rs17349743

The aim of this research was to investigate the role of genetic and nutritional variation within the folate-mediated one-carbon network in relation to cardiovascular disease risk. The enzymes serine hydroxymethyltransferase 1 (gene name SHMT1) and methylenetetrahydrofolate reductase (gene name MTHFR) regulate key reactions in folate-mediated one-carbon metabolism. We investigated the effect of the SHMT1 rs1979277 SNP and the SHMT1 rs1979277 - MTHFR rs1801133 interaction in two epidemiologic cohorts. In the Nurses' Health Study, the MTHFR rs1801133 variant genotypes were associated with an increased CVD risk, and there was an interaction between SHMT1 and MTHFR such that the association of MTHFR rs1801133 CT genotype (vs. CC; the TT genotype could not be evaluated) was stronger in the presence of the SHMT1 rs1979277 TT genotype. In the Health Professionals FollowUp Study, the MTHFR rs1801133 genotype was not associated with CVD risk nor was there an interaction with SHMT1 rs1979277. Next, using data from the Normative Aging Study, 330 SNPs in 52 genes were studied in relation to cardiovascular disease biomarkers. Using a nominal significance threshold of P[LESS-THAN OR EQUAL TO]0.005, 20 SNPs were associated with homocysteine, 8 with Alu methylation, and 1 with LINE-1 methylation. Using a more stringent false discovery rate threshold, SNPs in FTCD, SLC19A1, and SLC19A3 genes were associated with plasma homocysteine, gene x vitamin B-6 interactions were identified for Alu and LINE-1 methylation, and epistatic interactions involving the MTHFR rs1801133 SNP were identified for the plasma homocysteine phenotype. Finally, the SNPs were prospectively evaluated for their association with cardiovascular disease in a U.S. population studied prior to mandatory folate fortification. Using a nominal significance threshold of P[LESS-THAN OR EQUAL TO]0.005, 8 SNPs were associated with CVD risk. Using a more stringent false discovery rate threshold, a polymorphism in the GGH gene was associated with reduced CVD risk. A gene x folate interaction was identified (MAT2B) and two gene x vitamin B-12 interactions were identified (BHMT and SLC25A32). Hypotheses related to SHMT1 were explored and significant gene x gene interactions were identified. Overall, genetic variation in folate-mediated one-carbon metabolism, other than the wellknown effects of the MTHFR 677 C[RIGHTWARDS ARROW]T rs1801133, is predictive of cardiovascular disease risk.

2011 · Susan M. Wernimont

Genome-wide association studies (GWAS) of late-onset Alzheimer disease (LOAD) have consistently observed strong evidence of association with polymorphisms in APOE. However, until recently, variants at few other loci with statistically significant associations have replicated across studies. The present study combines data on 483,399 single nucleotide polymorphisms (SNPs) from a previously reported GWAS of 492 LOAD cases and 496 controls and from an independent set of 439 LOAD cases and 608 controls to strengthen power to identify novel genetic association signals. Associations exceeding the experiment-wide significance threshold () were replicated in an additional 1,338 cases and 2,003 controls. As expected, these analyses unequivocally confirmed APOE's risk effect (rs2075650, ). Additionally, the SNP rs11754661 at 151.2 Mb of chromosome 6q25.1 in the gene MTHFD1L (which encodes the methylenetetrahydrofolate dehydrogenase (NADP+ dependent) 1-like protein) was significantly associated with LOAD (; Bonferroni-corrected P = 0.022). Subsequent genotyping of SNPs in high linkage disequilibrium () with rs11754661 identified statistically significant associations in multiple SNPs (rs803424, P = 0.016; rs2073067, P = 0.03; rs2072064, P = 0.035), reducing the likelihood of association due to genotyping error. In the replication case-control set, we observed an association of rs11754661 in the same direction as the previous association at P = 0.002 ( in combined analysis of discovery and replication sets), with associations of similar statistical significance at several adjacent SNPs (rs17349743, P = 0.005; rs803422, P = 0.004). In summary, we observed and replicated a novel statistically significant association in MTHFD1L, a gene involved in the tetrahydrofolate synthesis pathway. This finding is noteworthy, as MTHFD1L may play a role in the generation of methionine from homocysteine and influence homocysteine-related pathways and as levels of homocysteine are a significant risk factor for LOAD development.

2010 · Adam C Naj, Gary W. Beecham, Eden R. Martin, Paul J. Gallins, Eric Powell, Ioanna Konidari, Patrice L. Whitehead, Guiqing Cai, Yuji Kajiwara, Vahram Haroutunian, William K. Scott, Jeffery M. Vance, Michael A. Slifer, Harry E. Gwirtsman, John R. Gilbert, Jonathan L. Haines, Joseph D. Buxbaum, Margaret A. Pericak‐Vance