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A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans.

ABSTRACT: CONTEXT:Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions. OBJECTIVE:We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD. DESIGN, SETTING, AND PATIENTS:This case-control association study was performed in two phases using Taqman chemistry. In the first phase, the rs3757247 SNP was genotyped in 358 UK AAD subjects and 166 local control subjects. Genotype data were also available from 5154 healthy UK controls from the Wellcome Trust (WTCCC2) for comparison. In the second phase, the SNP was genotyped in a validation cohort comprising 317 Norwegian AAD subjects and 365 controls. RESULTS:The frequency of the minor T allele was significantly higher in subjects with AAD from the United Kingdom compared to both the local and WTCCC2 control cohorts (58% vs 45 and 48%, respectively) (local controls, P = 1.1 × 10-4; odds ratio [OR], 1.68; 95% confidence interval [CI], 1.29-2.18; WTCCC2 controls, P = 1.4 × 10-6; OR, 1.44; 95% CI, 1.23-1.69). This finding was replicated in the Norwegian validation cohort (P = .0015; OR, 1.41; 95% CI, 1.14-1.75). Subgroup analysis showed that this association is present in subjects with both isolated AAD (OR, 1.53; 95% CI, 1.22-1.92) and autoimmune polyglandular syndrome type 2 (OR, 1.37; 95% CI, 1.12-1.69) in the UK cohort, and with autoimmune polyglandular syndrome type 2 in the Norwegian cohort (OR, 1.58; 95% CI, 1.22-2.06). CONCLUSION:We have demonstrated, for the first time, that allelic variability at the BACH2 locus is associated with susceptibility to AAD. Given its association with multiple autoimmune conditions, BACH2 can be considered a "universal" autoimmune susceptibility locus.

SUBMITTER: Pazderska A

PROVIDER: S-EPMC5095240 | biostudies-literature | 2016 Nov

REPOSITORIES: biostudies-literature

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A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans.

Pazderska Agnieszka A Oftedal Bergithe E BE Napier Catherine M CM Ainsworth Holly F HF Husebye Eystein S ES Cordell Heather J HJ Pearce Simon H S SH Mitchell Anna L AL

The Journal of clinical endocrinology and metabolism 20160928 11

<h4>Context</h4>Autoimmune Addison's disease (AAD) is a rare but highly heritable condition. The BACH2 protein plays a crucial role in T lymphocyte maturation, and allelic variation in its gene has been associated with a number of autoimmune conditions.<h4>Objective</h4>We aimed to determine whether alleles of the rs3757247 single nucleotide polymorphism (SNP) in the BACH2 gene are associated with AAD.<h4>Design, setting, and patients</h4>This case-control association study was performed in two ...[more]

PMID: 27680876

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Project description:Abstract Background Crohn’s disease often requires intestinal resection, which is not considered curative. Repeat surgical intervention is necessary in over half of the patients following their initial operation. Although many genetic loci are implicated in Crohn’s disease, few have been associated with post-resection recurrence. Aims To identify genetic factors that predict recurrence of CD following intestinal resection. Methods A cohort of Crohn’s disease subjects who underwent intestinal resection was analyzed to determine genetic and clinical factors associated with post-resection recurrence. Genotype was assessed at eight loci associated with adaptive immunity (SMAD3, IL10RB, IL15RA, BACH2, IL12B, IL18RAP, IFNGR2, and JAK2). Univariate and multivariate survival analyses were performed using a log-rank test and Cox-proportional hazard model, respectively. Results 191 Crohn’s disease subjects with 11.2 years mean post-operative follow-up were included. 46% experienced a surgical recurrence. Factors associated with increased incidence of recurrence included male gender(p=0.05), and shortened time to first intestinal surgery(5.0 vs 7.3years p=0.03), while inflammatory disease behaviour was associated with a lower chance of repeat surgery(p<0.01). Of the loci assessed on multivariate analysis, homozygosity for a risk allele at BACH2 (rs1847472) was significantly associated with disease recurrence(HR-1.24 CI-1.00–1.54 p<0.05). Conclusions We identify BACH2 as a susceptibility locus for post-operative recurrence of Crohn’s disease in our cohort. BACH2 is critical in the differentiation and function of T-cells, as a regulator of B-cell activity, and is associated with several dysregulated immunologic phenomena. Its identification as a risk locus in post-operative Crohn’s disease recurrence suggests a potential role for regulatory T cells, effector T cells, humoral immunity, and immunologic memory in the development of this disease process. Funding Agencies CIHR

Dataset Information

A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans.

Publications

A Variant in the BACH2 Gene Is Associated With Susceptibility to Autoimmune Addison's Disease in Humans.

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