In this cohort with high prevalence of inflammatory vascular disease, salivary lysozyme was significantly associated with metabolic syndrome, independent of CRP. This finding is consistent with our previous observation that approximately 26% of CRP can be explained by oral infection (Janket et al., 2010
) and further confirms that SLZ has been significantly associated with every step in the continuum of the inflammatory cardiovascular disease risk, called the “common soil” of atherogenesis (Stern, 1995
) as illustrated in . Increasing level of SLZ coincided with increasing intensity of postulated atherogenicity (in and ) while CRP showed distinct threshold effect (). As shown in , SLZ was nearly significantly associated with metS in both subgroups (p= ~0.08) with or without CAD. On the contrary, CRP was not significantly associated with metS in either group (p=~0.54). These subtle differences may not be obvious in large cohorts because significant p-value is a function of sample size.(Gardner and Altman, 1986
; Panagiotakos, 2008
After the JUPITER results publication, dispensation of rosuvastatin has been approved by the U.S. FDA in individuals without
clinically evident coronary heart disease but with an increased risk of cardiovascular disease (CVD) based on age (men ≥50 and women ≥60), CRP ≥ 2 mg/L, and the presence of at least one additional CVD risk factor.(FDA, 2010
) The median CRP levels and mean age of our cohort are similar to those of JUPITER cohort (Ridker et al., 2009
). CRP alone was not a significant predictor of met S in the group with CAD in the current study. Only when SLZ was added to the model CRP became significant. This suggests that SLZ and CRP are confounders (). As reported in the previous publication, CRP appeared to be more strongly associated with the BMI and diabetes components (Ridker et al., 2003
) while SLZ was more closely associated with the hypertension, triglyceride and HDL cholesterol components of metS.( in the current study) This is in agreement with the latest report that hypertension and cholesterol levels were more powerful markers of atherosclerosis than dysglycemia (Sarwar et al., 2010
) and supports our hypothesis illustrating the echelon of dysglycemia and hypertension on the continuum of the atherosclerosis pathway (). Furthermore, a newly published report demonstrated that arterial lysozyme was a more powerful predictor of atherosclerosis than CRP and indirectly supports our observation presented herein.(Abdul-Salam et al., 2010
) Considering our results together with the fact that high proportions of current smokers (16%) and of individuals with metabolic syndrome (41%) in the JUPITER cohort (Ridker et al., 2008
), we find that remediating the underlying factors contributing to elevated CRP such as oral inflammation, smoking or metabolic syndrome may be a more prudent approach than statin administration.
Although lysozymes are expressed in various mucosal surfaces through out the human body, e.g., in the ophthalmic, respiratory and digestive mucosae, its local production is not affected by the expression in other locations.(Wagner and Wagnerova, 1989
) The variability of SLZ and CRP assays being similar (at approximately 10%), the differences we observed in SLZ and CRP in relation to metS could be measurement errors. It, however, could also be due to a non-specific nature of CRP, which has been noted by several researchers. (Kushner et al., 2006
; Levinson and Elin, 2002
Poor oral health is a restricting factor for a healthy diet. Edentulous persons have been shown to have lower intake of fruits and vegetables, (Nowjack-Raymer and Sheiham, 2003
) which is a significant predictor for future diabetes.(Liu et al., 2004
) The mastication difficulties force the edentulous persons to favor soft, easily chewable carbohydrates with high glycemic index.(Liu and Willett, 2002
) This impact of oral health on diet has been largely ignored by nutrition research and is often attributed to dietary effects. Nonetheless, reverse causation cannot be completely ruled out due to our cross-sectional study design.
A major strength of the present study is that we explicitly adjusted for CRP to control for the systemic inflammation. Many reports involving CRP have not adjusted for the multitude of other potential contributors to systemic inflammation (Kushner et al., 2006
) including oral infection.
Several limitations are also noted. The cross-sectional study design is one of them. Therefore, our results may not be interpreted in a causal context. However, the significant association of SLZ with every early stage on the pathway to CAD suggests that the relationship of SLZ and atherosclerosis may be longitudinal (). However, whether the relationship between SLZ and metS is causal or not must be determined from future studies. Also it should be noted that not all significant risk factors identified in longitudinal studies have causal relationship.(Janket et al., 2008b
; Wang, 2008
Another limitation is that we did not have information regarding alcohol consumption or fasting glucose levels. Thus, some participants in non-metS group actually might have metS, and our results might have under-estimated the true association of SLZ and metS.
In summary, our results suggest an association of salivary lysozyme with metabolic syndrome above and beyond CRP. Future longitudinal studies may establish this novel marker as a risk factor for metabolic syndrome.
Unlike previous studies, we examined the relationship between oral inflammation measured by salivary lysozyme and metabolic syndrome in a population with high prevalence of inflammatory vascular disease.
Salivary lysozyme was significantly associated with metabolic syndrome (metS) controlling for C-reactive protein (CRP) and other risk factors.
The positive results of the JUPITER trial brought greater public attention to CRP, a non-specific inflammatory marker. Additionally, U.S. Food and Drug Administration (FDA) approved the administration of rosuvastatin based on CRP levels along with one additional risk factor in men aged 50 and older, and women aged 60 and older. However, considering the pleiotropic nature of statins and the non-specific characteristic of CRP, rosuvastatin dispensation based on CRP level and one unspecified risk factor leaves many unanswered questions. The present study is consistent with our previous observation that oral infection explains approximately 26% of CRP and reducing oral inflammation prior to statin administration may be prudent.