The Association Between Circulating Lipoprotein(a) and

Diabetes Volume 63, August 2014
e14
Altan Onat,1 Servet Altay,2 and Hüsniye Yüksel1
COMMENT ON YE ET AL.
The Association Between
Circulating Lipoprotein(a) and
Type 2 Diabetes: Is It Causal?
Diabetes 2014;63:332–342
e-LETTERS – COMMENTS AND RESPONSES
Diabetes 2014;63:e14 | DOI: 10.2337/db14-0521
Excess levels of lipoprotein(a) [Lp(a)] has long been
recognized as a cause of coronary heart disease (CHD),
though the association of Lp(a) with diabetes risk has
challenged medical researchers for several reasons,
mainly because the association shape is fundamentally
a U-shaped one. Ye et al. (1) have newly confirmed such
an inverse association in the combined sex of the European Prospective Investigation of Cancer (EPIC)-Norfolk
cohort, after the first demonstration in the Women’s
Health Study (2). Hazard ratios of the bottom to top
Lp(a) quintile corresponded to a significant 1.59. The
authors analyzed the effect of the single nucleotide
polymorphism (SNP) rs10455872 on elevating circulating Lp(a), which failed to be associated with risk of diabetes. They concluded that elevated Lp(a) levels were
not causally associated with lower diabetes risk.
This conclusion is misleading because it disregards
autoimmune activation as a fundamental pathophysiology
of diabetes and other chronic diseases (3–5). Serum Lp(a) is
a proinflammatory protein that activates or is itself involved
in aggregating to autoimmune components, such as apolipoprotein A-I or adiponectin, resulting in apparently
“reduced” Lp(a) levels secondary to a mechanism of immune
complex formation and interfered Lp(a) assay results due to
failure by capture antibodies (4). Thus, it is the oxidative
stress along with autoimmune activation that primarily
causes autoimmune-based diabetes.
We have evidence that the amount of “differential” Lp(a)
[e.g., lower serum Lp(a) levels than expected], based on
an adjustment of SNP rs10455872 genotype, sex, total
cholesterol, and fasting insulin, is a significant independent
1Department
of Cardiology, Cerrahpaşa Medical Faculty, Istanbul University,
Istanbul, Turkey
2Edirne Educational Hospital, Edirne, Turkey
Corresponding author: Altan Onat, [email protected].
predictor of future diabetes, additively to waist girth and
fasting insulin (5). It is the common AA genotype of this
SNP that is usually associated with lower serum Lp(a)
levels and, in women, with a setting of proinflammatory
state without protection against insulin resistance leading
to autoimmune activation. The rare GA genotype [associated with three to fourfold serum Lp(a)] protects men
against insulin resistance, whereas the converse is valid
in women.
The pathophysiological significance of apparently “reduced” Lp(a) levels needs to be widely recognized with the
purpose of mobilizing new avenues of prevention and
treatment of diabetes and other chronic diseases.
Duality of Interest. No potential conflicts of interest relevant to this article
were reported.
References
1. Ye Z, Haycock PC, Gurdasani D, et al. The association between circulating lipoprotein(a) and type 2 diabetes: is it causal? Diabetes 2014;63:
332–342
2. Mora S, Kamstrup PR, Rifai N, Nordestgaard BG, Buring JE, Ridker PM.
Lipoprotein(a) and risk of type 2 diabetes. Clin Chem 2010;56:1252–1260
3. Onat A, Direskeneli H. Excess cardiovascular risk in inflammatory rheumatic diseases: pathophysiology and targeted therapy. Curr Pharm Des 2012;
18:1465–1477
4. Onat A, Can G. Enhanced proinflammatory state and autoimmune activation:
a breakthrough to understanding chronic diseases. Curr Pharm Des 2014;20:
575–584
5. Onat A, Dönmez İ, Karadeniz Y, Çakir H, Kaya A. Type-2 diabetes and coronary heart disease: common physiopathology, viewed from autoimmunity. Expert Rev Cardiovasc Ther 2014;12:667–679
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