'SEPS1 is a good target in defeating inflammation, which plays an important role in virtually every disease of major public health importance.'

Their findings are published in Nature Genetics.

"Practically every common disease involves an inflammation component," says senior author John Blangero, PhD, of the Southwest Foundation for Biomedical Research (SFBR) in San Antonio, Texas. "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 gene's influence on inflammation were SFBR's Joanne Curran, PhD, 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) and Ahmed H. Kissebah, MD, professor of medicine at the Medical College of Wisconsin and medical director of TOPS (Take Off Pounds Sensibly).

Other scientists from SFBR, ChemGenex, Deakin University (Geelong, Australia) and the International Diabetes Institute (Melbourne, Australia) also contributed to the work.

Cellular 'Garbage Truck'

Their research identifies SEPS1 as a type of "garbage truck" that helps clear faulty proteins that accumulate in cells when they are placed under stress, causing inflammation to develop.

People with a genetic variation that impairs SEPS1's 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 same relationship between SEPS1 and inflammation was seen in two geographically and ethnically distinct populations in the United States, one in Wisconsin and one in Texas.

The discovery of SEPS1 and its function could yield new approaches for inhibiting inflammation, perhaps through medications that regulate the gene, says ChemGenex CEO Greg Collier, PhD. A 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.

The finding provides new insight into research on the genetics of obesity, says Kissebah. "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 notes.

Desert Sand Rat

The current 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 now is known to be SEPS1. Given the results in animals, the SFBR-led team was brought in to determine whether the gene might be relevant to inflammation in humans.

Blangero, who designed the study, first teamed up with Kissebah, who leads a large-scale, family-based study 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.

Back in San Antonio, researchers used novel statistical methods developed by Blangero and other SFBR scientists to sift through this information and predict which of these genetic variants was most likely to have a direct effect on inflammation.

For this effort, they relied on 1,500 parallel processors in the foundation’s SBC Genomics Computing Center, which sped an otherwise time-consuming comprehensive analysis and eliminated scientific "guesswork" on which variants ought to be investigated in the laboratory.

Good Target in Defeating Inflammation

The statistical analysis identified one particular variant in the SEPS1 gene -- a variation in the gene’s promoter region, which regulates SEPS1 expression -- as the most important factor among the individuals with the highest levels of inflammation. This allowed an Australian research team at Deakin University led by ChemGenex Pharmaceuticals to conduct laboratory investigations to discover the function of the SEPS1 gene and this particular variant.

"These experiments showed that this genetic variation affects how the cell responds to stress," Curran says.

"The more common variant -- the one most people have -- is the 'good form' of SEPS1 that is more efficient at perceiving and responding to cellular stress. The alternative, rarer variant weakens SEPS1 and puts it at a disadvantage in dealing with cellular stress," she adds.

"Basically," Blangero explains, "this rarer form of SEPS1 gives you a lazy cellular 'garbage truck' that doesn't properly do its job of clearing out the misfolded proteins that lead to inflammation."

As further confirmation of their study results with the Wisconsin population, the researchers looked to see if they would replicate their findings in a distinct group of Texas families. A team of SFBR scientists led by Dr. Jean MacCluer is conducting a long-term, National Institutes of Health-sponsored study on the genetics of heart disease, diabetes and obesity in 1,400 Mexican Americans from 90 San Antonio families.

Researchers studied an additional 500 individuals from 20 families of this San Antonio Family Heart Study and performed the same genetic analysis that previously was carried out with the Wisconsin families.

"Once again, we obtained the same results," says Blangero. "We replicated our findings in another study with a different population of a different ethnic group, which is rare in human genetics. This adds to other clear evidence that SEPS1 is a good target in defeating inflammation, which plays an important role in virtually every disease of major public health importance," he concludes.