Dear Editor,
The article by Corsetti and co-workers (1) recently published is of deep importance in regard to the pathogenesis of cardiovascular disease, particularly in women. Utilizing a large sample derived from the Dutch PREVEND cohort, authors investigated reasons for their previously reported observation of apolipoprotein (apo)E-associated cardiovascular disease risk in women with high levels of both HDL-cholesterol and C-reactive protein (CRP). The sample excluded only the insulin-using diabetics and comprised a relatively high proportion of subjects with urinary albumin excretion. Concentrations of the two major HDL subclasses were estimated and multivariable risk models were constructed. Investigators found that the highest quartile of LpA-I:A-II, as the sole variable, displayed for CVD a 5-fold hazard ratio, in addition to interacting with high apoE levels. The high pathogenetic relevance of this study is due to, first in clearly confirming a subgroup of women with enhanced low-grade inflammation and HDL-dysfunctionality of being at high CVD risk and secondly in demonstrating that apoE is directly linked to high risk in such women. We possess as yet unpublished observations supporting those under discussion (1) and had previously reported that serum apoE levels in Turkish adults are associated with hypertriglyceridemic dyslipidemias and the metabolic syndrome (MetS), additively to genotype (2). Serum apoE was a major determinant of apoB beyond apoE genotype, CRP and triglyceride levels in multivariable analysis (3) reflecting a proinflammatory nature. Furthermore, serum apoA-II concentrations, by conferring risk for MetS and diabetes, exhibited also evidence of pro-inflammatory properties among Turks (4).
I believe that the findings in the PREVEND cohort can be better explained by a notion of excess circulating lipoprotein (Lp)(a) with or without induction of autoimmune complex formation employing apoE and LpA-I:A-II. The female low HDL-C/high CRP high-risk subgroup (HR1) actually represents excess Lp(a) accompanied by higher pre-beta apoA-I [risk illustrated in Fig. 3b] (without autoimmune activation or) with aggregation of apoE to a damaged protein beyond Lp(a), inasmuch as a combination of significantly higher triglycerides, apoB and total cholesterol are displayed (in a context of highly prevalent MetS selected by low HDL-C in subset definition). Excess (1.5-fold levels) apoE under these conditions is linked to a 4.3-fold excess CVD in this subset compared with the base female population.
HR2 subgroup represents in my opinion autoimmune activation involving Lp(a) protein subjected to damage by oxidative stress, inasmuch as a combination of (by one-quarter) lower triglycerides, lower apoB but similar total cholesterol are displayed (in a context of low MetS prevalence) compared to HR1. Excess (1.5-fold levels) apoE again contributes to a 6-fold CVD risk in this subset compared with the base female population. Though data are not provided, I would anticipate a high prevalence of pre-diabetes (and to some degree of non-insulin-dependent diabetes) in this subgroup, in whom Lp(a) is a recognized inverse covariate (5). These women are at high CVD risk due to a combination of enhanced low-grade inflammation, immune activation comprising aggregation between Lp(a) and both apoE and LpA-I:A-II, and dysfunctionality of apoA-I and HDL.
Univariate HRs for biomarkers in the HR2 high risk subgroup (Table 5) reveal that HRs of triglycerides (derived from excess oxidized phospholipids on Lp(a)), apoB (from Lp(a)) and total cholesterol (from cholesterol on Lp(a) lipoprotein) are highly elevated, but not of LDL-C.
The concepts of dysfunction of protective proteins (reviewed in Ref. 6) and autoimmune activation underlying cardiovascular disease and other chronic diseases (7) are not widely recognized, but further research and approaches in this direction are sorely needed if the tide of obesity and chronic diseases (including renal dysfunction) is to be stemmed.
1. Corsetti JP, Bakker SJ, Sparks CE, Dullaart RP. (2012) Apolipoprotein A-II influences apolipoprotein E-linked cardiovascular disease in women with high levels of HDL cholesterol and C-reactive protein. PLoS One 7:e39110
2. Onat A, Hergenç G, Ayhan E, Kaya Z, Küçükdurmaz Z, Bulur S, et al. (2007) Serum apolipoprotein E concentrations among Turks: Additive information to genotype relative to dyslipidemia and metabolic syndrome. Arch Turk Soc Cardiol 35:449-57
3. Onat A, Kömürcü-Bayrak E, Can G, Küçükdurmaz Z, Hergenç G, Erginel-Ünaltuna N. (2010) Apolipoprotein A-I positively associated with diabetes in women independently of apo E genotype and apolipoprotein B levels. Nutrition 26:975-80
4. Onat A, Hergenç G, Ayhan E, Uğur M, Can G. (2009) Impaired anti-inflammatory function of apolipoprotein A-II concentrations predict metabolic syndrome and diabetes at 4 years follow-up in elderly Turks. Clin Chem Lab Med 47:1389-94
5. Emerging Risk Factors Collaboration, Erqou S, Kaptoge S, Perry PL, Di Angelantonio E, Thompson A, White IR, et al. (2009) Lipoprotein(a) concentration and the risk of coronary heart disease, stroke and nonvascular mortality. JAMA 302:412-23
6. Onat A, Hergenç G. (2011) Low-grade inflammation and dysfunction of high-density lipoprotein and its apolipoproteins as a major driver of cardiometabolic risk. Metabolism 60:499-512
7. Onat A, Direskeneli H. (2012) Excess cardiovascular risk in inflammatory rheumatic diseases: pathophysiology and targeted therapy. Curr Pharmaceut Des 18:1465-77

Prof.Dr. Altan Onat

Correspondence: Nisbetiye cad. 59/24, Etiler 34335, Istanbul, Turkey.
Tel. +90 212 351 6217, E-mail: alt_onat@yahoo.com.tr