Genetics of Hypertension: Multiple Culprits, No Kingpin

The most comprehensive genome-wide analysis for the genetic causes of hypertension ever conducted shows that this health threat to 50 million Americans has diverse and subtle genetic roots.

Five papers and two editorials published together in a recent edition of the American Journal of Hypertension highlight a series of areas in the genome but no “silver bullet” gene with large effects across all populations. Findings come from an unusually collaborative alliance called the Family Blood Pressure Program made up of four research networks based at the University of Michigan, the Pacific Health Research Institute at Stanford University, the University of Utah and The University of Texas Health Science Center at Houston. The program is funded by the National Heart, Lung and Blood Institute.

“The Family Blood Pressure Program has identified regions of the genome that house hypertension susceptibility genes that have small or moderate effects,” said Eric Boerwinkle, Ph.D., program director and director of the Human Genetics Center at The UT School of Public Health at Houston.

“We also found there are no common genes with large effects that influence risk for hypertension. That’s something we previously had assumed, but this study provides definitive confirmation. It’s the largest study by far in terms of sample size at 6,250 individuals and the most racially diverse,” Boerwinkle said.

Findings are consistent with evidence that hypertension springs from a complex blend of causes – multiple genes, demographics and behavioral factors. Family studies have established that genetics account for 30 to 50 percent of blood pressure variation in a population.

An accompanying editorial in the journal describes the papers “as a progress report on what is undoubtedly the largest frontal assault ever directed at the genetics of a common disease.”

Such common diseases as hypertension, diabetes, cardiovascular disease, and cancer have a genetic aspect but are not caused solely by genetic variation. This makes pinpointing genetic causes more difficult than in diseases caused strictly by genetic factors.

Hypertension is a major risk factor for stroke, renal failure and cardiovascular disease, all among the most common causes of death and illness in the United States.

Network members conducted genome-wide linkage scans for genetic variations that contribute to hypertension among groups of relatives in geographically diverse populations of African-Americans, non-Hispanic Caucasians, and people of Japanese or Chinese ancestry. They then conducted a meta-analysis of all four studies that encompassed 6,250 individuals.

Among African-Americans, portions of chromosomes 1 and 2 were found likely to harbor susceptibility genes for hypertension. Among people of Japanese or Chinese ancestry, a portion of chromosome 10 was most significant. Results for non-Hispanic Caucasians showed several genetic areas with possible small effects but none as statistically significant as the leading areas among African-American and Asian populations. Across populations, small effects were noted in portions of a variety of chromosomes including 1, 2, 5, 9, 10, and 14.

Boerwinkle said Family Blood Pressure Program research networks are following up on these results in a variety of ways. Association studies of candidate genes are being conducted to narrow down areas identified by the linkage study. One network is subjecting the program data, which today includes more than 14,000 individuals, to complex statistical analyses both to clarify the implicated regions and to identify new areas of the genome housing hypertension susceptibility genes.

Another strategy is to subdivide populations and more closely examine smaller groups that share common characteristics.

Because age, gender, diet, obesity, tobacco use and other factors contribute to hypertension, it’s likely that genes interact with these factors to affect a person’s risk, Boerwinkle said.

Program networks are analyzing these specific sub-samples – for example, looking at the genetics of hypertensive smokers or of lean people who have hypertension. Boerwinkle’s group also is making a concerted effort to identify a gene on chromosome 2, an area that has provided convincing and consistent evidence for a hypertension gene.

“Given the public health impact of hypertension, it’s crucial to identify the genes involved,” Boerwinkle said. The complexity of hypertension’s causes – genes interacting with other genes, or genes interacting with other risk factors – holds promise for highly customized treatment.

• Knowledge of the genes involved could be used to identify people most at risk for hypertension and to prescribe healthy lifestyles that would prevent it.

• New and better treatments could focus on the underlying molecular causes of the disease, rather than on the symptoms.

• Medication could be tailored to the individual based on her genetic makeup. Presently, the dozens of medications available for hypertension vary in their effectiveness from person to person. Genetic differences are one suspected cause.

The American Journal of Hypertension is a forum of scientific inquiry of the highest standards in the fields of hypertension and related cardiovascular disease. It is the journal of the American Society of Hypertension, the largest U.S. organization devoted exclusively to hypertension and related cardiovascular disease.

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©2006 Texas Medical Center

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