Genetic modifiers of folate, vitamin B-12, and homocysteine status in a cross-sectional study of the Canadian population

Abstract

Genetic variation can cause variable responses to environmental stimuli. A number of single-nucleotide polymorphisms (SNPs) have been associated with B vitamin status or chronic diseases related to vitamin B-12 and folate metabolism. Our objective was to identify associations between common SNPs in genes related to folate and vitamin B-12 metabolism or associated with B vitamin-related chronic diseases and biomarkers of nutrient status in a population exposed to folic acid fortification. A panel of 116 SNPs was sequenced by using the Sequenom iPLEX Gold platform in a sample of 3114 adults aged 20-79 y from the Canadian Health Measures Survey, cycle 1. Associations between these SNPs and red blood cell (RBC) folate, serum vitamin B-12, and plasma total homocysteine were determined. Twenty-one SNPs and 6 haplotype blocks were associated with RBC folate, serum vitamin B-12, and/or plasma homocysteine concentrations. Vitamin status was associated mainly with SNPs in genes directly involved in vitamin absorption/uptake (CUBN, CD320), transport (TCN1, TCN2), or metabolism (BHMT2, CBS, MTHFR, MUT, SHMT1). Other SNPs included those in the DNMT2, DPEP1, FUT2, NOX4, and PON1 genes. We identified novel associations between SNPs in CD320 and DNMT2, which had been previously associated with neural tube defects, and vitamin B-12 status, as well as between SNPs in SHMT1, which had been previously associated with colorectal cancer and cardiovascular disease risk, and RBC folate status. These novel associations provide a plausible metabolic rationale for the association of these SNPs with B vitamin-related diseases. We also observed a novel association between an SNP in CUBN with RBC folate and confirmed the association of a number of SNPs with B vitamin status in this large cross-sectional study.