GENETIC DATA NIX FOLATE ROLE IN HEART DISEASE

By: Michael Smith, North American Correspondent, MedPage Today
Published: February 22, 2012
Reviewed by: Robert Jasmer, MD; Associate Clinical Professor of Medicine, University of California, San Francisco and Dorothy Caputo, MA, RN, BC-ADM, CDE, Nurse Planner

The final nail may have been placed in the coffin of homocysteine-lowering therapy as a preventive measure for coronary heart disease.

The overall result from large, unpublished data sets shows lifelong moderate homocysteine elevation has little or no effect on coronary heart disease.

A comprehensive analysis -- including published and unpublished research that involved more than 236,000 participants -- suggests that even lifelong exposure to elevated homocysteine "has little or no effect," according to Robert Clarke, MD, of the Clinical Trial Service Unit at the University of Oxford, in Oxford, England, and colleagues.

The key finding is that, in several large unpublished data sets, genetic variation that increases or decreases natural homocysteine levels did not significantly affect the risk of coronary heart disease, Clarke and colleagues reported online in PLoS Medicine.

That was coupled with a null effect in an updated meta-analysis of 10 clinical trials testing the effect of folic acid, a homocysteine-lowering compound.

Taken together, that evidence suggests that a significant but modest benefit of lower homocysteine in an updated meta-analysis of 86 published case-control studies was an "artifact of publication bias," the researchers argued.

Clarke and colleagues noted that a common genetic variant -- named C677T -- in the methylene tetrahydrofolate reductase gene (MTHFR) markedly affects homocysteine levels.

Specifically, people with the TT genotype (individuals in whom both copies of the MTHFR gene have the nucleotide thymine at position 677) of the C677T polymorphism have natural levels that are about 20% higher than those with the CC variant. The CT variant has an effect that is intermediate but closer to CC than TT.

That suggests the possibility of a natural "Mendelian" experiment, and luckily the increasing use of large scale-genomics analysis has led to the creation of 19 large datasets -- with a total of more than 100,000 participants -- in which variation in the MTHFR gene was analyzed, although not as a primary focus.

Clarke and colleagues designated those studies as "unpublished" because odds ratios for coronary heart disease were not the primary aim and have not been reported. The studies had a total of 48,175 coronary heart disease cases and 67,961 controls.

If the associations seen in the earlier case-control studies were causal, the researchers argued, the 20% higher homocysteine in those with the TT variant should imply about an 8% increase in coronary heart disease risk, compared with CC carriers.

But a meta-analysis of the effect of the TT variant in the 19 studies showed a nonsignificant odds ratio of 1.02, with a 95% confidence interval from 0.98 to 1.07, they reported.

Even in the sub-population of participants who had not been given folate supplements in food, where the effect of the TT variant might be expected to be stronger, it remained nonsignificant, with an odds ratio of 1.01.

On the other hand, Clarke and colleagues reported, the updated analysis of the 86 biochemical studies -- with 28,617 cases and 41,857 controls -- suggested that having the TT variant increased the risk of coronary heart disease by 15% (odds ratio 1.15, 95% CI from 1.09 to 1.21).

The results of the two analyses are "discrepant," the researchers noted, and the discrepancy "is too extreme to be plausibly dismissed as a chance finding."

Instead, they argued for a "substantial" effect of publication bias.

To bolster the argument, they noted that their analysis of the 10 intervention studies, with a total of more than 50,000 participants, found that lowering homocysteine for at least five years had no significant effect on the risk of coronary heart disease. The odds ratio was 1.02 (95% CI from 0.96 to 1.08).

"Both the genetic studies and the trials argue against the use of (homocysteine-lowering agents) as a means of reducing coronary heart disease risk," they concluded.

The journal editors agreed, noting that "these findings reveal a serious example of publication bias and argue against the use of folate supplements as a means of reducing [coronary heart disease] risk."

POSTED BY DAVID R. CRAGG, MD

Primary source: PLoS Medicine
Source reference:
Clarke R, et al "Homocysteine and coronary heart disease: meta-analysis of MTHFR case-control studies, avoiding publication bias" PLoS Med 2012; 9(2): e1001177.