A team of international researchers has discovered that a specific gene on chromosome 15 regulates inflammation, a finding with implications for a wide range of disorders, including cancer, cardiovascular disease, diabetes, obesity, Alzheimer's, and infections. The findings are published in the October 9 online issue of Nature Genetics.
Investigators believe this discovery will be of great interest to biomedical and pharmaceutical researchers because of an already heightened understanding of the role of inflammation in so many human disorders.
"Practically every common disease involves an inflammation component," said John Blangero, Ph.D., a scientist at the Southwest Foundation for Biomedical Research (SFBR) in San Antonio and the paper's senior author. "So the discovery of a new player in the inflammation pathway opens up many potential avenues for intervention on a broad range of health issues."
Along with Blangero, lead researchers in identifying the SEPS1 (Selenoprotein S) gene's influence on inflammation were Joanne Curran, Ph.D., and Ahmed H. Kissebah, M.D. Curran, who also is a geneticist at SFBR, was formerly with ChemGenex Pharmaceuticals, an Australian-based company that initially identified the gene through animal studies and funded this latest analysis of its role in humans. Kissebah is professor of medicine at the Medical College of Wisconsin and medical director of TOPS (Take Off Pounds Sensibly), an international weight-loss organization whose members provided genetic material for analysis. Dr. Kissebah practices at Froedtert Hospital, a major teaching affiliate of the Medical College. Other scientists from SFBR, ChemGenex, Deakin University (Geelong, Australia) and the International Diabetes Institute (Melbourne, Australia) also contributed to the work.
Their research study identified SEPS1 as a type of "garbage truck" that helps clear cells of misfolded proteins that build up when cells are placed under stress, Blangero said. Inflammation develops when those faulty proteins accumulate in a cell. People with a genetic variation that impairs SEPS1' ability to purify the cells by clearing out the bad proteins tend to suffer higher levels of inflammation than people in whom the gene fulfills that role more efficiently, according to the study.
The study found the same relationship between SEPS1 and inflammation in two geographically and ethnically distinct populations of people in the United States, one in Wisconsin and one in Texas.
Greg Collier, Ph.D., CEO of ChemGenex, said the discovery of SEPS1 and its function could yield new approaches for inhibiting inflammation, perhaps through medications that regulate SEPS1. An expected search for other genes that influence SEPS1 also could lead to other potential areas for drug intervention.
Researchers studying diseases impacted by inflammation also might look to see what role SEPS1 plays in disease susceptibility. Already, ChemGenex and SFBR scientists are beginning to study how this gene influences a variety of complex diseases, including cardiovascular disease, diabetes, obesity, preeclampsia, and various infectious diseases.
Kissebah said it provides new insight into studies he leads on the genetics of obesity. "Now that we have identified SEPS1' role in inflammation, which is known to initiate the process of arterial wall hardening and the onset of Type 2 diabetes, we are developing an understanding of why obese persons with a faulty SEPS1 gene may be at higher risk of developing heart disease and diabetes," he said.
The path to discovery: finding SEPS1 and its influence
These groundbreaking findings about SEPS1 are built upon a discovery five years ago by ChemGenex Pharmaceuticals. The company was studying the desert sand rat, an animal that, like humans, has certain individuals with a greater propensity than others for obesity and diabetes, as well as the inflammation associated with those conditions. ChemGenex researchers found that the obese and diabetic sand rats exhibited a different pattern of a previously undiscovered gene, which is now known to be SEPS1. Given the results in animals, the SFBR-led team was brought in to determine whether this gene is relevant to inflammation in humans.
Blangero, who designed the study, first teamed up with Kissebah and the large-scale, family-based study Kissebah leads with TOPS members. This study population is largely of Northern European ancestry and has a high incidence of diabetes and obesity.
Scientists worked with 522 individuals from 92 families in the TOPS program, sequencing their entire SEPS1 gene and identifying all the genetic variations among individuals. These molecular genetic analyses were performed at the International Diabetes Institute in Melbourne, Australia, and directed by Curran and Dr Jeremy Jowett.