The Genetics of Vascular Complications in Diabetes Mellitus
Section snippets
The Paraoxonase Family
Located at locus 7q21.3, the cluster of the paraoxonase (PON) gene family is comprised of three members: PON1, PON2, and PON3. The three members are highly homogenous, presenting with 70% similarity at the nucleotide level and 60% similarity of the amino acid sequence.40 However, their expression patterns are varied. Although PON1 and PON3 are expressed mainly in the liver and associate with high density lipoprotein (HDL) in the circulation,41, 42 PON2 is expressed in a variety of tissues and
Metabolic Pathways of Homocysteine
Homocysteine (Hcy) is positioned at the crossroads of several metabolic pathways. Hcy is synthesized from methionine in a three-step reaction, which includes activation of methionine by ATP, loss of a methyl group, and enzymatic hydrolysis. Remethylation of Hcy to methionine is catalyzed by betaine-homocysteine methyltransferase in the liver or by methionine synthase (MS) in most bodily tissues, the latter depending on methyltetrahydrofolate as a methyl donor and vitamin B12 as a cofactor.
Role of Nitric Oxide and Endothelial Nitric Oxide Synthase in Cardiovascular Physiology
NO has been identified as an important factor in maintaining normal cardiovascular function and preserving the integrity of the vascular bed. It inhibits thrombosis and coagulation not only by maintaining anticoagulatory and anti-thrombogenic properties of the endothelium137 but also by inhibiting platelet activation and aggregation and thereby reducing platelet derived growth factor (PDGF)-induced proliferation of vascular smooth muscle cells in the vessel wall.138 Acting directly on VSMCs, NO
Haptoglobin Metabolism
Haptoglobin (Hp) is an acute-phase, plasma-born glycoprotein produced mainly by hepatocytes, most widely known for its ability to strongly bind free hemoglobin (Hb) following its release from erythrocytes.177 The concentrations of Hp in the plasma are high, ranging from 0.3 mg/ml to 3.0 mg/ml, producing an Hp/Hb molar ratio of 400:1. This concentration allows effective scavenging of free Hb, even in the scenario of hemolysis when its levels are sharply increased.178 In fact, Hp has a major role
Summary and future perspectives
With the advent of genome-wide association studies, hundreds of genetic polymorphisms with a possible impact on diabetic CVD are being investigated. However, most of these polymorphisms have failed to show any significant effect when tested across various populations. These findings are caused by the nature of the polymorphisms being tested, which are usually SNPs that have no established effect on protein activity or expression. Such polymorphisms are likely in linkage disequilibrium with
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This work was supported by grants from the United States-Israel Binational Science Foundation, Israel Science Foundation, Juvenile Diabetes Research Foundation, the Kennedy Leigh Charitable Trust, and grant RO1KD085226 from the NIH to Andrew P. Levy.
Financial Disclosure Information: Dr Levy has served in the past as a consultant for Synvista Therapeutics.