Association between autoimmune diseases and thyroid dysfuction: a Mendelian randomization study
REN Shouze1, LI Zeguang2, LI Linwei3, XIA Kaiyu1, LIANG Hua1
1. Department of Basic Medical Sciences, Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, China; 2. The First Affiliated Hospital of Heilongjiang University of Traditional Chinese Medicine, Harbin, Heilongjiang 150040, China; 3. Heilongjiang Provincial Hospital, Harbin, Heilongjiang 150040, China
Abstract：Objective To evaluate the association between autoimmune diseases (ADs) and thyroid dysfunction using a Mendelian randomization (MR) approach. Methods Genetic predictors of hypothyroidism and hyperthyroidism were collected through the UK Biobank, including 337 159 individuals and 10 894 596 single nucleotide polymorphisms (SNPs). Genetic predictors of 6 ADs including systemic lupus erythematosus (SLE), ankylosing spondylitis (AS), type 1 diabetes mellitus (T1DM), rheumatoid arthritis (RA), primary biliary cholangitis (PBC), and multiple sclerosis (MS) were collected through the GWAS Catalog database, including 14 267 individuals and 7 071 163 SNPs, 22 647 individuals and 99 962 SNPs, 24 840 individuals and 12 783 129 SNPs, 58 284 individuals and 13 108 512 SNPs, 13 239 individuals and 1 124 241 SNPs, and 38 589 individuals and 156 632 SNPs. MR analysis was performed using the inverse-variance weighted (IVW) method. The horizontal pleiotropy was assessed using the MR-Egger regression, and sensitivity analysis was conducted with the leave-one-out. Results IVW results showed that a higher risk of hypothyroidism was associated with T1DM (OR=1.007, 95%CI: 1.003-1.011, P<0.05), SLE (OR=1.005, 95%CI: 1.002-1.009, P<0.05), and RA (OR=1.013, 95%CI: 1.009-1.016, P<0.05); a higher risk of hyperthyroidism was associated with T1DM (OR=1.002, 95%CI: 1.001-1.003, P<0.05) and SLE (OR=1.002, 95%CI: 1.001-1.003, P<0.05). Conclusions Genetically predicted ADs are associated with an increased risk of thyroid dysfunction. A higher risk of hypothyroidism is associated with T1DM, SLE and RA; a higher risk of hyperthyroidism is associated with T1DM and SLE.
[1] MARRACK P,KAPPLER J,KOTZIN B L.Autoimmune disease:why and where it occurs[J].Nat Med,2001,7(8):899-905. [2] MCLEOD D S,COOPER D S.The incidence and prevalence of thyroid autoimmunity[J].Endocrine,2012,42(2):252-265. [3] 王玉琢,沈洪兵.孟德尔随机化研究应用于因果推断的影响因素及其结果解读面临的挑战[J].中华流行病学杂志,2020,41(8):1231-1236. [4] WATANABE K,STRINGER S,FREI O,et al.A global overview of pleiotropy and genetic architecture in complex traits[J].Nat Genet,2019,51(9):1339-1348. [5] BENTHAM J,MORRIS D L,GRAHAM D S C,et al.Genetic association analyses implicate aberrant regulation of innate and adaptive immunity genes in the pathogenesis of systemic lupus erythematosus[J].Nat Genet,2015,47(12):1457-1464. [6] International Genetics of Ankylosing Spondylitis Consortium(IGAS),CORTES A,HADLER J,et al.Identification of multiple risk variants for ankylosing spondylitis through high-density genotyping of immune-related loci[J].Nat Genet,2013,45(7):730-738. [7] FORGETTA V,MANOUSAKI D,ISTOMINE R,et al.Rare genetic variants of large effect influence risk of type 1 diabetes[J].Diabetes,2020,69(4):784-795. [8] HA E,BAE S C,KIM K.Large-scale meta-analysis across East Asian and European populations updated genetic architecture and variant-driven biology of rheumatoid arthritis,identifying 11 novel susceptibility loci[J].Ann Rheum Dis,2021,80(5):558-565. [9] CORDELL H J,HAN Y,MELLS G F,et al.International genome-wide meta-analysis identifies new primary biliary cirrhosis risk loci and targetable pathogenic pathways[J/OL].Nat Commun,2015,6[2023-10-30].https://doi.org/10.1038/ncomms9019. [10] International Multiple Sclerosis Genetics Consortium(IMSGC),BEECHAM A H,PATSOPOULOS N A,et al.Analysis of immune-related loci identifies 48 new susceptibility variants for multiple sclerosis[J].Nat Genet,2013,45(11):1353-1360. [11] 于天琦,徐文涛,苏雅娜,等.孟德尔随机化研究基本原理、方法和局限性[J].中国循证医学杂志,2021,21(10):1227-1234. [12] LIU Y J,MIAO H B,LIN S,et al.Association between rheumatoid arthritis and thyroid dysfunction:a meta-analysis and systematic review[J/OL].Front Endocrinol(Lausanne),2022,13[2023-10-30].https://doi.org/10.3389/fendo.2022.1015516. [13] MEENA L,CHEJARA R,MEENA P D,et al.A study to evaluate the thyroid function in sero positive rheumatoid arthritis[J].J Assoc Physicians India,2022,70(4):11-12. [14] BARUAH M P,BHATTACHARYA B,BARUAH U M.C-reactive protein level can be a better indicator than erythrocyte sedimentation rate in assessing the severity of inflammation and guiding glucocorticoid therapy in subacute thyroiditis[J].Indian J Endocrinol Metab,2022,26(4):328-333. [15] ALHEFDHI A,BURKE J F,REDLICH A,et al.Leflunomide suppresses growth in human medullary thyroid cancer cells[J].J Surg Res,2013,185(1):212-216. [16] TERLEMEZ R,AKGÜN K,PALAMAR D,et al.The clinical importance of the thyroid nodules during anti-tumor necrosis factor therapy in patients with axial spondyloarthritis[J].Clin Rheumatol,2017,36(5):1071-1076. [17] CHANG C H,YEH Y C,SHIH S R,et al.Association between thyroid dysfunction and dysglycaemia:a prospective cohort study[J].Diabet Med,2017,34(11):1584-1590. [18] SHUN C B,DONAGHUE K C,PHELAN H,et al.Thyroid autoimmunity in type 1 diabetes:systematic review and meta-analysis[J].Diabet Med,2014,31(2):126-135. [19] BIONDI B,KAHALY G J,ROBERTSON R P.Thyroid dysfunction and diabetes mellitus:two closely associated disorders[J].Endocr Rev,2019,40(3):789-824. [20] HAUGEN B R.Drugs that suppress TSH or cause central hypothyroidism[J].Best Pract Res Clin Endocrinol Metab,2009,23(6):793-800. [21] 倪佳佳. 甲状腺功能减退症与系统性红斑狼疮器官损伤的相关性研究[D].济南:山东大学,2023. [22] ZHANG Q Y,LIU W,LI L,et al.Genetic study in a large cohort supported different pathogenesis of Graves' disease and Hashimoto's hypothyroidism[J/OL].J Clin Endocrinol Metab,2020,105(7)[2023-10-30].https://doi.org/10.1210/clinem/dgaa170. [23] NAKAMURA H,USA T,MOTOMURA M,et al.Prevalence of interrelated autoantibodies in thyroid diseases and autoimmune disorders[J].J Endocrinol Invest,2008,31(10):861-865.
