Genetic Connection To Human Herpes Susceptibility Discovered

(Adapted by ScienceDaily.com from materials provided by University of Utah Health Sciences)

ScienceDaily (Jan. 31, 2008) — There's a high likelihood that people who are at risk to herpes simplex virus (HSV) outbreaks may have a genetic predisposition to the virus, researchers from University of Utah have discovered in a new study.

Researchers have identified an area on the long arm of human chromosome 21 with high odds--at least 1,000-to-1--of being linked to cold sore susceptibility. The researchers further report they identified six specific genes in that chromosomal region as candidates for making people susceptible to outbreaks of cold sores (or "fever blisters"). Cold sores arise when the herpes virus awakens from dormancy within the nerve, resulting in infections in the face lip, or nose.

Another contributor to this research study, John D. Kriesel, M.D., and research associate professor in the U School of Medicine's Division of Infectious Diseases (Primary author of this study is Maurine R. Hobbs, Ph.D., research assistant professor in the Division of Endocrinology and Metabolism.) says that this finding may lead to the production of new drugs on the market that decrease the occurrence of herpes outbreaks.

"…these genes might make excellent targets…to decrease … herpes outbreaks," Kriesel said.

The herpes simplex virus occurs in two forms. Type 1 (HSV-1) is responsible for the vast majority of cold sores—the most common recurring viral infection in humans, as well as herpes keratits, an eye infection that can lead to corneal scarring and blindness. While most of the U.S. population has the HSV-1 virus, millions go undiagnosed due to the lack of symptoms. Even still, about 40 percent of the population will have at least one cold sore during their lives.

The second form of the herpes virus is herpes simplex type 2 (HSV-2). This virus is the major cause of genital herpes, and infects about 17 percent of the U.S. population or approximately 50 million people. There are between 5 million and 10 million people in this group with identified cases of HSV-2.

To detect cold sore susceptibility genes, researchers traced genetic markers in families to determine areas on chromosomes that harbor disease genes. This process is called linkage analysis. When genetic mutations are transmitted from parent to offspring, genetic markers near the disease gene are also transmitted. By detecting markers shared among family members, researchers can identify areas of chromosomes where genes that are responsible for disease may lie. The study set a precedent because it was the first whole-genome study of the herpes simplex virus to employ linkage analysis to determine susceptibility genes.

Researchers used a pool of 421 people from 39 large Utah families as their test subjects in a genomic study known as the Utah Genetic Reference Project. Researchers categorized subjects according to how often they experienced cold sore outbreaks:

* Frequently affected--HSV-1 infected and two or more outbreaks annually (89 participants)

* Mildly affected--HSV-1 infected and two or less outbreaks annually (111)

* Unaffected--HSV-1 infected but had never experienced an outbreak (85)

* Unknown or HSV uninfected--could not be categorized (146)

The researchers compared the "recurrently affected" and "unaffected" groups (both proven to be HSV-1 infected) to illustrate the greatest possible distinction of outbreak occurrences. Subjects who couldn't be categorized were excluded from the study, as well as the 111 mildly affected people. Upon collection of all genetic data, a mathematical analysis concluded the probability of a relationship between cold sores and the long arm of chromosome 21 to have at least a 1000:1 ratio.

The likely genetic relationship is not the sole factor thought to be responsible for reactivation of HSV and cold sores. Environmental factors, i.e. fever, wind, and sunburn, also are believed to contribute to the virus. Viral factors, like strain and burden of dormant infection, are also believed to trigger HSV outbreak occurrences.

To be sure the study was unbiased, researchers began with no preconceived notions about which areas of the human genome may be related to cold sore susceptibility. Therefore, the relationship with the long arm of chromosome 21 was truly a new finding. "We didn't start with the thought … [which] helped ensure an unbiased study..." Kriesel said.

Now Kriesel, Hobbs, and other researchers are examining the six possible susceptibility genes to determine which ones are linked to cold sores. The group believes they will find that three of the genes will prove related in future studies.

"…a …target to reduce … cold sores would… expand our study results to include genital herpes or herpes keratitis," Kriesel said.

The full report of this research is now available on the Journal of Infectious Diseases web site and in the Feb 1 print edition.

In addition to Kriesel and Hobbs, co-authors of this research project are Mark F. Leppert, Ph.D., distinguished professor and co-chair of the Department of Human Genetics; Brandt B. Jones (B.S., senior research scientist), Division of Infectious Diseases; and Brith E.M. Otterud (B.S., computer professional), Department of Human Genetics.