Thyroid peroxidase gene variants and autoimmunity in subclinical hypothyroidism: molecular mechanisms and clinical implications.

Subclinical hypothyroidism (SCH), characterized by elevated thyroid-stimulating hormone (TSH) levels with normal thyroid hormone concentrations, is a common endocrine disorder with potential to progress to overt hypothyroidism. Autoimmune thyroiditis particularly Hashimoto's disease is the predominant cause, often marked by the presence of anti-thyroid peroxidase (TPOAbs) antibodies. Thyroid peroxidase (TPO), a key enzyme in thyroid hormone biosynthesis, also serves as a major autoantigen in autoimmune thyroid disorders. This review highlights the dual enzymatic and immunogenic roles of TPO, emphasizing the structural domains critical for both hormone synthesis and antibody binding. Recent evidence links several TPO gene polymorphisms especially in exons 8, 11, and to increased TPOAbs antibody titers and susceptibility to SCH. We further examine the role of gene-environment interactions, including micronutrient deficiencies (vitamin D, B12, iron), iodine status, and demographic factors (age, sex), in modulating immune responses and thyroid function. Exon 8 variants are increasingly recognized as immunogenic hotspots but remain underexplored, particularly in Middle Eastern populations. Understanding these genetic and environmental determinants may improve early diagnosis, enable risk-based screening, and inform personalized prevention strategies. This review advocates for expanded population-specific studies and supports integrating genetic markers with clinical parameters to refine SCH detection and management.