title: Association of Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) and Thyroglobulin (TG) Genetic Variants with Autoimmune Hypothyroidism.
abstract: Autoimmune hypothyroidism is known to be caused by immune responses related to the thyroid gland and its immunological feature includes presence of autoimmune antibodies. Therefore the aim was to analyze presence of anti-TPO antibodies in hypothyroidism patients in Gujarat. Cytotoxic T-Lymphocyte Antigen 4 (CTLA4) is one of the susceptibility genes for various autoimmune diseases. Hence, exon1 +49A/G and 3'UTR CT60A/G single nucleotide polymorphisms (SNPs) in CTLA4 and its mRNA expression levels were investigated in autoimmune hypothyroidism patients. Thyroglobulin (TG) is known to be associated with autoimmune thyroid disorders and thus exon 33 (E33) SNP in TG was investigated. We analyzed the presence of anti-TPO antibodies in the plasma samples of 84 hypothyroidism patients and 62 controls by ELISA. PCR-RFLP technique was used for genotyping of polymorphisms. sCTLA4 and flCTLA4 mRNA expression levels were assessed by real time PCR. 59.52% of hypothyroid patients had anti-TPO antibodies in their circulation. The genotype and allele frequencies differed significantly for +49A/G (p = 0.0004 for +49AG, p = 0.0019 for +49GG & p = 0.0004 for allele), CT60 (p = 0.0110 for CT60AG, p = 0.0005 for CT60GG & p<0.0001 for allele) and TG E33 (p = 0.0003 for E33TC p<0.0001 for E33CC& p<0.0001 for allele) SNPs between patients and controls. Patients had significantly decreased mRNA levels of both sCTLA4 (p = 0.0017) and flCTLA4 (p<0.0001) compared to controls. +49A/G and CT60 polymorphisms of CTLA4 were in moderate linkage disequilibrium. Logistic regression analysis indicated significant association of CT49A/G, CT60A/G and TG exon 33 polymorphisms with susceptibility to autoimmune hypothyroidism when adjusted for age and gender. Our results suggest +49A/G and CT60 polymorphism of CTLA4 and E33 polymorphism of TG may be genetic risk factors for autoimmune hypothyroidism susceptibility and down regulation of both forms of CTLA4 advocates the crucial role of CTLA4 in pathogenesis of autoimmune hypothyroidism.
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Hinal
authors.initials: H
authors.lastname: Patel
authors.affiliation: Biochemistry Department, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Mohmmad Shoab
authors.initials: MS
authors.lastname: Mansuri
authors.affiliation: Biochemistry Department, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Mala
authors.initials: M
authors.lastname: Singh
authors.affiliation: Biochemistry Department, Faculty of Science, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Rasheedunnisa
authors.initials: R
authors.lastname: Begum
authors.affiliation: Medicine Department, Faculty of Medicine, Sir Sayajirao Gaekwad Hospital, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Minal
authors.initials: M
authors.lastname: Shastri
authors.affiliation: Pharmacy Department, Faculty of Technology & Engineering, The Maharaja Sayajirao University of Baroda, Vadodara, Gujarat, India.
authors.forename: Ambikanandan
authors.initials: A
authors.lastname: Misra
mesh_terms: D020413:3' Untranslated Regions / Q000235:genetics; D060908:CTLA-4 Antigen / Q000235:genetics* / Q000378:metabolism; D016022:Case-Control Studies; D005091:Exons / Q000235:genetics; D005260:Female; D005786:Gene Expression Regulation; D056726:Genetic Association Studies; D020022:Genetic Predisposition to Disease; D006239:Haplotypes / Q000235:genetics; D050031:Hashimoto Disease / Q000235:genetics*; D006801:Humans; D007453:Iodide Peroxidase / Q000276:immunology; D015810:Linkage Disequilibrium / Q000235:genetics; D016015:Logistic Models; D008297:Male; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D012333:RNA, Messenger / Q000235:genetics / Q000378:metabolism; D013954:Thyroglobulin / Q000235:genetics* / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000235:genetics*
chemical_list: D020413:3' Untranslated Regions; D060908:CTLA-4 Antigen; D012333:RNA, Messenger; D013954:Thyroglobulin; D007453:Iodide Peroxidase