Genetic protection against fetal alcohol syndrome?

December 16, 2001

Fetal Alcohol Syndrome (FAS) is the most common cause of preventable mental retardation among children in the world today. Scientists believe that the development of FAS following excessive alcohol exposure is likely influenced by genetic factors in both the mother and child. Mixed-ancestry children in the Western Cape Province of South Africa have the highest frequency of FAS in the world. Knowing that allelic variation influences alcohol metabolising genes, researchers in the December issue of Alcoholism: Clinical & Experimental Research examine what role polymorphisms of the alcohol dehydrogenase (ADH2) gene might have among this population.

"The socioeconomically deprived mixed-ancestry population of the Western Cape has a prevalence of FAS amongst school-entry children of 40 - 70 per thousand," explained Denis Lowe Viljoen, head of the department of human genetics at the National Health Laboratory Service and University of the Witwatersrand Faculty of Health Sciences. Viljoen, also the study's lead author, uses "mixed-ancestry" to refer to descendents of the original Khoisan inhabitants and colonizing Europeans. Some farm laborers in these communities have received part of their wages in the form of alcohol for close to 300 years.

"This prevalence contrasts," he continued, "with approximately 0.33 - 2.2 per thousand for the United States, 8 per thousand amongst birth cohorts for North American Indians between 1970-1980, and 2.29 per thousand for selected inner-city African Americans."

"The incidence of FAS in the Western Cape is frighteningly high, particularly if one considers two factors," said Amanda Krause, researcher and associate professor at the National Health Laboratory Service and University of the Witwatersrand Faculty of Health Sciences. "One, these are minimum estimates, looking at children who reached school entry. Some FAS children may never reach school entry because of major birth defects. Two, FAS is the tip of the iceberg. Thus, the number of school children with fetal alcohol effects is likely exceedingly high." The term fetal alcohol effects (FAE) is used to describe individuals known to be exposed to alcohol before birth who have discernible health anomalies yet do not have the facial features characteristic of FAS.

"There is some good scientific evidence to suggest that FAS, like virtually all diseases, has some genetic and some environmental influences," said Krause. "There is a small amount of data pointing to the obvious candidate genes, that is, genes involved in the body's handling of alcohol." ADH is one of two enzymes that act sequentially to metabolize alcohol in the liver. ADH converts alcohol to acetaldehyde. Aldehyde dehydrogenase (ALDH) subsequently converts acetaldehyde to acetate. Acetate is then metabolized by tissues outside of the liver.

"We evaluated all isozymes of the ADH2 gene following on from the findings of a previous study that demonstrated protection of the ADH2*3 allele against alcohol-related birth defects," said Viljoen. "The latter allele was no different in the mothers and FAS children than in the ethnically similar control population in our study, nor was the ADH2*1 allele. However, there was a significant, protective difference between FAS children and the controls regarding the ADH2*2 allele." Viljoen noted that the ADH2*2 allele, like the ADH2*3 allele, has a high "Vmax," which results in a more rapid breakdown of alcohol to acetaldehyde than would occur with the ADH2*1 allele (which has a low Vmax).

"The inference is that the metabolism of alcohol by individuals from the control group would proceed more rapidly than in the mothers and FAS children, and result in lower blood alcohol levels than the latter subjects. Alternatively, the presence of such an allele may discourage the control persons from drinking as heavily as the latter subjects. However, this was not tested as the controls were anonymous participants."

Krause calls the study's findings "one piece in a large puzzle of undefined size, with many missing pieces. The exact factors or genes involved," she said, "are still poorly understood. The individual role of each factor and how they interact with each other requires a great deal of future research."

"This is the first study to find any connection between a gene and FAS," said Viljoen. "Presumably, many genes are working in concert within each person to provide either susceptibility to or protection from the effects of alcohol. Should these 'major' genes be found, they would provide a means of screening 'at-risk' persons for having a child with FAS. Also, the pathogenesis of FAS could become clearer. This raises the real possibility of treating high-risk, alcohol-abusing pregnant women, thereby reducing the risk of producing a baby with FAS."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: L.G. Carr and T.-K. Li of the Department of Medicine at the Indiana University School of Medicine; T.M. Foroud of the Department of Medical and Molecular Genetics at the Indiana University School of Medicine; L. Brooke of the Foundation for Alcohol Related Research at the University of Cape Town Medical School; and M. Ramsay of the Foundation for Alcohol Related Research at the National Health Laboratory Service. The study was funded by the National Institutes of Health, the Foundation for Alcohol Related Research, the South African Medical Research Council, and the National Health Laboratory Service.

Alcoholism: Clinical & Experimental Research

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