Interaction Between CTLA-4, FOXO-3, and PTPN-22 Variants and Environmental Factors in Type 1 Diabetes—Observational Association Study

<b>Background</b>: Immune-regulatory genes such as <i>CTLA-4</i>, <i>FOXO-3</i>, and <i>PTPN-22</i> influence immune tolerance and metabolic adaptation, but their interaction with environmental factors in type 1 diabetes (T1DM) remains unclear. <b>Methods</b>: In this observational associated study, we analyzed <i>CTLA-4</i> (rs3087243, rs231775), <i>FOXO-3</i> (rs2802292, rs9400239), and <i>PTPN-22</i> (rs12730735) polymorphisms in 277 adults with T1DM, assessing associations with probiotic and vitamin D use, self-reported dietary patterns, metabolic control, autoimmune thyroid disease (AITD), and metabolic dysfunction-associated steatotic liver disease (MASLD). <b>Results</b>: Across the cohort, <i>CTLA-4</i> rs3087243 G and <i>FOXO-3</i> rs2802292 T alleles were associated with higher AITD risk (<i>p</i> = 0.016-0.03), significant in both dominant and additive models. The effect persisted by sex: <i>CTLA-4</i> in women and <i>FOXO-3</i> in men. Stratified analyses revealed metabolic advantages for <i>CTLA-4</i> G and <i>FOXO-3</i> T carriers (vegetarian diet, lower HbA1c, stress adaptation). <i>FOXO-3</i> rs9400239 T was linked to MASLD (<i>p</i> ≈ 0.037-0.041), with similar trends for <i>CTLA-4</i> rs231775, stronger in men. Vitamin D supplementation showed protective trends, particularly in <i>FOXO-3</i> rs2802292 GG and <i>CTLA-4</i> GG/AG carriers. Conversely, probiotic use was associated with higher AITD in <i>FOXO-3</i> rs2802292 GT and <i>CTLA-4</i> rs3087243 GG genotypes. <b>Conclusions</b>: <i>CTLA-4</i>, <i>FOXO-3</i>, and <i>PTPN-22</i> variants may modulate the metabolic and autoimmune response to environmental factors including nutrients in T1DM.