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.
"In light of the study being stopped early, a fundamental understanding of the genetics underlying CRP becomes even more important," said Ridker, who also chaired the JUPITER trial.
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.
"It all fits together nicely," said Alexander Reiner of the University of Washington, Seattle, who led the second report. "In both studies, HNF1A came out as one of the strongest predictors of plasma CRP."