Targeted next‐generation sequencing of the 1‐carbon metabolism pathway: in search for novel genetic modulators of choline deficiency‐mediated organ dysfunction (135.4)

Abstract

We previously identified three functional single nucleotide polymorphisms (SNPs) that modulate sensitivity to dietary choline deficiency‐mediated organ dysfunction: CHDH rs12676, MTHFD1 rs2236225 and PEMT rs12325817. We aimed to broaden our understanding of the contribution of genetic aberrations in the 1‐carbon pathway to choline deficiency sensitivity. We performed targeted next‐generation sequencing on the following genes: ABCB4, BHMT, CBS, CHDH, CHKA, CHKB, MTHFD1, MTHFR, MTR, PCYT1A, PCYT1B, PEMT, SHMT1, SLC44A1, SLC5A7. The subjects in our study were divided into the following groups based on their response to a choline deficient diet: 1) did not exhibit symptoms of choline deficiency (n = 13); 2) had fatty liver and elevated liver enzymes (n = 15); 3) had elevated skeletal muscle creatine phosphokinase (n = 9). Although our study was underpowered, we identified a set of SNPs that are potential novel genetic modifiers of sensitivity to choline deficiency (primarily in PEMT and MTHFD1) and to organ‐specific deficiency symptoms (primarily in SLC44A1). Importantly, principal components analysis identified a set of SNPs that differentiated those who were sensitive to dietary choline deficiency vs. those that were not (PC1 p‐value = 0.018). Our results delineate candidate SNPs for differentiating individuals that are sensitive to dietary choline deficiency. These SNPs warrant further investigation.Grant Funding Source: NIH U24‐CA143848‐03; P30‐CA016086‐37; P50‐CA058223‐19A1 (JP)