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<p>Autism spectrum disorders (ASD) represent a complex medical and social issue with a multifactorial etiology, often correlated with the host genetic background, particularly with the folate metabolic pathway. This study aimed to investigate the association between MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms and ASD susceptibility in an Apulian cohort. We analyzed 73 patients diagnosed with ASD and 84 healthy controls recruited at the University Hospital Policlinico, Bari. Genotyping was performed using a Real-time/FRET method. Statistical analysis evaluated genotypic/allelic distributions and haplotype frequencies. While single genotype distributions did not differ significantly between groups, the MTHFR 677T allele frequency was significantly higher in controls (50%) compared to the ASD group (37.67%; <i>p</i> = 0.038), suggesting a potential protective role. Haplotype analysis identified the C-C-G combination as a significant risk factor for ASD (OR = 3.60; <i>p</i> = 0.019). In silico analysis confirmed that the C677T polymorphism (A222V) significantly destabilizes the MTHFR protein structure, in agreement with previous findings. Our findings suggest that an unknown evolutionary advantage may explain the circulation of the MTHFR 677T allele in the general Apulian population, supported by the high folate intake peculiar to the Mediterranean diet. The enzymatic alterations caused by the C-C-G haplotype, selected by the ASD Apulian group, are herein detrimental for folate metabolism.</p>

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Genetic Susceptibility to Autism Spectrum Disorders: Folate Pathway Polymorphisms, Mediterranean Diet and Evolutionary Insights

  • 期刊论文

  • 发表日期：

    2026年5月29日

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  • Maria Addolorata Bonifacio,
  • Angela Vinella,
  • Mariella Pafundi,
  • Lucia Margari,
  • Maria Addolorata Mariggiò

摘要

Autism spectrum disorders (ASD) represent a complex medical and social issue with a multifactorial etiology, often correlated with the host genetic background, particularly with the folate metabolic pathway. This study aimed to investigate the association between MTHFR (C677T and A1298C) and MTRR (A66G) polymorphisms and ASD susceptibility in an Apulian cohort. We analyzed 73 patients diagnosed with ASD and 84 healthy controls recruited at the University Hospital Policlinico, Bari. Genotyping was performed using a Real-time/FRET method. Statistical analysis evaluated genotypic/allelic distributions and haplotype frequencies. While single genotype distributions did not differ significantly between groups, the MTHFR 677T allele frequency was significantly higher in controls (50%) compared to the ASD group (37.67%; p = 0.038), suggesting a potential protective role. Haplotype analysis identified the C-C-G combination as a significant risk factor for ASD (OR = 3.60; p = 0.019). In silico analysis confirmed that the C677T polymorphism (A222V) significantly destabilizes the MTHFR protein structure, in agreement with previous findings. Our findings suggest that an unknown evolutionary advantage may explain the circulation of the MTHFR 677T allele in the general Apulian population, supported by the high folate intake peculiar to the Mediterranean diet. The enzymatic alterations caused by the C-C-G haplotype, selected by the ASD Apulian group, are herein detrimental for folate metabolism.