Pittsburgh, December 1, 2004 – Specific variants in genes that encode proteins regulating inflammation may hold a key to explaining a host of disease processes known to cause increased risk of illness and death among African Americans, according to a study from the University of Pittsburgh’s Graduate School of Public Health (GSPH). The study, “Differential Distribution of Allelic Variants in Cytokine Genes Among African Americans and White Americans,” appears in the Dec. 1 issue of the American Journal of Epidemiology.
“We found that African Americans were significantly more likely to carry genetic variants known to stimulate the inflammatory response,” said Roberta B. Ness, M.D., M.P.H., professor and chair of the department of epidemiology at GSPH and the study’s primary author. “At the same time, genotypes known to dampen the release of anti-inflammatory proteins were more common among African Americans. This is kind of a double whammy.”
The genes for some major immune regulatory proteins were looked at. Note that advances in assay techniques are allowing scientists like these folks to examine many more genes at once than was done in past studies.
Specifically, scientists compared genetic data on 179 African-American and 396 white women who sought prenatal care and delivered uncomplicated, single, first births at Magee-Womens Hospital of the University of Pittsburgh Medical Center between 1997 and 2001. Blood samples were analyzed for a multitude of functionally relevant allelic variants in cytokine-regulating genes. Among these were several genes regulating the immune system proteins interleukin-1, interleukin-1 alpha, interleukin-1 beta, interleukin-6, interleukin-10, interleukin-18 and tumor necrosis factor-alpha.
“In the past, people looked at one or two variants,” said Dr. Ness. “We looked at a whole host, and saw trends that perhaps point to some evolutionary-mediated change in the human genome that has had an impact on inflammation.”
There has been a marked trend in recent years in the discovery of a major role for inflammation as a driver for the development of a large range of diseases including atherosclerosis and cancer. The anti-inflammatory COX2 inhibitor drug celecoxib (brand name Celebrex) is currently being used in a number of cancer treatment trials. Chronic inflammation accelerates the aging process. A genetic difference between groups in their propensity for inflammation is inevitably going to cause group average differences in disease incidence.
Odds ratios for African Americans versus Whites in genotypes up-regulating proinflammatory interleukin (IL) 1 (IL1A-4845G/G, IL1A-889T/T, IL1B-3957C/C, and IL1B-511A/A) ranged from 2.1 to 4.9. The proinflammatory cytokine interleukin-6 IL6-174 G/G genotype was 36.5 times (95% confidence interval (CI): 8.8, 151.9) more common among African Americans. Genotypes known to down-regulate the antiinflammatory interleukin-10 (IL10-819 T/T and IL10-1082 A/A) were elevated 3.5-fold (95% CI: 1.8, 6.6) and 2.8-fold (95% CI: 1.6, 4.9) in African Americans. Cytokine genotypes found to be more common in African-American women were consistently those that up-regulate inflammation.
Note that interleukin-19 (IL-10) is among the genes found to occur in different frequency in blacks and whites. Well, another study found that IL-10 promoter polymorphisms appear to influence the rate of advance of HIV infection. So this result also has implications for the spread of HIV and likely for vulnerability to other pathogens.
The differing frequencies of genetic variations for genes that regulate inflammation response were selected for by the radically different ecological niches humans found as they spread out around the world. Therefore it is not surprising the frequencies of variations are different in human groups which have long settled different parts of the world. What is more interesting than the differences in genetic variation frequencies (at least to me) is that it is likely that neither the frequencies of genotypes in whites or the frequency of genotypes in blacks are ideal for the environments we find ourselves living in today. Our inflammation responses are in all likelihood maladaptive for industrial society. My guess is that humans in general in modern society are experiencing more inflammation on average than is beneficial for them.
We need better smarter ways to control the inflammation response and easier ways to detect triggering of the inflammation response. Lots of people are walking around with chronic inflammation who do not even know it. Think of it as analogous to the people who are walking around with undiagnosed high blood pressure. Some people have chronic inflammation due to an undiagnosed infection. Others have it due to a nutritional deficiency (e.g lack of folic acid, B-6, and B-12 to brake down homocysteine). Still others may have it due to a low grade auto-immune response that they are unaware of. We need to be able to detect and more consciously control our inflammatory responses. But just how what sort of treatment will be optimal to exert on our inflammatory responses will depend at least in part on which particular set of genetic variations we possess for genes that regulate the inflammatory response.
|Share |||Randall Parker, 2004 December 04 01:36 AM Human Population Genetics|