CRP has been shown in numerous studies to have a positive association with clinical CVD 26, 27
. Gender differences, however, may exist in CRP association with CVD 19-21
and little is known of CRP as a predictor of CVD in T2DM, a chronic inflammatory state conferring increased CVD risk. In fact, CRP association with measures of subclinical atherosclerosis has been equivocal and such studies have largely lacked diabetic individuals. In the largest such study of CAC in T2DM subjects free of clinical CVD, we show that CRP was significantly associated with CAC in women, but not in men, even after controlling for traditional risk factors, metabolic syndrome and BMI. Remarkably, this gender difference in CAC association was similar in a non-diabetic sample. There was no evidence of CRP-CAC association in men, either diabetic or non-diabetic. Our findings suggest that CRP may be a useful marker of cardiovascular risk in women particularly in diabetic women who otherwise have no known CVD.
Gender differences in plasma CRP are well established with higher circulating levels in women 19-21
. This difference is incompletely understood but may relate to gender differences in both visceral and subcutaneous fat, a strong determinant of CRP levels 21
, or to differences in estrogen, which is known to increase levels of CRP 28
. However, studies which adjusted for measures of adiposity, menopausal status and hormone replacement therapy or that looked only at post menopausal women still found higher levels of CRP in women. Similarly, we found that women had higher CRP values than men independent of other demographic and cardiometabolic risk factors. Although CRP levels were higher in T2DM subjects compared to non diabetics, levels were higher in women than men independent of T2DM status. Furthermore, we and others 21
report gender differences in the association of CRP with cardiovascular risk factors, particularly adipose and metabolic syndrome related parameters.
One difficulty in interpreting gender-differences in CRP and the association of CRP with risk factors and disease relates to the uncertainty of whether the relationship of CRP with CVD is causal or simply due to complex confounding with CVD risk factors. While a few animal models support CRP's role in atherothrombosis 4
, this has been harder to show in humans. Several lines of evidence to the contrary include recent large studies of genetic variations in CRP that affect CRP levels but have no association with atherosclerotic CVD 3, 5
. Nonetheless, even if CRP is not causal in its relationship to atherothrombosis, it remains an important correlative biomarker that captures aspects of CVD risk that are not fully captured by established risk strategies.
Gender differences in circulating CRP and the correlation of CRP with cardiometabolic risk factors may have a confounding influence on the relationship of CRP with T2DM and atherosclerotic CVD. Conversely, higher CRP in women may reflect gender differences in the inflammatory environment caused by metabolic stress and thus reflect a true increase in risk of T2DM and CVD risk. Indeed, several studies support this notion. In 923 middle aged Caucasians, CRP was significantly higher in women with metabolic syndrome than in men 29
. Hu et al found in a cross-sectional population-based Finnish study of over 12,000 subjects that higher baseline levels of CRP was more strongly associated with development of diabetes in women compared to men 30
. Remarkably, Erbel and colleagues recently reported that CRP was more important in re-classifying higher CVD risk women than men 31
. Our findings of CRP association with CAC in women but not men with T2DM is novel and consistent with the concept that CRP may be a more useful CVD risk predictor in women than men at increased cardiometabolic risk.
The association of CRP with CAC has been controversial to date, perhaps because of limited sample size and failure to account appropriately for the heterogeneous influence of demographic factors including gender and race. Initial studies by Hunt and colleagues looked at healthy male army personnel and found no association between CRP and CAC 15
. Redberg et al also showed no association among 172 non diabetic postmenopausal women 16
. Wang et al published a study of 321 individuals from the Framingham Heart Study without clinical CVD and found a positive association between CRP and CAC in men and women by spearman correlation which only remained significant in men after an adjustment for BMI 12
. Khera et al looked at 3373 subjects from the Dallas Heart Study found a trend for increasing CRP levels with CAC in men but not women. This association was lost in multivariate analysis and, notably, this study did not include many diabetic patients 13
. We previously reported a lack of association of CRP with CAC in fully adjusted models in non diabetic participants in the SIRCA study 32
. However, there was a trend toward gender differences - CRP was positively associated with CAC in women, not men, in models that did not include BMI.
Few studies to date have included a significant number of diabetic subjects in assessing the relationship of CAC with CRP. Colhoun and colleagues examined 199 type-1 diabetics and 201 non diabetics and found a positive association of CRP with CAC in men but not in women after adjustment for other risk factors. 14
However, this was a small study with only 94 diabetic women and subjects were younger and had type-1 diabetics. A recent paper in press from the MESA cohort study of 6783 subjects (53% female) of varying race including~14% diabetic subjects found a weak association of CRP with CAC that was attenuated in fully adjusted models 33
. However, stratified analyses in women and diabetics were not reported. The largest study prior to ours of diabetic patients was reported by Bowden and colleagues and included 551 diabetic patients (59% women, 83% with T2DM) in the family-based Diabetes Heart Study 18
. They found no significant association with the presence or extent of CAC in fully adjusted models. Compared to our findings in PDHS, potential reasons for conflicting results in this study are sample size, family-based design, inclusion of type-1 diabetes mellitus and prevalent CVD, and differences in the analytic approach to CAC data. The study of CRP in diabetics for the prediction of clinical CVD has been limited, in part, because T2DM has been considered a CVD risk equivalent. Yet among diabetics, without established CVD or multiple CVD risk factors, additional discrimination of those with highest CVD risk has implications for therapeutic goals and strategies 34, 35
. Of a few studies of CRP in CVD risk prediction in T2DM, Soinio and colleagues found that CRP values were independent predictors of cardiovascular death over a 7-year follow-up, even after adjusting for traditional risk factors and BMI in 1059 T2DM subjects 36
. Our findings for CRP-CAC associations in diabetic women are broadly consistent with this clinical finding at least for women. Overall, plasma CRP may be a hallmark of the chronic inflammation that is a feature of adipose dysfunction and insulin resistance in T2DM, particularly in women, and thereby reflects this mechanism of increased CVD risk in T2DM.
Limitations of our study include cross-sectional analysis preventing causal inference. While we evaluated two study samples whose demographics differed somewhat, they were contemporary and derived from the same community, using similar lab assays and protocols. We used the surrogate, non-clinical endpoint of CAC, which is an estimate, and not a direct measure of coronary atherosclerosis. While CAC scores do not detect all types of coronary atherosclerotic plaques, they are clinically relevant because they are strong, independent predictors of CVD including in diabetic subjects 37
. Furthermore, since our non diabetic subjects were recruited on the basis of a family history of premature CVD, our results may not be generalizable to all non diabetic individuals. Replication is needed in more diverse populations to assess for the relevance of clinical CVD outcomes.
In conclusion, CRP may be particularly useful as a marker of atherosclerotic CVD in women. While current guidelines make no recommendation for measurement of CRP in diabetic subjects, our study may suggest otherwise, particularly in diabetic women who otherwise have no known clinical CVD. Further prospective studies are needed to better assess gender differences in CRP utility in CVD risk prediction and its application in T2DM where it might impact novel therapeutic strategies and targets.