Association of MTHFR Gene Variants (rs1801133 and rs1801131) with Serum Trace Elements Copper and Zinc and Biochemical Parameters (Homocysteine, Folic Acid, and Vitamin B12) in Individuals with Short Stature

Background: Human height generally follows a normal distribution; thus, short stature is defined as height below the 3rd percentile or 2 standard deviations (SD) from the mean. Homocysteine metabolism, which involves folate and vitamin B12, is regulated by the methylenetetrahydrofolate reductase (MTHFR) enzyme. This study aimed to investigate the association of MTHFR polymorphisms with trace elements (copper and zinc), homocysteine, folic acid, and vitamin B12 in children with short stature. Methods: A total of 280 participants (130 short stature cases and 150 healthy controls), aged 4–12 years, were included. Serum homocysteine, folic acid, and vitamin B12 were measured using ELISA. MTHFR polymorphisms (rs1801133 and rs1801131) were genotyped using TaqMan® SNP Genotyping Assay via RT-PCR. Copper and zinc levels were measured by atomic absorption spectrophotometry. Results: The MTHFR rs1801133 polymorphism showed a significant association with short stature, with individuals carrying the TT genotype exhibiting higher homocysteine levels (26.3 ± 9.6 µmol/L), and lower folic acid (22.4 ± 4.3 ng/mL) and B12 levels (194.4 ± 27.9 pg/mL) compared to controls (p < 0.001). The TT genotype was also associated with higher copper (110.4 ± 14.94 µg/dL) and lower zinc levels (65.88 ± 16.69 µg/dL) in cases versus controls (p < 0.001). No significant association was observed for rs1801131. Conclusion: The MTHFR rs1801133 (TT genotype) is associated with elevated homocysteine, altered trace elements, and increased risk of short stature. These findings highlight the role of genetic and nutritional factors in growth regulation.