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On the Way to Individualized Prevention of Spina Bifida
CHORI Collaboration Reveals First-Time Association Between Spina Bifida and the Folate Pathway

December, 2011 –CHORI scientist Edward Lammer, MD, and California Institute for Quantitative Biosciences scientist Nicolas J. Marini, PhD have just published in PLoS One the most comprehensive genetic DNA sequencing study ever performed to identify genetic factors that might explain the risk factors for spina bifida and why maternal folic acid supplementation can prevent it. In collaboration with University of California Berkeley, University of California San Francisco, Stanford University, and the Department of Energy’s Joint Genome Institute, the study is the first to analyze genetic risk factors for spina bifida from a pathway approach, rather than looking for associations based on individual genes.

“There is a long legacy of genetic studies in which researchers have focused primarily on only one folate-related gene at a time and have been unable to discover clues about how maternal folic acid supplementation prevents most spina bifida,” says Dr. Lammer. “What we have discovered here, however, is that if you take the group of enzymes that all use folates and group them into the three major biochemical processes for which folates are essential, it is possible to find some risk differences for spina bifida.”

“ If you take the group of enzymes that all use folates and group them into the three major biochemical processes for which folates are essential, it is possible to find some risk differences for spina bifida.”



Neural tube defects (NTDs), of which spina bifida is one, are some of the most common forms of birth defects. Over two decades of research trying to elucidate the cause of NTDs have clearly indicated only one thing, however: that maternal supplementation with folic acid significantly reduces the risk of NTDs like spina bifida.

"The mechanism for prevention that has been primarily proposed is that taking extra folic acid helps make certain enzymes work better," says Dr. Lammer. "These would be enzymes that involve folate, which is involved in all kinds of biochemical reactions that need to take place during an embryo's development."

Investigators have analyzed individually the various genes that encode folate-related enzymes and found inconsistent correlations between DNA sequence variation and NTDs. By taking a step back to look at the bigger picture, however, and sequencing 31 folate-related genes in order to analyze the total amount of genetic variation (rare plus common) that occurs in spina bifida cases, Drs. Lammer and Marini and their colleagues have for the first time shown a correlation between folic acid pathways and spina bifida.

Utilizing data from 250 children born with spina bifida and 250 controls, the massive project involved grouping the 31 folate-related genes based on their involvement in the three different folate-related processes of purine biosynthesis, pyrimidine biosynthesis and homocysteine metabolism, and sequencing the coding regions of all 31 folate-related genes to look for genetic variation in the spina bifida cases compared to the controls.

“When analyzing the data using a pathway approach, the total number of mutations, or the amount of genetic variation, was greater among spina bifida cases than among controls.”

In addition, the data revealed two different genetic profiles based on ethnicity, suggesting that the mechanism for spina bifida birth defects may be different in different ethnicities.

"The profile of excessive genetic variation in Hispanics points to alterations in purine biosynthesis, the making of the A and G bases of DNA, as the source of the higher risk for the spina bifida, whereas in Caucasians, the greater excess in variation pointed more toward the homocysteine metabolism pathway," explains Dr. Lammer.

Even more significantly, analyses of individual folate-related genes, one at a time, revealed none of these same associations.

Longer term goals of screening individuals for higher or lower doses of folate to prevent NTDs by analyzing the effects of multiple genes on the folate pathway is still in the future. The latest study by Dr. Lammer and his colleagues, however, clearly demonstrates that the key to achieving that future lies in pathway analysis.

Longer term goals of screening individuals for higher or lower doses of folate to prevent NTDs by analyzing the effects of multiple genes on the folate pathway is still in the future. The latest study by Dr. Lammer and his colleagues, however, clearly demonstrates that the key to achieving that future lies in pathway analysis.

“There isn't good reason any longer to be spending valuable resources on investigating each one of these individual genes that are involved in the folate pathways.”

"These results need to be replicated, but this study should go a long way toward helping us understand that it is genetic variation of folate biology pathways that are conferring the increased risk for NTDs and to use this kind of big-picture pathway analysis."

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