In these 2 study cohorts free of clinically apparent cardiovascular disease, we describe the distribution of circulating MGP concentrations and we report that MGP concentrations are associated with higher levels of a number of coronary risk factors, as well as the overall Framingham CHD risk score. In study A, subjects were drawn from a well-characterized, community-based cohort free of cardiovascular disease and sampled to represent a broad spectrum of ages and cardiovascular risk. In study B, subjects were older men and women selected for their low usual dietary vitamin K intake (<90 μg/d) to participate in a vitamin K supplementation study, and were also free of cardiovascular disease. To our knowledge, there are no other reports of associations between circulating concentrations of MGP and coronary risk factors in men and women free of clinically apparent CHD.
The findings of associations of MGP concentrations with HDL cholesterol and total:HDL cholesterol, and with Framingham CHD risk score in 2 independent studies provides consistent evidence that traditional lipid risk factors are significantly associated with circulating MGP. In further analyses, there is no significant difference in high total cholesterol (> 240 mg/dL) or prevalence of total cholesterol-lowering drug treatment across MGP quartiles in either men or women (analyses not shown), suggesting that the predominant lipid association is with HDL cholesterol.
Increasing concentrations of MGP were modestly associated with higher levels of coronary calcium deposition after adjustment for CHD risk score in women but not men in the more elderly cohort study B. Our study sample sizes are relatively small, and estimates of association may be more reliable in larger sample sizes. Further research is justified in larger prospective cohorts to confirm associations with specific vascular risk factors and to assess the magnitude of association, independence from other risk factors, and sex-specificity of the positive relationship of MGP with vascular calcium deposits.
Increased concentrations of circulating MGP have been associated with arterial calcification in the rat9
and in patients with severe atherosclerosis.13
MGP is found at high levels in the vicinity of calcium deposits in mice and humans.24
In humans, polymorphisms in the MGP gene have been associated with MGP promoter activity and circulating serum concentrations of MGP,25
and evidence from one study suggests that variants in the MGP gene may be linked to CHD and CAC,26
although in another study the associations with CAC are weak and not statistically significant.27
Taken together, these findings suggest that arterial calcification may lead to increased MGP expression, perhaps in a feedback attempt to physiologically reduce bone-like formation of calcium deposits in the artery. Conversely, a more recent, small study attributed an inverse association between circulating MGP concentrations and coronary calcification to poor overall vitamin K status.14
These conclusions were not consistent with our observations in either cohort. Of note, both study A and study B were conducted in subjects free of CHD, likely at substantially lower risk than subjects in the previous study. It will be of interest to examine the role of randomization to vitamin K supplementation to progression of CAC and to change in MGP levels in study B, which is ongoing. Finally, increased serum levels of MGP, without concomitant increased MGP expression in the arterial walls does not inhibit the abnormal mineralization observed in mice lacking MGP.12
Our finding of an inconsistent association of MGP with CAC in women, and no consistent association in men suggests that serum MGP concentrations are not robust in their predictive value of CAC, and that confounding by risk factors may explain much of the association.
Several limitations of these studies deserve consideration. MGP and risk factors were measured at the same time, but there was a time interval of ≈2 years between MGP measurement and EBCT testing in Study A. This might have led to an underestimation of the true magnitude of association between MGP and CAC score. However, the findings of study A are consistent with study B, in which MGP concentrations were determined at the same time as the CT scan. Image noise is correlated with body mass index in CT scans (r=0.8 in study A) and may confound coronary calcium readings in obese individuals. We found that body mass index and image noise are highly correlated, and in study A, we conducted further analyses of associations between MGP and body mass index and found no significant association between MGP and body mass index (P=0.14). Subsequent analyses of the association of MGP and CAC, adjusting for body mass index, did not show any marked confounding of the association. Both studies were conducted in primarily white populations, so the findings may not be generalizable to non-white populations.
In our community-based cohorts, MGP levels are higher with increasing age and are associated with higher levels of individual coronary risk factors in middle aged and older men and women. Larger prospective cohorts need to be studied to confirm the strength of an independent positive relationship of MGP with vascular calcium deposits in women.