Metabolic genes tied to inflammatory predictor of heart disease and stroke risk

Two new studies provide evidence that differences in people’s blood levels of C reactive protein (CRP) stem in part from natural variation in known metabolic genes. The researchers report their findings in the May American Journal of Human Genetics, a publication of Cell Press.

“ Many years ago, we showed that CRP levels in healthy, middle aged men can predict—better than cholesterol—who would die from a cardiac event,” said Paul Ridker of Harvard Medical School, who led one of the two studies. “We’ve now confirmed that the CRP gene itself plays a role in setting CRP levels. And the most extraordinary finding is that some of the other genes involved relate to metabolic syndrome pathways.”

The findings come just weeks after the “JUPITER Trial,” designed to test whether cholesterol-lowering statins can prevent heart disease in people with normal cholesterol but increased CRP levels, was ended early. The drug company AstraZeneca announced that they were halting the trial of rosuvastatin calcium (trade name Crestor) because early results showed that the drug reduced death and risk of heart problems in patients compared to placebo.

CRP has long been considered a hallmark of low-grade, systemic inflammation. Although researchers have known for more than a decade that CRP levels can predict the risk of heart disease, stroke, metabolic syndrome and diabetes, it hasn’t been entirely clear why. Environmental factors, including obesity, smoking and stress, contribute to CRP, but studies have also shown that its levels have a strong genetic component.

In search of the genes responsible, Ridker’s team conducted a genome-wide association study among 6,345 apparently healthy women participating in the Women’s Genome Health Study. Specifically, the women were evaluated for hundreds of thousands of single nucleotide polymorphisms (sites in the genome that harbor lots of variation among individuals) that they thought might possibly determine plasma CRP level.

The study turned up seven sites that were significantly associated with CRP. Two of those, responsible for proteins known as glucokinase regulatory protein (GCKR) and hepatic nuclear factor-1A (HNF1A), are suspected or known to be associated with maturity-onset diabetes of the young, they noted. GCKR had earlier been linked to triglyceride and glucose levels, but not to CRP, Ridker said.

A second report of two additional genetic association studies (from the Pharmacogenomics and Risk of Cardiovascular Disease study and the Cardiovascular Health Study), each including thousands of participants, provided independent and confirmatory evidence for an association between common variants of HNF1A and CRP concentrations.

HNF1A is produced in the liver and pancreas, where it regulates the activity of other genes, he explained. An earlier study also showed that the promoter region of the human CRP gene contains an HNF1A-binding site.

“ The protein products of six of the seven loci [we’ve uncovered] are directly involved in metabolic syndrome, insulin resistance, [insulin-producing] beta-cell function, weight homeostasis, and/or premature atherothrombosis,” Ridker’s team concluded. “Thus, common variation in several genes involved in metabolic and inflammatory regulation have significant effects on CRP levels, consistent with CRP’s identification as a useful biomarker of risk for incident vascular disease and diabetes.”

“ Together, these observations suggest the possibility that CRP and metabolic phenotypes may, at least in part, be under coordinate genetic control,” Reiner and his colleagues said. “Given the association between plasma CRP concentration and various metabolic and cardiovascular diseases, larger studies assessing the potential association of HNF1A genotype with more complex, clinical disease-related endpoints may shed additional light on the role of genetic regulation of CRP in the occurrence of disorders such as myocardial infarction, stroke, diabetes, and metabolic syndrome.”

Source: Cell Press

Related stories:

Research suggests fitness reduces inflammation
Although a number of studies have suggested that regular exercise reduces inflammation – a condition that is predictive of cardiovascular and other diseases, such as diabetes – it is still not clear whether there is a definitive link. And if such a link exists, the nature of the relationship is by no means fully understood.
Israeli study finds obstructive sleep apnea is health factor from day 1
Obstructive sleep apnea (OSA) in very young children may cause some of the adverse cardiovascular health consequences seen in older children and adults with the condition, according to researchers in Israel, who will present their findings at the American Thoracic Society’s 2008 International Conference in Toronto on Wednesday, May 21.
What else may probiotics do in adults?
Probiotic bacteria, defined as living microorganisms that have beneficial effects on human health, have mostly been studied in the prevention and treatment of different gastrointestinal diseases and allergies. Probiotic products, however, are usually consumed by the general, healthy population but not much is known what kind of effects they have on the immune system in healthy adults. It is not clear how probiotics exert their health effects, but one of the most probable action mechanisms is the modulation of immune responses via the gut's mucosal immune system.
Association between low birth weight, excessive weight gain and heart problems in later life
Researchers who have followed 5,840 people from before birth to the age of 31 have found evidence suggesting that small size at birth and excessive weight gain during adolescence and young adulthood may lead to low grade inflammation, which, in turn, is associated with an increased risk of developing heart disease.
The HLA-DRB1 gene and premature death in rheumatoid arthritis
People with rheumatoid arthritis (RA), an inflammatory autoimmune disease, tend to die younger and, largely from cardiovascular disease (CVD). One explanation for this increasingly recognized fact is that inflammation promotes atherosclerosis. A marker of inflammation, elevation of the C-reactive protein (CRP) level has been shown to predict CVD in the general population. However, other highly inflammatory diseases—Crohn’s, for example—do not carry the same high risk of premature death from heart disease.
Landmark trial to evaluate cardioprotective properties of insulin
The ability of insulin to limit heart-tissue damage during a heart attack will be tested in a landmark clinical trial led by Paresh Dandona, M.D., Ph.D., University at Buffalo Distinguished Professor in the departments of Medicine and Pharmacology and Toxicology in the UB School of Medicine and Biomedical Sciences.
Why quitting may be good for you
Are there times when it is better to simply give up? Psychologists have been exploring this question, and more specifically a possible link between tenacity and both physical and mental health.
Human C-reactive protein regulates myeloma tumor cell growth and survival
Scientists report that a protein best known as a common marker of inflammation plays a key role in the progression of human cancer. The research, published by Cell Press in the September issue of the journal Cancer Cell, implicates C-reactive protein (CRP) as a potential target for cancer treatment.

News discussion:

Medicine & Health news