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The two primary MTHFR variants are C677T (rs1801133) which substitutes valine for alanine at position 222, reducing enzyme activity by approximately 35% in heterozygotes and 70% in T/T homozygotes at physiological folate concentrations and A1298C (rs1801131) which substitutes glutamate for alanine at position 429, reducing activity by approximately 20% in heterozygotes, with compound heterozygosity (C677T + A1298C) producing effects between the two individual homozygous states

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and A.E

Both of these transcription factors participate in the oxidative stress response and become activated by redox switches

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This self-directed immune response causes widespread tissue damage and systemic inflammation [87,88]