Scientists Pinpoint Inflammation Gene; Discovery Has Implications For Wide Range Of Diseases

Investigators believe this discovery will be of great interest tobiomedical and pharmaceutical researchers because of an alreadyheightened understanding of the role of inflammation in so many humandisorders.

"Practically every common disease involves an inflammationcomponent," said John Blangero, Ph.D., a scientist at the SouthwestFoundation for Biomedical Research (SFBR) in San Antonio and thepaper's senior author. "So the discovery of a new player in theinflammation pathway opens up many potential avenues for interventionon 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 atSFBR, was formerly with ChemGenex Pharmaceuticals (NASDAQ: CXSP; ASX:CXS), an Australian-based company that initially identified the genethrough animal studies and funded this latest analysis of its role inhumans. Kissebah is professor of medicine at the Medical College ofWisconsin and medical director of TOPS (Take Off Pounds Sensibly), aninternational weight-loss organization whose members provided geneticmaterial for analysis. Dr. Kissebah practices at Froedtert Hospital, amajor teaching affiliate of the Medical College. Other scientists fromSFBR, ChemGenex, Deakin University (Geelong, Australia) and theInternational Diabetes Institute (Melbourne, Australia) alsocontributed to the work.

Their research study identified SEPS1 as a type of"garbage truck" that helps clear cells of misfolded proteins that buildup when cells are placed under stress, Blangero said. Inflammationdevelops when those faulty proteins accumulate in a cell. People with agenetic variation that impairs SEPS1' ability to purify the cells byclearing out the bad proteins tend to suffer higher levels ofinflammation than people in whom the gene fulfills that role moreefficiently, according to the study.

The study found the same relationship between SEPS1 andinflammation in two geographically and ethnically distinct populationsof people in the United States, one in Wisconsin and one in Texas.

Greg Collier, Ph.D., CEO of ChemGenex, said the discovery ofSEPS1 and its function could yield new approaches for inhibitinginflammation, perhaps through medications that regulate SEPS1. Anexpected search for other genes that influence SEPS1 also could lead toother potential areas for drug intervention.

Researchers studying diseases impacted by inflammation also might lookto see what role SEPS1 plays in disease susceptibility. Already,ChemGenex and SFBR scientists are beginning to study how this geneinfluences a variety of complex diseases, including cardiovasculardisease, diabetes, obesity, preeclampsia, and various infectiousdiseases.

Kissebah said it provides new insight into studies he leads onthe genetics of obesity. "Now that we have identified SEPS1' role ininflammation, which is known to initiate the process of arterial wallhardening and the onset of Type 2 diabetes, we are developing anunderstanding of why obese persons with a faulty SEPS1 gene may be athigher 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 adiscovery five years ago by ChemGenex Pharmaceuticals. The company wasstudying the desert sand rat, an animal that, like humans, has certainindividuals with a greater propensity than others for obesity anddiabetes, as well as the inflammation associated with those conditions.ChemGenex researchers found that the obese and diabetic sand ratsexhibited a different pattern of a previously undiscovered gene, whichis now known to be SEPS1. Given the results in animals, the SFBR-ledteam was brought in to determine whether this gene is relevant toinflammation in humans.

Blangero, who designed the study, first teamed up with Kissebah and thelarge-scale, family-based study Kissebah leads with TOPS members. Thisstudy population is largely of Northern European ancestry and has ahigh incidence of diabetes and obesity.

Scientists worked with 522 individuals from 92 families in the TOPSprogram, sequencing their entire SEPS1 gene and identifying all thegenetic variations among individuals. These molecular genetic analyseswere 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 methodsdeveloped by Blangero and other SFBR scientists to sift through thisinformation and predict which of these genetic variants was most likelyto have a direct effect on inflammation. For this effort, they reliedon 1,500 parallel processors in the foundation's SBC Genomics ComputingCenter. An unparalleled resource for genetic analysis, the centerenabled an otherwise too-time-consuming comprehensive analysis toeliminate scientific "guesswork" on which variants ought to beinvestigated in the laboratory.

The statistical analysis identified one particular variant inthe SEPS1 gene -- a variation in the gene's promoter region, whichregulates SEPS1 expression -- as the most important factor among theindividuals with the highest levels of inflammation.

This allowed an Australian research team at Deakin University led byChemGenex Pharmaceuticals to conduct laboratory investigations todiscover the function of the SEPS1 gene and this particular variant.

"These experiments showed that this genetic variation affects how thecell responds to stress," Curran said. "The more common variant -- theone most people have -- is the 'good form' of SEPS1 that is moreefficient at perceiving and responding to cellular stress. Thealternative, rarer variant weakens SEPS1 and puts it at a disadvantagein dealing with cellular stress."

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

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

Researchers studied an additional 500 individuals from 20 families ofthis San Antonio Family Heart Study and performed the same geneticanalysis that was previously done with the Wisconsin families. "Onceagain, we obtained the same results," said Blangero. "We replicated ourfindings in another study with a different population of a differentethnic group, which is rare in human genetics. This adds to other clearevidence that SEPS1 is a good target in defeating inflammation, whichplays an important role in virtually every disease of major publichealth importance."