|CHEN, KEHUI - University Of California|
|GONZALO, RINCON - University Of California|
|KIM, SEUNG-HYUN - University Of California|
|HOLSTEGE, DIRK - University Of California|
|OWENS, JANEL - University Of California|
|LIU, BITAO - Affymetrix, Inc|
|MULLER, HANS-GEORG - University Of California|
|MEDRANO, JUAN - University Of California|
|FADEL, JAMES - University Of California|
|CLIFFORD, ANDREW - University Of California|
|MCWADE, LAURA - University Of California|
Submitted to: Journal of Nutrition
Publication Type: Peer Reviewed Journal
Publication Acceptance Date: 5/2/2012
Publication Date: 6/23/2012
Citation: Novotny Dura, J., Baer, D.J., Chen, K., Gonzalo, R., Kim, S., Holstege, D., Owens, J., Liu, B., Muller, H., Medrano, J., Fadel, J., Clifford, A., Mcwade, L., Moshfegh, A.J. 2012. Gender and single nucleotide polymorphisms in MTHFR, BHMT, SPTLC1, CRBP2, and SCARB1 are significant predictors of plasma homocysteine normalized by RBC folate in healthy adults. Journal of Nutrition. 142:1764-1771.
Interpretive Summary: Folate is an essential vitamin that plays a role in prevention of cardiovascular disease, dementia, and hypertension, as well as reducing occurrence of neural tube defect. The risk factor for heart disease that is especially closely related to folate intake is blood homocysteine. Fortification of grain and cereal products with folate in the United States has led to a reduction in the number of NTD-affected births and to an increase in blood folate levels, as well as to a reduction in blood homocysteine levels, suggesting reduced risk for heart disease. In 1995, a gene was discovered that is a risk factor for neural tube defect, a disease that is sensitive to folate supplementation. In 2009, a large study of the whole human genome revealed three genes that were predictive of concentrations of folate and its related B vitamins. However, the understanding of how these genes and other individual characteristics function together to determine folate status and how these factors impact folate-related health has been unknown. Therefore, we investigated the interactive effects of individual traits of gender, age, BMI, and 64 gene variations on heart disease risk factor blood homocysteine. Gender and four specific genes were found to be particularly important in determining blood homocysteine levels. For some genes, the importance of that gene on homocysteine was different for men and women. Therefore, gender and genotype for several specific genes are important determinants in heart disease risk factor blood homocysteine. This information will be useful for scientists studying folate and B vitamin metabolism, and health professionals studying heart disease.
Technical Abstract: Using linear regression models, we studied the main and two-way interaction effects of the predictor variables gender, age, BMI, and 64 folate/vitamin B-12/homocysteine/lipid/cholesterol-related single nucleotide polymorphisms (SNP) on log-transformed plasma homocysteine normalized by red blood cell folate measurements (nHcy) in 373 healthy Caucasian adults, 50% women. Variable selection was conducted by stepwise Akaike Information Criterion (AIC) or Least Angle Regression (LASSO), and both methods led to the same final model. Statistically significant predictors (where P values were adjusted for false discovery rate) included type of blood sample (whole blood versus plasma-depleted whole blood; P < 0.001) used for folate analysis, gender (P < 0.001), and SNP in genes SPTLC1 (rs11790991; P = 0.040), CRBP2 (rs2118981; P < 0.001), BHMT (rs3733890; P = 0.019), and CETP (rs5882; P = 0.017). Statistically significant two-way interaction effects included gender × MTHFR (rs1801131; P = 0.012), gender × CRBP2 (rs2118981; P = 0.011), gender × SCARB1 (rs83882; P = 0.003). The relation of nHcy concentrations with the statistically significant SNP (SPTLC1, BHMT, CETP, CRBP2, MTHFR, and SCARB1) is of interest, especially as we surveyed the main and interaction effects in healthy adults, but is an important area of future study. As discussed, understanding Hcy and genetic regulation is hugely important as Hcy may be related to inflammation, obesity, cardiovascular disease, and diabetes mellitus. We conclude that gender and SNP statistically significantly affect nHcy.