Inflammatory Genes
Genes may put African Americans at higher risk of disease />

CONTEXT: Heart disease, stroke, transplant rejection, and autoimmune diseases kill African Americans at a higher rate than white Americans. Access to health care, health behaviors, and socioeconomic and community factors explain many, but not all, of these disparities. Genetic differences are often discounted, because variations within a single racial group are larger than variations among racial groups and because race is increasingly viewed as a social construct rather than a biological one. Nonetheless, race-based medicine is hotly debated, and race-specific therapies are being studied. Many diseases that disproportionately afflict African Americans are linked to inflammation or an overactive immune system. To test whether genetics plays a role in these diseases, Roberta Ness and colleagues at the University of Pittsburgh tracked nearly 600 women to examine genetic variants known to promote inflammation.

METHODS AND RESULTS: The researchers tested for variants of six different genes among healthy women who received prenatal care before successful first births. Of these, 179 identified themselves as black, 387 as white. The genes coded for proteins, called cytokines, that regulate the immune system. For five of the six genes studied, black women were more likely than their white counterparts to carry a proinflammatory variant; the difference was statistically significant for four genes. For one gene, black subjects were 36.5 times more likely than whites to carry two copies of the proinflammatory variant. However, for any single gene, many white women carried a proinflammatory variant, and many black women did not.

WHY IT MATTERS: Improving unhealthy living conditions and habits and reducing social disparities will be most effective in preventing inflammatory disease; still, tests that show who is most likely to fall ill could help those at risk get preventive counseling and care. By demonstrating a genetic contribution to disease that is race-specific, this work suggests that race could be used as a shorthand for genetic predisposition to guide medical advice. This notion is controversial because of the high genetic variation within racial groups. Making decisions based on race alone will include some people who can’t benefit from treatment and exclude others who can. To resolve this issue, genetic tests to assess risk factors should be developed. Meanwhile, using race as a kind of genetic proxy to inform preventive care might deliver the most good to the most people.

SOURCE: Ness, R. B., et al. 2004. Differential distribution of allelic variants in cytokine genes among African Americans and white Americans. American Journal of Epidemiology 160:1033-1038.

Insulin Version 2.0
Fat secretes hormone that may control diabetes

CONTEXT: Abdominal fat is a dangerous thing. This is not because the fat clings to internal organs (which it does), but because it secretes a suite of hormones that preserve the fat’s existence and affect metabolism. The result is an increased risk of a number of maladies, from diabetes to heart disease. In a series of experiments, researchers led by Iichiro Shimomura at Osaka University found yet another hormone made by abdominal, or visceral, fat – one that, surprisingly, mimics the beneficial effects of insulin.

METHODS AND RESULTS: Using tissue samples taken from two human volunteers, Shimomura’s team first identified genes that were active in visceral fat. The researchers tracked one of these genes to a protein known to help immune cells mature. Next, they studied more than a hundred people and found that the more visceral fat they had, the higher their blood levels of the protein. Another experiment observed mice genetically predisposed to obesity; as they got fatter, blood levels of the protein rose. Because the protein comes from visceral fat, the researchers named the protein “visfatin.” Mice completely lacking the gene for visfatin died before birth; mice carrying only one functional copy of the gene had elevated glucose levels. Adding visfatin to liver, fat, and muscle cells had the same effect that insulin did; visfatin even lowered glucose levels in insulin-resistant mice. Still more studies indicated that insulin and visfatin bound to different spots on the same protein (the insulin receptor), which, when activated, causes cells to take in glucose. In fact, when the spot where insulin binds to its receptor was mutated such that insulin could not bind, visfatin still could bind, triggering the same response as insulin.

WHY IT MATTERS: Diabetes occurs when the body doesn’t make enough insulin or doesn’t respond properly to the hormone. The disease afflicts nearly 200 million people worldwide and is the sixth leading cause of death in the United States. This research opens another route to finding diabetes drugs. Either visfatin or molecules that fit visfatin’s binding site could help control the disease. Teasing out the natural role of visfatin may yield insights; though greater amounts of fat produce greater amounts of visfatin, these levels are insufficient to counter the ill effects of obesity. Studies that resolve this paradox may show how obesity and its associated diseases could be prevented or treated.

SOURCE: Fukuhara, A., et al. 2005. Visfatin: a protein secreted by visceral fat that mimics the effects of insulin. Science 307:426-430.

Cholesterol Cure?
Toward a plausible RNAi therapy />

CONTEXT: RNA interference (RNAi) – once thought to be an experimental artifact, then considered an unimportant anomaly – is now recognized as an important technique for regulating gene expression in animals, plants, and fungi. In essence, RNAi occurs when small RNA molecules (short interfering RNA or siRNA) ambush messenger RNA, the molecule through which the instructions in a gene are translated into the protein that will act them out. At least three companies hope to transform the technology into new therapies. It’s tough to do, because siRNA is rapidly destroyed in blood and has trouble getting into cells. Now, a team that is headed by Jürgen Soutschek and Hans-Peter Vornlocher at the biotech company Alnylam has shown that a new version of siRNA can travel through the bloodstream into cells and lower cholesterol levels.

METHODS AND RESULTS: Soutschek and colleagues made siRNA that would silence the gene for a cholesterol-boosting protein, apolipoprotein B. Using established techniques, they modified the chemical backbone of siRNA to make it more stable. In a novel approach, they linked siRNA to another molecule (ironically, cholesterol) that enters cells easily and injected the linked molecules into mice. The treatment lowered “bad” cholesterol levels by more than 40 percent, and follow-up tests showed that siRNA had entered cells and stopped production of apolipoprotein B.

WHY IT MATTERS: Drugs available today work in just a handful of ways. Most bind to a protein and affect its function. Others replace a protein. RNAi drugs would do something completely different: they would stop a protein from being made at all, and so treat diseases in ways that other techniques cannot. By showing that RNAi drugs can be delivered through blood, this research counters the strongest criticism of the technique. But more obstacles remain: in humans, siRNA must travel farther in the bloodstream than in mice, the amounts of drug required are still prohibitively high, and long-term treatments with cholesterol-linked siRNA may have side effects worse than the disease. Nonetheless, these results, and more like them, will begin to sway the skeptics.

SOURCE: Soutschek, J., et al. 2004. Therapeutic silencing of an endogenous gene by systemic administration of modified siRNAs. Nature 432:173-178.