Association of the CYP27B1 C(−1260)A Polymorphism with Autoimmune Addison's Disease

Abstract

Autoimmune Addison's disease (AAD) is a complex endocrine disorder with several susceptibility loci. This study was aimed to investigate the associations of CYP27B1 C(−1260)A and PDCD1 G7146A polymorphisms with AAD in a Polish cohort, comprising 101 AAD patients and 251 healthy controls. CYP27B1 encodes 1alpha-hydroxylase, responsible for conversion of the vitamin D₃ precursor into its active form, involved in the immune function. PDCD1 gene gives rise to an inhibitory immune receptor, expressed on activated lymphocytes. Polymorphic variants of these genes had previously been associated with various autoimmune disorders. Genotyping was performed by PCR-RFLP method. The CYP27B1 C(−1260) allele appeared significantly more frequent in AAD compared to controls (p=0.020), yielding an OR of 1.53 (95% CI 1.07–2.19). The distribution of C(−1260)A genotypes also demonstrated significant difference (p=0.003). Stratification according to the presence of concomitant autoimmune disorders revealed an association of the C(−1260) allele with the polyendocrine cases of AAD (p=0.031), while no significance was found for the isolated ADD compared with healthy controls (p=0.253). Overall, the association between AAD and C(−1260)A was confirmed in a meta-analysis of 325 AAD patients and 952 controls from three different European populations. Under a fixed-effect model, C(−1260) allele and CC genotype were associated with AAD susceptibility with a pooled OR of 1.44 (95% CI 1.18–1.75) and 1.88 (95% CI 1.42–2.36), respectively. No differences were observed for the PDCD1 G7146A between affected subjects and controls (p>0.05). In conclusion, this study confirms the association of the CYP27B1 C(−1260)A polymorphism with AAD, whereas the contribution of PDCD1 G7146A seems less likely.

Key words

Addison's disease - autoimmunity - polymorphism - CYP27B1 - PDCD1

References

• 1 Agata Y, Kawasaki A, Nishimura H. et al . Expression of the PD-1 antigen on the surface of stimulated mouse T and B lymphocytes.  Int Immunol. 1996;  8 765-772
• 2 Ansari MJ, Salama AD, Chitnis T. et al . The programmed death-1 (PD-1) pathway regulates autoimmune diabetes in nonobese diabetic (NOD) mice.  J Exp Med. 2003;  198 63-69
• 3 Arai H, Miyamoto KI, Yoshida M. et al . The polymorphism in the caudal-related homeodomain protein Cdx-2 binding element in the human vitamin D receptor gene.  J Bone Miner Res. 2001;  16 1256-1264
• 4 Asad S, Nikamo P, Torn C. et al . Diabetes Incidence in Sweden Study Group: No evidence of association of the PDCD1 gene with type 1 diabetes.  Diabet Med. 2007;  24 1473-1477
• 5 Bailey R, Cooper JD, Zeitels L. et al . Association of the vitamin D metabolism gene CYP27B1 with type 1 diabetes.  Diabetes. 2007;  56 2616-2621
• 6 Bertsias GK, Nakou M, Choulaki C. et al . Genetic, immunologic, and immunohistochemical analysis of the programmed death 1/programmed death ligand 1 pathway in human systemic lupus erythematosus.  Arthritis Rheum. 2009;  60 207-218
• 7 Betterle C, Dal Pra C, Mantero F. et al . Autoimmune adrenal insufficiency and autoimmune polyendocrine syndromes: autoantibodies, autoantigens, and their applicability in diagnosis and disease prediction.  Endocr Rev. 2002;  23 327-364
• 8 Bottini N, Musumeci L, Alonso A. et al . A functional variant of lymphoid tyrosine phosphatase is associated with type I diabetes.  Nat Genet. 2004;  36 337-338
• 9 Carter L, Fouser LA, Jussif J. et al . PD-1: PD-L inhibitory pathway affects both CD4(+) and CD8(+) T cells and is overcome by IL-2.  Eur J Immunol. 2002;  32 634-643
• 10 Deluca HF, Cantorna MT. Vitamin D: its role and uses in immunology.  FASEB J. 2001;  15 2579-2585
• 11 Erichsen MM, Lovas K, Fougner KJ. et al . Normal overall mortality rate in Addison's disease, but young patients are at risk of premature death.  Eur J Endocrinol. 2009;  160 233-237
• 12 Fournier C, Gepner P, Sadouk M. et al . In vivo beneficial effects of cyclosporine A and 1,25-dihydroxyvitamin D3 on the induction of experimental autoimmune thyroiditis.  Clin Immunol Immunopathol. 1990;  54 53-63
• 13 Higgins JP, Green S. Cochrane Handbook for Systematic Reviews of Interventions. Version 5.0.1  2008;  http://www.cochrane-handbook.org
• 14 Hyppnen F, Läärä E, Reunanen A. et al . Intake of vitamin D and risk of type 1 diabetes: A birth-cohort study.  Lancet. 2001;  358 1500-1503
• 15 Jennings CE, Owen CJ, Wilson V. et al . A haplotype of the CYP27B1 promoter is associated with autoimmune Addison's disease but not with Graves’ disease in a UK population.  J Mol Endocrinol. 2005;  34 859-863
• 16 Kim CJ, Kaplan LE, Perwad F. et al . Vitamin D 1apha-hydroxylase gene mutations in patients with 1alpha-hydroxylase deficiency.  J Clin Endocrinol Metab. 2007;  92 3177-3182
• 17 Lee YH, Woo JH, Choi SJ. et al . Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: A meta-analysis.  Lupus. 2009;  18 9-15
• 18 Mathieu C, Waer M, Laureys J. et al . Prevention of autoimmune diabetes in NOD mice by 1,25 dihydroxyvitamin D3.  Diabetologia. 1994;  37 552-558
• 19 Myhre AG, Undlien DE, Lovas K. et al . Autoimmune adrenocortical failure in Norway autoantibodies and human leukocyte antigen class II associations related to clinical features.  J Clin Endocrinol Metab. 2002;  87 618-623
• 20 Nagamine K, Peterson P, Scott HS. et al . Positional cloning of the APECED gene.  Nature Genet. 1997;  17 393-398
• 21 Neufeld M, Blizzard RM. Polyglandular autoimmune diseases. In: Pinchera A, Doniach D, Fenzi GF, Baschieri L, eds. Symposium on autoimmune aspects of endocrine disorders. Academic Press, New York 1980: 357-365
• 22 Nielsen C, Hansen D, Husby S. et al . Association of a putative regulatory polymorphism in the PD-1 gene with susceptibility to type 1 diabetes.  Tissue Antigens. 2003;  62 492-497
• 23 Panda DK, Miao D, Tremblay ML. et al . Targeted ablation of the 25-hydroxyvitamin D 1alpha-hydroxylase enzyme: evidence for skeletal, reproductive, and immune dysfunction.  Proc Natl Acad Sci USA. 2001;  98 7498-7503
• 24 Pozzilli P, Manfrini S, Crino A. et al . IMDIAB group   Low levels of 25-hydroxyvitamin D3 and 1,25-dihydroxyvitamin D3 in patients with newly diagnosed type 1 diabetes.  Horm Metab Res. 2005;  37 680-683
• 25 Prokunina L, Castillejo-López C, Öberg F. et al . A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans.  Nat Genet. 2002;  32 666-669
• 26 Ramos-Lopez E, Zwermann O, Segni M. et al . A promoter polymorphism of the CYP27B1 gene is associated with Addison's disease, Hashimoto's thyroiditis, Graves’ disease and type 1 diabetes mellitus in Germans.  Eur J Endocriol. 2004;  151 193-197
• 27 Ramos-Lopez E, Brück P, Jansen T. et al . CYP2R1-, CYP27B1- and CYP24-mRNA expression in German type 1 diabetes patients.  J Steroid Biochem Mol Biol. 2007;  103 807-810
• 28 Sakthivel P, Ramanujam R, Wang XB. et al . Programmed Death-1: from gene to protein in autoimmune myasthenia gravis.  J Neuroimmunol. 2008;  193 149-155
• 29 Sutherland A, Davies J, Owen CJ. et al . Genomic polymorphism at the interferon-induced helicase (IFIH1) locus contributes to Graves’ disease susceptibility.  J Clin Endocrinol. 2007;  92 3338-3341
• 30 Torkildsen O, Knappskog PM, Nyland HI. et al . Vitamin D-dependent rickets as a possibile risk factor for multiple sclerosis.  Arch Neurol. 2008;  65 809-811
• 31 Wellcome Trust Case Control Consortium. . Genome-wide association study of 14 000 cases of seven common diseases and 3 000 shared controls.  Nature. 2007;  447 661-678
• 32 Wellcome Trust Case Control Consortium . Association scan of 14 500 nonsynonymous SNPs in four diseases identifies autoimmunity variants.  Nat Genet. 2007;  39 1329-1337

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