Columbia University Medical Center

Venezuela Kindreds Reveal Genetic And Environmental Factors Influence Onset Of Huntington’s Disease

New York, New York – March 2, 2004– The age at which Huntington’s disease starts is not solely determined by the Huntington’s disease gene, as previously believed, but is strongly influenced by genetic and environmental factors, according to new findings from a team led by Columbia University Medical Center researcher and president of the Hereditary Disease Foundation Dr. Nancy Wexler. All authors of the new study belong to the U.S.-Venezuela Collaborative Research Project, a group of 57 international researchers who have participated in the project.

The dogma-breaking finding suggests there are more ways to attack Huntington’s than investigators realized and raises hope that scientists can mimic the protective genetic and environmental factors with drugs that delay the onset of the disease or push the age of onset out of the normal lifespan. The research will be published this week on the Proceedings of the National Academy of Sciences web site (http://www.pnas.org/).

This discovery is due to the extraordinary contribution of more than 18,000 Venezuelans participating in the research and, for the first time, details of this large pedigree have been published and appear in the same paper.

Since 1979, Dr. Wexler’s international team of researchers has traveled annually to Lake Maracaibo, Venezuela, to identify families with Huntington’s disease (HD) and document their disease. Over these 23 years, they have identified 18,149 individuals spanning 10 generations, 15,409 of whom are living. The Venezuelan families with Huntington’s disease comprise 83 independent kindreds (a group of related families stemming from a common ancestor). One kindred comprises 14,761 individuals. This kindred inherited the HD gene from a woman living in a stilt village on the lake in the early 19th century. Though not all of the 15,000 now living will develop Huntington’s, all will be affected in some way by the disease as it strikes their parents, children, siblings, aunts and uncles, cousins and other family members.

“The Venezuelan kindreds are unique in that they encompass the world’s largest genetically related HD community and have already provided a wealth of genetically and phenotypically informative data,” Dr. Wexler, Higgins Professor of Neurology at Columbia University College of Physicians & Surgeons, explains. “The sheer magnitude of the overall kindreds, the size of individual nuclear families – from 1 to 21 children – the interrelationships among the branches, the high level of genetic heterogeneity, the relative immobility among the branches and their extraordinary cooperation has taught us immensely and promises to reveal more in the future.” Genetic and clinical data from these Venezuelan kindreds were responsible for localizing the HD gene on chromosome 4 in 1983 – the first such localization using DNA markers when the chromosomal assignment was unknown – and subsequently discovering the defective gene itself in 1993.

“Huntington’s has been touted as the least malleable disease, but we’re finding there is a huge amount of variation in age of onset and severity of symptoms,” Dr. Wexler says. “We hope that our project will find the genes and environmental factors that offer treatments and cures. We do not merely want to make the disease milder but to prevent it from ever appearing or push the disease’s onset to 110 years of age and out of a normal lifespan.”

Huntington’s disease is invariably fatal for people who carry the disease-causing Huntington gene, but the age at which symptoms start appearing varies anywhere between age 2 and age 84.

The gene causing Huntington’s disease codes for a protein called “huntingtin.” This gene carries a stretch of DNA that is repeated over and over again, a string of three base pairs called CAG, which code for the amino acid glutamine. A normal gene will carry from 9 to 34 such repetitions. For unknown reasons, in some people the gene expands to include many more repetitions. A person carrying a gene with 35 to 39 repeats of CAG may or may not become ill with HD. If just one single extra CAG, or glutamine, is added to the gene, the person carrying this abnormal gene will inevitably die a devastating death. Repeats of between 60 to 125 CAGs will produce an age of onset of 20 years or younger. Each child – males and females equally – of a parent with HD has a 50 percent risk of inheriting the disease. The size of the repeat frequently expands as it is passed from parent to child.

The new study analyzed the DNA of 443 people with Huntington’s disease for whom the researchers have ages of onset, who live mainly in fishing villages along the coast of Lake Maracaibo, Venezuela.

Until now, most researchers believed that the number of repeats in the disease-causing gene completely controlled the age of onset. But an extraordinary finding of the study is that family members and even people with the exact same repeat sizes have significant variability in their ages of onset, suggesting that modifying factors exist.

When data from all of the 443 Venezuelans are combined, with repeat lengths from 40 to 86 CAGs, the size of the repeat accounts for as much as 72 percent of the variation in age of onset. But the investigators then studied only people with repeat sizes between 40 and 50 CAGs. Fortunately, people with smaller repeat sizes comprise 87 percent of these Venezuelan kindreds and the majority of HD families worldwide. Among this group, the size of the repeat only accounts for 44 percent of the variability in age of onset. What accounts for the rest? Using sophisticated statistical analyses of the Venezuelan kindreds, the group determined that, of the remaining variability in age of onset, 40 percent can be ascribed to gene(s) other than the HD gene. This figure is similar to other multifactorial diseases of interest. Fully 60 percent of the variability in age of onset is due to environmental factors, and of this, approximately 20 percent is due to shared environments and 40 percent is due to non-shared environments.

The Venezuelan families also averaged a significantly earlier age of onset, 34 years, compared with 37 in the United States and 40 in Canada. Whether this earlier age of onset is due to shared genetic or environmental factors is under study.

Members of the Venezuela Project research team are now analyzing the same DNA samples for other genes that may influence the disease’s age of onset and are setting up studies to find environmental factors.

“The Venezuelan families have given us many gifts,” Dr. Wexler says. “In 1983 and 1993, they helped us find the Huntington’s gene and understand its mistake. Now they are critical players in our search for the cure. It’s important that the world understand how much they’ve given and it would be fitting if they could be the first to reap the benefits of all future therapies.”
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