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Hutterites breathe new life into asthma research
By Bijal P. Trivedi

Two teams of researchers have identified a dozen new locations around the genome that may harbor genes involved in asthma, the causes of which remain largely unknown. Over the years independent studies using different populations have revealed various candidate genes, but few results have proved robust.

"What we have right now are a lot of good clues, but no genes that all the experts in the field would agree on," says Nancy Cox, of The University of Chicago. Cox's work and the study from Wake Forest University School of Medicine in Winston-Salem, NC, contribute more pieces to the puzzle.

The Chicago study screened 693 Hutterites, who were all members of a single pedigree that extended back 15 generations, for genes associated with asthma and atopy, an allergic response that can trigger an asthma attack. The team found regions on chromosome 11p and 19q that they believe play a large role in the disease because they have also been detected in studies of other populations. But it will take time to whittle down these huge chromosomal regions to find the genes responsible.

The screen also revealed the IL4RA gene on chromosome 16p, the HLA-DRB1 on chromosome 6, and the IFNA gene on chromosome 9q that may play a minor role in the disease. All of these genes could fit the bill, says Cox. They are all involved in the inflammatory and immune response.

In asthma, no one gene shoulders the full responsibility

Asthma is a complex disease that affects more than 17 million Americans. It is caused by the interaction of many genes with environmental triggers like pollution, cigarette smoke, and other allergens. Unlike a monogenic disease, which is caused by a mutation in a single gene, in a complex disease no one gene shoulders the full responsibility. Each variant of a gene influences the likelihood of disease by slightly raising or lowering the risk, so it is the final tally that is important. And since the contribution made by each gene is fairly small, they are especially difficult to find.

To make the search a little easier, researchers at The University of Chicago chose to search for asthma genes in a distinct group of people called the Hutterites. The Hutterites are members of the Anabaptist religion that was founded in the early 1500s by about 64 individuals. The group was severely persecuted by Catholics and Protestants, and their leader, Jacob Hutter, was labeled a heretic and burned at the stake in 1528. In 1870 persecution drove the Hutterites to South Dakota where they formed small colonies.

The Hutterite culture makes them particularly useful to geneticists. They arose from a small number of founders and their insular way of life has kept their gene pool relatively pure for about 15 generations. They are predominantly a communal farming community in which all the members eat their meals together in the same kitchen. "These people are basically all farmers, they all share the same diet, and they are all pretty much exposed to the same environmental factors, so it should be easier to observe genetic factors affecting a disease," says Cox.

Deborah Meyers' team at Wake Forest University is screening the genome for genes that regulate the IgE antibody levels. High levels of IgE in the serum are associated with the development of asthma later in life. Wake Forest's study of 200 Dutch families indicates that major genes affecting IgE may lie on chromosomes 5q, 12q and 6p, which have been previously reported. The most striking association was with a new region on chromosome 7. No genes have been pinpointed at this time.

Both studies were electronically published in October and will appear in the November issue of the American Journal of Human Genetics.

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Ober, C. et al. A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am J Hum Genet 67, 1154-1162 (November 2000).
Xu, J. et al. Major genes regulating total serum immunoglobulin E levels in families with asthma. Am J Hum Genet 67, 1163-1173 (November 2000).

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