Abstract
The Vitamin Intervention for Stroke Prevention (VISP) trial was a multi-center, controlled, double blinded clinical trial, designed to determine whether the daily intake of high dose folic acid, vitamins B6 and B12 reduced recurrent cerebral infarction. Baseline post-methionine load homocysteine levels were predictive of recurrent stroke risk in VISP. We have conducted a genome-wide association study (GWAS), investigating 2100 VISP stroke cases required to have homocysteine levels greater than the 25th percentile at enrolment. Using imputation with 1000 genomes and principal component analysis, we were able to detect an association of p≤6.70x10-17 for SNPs within, or flanking, the glycine N-methyltransferase (GNMT) gene and post-methionine load test homocysteine level. Change in homocysteine levels pre and post-methionine load test also resulted in significant GWAS scores in the chromosome 6 region (p = 2.54x10-23, rs7760250). GNMT catalyzes the conversion of S-adenosyl-L-methionine to S-adenosyl-L-homocysteine and sarcosine via the folate one-carbon metabolism pathway. In addition to being an essential component in the conversion of methionine to homocysteine, GNMT plays a significant role in the global epigenetic state as homocysteine is an important methyl donor. This region displays significant linkage disequilibrium, warranting close analysis of the entire GNMT locus in search of both rare and common variants. Cases who carry the minor allele haplotype at associated loci had a higher level of post-methionine load homocysteine (37.69µM/L) than those who carry the major allele haplotype (27.33µM/L), inferring functional differences due to GNMT variants. Taken together these data suggest a clear and important role for GNMT in post-methionine load test homocysteine level, epigenetic state and stroke risk.
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