Polymorphism in BACH2 gene is a marker of polyglandular autoimmunity

Marta Fichna,Marek Ruchała,Bartosz Słomiński,Piotr Fichna,Magdalena Żurawek,Agata Czarnywojtek,Natalia Rozwadowska,Marta Sumińska,Małgorzata Myśliwiec

doi:10.1007/s12020-021-02743-9

Abstract

PurposeGenetically predisposed individuals may develop several autoimmune diseases—autoimmune polyendocrine syndromes (APS). APS types 2–4, are complex disorders, which combine various organ-specific autoimmune conditions. Recent reports support the considerable role of the BACH2 gene in immune cell differentiation and shifting the T-cell balance towards regulatory T-cells. BACH2 polymorphisms are associated with autoimmune disorders, including Addison’s disease (AD), Graves’ disease (GD), and probably type 1 diabetes (T1D). Our study was aimed to investigate the BACH2 variant, rs3757247, in endocrine autoimmunity in the Polish population.MethodsThe analysis comprised 346 individuals with APS, 387 with T1D only, and 568 controls. Genotyping was performed using TaqMan chemistry.ResultsAPS type 2 was found in 219 individuals, type 3 in 102, and type 4 in 25 subjects. Overall, AD was diagnosed in 244 subjects, Hashimoto’s thyroiditis—in 238, T1D—in 127, GD—in 58, vitiligo and chronic gastritis each in 40 patients, celiac disease—in 28, premature menopause in 18, and alopecia in 4 patients. Minor T allele at rs3757247 was found in 56.4% APS vs. 44.1% control alleles (OR 1.59; 95%CI: 1.30–1.95, p < 0.0001). The distribution of genotypes revealed excess TT homozygotes in the APS cohort (33.2 vs. 20.1% in controls, p < 0.0001). The frequencies of rs3757247 alleles and genotypes in T1D patients did not present significant differences vs. controls (p-values > 0.05).ConclusionsThese results provide evidence of the association between BACH2 polymorphism and polyglandular autoimmunity. Since carriers of rs3757247 display increased risk for additional autoimmune conditions, this variant could identify individuals prone to develop APS.

Highlights

Autoimmunity accounts for up to one hundred diseases, which, taken together, are responsible for considerable morbidity and mortality worldwide [1]
Endocrine (2021) 74:72–79 disease (AD) combined with autoimmune thyroid disease (AITD) and/or type 1 diabetes (T1D), autoimmune polyendocrine syndromes (APS) type 3, which designates any combination of autoimmune diseases without Addison’s disease (e.g., AITD together with chronic atrophic gastritis [CAG]), and APS type 4, which includes any combination of AD with autoimmune conditions other than AITD and T1D, such as CAG, or vitiligo [5]
Homozygous carriers of the minor rs3757247 allele appeared at increased risk for multiple autoimmune conditions, no effect on a number of disorders was detected

Summary

Introduction

Autoimmunity accounts for up to one hundred diseases, which, taken together, are responsible for considerable morbidity and mortality worldwide [1]. Autoimmune conditions tend to cluster within families, their inheritance pattern is rarely straightforward [3, 4]. Genetically predisposed individuals may develop several autoimmune diseases, traditionally categorized into four distinct autoimmune polyendocrine syndromes (APS) [5]. This canonical classification, established by Neufeld and Blizzard, enables to distinguish APS type 1, which is a unique monogenic entity, APS type 2, which comprises Addison’s. Some authors distinguish APS type 1 due to autosomal recessive mutations in the AIRE gene, and APS type 2, for all other autoimmune disease combinations that do not follow mendelian inheritance [6]

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