Increasing the number of SNP loci does not necessarily improve prediction power at least in the comparison of MTHFR SNP and haplotypes.
BACKGROUND
Rapid advances in genotyping technology have made it possible to easily utilize a large number of genetic markers. According to information theory, an increase in the number of markers provides more information; however, the clinical usefulness does not increase linearly. This study aimed to assess the effect of folic acid supplementation quantitatively in MTHFR haplotypes, and compare its prediction power with that of the C677T single nucleotide polymorphism (SNP) alone.


METHODS
The study was a randomized, double-blind, placebo-controlled trial, designed in accordance with the CONSORT statement. The participants were 202 healthy Japanese males who were administered either folic acid at 1 mg/day or a placebo postoperatively for 3 months. The primary endpoint was the total plasma homocysteine levels (tHcy). Stratified analysis by HapMap-based tag SNPs was performed.


RESULTS
Of 52 SNPs on the MTHFR gene, 4 SNP loci covering more than 80% of the information were selected, and the haplotypes were estimated. The haplotypes were classified into 3 groups (Hap0, Hap1, and Hap2), on the basis of the number of times the most frequent haplotype was present. The greatest decrease was observed in Hap2 (6.61 micromol/L), compared with the other haplotypes (Hap0, 2.67; Hap1, 2.60) (trend test, P < 0.01). The haplotype information obtained was not more informative than that obtained with grouping by a single SNP, C677T, which strongly influences enzyme activity.


CONCLUSIONS
Grouping by the C677T SNP alone was almost as good a predictor of the homocysteine-lowering effects as was grouping by the 4 best SNPs. This shows that increasing the number of typed SNPs does not necessarily provide more information, at least for this gene. A more efficient, cost-informative method for analyzing genomic data is required.
Miyaki
Koichi
K
Preventive Medicine for Cerebrovascular Disease, Department of Neurology, Shool of Medicine, Keio University, Tokyo, Japan. miyaki-keio@umin.net
Takahashi
Yoshimitsu
Y
Song
Yixuan
Y
Zhang
Ling
L
Muramatsu
Masaaki
M
Nakayama
Takeo
T
D050197:Atherosclerosis / Q000097:blood / Q000235:genetics / Q000517:prevention & control; D003545:Cysteine; D004311:Double-Blind Method; D005492:Folic Acid / Q000008:administration & dosage / Q000494:pharmacology*; D005819:Genetic Markers / Q000187:drug effects; D006239:Haplotypes / Q000187:drug effects; D006710:Homocysteine / Q000097:blood* / Q000187:drug effects; D006801:Humans; D015810:Linkage Disequilibrium; D008297:Male; D042965:Methylenetetrahydrofolate Reductase (NADPH2) / Q000097:blood / Q000235:genetics*; D008875:Middle Aged; D009419:Nerve Tissue Proteins / Q000097:blood / Q000235:genetics; D020641:Polymorphism, Single Nucleotide / Q000187:drug effects; D011237:Predictive Value of Tests; D017422:Sequence Analysis, DNA / Q000379:methods; D013912:Threonine; D014041:Tokyo / Q000453:epidemiology; D014803:Vitamin B Complex / Q000494:pharmacology
D005819:Genetic Markers; C096896:HAP1 protein, human; D009419:Nerve Tissue Proteins; D006710:Homocysteine; D014803:Vitamin B Complex; D013912:Threonine; D005492:Folic Acid; D042965:Methylenetetrahydrofolate Reductase (NADPH2); D003545:Cysteine