The Role of Genes in Choline Deficiency (PEMT)

Before diving into genetics, let’s see why you should care about getting enough choline in the first place. Your body needs this nutrient for [R, R, R]:

• Brain, liver, and muscle health
• Fetal development
• Fat transport and metabolism
• Cell structure and signaling

Choline deficiency can cause liver and muscle damage in just a few weeks. An expectant mother’s poor choline status is associated with neural tube defects and other anomalies [R, R, R, R].

According to data from 2003-2004, around 90% of people don’t get enough of this nutrient [R].

Choline is essential for brain and liver health, fetal development, fat metabolism, and more. Choline deficiency affects up to 90% of people; it can result in liver and muscle damage.

During evolution, our bodies came up with a way to produce choline in the absence of food sources—that’s where PEMT kicks in.

PEMT encodes an enzyme (phosphatidylethanolamine N-methyltransferase) which produces phosphatidylcholine (PC). It converts phosphatidylethanolamine (PE) into PC, using S-adenosylmethionine (SAM-e) as a methyl group donor [R].

PC can then release choline and, to a certain extent, compensate for the lack of this nutrient. PEMT is mainly expressed in the liver and accounts for 30% of liver PC production [R, R, R].

This enzyme is crucial for maintaining liver choline levels. PEMT-deficient mice lack choline in the liver, despite the adequate intake and supplementation [R].

PEMT encodes an enzyme that produces phosphatidylcholine and choline in the liver. It can make up for a mild choline deficiency due to poor diet.

Men vs. Women — the Power of Estrogen

Compared with men and postmenopausal women, younger women are almost two times less likely to develop fatty liver and muscle damage due to choline deficiency [R, R].

Estrogen boosts PEMT activity in the liver. High levels of estrogen during pregnancy and breastfeeding ensure proper choline supply for a growing baby [R, R].

A 2006 study identified one PEMT variation, rs12325817, strongly associated with choline deficiency. Women with a “G” allele were 25 times more likely to experience organ damage on a low-choline diet (<50 mg/70 kg daily) [R].

Further analysis revealed that postmenopausal women were driving this connection, with the rates for ladies with the “G” allele being 42 times higher! In men and younger women, this variation had a lower impact [R].

That said, a small sample of just 57 participants (31 women) calls for further investigation.

The research team added 33 women to the study and identified four additional variants with a weaker effect: rs4646343-T, rs3760188-T, rs1531100-A, and rs4646365-T. The last two were significant only in postmenopausal women and their impact was marginal [R].

Fatty liver is usually the first clinical sign of choline deficiency. One PEMT variant, rs7946-T,  correlates with fatty liver and reduced choline supply. If you have this variant, you’re more likely to experience liver damage due to poor choline intake, sedentary lifestyle, and overeating [R, R].

The "G" allele on rs12325817 and five more PEMT variants correlate with organ damage due to choline deficiency. Their impact is strongest among postmenopausal women.

How It Works

The authors conducted lab experiments to figure out the mechanisms at play. They found that the PEMT variant makes the gene less responsive to estrogen stimulation. It prevents estrogen from binding to this gene and boosting its expression [R, R].

As a result, PEMT activity drops, the liver doesn’t make enough choline to prevent deficiency, and organ damage kicks in. 

Premenopausal women usually have estrogen levels high enough to overcome this effect, while men's PEMT doesn't rely on estrogen that much. That's why the impact of PEMT variations was the strongest in postmenopausal women with low estrogen [R].

Apparently, you should pay special attention to your PEMT risk alleles if you are a postmenopausal woman.

Specific variants can make PEMT less responsive to estrogen stimulation, reducing its ability to produce choline. Postmenopausal women are more susceptible to this effect due to low estrogen.

SNP Summary and Table

Primary SNP:

PEMT rs12325817

• ‘C’ = Doesn’t correlate with choline deficiency
• ‘G’ = Correlates with choline deficiency

Other important SNPs:

PEMT rs4646343

• ‘G’ = Doesn’t correlate with choline deficiency
• ‘T’ = Correlates with choline deficiency

PEMT rs3760188

• ‘C’ = Doesn’t correlate with choline deficiency
• ‘T’ = Correlates with choline deficiency

PEMT rs7946

• ‘C’ = Doesn’t correlate with choline deficiency
• ‘T’ = Correlates with choline deficiency

PEMT rs1531100

• ‘G’ = Doesn’t correlate with choline deficiency
• ‘A’ = Correlates with choline deficiency

PEMT rs4646365

• ‘C’ = Doesn’t correlate with choline deficiency
• ‘T’ = Correlates with choline deficiency

Population frequency

All five variants are more common among people of European ancestry, compared with other populations.

The first three—rs12325817, rs4646343, rs3760188—are almost always inherited together, which means you will either have all 'negative' alleles or none of them. For these variants:

• Around 23% of European descendants have the problematic genotypes: GG, TT, TT
• These genotypes are nearly non-existent among African and Asian descendants

For the third variation, rs7946:

• 50% of European descendants have the problematic “TT” genotype
• 2-4% of Asian descendants have this genotype

The last two—rs1531100 and rs4646365—are always inherited together. For these variations:

• Around 28% of European descendants have the problematic genotypes: AA and TT
• Around 10% of African and Asian descendants have these genotypes