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

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