| 249 | 5 | 57 |
| 下载次数 | 被引频次 | 阅读次数 |
自身免疫性甲状腺疾病(autoimmune thyroid disease, AITD)是一种主要由T细胞介导的器官特异性自身免疫性疾病，包括格雷夫斯病(Graves disease, GD)和桥本甲状腺炎(Hashimoto thyroiditis, HT),其发病率与遗传因素紧密相关。本研究旨在确定与AITD相关的易感基因及位点。本研究通过对100例AITD(51例HT和49例GD)患者和50例健康体检者的基因组进行目标区域测序，并对基因多态性与AITD之间的相关性进行了统计学分析，进一步进行连锁分析找到易感基因及相关位点。本研究发现了BACH2基因的5个单核苷酸多态性(single nucleotide polymorphism, SNP)位点(rs12205059、 rs62408219、 rs7742121、 rs7756574、 rs12204886)完全连锁，ARID5B基因10个SNP位点(rs12778514、 rs3740354、 rs3740353、 rs9633555、 rs9633557、 rs9633534、 rs3740352、 rs2393730、 rs2393729、 rs2393728)连锁程度较高，NFKB1基因7个SNP位点(rs230528、 rs230526、 rs230521、 rs230517、 rs230512、 rs4648011、 rs230505)连锁程度较高，它们显示与GD显著相关；BACH2基因24个SNP位点(rs77175037、 rs16882370、 rs77758469、 rs78777913、 rs117721419、 rs78336372、 rs76671310、 rs76587383、 rs75249386、 rs79815784、 rs57765055、 rs75199762、 rs75340880、 rs9444735、 rs61246723、 rs9451336、 rs78318422、 rs117023048、 rs74639869、 rs75487886、 rs80029445、 rs78252829、 rs60148132、 rs58745003)完全连锁，以及4个SNP位点(rs60519986、 rs56835438、 rs58205153、 rs9451298)连锁程度较高，显示与HT显著相关；BACH2基因4个SNP位点(rs12205059、 rs7742121、 rs7756574、 rs12204886)连锁程度较高，ARID5B基因5个SNP位点(rs9633555、 rs9633556、 rs2393730、 rs2393729、 rs2393728)连锁程度较高，它们与GD和HT易感性均显著相关。本研究揭示了BACH2、ARID5B和NFKB1基因的多态性与AITD易感性有关，它们可能参与了AITD的发病机制。
Abstract：Autoimmune thyroid disease(AITD) is an organ-specific autoimmune disease mainly mediated by T cells, including Graves disease(GD) and Hashimoto thyroiditis(HT). The incidence of AITD is closely related to genetic factors. The aim of this study is identifying susceptibility genes and loci associated with AITD. In this study, the genomes of 100 patients with AITD(51 HT and 49 GD) and 50 healthy subjects were sequenced in targeted regions, and the correlation between gene polymorphisms and AITD was statistically analyzed, and further linkage analysis was performed to find susceptibility genes and associated loci in genes. In this study, five SNP loci(rs12205059, rs62408219, rs7742121, rs7756574, rs12204886) in BACH2 gene were found to be completely linked, ten SNP loci(rs12778514, rs3740354, rs3740353, rs9633555, rs9633557, rs9633534, rs3740352, rs2393730, rs2393729, rs2393728) in ARID5B gene were highly linked, seven SNP loci(rs230528, rs230526, rs230521, rs230517, rs230512, rs4648011, rs230505) in NFKB1 gene were highly linked, and they showed significant correlation with GD; twenty-four SNP loci(rs77175037, rs16882370, rs77758469, rs78777913, rs117721419, rs78336372, rs76671310, rs76587383, rs75249386, rs79815784, rs57765055, rs75199762, rs75340880, rs9444735, rs61246723, rs9451336, rs78318422, rs117023048, rs74639869, rs75487886, rs80029445, rs78252829, rs60148132, rs58745003) in BACH2 gene were completely linked, and four SNP loci(rs60519986, rs56835438, rs58205153, rs9451298) were highly linked, showing significant correlation with HT; four SNP loci(rs12205059, rs7742121, rs7756574, rs12204886) in BACH2 gene were highly linked, and five SNP loci(rs9633555, rs9633556, rs2393730, rs2393729, rs2393728) in ARID5B gene were highly linked, and they all showed significant association with GD and HT susceptibility. This study reveals that the polymorphisms of BACH2, ARID5B and NFKB1 genes are associated with AITD susceptibility, and they may be involved in the pathogenesis of AITD.
ANTONELLI A,FERRARI S M,CORRADO A,et al.,2015.Autoimmune thyroid disorders.Autoimmun.Rev.,14(2):174-180.
DU P,ZHU J L,YAO Q M,et al.,2022.HLA-DRA gene polymorphisms are associated with Graves′disease as an autoimmune thyroid disease.Biomed Res.Int.,2022:6839634.
ELKHAWAGA S Y,GOMAA M H,ELSAYED M M,et al.,2021.NFKB1 promoter-94 insertion/deletion ATTG polymorphism (rs28362491) is associated with severity and disease progression of rheumatoid arthritis through interleukin-6 levels modulation in Egyptian patients.Clin.Rheumatol.,40(7):2927-2937.
FICHNA M,■urawek M,S?OMI'NSKI B,et al.,2021.Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity.Endocrine,74(1):72-79.
GAO C Q,ZHU J E,QIN Q,et al.,2022.The relationship between VEGFC gene polymorphisms and autoimmune thyroiditis.Biomed Res.Int.,2022:2603519.
GOODINGS C,ZHAO X J,MCKINNEY-FREEMAN S,et al.,2023.ARID5B influences B-cell development and function in mouse.Haematologica,108(2):502-512.
HASHAM A,TOMER Y,2012.Genetic and epigenetic mechanisms in thyroid autoimmunity.Immunol.Res.,54(1-3):204-213.
KOC A,BATAR B,CELIK O,et al.,2014.Polymorphism of the NFKB1 affects the serum inflammatory levels of IL-6 in Hashimoto thyroiditis in a Turkish population.Immunobiology,219(7):531-536.
LI C W,SACHIDANANDAM R,JAYAPRAKASH A,et al.,2021.Identification of new rare variants associated with familial autoimmune thyroid diseases by deep sequencing of linked loci.J.Clin.Endocrinol.Metab.,106(11):e4680-e4687.
LI Q,WANG B,MU K D,et al.,2019.The pathogenesis of thyroid autoimmune diseases:New T lymphocytes-Cytokines circuits beyond the Th1-Th2 paradigm.J.Cell.Physiol.,234(3):2204-2216.
LIN C,SONG W,BI X Y,et al.,2014.Recent advances in the ARID family:focusing on roles in human cancer.Onco.Targets Ther.,7:315-324.
LIU G,LIU F,2022.Bach2:a key regulator in Th2-related immune cells and Th2 immune response.J.Immunol.Res.,2022:2814510.
MAZZIERI A,MONTANUCCI P,BASTA G,et al.,2022.The role behind the scenes of Tregs and Th17s in Hashimoto′s thyroiditis:toward a pivotal role of FOXP3 and BACH2.Front.Immunol.,13:1098243.
MIURA Y,MOROOKA M,SAX N,et al.,2018.Bach2 promotes B cell receptor-induced proliferation of B lymphocytes and represses cyclin-dependent kinase inhibitors.J.Immunol.,200(8):2882-2893.
OECKINGHAUS A,GHOSH S,2009.The NF-kappaB family of transcription factors and its regulation.Cold Spring Harb.Perspect.Biol.,1(4):a000034.
OKADA Y,TERAO C,IKARI K,et al.,2012.Meta-analysis identifies nine new loci associated with rheumatoid arthritis in the Japanese population.Nat.Genet.,44(5):511-516.
RYDZEWSKA M,JAROMIN M,PASIEROWSKA I E,et al.,2018.Role of the T and B lymphocytes in pathogenesis of autoimmune thyroid diseases.Thyroid Res.,11:2.
SCHR?DER C,SOGKAS G,FLIEGAUF M,et al.,2019.Late-onset antibody deficiency due to monoallelic alterations in NFKB1.Front.Immunol.,10:2618.
SHUKLA S K,SINGH G,AHMAD S,et al.,2018.Infections,genetic and environmental factors in pathogenesis of autoimmune thyroid diseases.Microb.Pathog.,116:279-288.
SIMMONDS M J,2013.GWAS in autoimmune thyroid disease:redefining our understanding of pathogenesis.Nat.Rev.Endocrinol.,9(5):277-287.
SONG R H,LIU X R,GAO C Q,et al.,2021.METTL3 gene polymorphisms contribute to susceptibility to autoimmune thyroid disease.Endocrine,72(2):495-504.
STERENBORG R B T M,GALESLOOT T E,TEUMER A,et al.,2022.The effects of common genetic variation in 96genes involved in thyroid hormone regulation on TSH and FT4 concentrations.J.Clin.Endocrinol.Metab.,107(6):e2276-e2283.
TOMER Y,2014.Mechanisms of autoimmune thyroid diseases:from genetics to epigenetics.Annu.Rev.Pathol.,9:147-156.
TOMER Y,HASHAM A,DAVIES T F,et al.,2013.Fine mapping of loci linked to autoimmune thyroid disease identifies novel susceptibility genes.J.Clin.Endocrinol.Metab.,98(1):E144-152.
TOMER Y,HUBER A,2009.The etiology of autoimmune thyroid disease:a story of genes and environment.J.Autoimmun.,32(3-4):231-239.
TUIJNENBURG P,LANGO ALLEN H,BURNS S O,et al.,2018.Loss-of-function nuclear factor kappaB subunit 1(NFKB1) variants are the most common monogenic cause of common variable immunodeficiency in Europeans.J.Allergy Clin.Immunol.,142(4):1285-1296.
WANG B,JIA X,YAO Q M,et al.,2019.CEP128 is a crucial risk locus for autoimmune thyroid diseases.Mol.Cell.Endocrinol.,480:97-106.
WU H Y,WAN S Y,QU M Y,et al.,2022.The relationship between PTPN22 R620W polymorphisms and the susceptibility to autoimmune thyroid diseases:an updated metaanalysis.Immunol.Invest.,51(2):438-451.
YAO C,LOU G H,SUN H W,et al.,2021.BACH2 enforces the transcriptional and epigenetic programs of stem-like CD8+cells.Nat.Immunol.,22(3):370-380.
ZHANG L Z,ZHOU L Y,FENG Q Q,et al.,2021.Mutation of hashimoto′s thyroiditis and papillary thyroid carcinoma related genes and the screening of candidate genes.Front.Oncol.,11:813802.
ZHOU Y,WU H J,ZHAO M,et al.,2016.The bach family of transcription factors:a comprehensive review.Clin.Rev.Allergy Immunol.,50(3):345-356.
基本信息:
DOI：10.13417/j.gab.043.000172
中图分类号:R581
引用信息:
[1]狄立强,李素丽,张洁,等.通过目标区域测序寻找新的自身免疫性甲状腺疾病候选基因及相关位点[J].基因组学与应用生物学,2024,43(01):172-180.DOI:10.13417/j.gab.043.000172.
基金信息:
国家自然科学基金项目(81860148)资助
2023-09-14
2023-09-14
2023-09-14