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Background <p>Autoimmune thyroid diseases (AITDs), particularly Graves’ disease (GD), are complex disorders characterized by thyroidal immune infiltration and autoantibody production influenced by genetic and environmental factors. HLA class II alleles (HLA-DQB2, HLA-DRB3) promote immune tolerance loss via altered antigen presentation, while vitamin D receptor (VDR) polymorphisms (<i>ApaI</i>-rs7975232; <i>BsmI</i>-rs1544410) disrupt immune homeostasis by affecting VDR signaling and Treg/Th1/Th2/Th17 balance. Furthermore, chronic endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) exacerbate inflammation, apoptosis and defective TSHR signaling. This study explores the indirect mechanistic association and coordinated signaling pathways among VDR polymorphisms, ER stress markers, and HLA class II alleles, revealing integrated mechanisms underlying GD pathogenesis.</p> Methods and Results <p>A cohort of 70 Graves’ disease patients and age-sex matched healthy controls were analyzed for genetic, molecular and biochemical parameters related to Graves’ hyperthyroidism. PBMCs, RNA, DNA and proteins were extracted for qRT-PCR, immunoblotting, and PCR-RFLP genotyping (VDR rs7975232, rs1544410) following standardized, ethically approved protocols. Graves’ disease (GD) patients, predominantly female, exhibited vitamin D deficiency without significant serum variation. VDR polymorphisms (<i>ApaI</i>, <i>BsmI</i>) were detected in 65.71% and 64.28% of patients respectively, correlating with heightened thyroid hormone levels, autoantibody titres, proinflammatory cytokines, ER stress and reduced FoxP3/CTLA-4 expression. HLA-DQB2 and HLA-DRB3 sub-alleles further indicated strong genetic susceptibility to GD pathogenesis.</p> Conclusion <p>This study demonstrates that VDR polymorphisms (<i>ApaI</i>, <i>BsmI</i>) exacerbate Graves’ disease by enhancing thyroid autoimmunity, inflammation and ER stress while diminishing immune tolerance. Despite comparable vitamin D levels, VDR-mutant patients exhibited heightened immune activation. HLA class II alleles influence susceptibility, whereas VDR variants dictate disease severity, underscoring VDR signaling as a therapeutic target.</p>

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Vitamin D receptor (ApaI/BsmI) polymorphisms, human leukocyte antigen-DQB2/DRB3 sub-alleles, and endoplasmic reticulum stress: unravelling their interplay in the pathogenesis of Graves’ disease in a tertiary care centre

  • 期刊论文

  • 发表日期：

    2026年4月16日

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  • Akash Kumar Haldar,
  • Ajitesh Roy,
  • Rinini Dastidar,
  • Shawan Kumar Banerjee,
  • Debdatta Talukdar,
  • Arnab Basu,
  • Soumitra Kumar,
  • Kunal Sikder

摘要

Background

Autoimmune thyroid diseases (AITDs), particularly Graves’ disease (GD), are complex disorders characterized by thyroidal immune infiltration and autoantibody production influenced by genetic and environmental factors. HLA class II alleles (HLA-DQB2, HLA-DRB3) promote immune tolerance loss via altered antigen presentation, while vitamin D receptor (VDR) polymorphisms (ApaI-rs7975232; BsmI-rs1544410) disrupt immune homeostasis by affecting VDR signaling and Treg/Th1/Th2/Th17 balance. Furthermore, chronic endoplasmic reticulum (ER) stress and the unfolded protein response (UPR) exacerbate inflammation, apoptosis and defective TSHR signaling. This study explores the indirect mechanistic association and coordinated signaling pathways among VDR polymorphisms, ER stress markers, and HLA class II alleles, revealing integrated mechanisms underlying GD pathogenesis.

Methods and Results

A cohort of 70 Graves’ disease patients and age-sex matched healthy controls were analyzed for genetic, molecular and biochemical parameters related to Graves’ hyperthyroidism. PBMCs, RNA, DNA and proteins were extracted for qRT-PCR, immunoblotting, and PCR-RFLP genotyping (VDR rs7975232, rs1544410) following standardized, ethically approved protocols. Graves’ disease (GD) patients, predominantly female, exhibited vitamin D deficiency without significant serum variation. VDR polymorphisms (ApaI, BsmI) were detected in 65.71% and 64.28% of patients respectively, correlating with heightened thyroid hormone levels, autoantibody titres, proinflammatory cytokines, ER stress and reduced FoxP3/CTLA-4 expression. HLA-DQB2 and HLA-DRB3 sub-alleles further indicated strong genetic susceptibility to GD pathogenesis.

Conclusion

This study demonstrates that VDR polymorphisms (ApaI, BsmI) exacerbate Graves’ disease by enhancing thyroid autoimmunity, inflammation and ER stress while diminishing immune tolerance. Despite comparable vitamin D levels, VDR-mutant patients exhibited heightened immune activation. HLA class II alleles influence susceptibility, whereas VDR variants dictate disease severity, underscoring VDR signaling as a therapeutic target.