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Single nucleotide polymorphisms in the phosphatidylethanolamine N‐methyltransferase gene may influence choline requirement

Humans derive the choline they require from their diet and from de novo biosynthesis catalyzed by the enzyme phosphatidylethanolamine N‐methyltransferase (PEMT). In previous studies, we found that pre‐menopausal women were resistant to developing organ dysfunction when consuming a low choline diet as compared to post‐menopausal women and men. Also, we showed that the gene PEMT is estrogen responsive, allowing pre‐menopausal women to form more of their required choline via PEMT. However, some pre‐menopausal women (44%) did develop choline deficiency and we found that they had a haplotype containing an allele for a single nucleotide polymorphism (SNP) in PEMT (rs12325817). To determine whether this effect of the SNP increased with the number of mutant alleles, we recruited 27 pre‐menopausal women with 0, 1 or 2 of the alleles. They were fed a baseline diet containing 550 mg choline/day for 10 days, followed by a choline deficient diet for up to 42 days, and a repletion diet with 850 mg choline for 10 days. Subjects were deemed clinically choline deficient if they developed hepatic steatosis or muscle dysfunction on the low choline diet and if the organ dysfunction disappeared when choline was returned to the diet. We found that 80% of the subjects who were homozygous for the SNP became choline deficient compared to 43% with 1 variant allele, and 13% without the SNP (p=0.02). We conclude that the risk of a pre‐menopausal woman becoming choline deficient is proportional to the allele dose for the SNP rs12325817.