Gene Changes Might Affect Hypertension

Genetic researchers from Case Western Reserve University's School of Medicine, University Hospitals of Cleveland, and Affymetrix Inc. (Nasdaq: AFFX) have taken a major step in identifying myriad gene changes that may be considered candidates for causing hypertension.

In the first detailed, systematic analysis of how gene sequences, and the proteins they encode, vary among human beings, the researchers studied 75 genes and found sequence changes in all but one gene. The genes studied are those in the blood pressure control pathway in humans, but the sequence patterns discovered have application to other common diseases.

Aravinda Chakravarti, senior author of the new study to be published in the July issue of the journal "Nature Genetics," called the amount of diversity striking.

"There is significant and widespread variation in genes in humans across the world," he said. "A surprisingly large fraction, 50 percent, of all the changes we identified lead to changes in the protein structure as well and are thus candidates for common disease susceptibility or protection."

Chakravarti, who is the James H. Jewell Professor of Genetics at CWRU and UHC, and his colleagues examined the genes in 74 people. Their paper is being published with a study from the Whitehead Institute which reports on a similar analysis and produces similar results on 106 genes that potentially influence heart disease, type II diabetes, and schizophrenia. The papers are important first steps in cataloging single nucleotide polymorphisms (SNPs, pronounced snips).

SNPs are single base pair differences in genetic sequences between genes in different humans. Genetic codes consist of chains of bases represented by the letters G, A, T, and C, paired in particular patterns in the double helix of our DNA. A SNP is a change in one of these letters that exists in some but not all humans.

SNPs are particularly important for mapping and discovering genes associated with common diseases, which are caused or influenced by complex interactions among multiple genes as well as environmental factors. Earlier this year, 10 large pharmaceutical companies and a foundation formed a nonprofit consortium with the goal of identifying 300,000 SNPs during the next two years. SNPs are believed to be the keys to designing "personalized" drugs matched to an individual's genetic makeup.

"In the past, geneticists have concentrated on rare genetic changes that impact on human diseases directly. For common diseases, such as hypertension, these genetic approaches have not been very successful because many genes contribute to the disease process and do so in a small, yet measurable manner. Finding changes in human genes, now possible because of the Human Genome Project, can lead to a more direct and efficient search for common disease genes," Chakravarti said.

"Our study shows that gene sequence changes that alter protein structure are common among humans. These changes might lead to somewhat altered physiology, therefore leading to a disease, in some humans. This wide range of protein diversity now allows us to have a very direct probe into human disease."

On the other hand, the study also showed the effects of natural selection for protecting against protein changes in spite of SNPs.

"Gene changes that do change the protein are about three times less frequent than expected, suggesting that gene changes that produce protein differences have been largely selected against in human evolution," he said. This makes the scientists suspect that when these gene changes occur and lead to protein differences, they are involved in human disease.

Other authors and institutions involved in the research were Marc K. Halushka and Kimberly Bentley from the Department of Genetics at CWRU and the Center for Human Genetics at UHC; Jian-Bing Fan, Linda Hsie, Naiping Shen, and Robert Lipshutz from Affymetrix Inc.; Alan Weder from the Department of Medicine at the University of Michigan; and Richard Cooper from the Department of Epidemiology at Loyola University Medical Center.

Research funds supporting the study came from CWRU, UHC, the National Human Genome Research Institute, and the National Heart, Lung, and Blood Institute.

WEB HOTLINKS:
CWRU School of Medicine: http://mediswww.meds.cwru.edu
University Hospitals of Cleveland: http://www.uhhs.com/
Affymetrix Inc.: http://www.affymetrix.com