S., Hunt, B. J., Talavera-Garcia, E., Lliso, G., Khamashta, M. A. & Cuadrado, M. J. The impact of hydroxychloroquine treatment on pregnancy outcome in women with antiphospholipid antibodies. Am. J. Obstet. Gynecol. 214 273, e1–e8 (2016).
Jaslow, C. R., Carney, J. L. & Kutteh, W. H. Diagnostic factors identified in 1020 women with two versus three or more recurrent pregnancy losses. Fertil. Steril. 93, 1234–1243 (2010).
Matsuura, E., Igarashi, Y., Yasuda, T., Triplett, D. A. & Koike, T. Anticardiolipin antibodies recognize β2-glycoprotein I structure altered by interacting with an oxygen modified solid phase surface. J. Exp. Med. 179, 457–462 (1994).
Nakamura, M., Nishida, N., Kawashima, M., Aiba, Y., Tanaka, A., Yasunami, M. et al. Genome-wide association study identifies TNFSF15 and POU2AF1 as susceptibility loci for primary biliary cirrhosis in Japanese. Am. J. Hum. Genet. 91, 721–728 (2012).
Ueta, M., Sawai, H., Sotozono, C., Hitomi, Y., Kaniwa, N. & Kim, M. K. et al. IKZF1, a new susceptibility gene for cold medicine-related Stevens-Johnson syndrome/toxic epidermal necrolysis with severe mucosal involvement. J. Allergy. Clin. Immunol 135, 1538–1545 (2015) pii:S0091-674903744-0.
Howie, B. N., Donnelly, P. & Marchini, J. A flexible and accurate genotype imputation method for the next generation of genome-wide association studies. PLoS. Genet 5, e1000529 (2009).
Freeman, C. & Marchini, J. GTOOL: A program for transforming sets of genotype data for use with the programs SNPTEST and IMPUTE, Oxford, UK. 2007. http://www.well.ox.ac.uk/~cfreeman/software/gwas/gtool.html (accessed 8 February 2017).
Pruim, R. J., Welch, R. P., Sanna, S., Teslovich, T. M., Chines, P. S., Gliedt, T. P. et al. LocusZoom: regional visualization of genome-wide association scan results. Bioinformatics 26, 2336–2337 (2010).
Khor, S. S., Yang, W., Kawashima, M., Kamitsuji, S., Zheng, X., Nishida, N. et al. High-accuracy imputation for HLA class I and II genes based on high-resolution SNP data of population-specific references. Pharmacogenomics J. 15, 530–537 (2015).
Navarrete, C. V. The HLA system in blood transfusion. Baillieres Best Pract. Res. Clin. Haematol. 13, 511–532 (2000).
Dechairo, B. M., Zabaneh, D., Collins, J., Brand, O., Dawson, G. J., Green, A. P. et al. Association of the TSHR gene with Graves' disease: the first disease specific locus. Eur. J. Hum. Genet. 13, 1223–1230 (2005).
Nicoletti, A., Bal, M., De Marco, G., Baldazzi, L., Agretti, P., Menabò, S. et al. Thyrotropin-stimulating hormone receptor gene analysis in pediatric patients with non-autoimmune subclinical hypothyroidism. J. Clin. Endocrinol. Metab. 94, 4187–4194 (2009).
de Carvalho, J. F. & Caleiro, M. T. Primary antiphospholipid syndrome and thyroid involvement. J. Clin. Rheumatol 16, 164–167 (2010).
Zamir, I., Dawson, J., Lavinsky, R. M., Glass, C. K., Rosenfeld, M. G. & Lazar, M. A. Cloning and characterization of a corepressor and potential component of the nuclear hormone receptor repression complex. Proc. Natl Acad. Sci. USA 94, 14400–14405 (1997).
Colicchia, M., Campagnolo, L., Baldini, E., Ulisse, S., Valensise, H. & Moretti, C. Molecular basis of thyrotropin and thyroid hormone action during implantation and early development. Hum. Reprod. Update 20, 884–904 (2014).
Thangaratinam, S., Tan, A., Knox, E., Kilby, M. D., Franklyn, J. & Coomarasamy, A. Association between thyroid autoantibodies and miscarriage and preterm birth: meta-analysis of evidence. BMJ 342, d2616 (2011).
Chen, E. S., Sutani, T. & Yanagida, M. Cti1/C1D interacts with condensin SMC hinge and supports the DNA repair function of condensin. Proc. Natl Acad. Sci. USA 101, 8078–8083 (2004).
Jackson, R. A., Wu, J. S. & Chen, E. S. C1D family proteins in coordinating RNA processing, chromosome condensation and DNA damage response. Cell. Div. 11, 2 (2016).
Quenby, S., Mountfield, S., Cartwright, J. E., Whitley, G. S. & Chamley, L. Antiphospholipid antibodies prevent extravillous trophoblast differentiation. Fertil. Steril. 83, 691–698 (2005).
GTEx Consortium The Genotype-Tissue Expression (GTEx) project. Nat. Genet. 45, 580–585 (2013).
Bertolaccini, M. L., Atsumi, T., Caliz, A. R., Amengual, O., Khamashta, M. A., Hughes, G. R. et al. Association of antiphosphatidylserine/prothrombin autoantibodies with HLA class II genes. Arthritis. Rheum. 43, 683–688 (2000).
Ho, I. C., Tai, T. S. & Pai, S. Y. GATA3 and the T-cell lineage: essential functions before and after T-helper-2-cell differentiation. Nat. Rev. Immunol. 9, 125–135 (2009).
Wegmann, T. G., Lin, H., Guilbert, L. & Mosmann, T. R. Bidirectional cytokine interactions in the maternal-fetal relationship: is successful pregnancy a TH2 phenomenon? Immunol Today 14, 353–356 (1993).
Pandolfi, P. P., Roth, M. E., Karis, A., Leonard, M. W., Dzierzak, E., Grosveld, F. G. et al. Targeted disruption of the GATA3 gene causes severe abnormalities in the nervous system and in fetal liver haematopoiesis. Nat. Genet. 11, 40–44 (1995).
Insidegen-lupus. Available from http://insidegen.com/insidegen-LUPUS-data.html (accessed 8 February 2017).
Remmers, E. F., Plenge, R. M., Lee, A. T., Graham, R. R., Hom, G., Behrens, T. W. et al. STAT4 and the risk of rheumatoid arthritis and systemic lupus erythematosus. N. Engl. J. Med. 357, 977–986 (2007).
Musone, S. L., Taylor, K. E., Lu, T. T., Nititham, J., Ferreira, R. C., Ortmann, W. et al. Multiple polymorphisms in the TNFAIP3 region are independently associated with systemic lupus erythematosus. Nat. Genet. 40, 1062–1064 (2008).
Gateva, V., Sandling, J. K., Hom, G., Taylor, K. E., Chung, S. A., Sun, X. et al. A large-scale replication study identifies TNIP1, PRDM1, JAZF1, UHRF1BP1 and IL10 as risk loci for systemic lupus erythematosus. Nat. Genet. 41, 1228–1233 (2009).
Acknowledgements
We thank Natsumi Baba, Kayoko Yamada and Kayoko Kato (The University of Tokyo) for their technical assistance. This study was supported by a Grant-in-aid for Scientific Research from the Ministry of Health, Labour and Welfare of Japan.
Author contributions
MS-O designed the study, collected the data and wrote the manuscript. YO contributed to the analysis of the data and the writing of the manuscript. YO’s contribution was equal to the first author. MK, LT-O, S-SK and HS helped to analyze the data. TH helped to collect the clinical data and revised the manuscript. TA supervised the study and revised the manuscript. AM, DF, TF, SM, EM, SK, TK, KK and YO helped to collect the clinical data, and KT supervised the study design and revised the manuscript.
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Competing interests
The authors declare no conflict of interest.
Additional information
Supplementary Information accompanies the paper on Journal of Human Genetics website
Supplementary information
Rights and permissions
About this article
Cite this article
Sugiura-Ogasawara, M., Omae, Y., Kawashima, M. et al. The first genome-wide association study identifying new susceptibility loci for obstetric antiphospholipid syndrome. J Hum Genet 62, 831–838 (2017). https://doi.org/10.1038/jhg.2017.46
Received:
Revised:
Accepted:
Published:
Issue date:
DOI: https://doi.org/10.1038/jhg.2017.46
This article is cited by
-
The association of APOH and NCF1 polymorphisms on susceptibility to recurrent pregnancy loss in women with antiphospholipid syndrome
Journal of Assisted Reproduction and Genetics (2023)
-
Mendelian randomization while jointly modeling cis genetics identifies causal relationships between gene expression and lipids
Nature Communications (2020)
-
Genetics of Antiphospholipid Syndrome
Current Rheumatology Reports (2019)
-
Moving towards a molecular taxonomy of autoimmune rheumatic diseases
Nature Reviews Rheumatology (2018)
-
Antiphospholipid antibody profile-based outcome of purely vascular and purely obstetric antiphospholipid syndrome
Journal of Thrombosis and Thrombolysis (2018)
