Elsevier

Cardiology Clinics

Volume 28, Issue 3, August 2010, Pages 477-496
Cardiology Clinics

The Genetics of Vascular Complications in Diabetes Mellitus

https://doi.org/10.1016/j.ccl.2010.04.005Get rights and content

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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References (207)

  • M. Romzova et al.

    NFkappaB and its inhibitor IkappaB in relation to type 2 diabetes and its microvascular and atherosclerotic complications

    Hum Immunol

    (2006)
  • S.J. Han et al.

    The C609T variant of NQO1 is associated with carotid artery plaques in patients with type 2 diabetes

    Mol Genet Metab

    (2009)
  • C.H. Saely et al.

    Type 2 diabetes significantly modulates the cardiovascular risk conferred by the PAI-1 -675 4G/5G polymorphism in angiographied coronary patients

    Clin Chim Acta

    (2008)
  • E.S. Tai et al.

    The L162V polymorphism at the peroxisome proliferator activated receptor alpha locus modulates the risk of cardiovascular events associated with insulin resistance and diabetes mellitus: the Veterans Affairs HDL Intervention Trial (VA-HIT)

    Atherosclerosis

    (2006)
  • G. Zalewski et al.

    P-selectin gene genotypes or haplotypes and cardiovascular complications in type 2 diabetes mellitus

    Nutr Metab Cardiovasc Dis

    (2006)
  • S.L. Primo-Parmo et al.

    The human serum paraoxonase/arylesterase gene (PON1) is one member of a multigene family

    Genomics

    (1996)
  • C.J. Ng et al.

    Paraoxonase-2 is a ubiquitously expressed protein with antioxidant properties and is capable of preventing cell-mediated oxidative modification of low density lipoprotein

    J Biol Chem

    (2001)
  • D.I. Draganov et al.

    Human paraoxonases (PON1, PON2, and PON3) are lactonases with overlapping and distinct substrate specificities

    J Lipid Res

    (2005)
  • F. Yang et al.

    Quorum quenching enzyme activity is widely conserved in the sera of mammalian species

    FEBS Lett

    (2005)
  • M.I. Mackness et al.

    Paraoxonase prevents accumulation of lipoperoxides in low-density lipoprotein

    FEBS Lett

    (1991)
  • D.M. Shih et al.

    Combined serum paraoxonase knockout/apolipoprotein E knockout mice exhibit increased lipoprotein oxidation and atherosclerosis

    J Biol Chem

    (2000)
  • M. Najafi et al.

    Paraoxonase 1 gene promoter polymorphisms are associated with the extent of stenosis in coronary arteries

    Thromb Res

    (2009)
  • L. Gaidukov et al.

    The 192R/Q polymorphs of serum paraoxonase PON1 differ in HDL binding, lipolactonase stimulation, and cholesterol efflux

    J Lipid Res

    (2006)
  • J.G. Wheeler et al.

    Four paraoxonase gene polymorphisms in 11212 cases of coronary heart disease and 12786 controls: meta-analysis of 43 studies

    Lancet

    (2004)
  • B. Mackness et al.

    Serum paraoxonase (PON1) 55 and 192 polymorphism and paraoxonase activity and concentration in non-insulin dependent diabetes mellitus

    Atherosclerosis

    (1998)
  • M. Inoue et al.

    Serum arylesterase/diazoxonase activity and genetic polymorphisms in patients with type 2 diabetes

    Metabolism

    (2000)
  • O. Rozenberg et al.

    Paraoxonase 1 (PON1) attenuates diabetes development in mice through its antioxidative properties

    Free Radic Biol Med

    (2008)
  • T. Kosaka et al.

    Investigation of the relationship between atherosclerosis and paraoxonase or homocysteine thiolactonase activity in patients with type 2 diabetes mellitus using a commercially available assay

    Clin Chim Acta

    (2005)
  • Y. Ikeda et al.

    Serum paraoxonase activity and its relationship to diabetic complications in patients with non-insulin-dependent diabetes mellitus

    Metabolism

    (1998)
  • S. Tsuzura et al.

    Correlation of plasma oxidized low-density lipoprotein levels to vascular complications and human serum paraoxonase in patients with type 2 diabetes

    Metabolism

    (2004)
  • J. Ruiz et al.

    Gln-Arg192 polymorphism of paraoxonase and coronary heart disease in type 2 diabetes

    Lancet

    (1995)
  • J. Li et al.

    PON1 polymorphism, diabetes mellitus, obesity, and risk of myocardial infarction: modifying effect of diabetes mellitus and obesity on the association between PON1 polymorphism and myocardial infarction

    Genet Med

    (2005)
  • J.D. Finkelstein

    Methionine metabolism in mammals

    J Nutr Biochem

    (1990)
  • R. Obeid et al.

    Homocysteine and lipids: S-adenosyl methionine as a key intermediate

    FEBS Lett

    (2009)
  • M.D. Jamaluddin et al.

    Homocysteine inhibits endothelial cell growth via DNA hypomethylation of the cyclin A gene

    Blood

    (2007)
  • H. Wang et al.

    Inhibition of growth and p21ras methylation in vascular endothelial cells by homocysteine but not cysteine

    J Biol Chem

    (1997)
  • N. Khandanpour et al.

    Homocysteine and peripheral arterial disease: systematic review and meta-analysis

    Eur J Vasc Endovasc Surg

    (2009)
  • L.L. Humphrey et al.

    Homocysteine level and coronary heart disease incidence: a systematic review and meta-analysis

    Mayo Clin Proc

    (2008)
  • American Diabetes Association

    Economic costs of diabetes in the U.S. in 2007

    Diabetes Care

    (2008)
  • D.W. Bowden et al.

    Genetic epidemiology of subclinical cardiovascular disease in the diabetes heart study

    Ann Hum Genet

    (2008)
  • A. Doria et al.

    Interaction between poor glycemic control and 9p21 locus on risk of coronary artery disease in type 2 diabetes

    JAMA

    (2008)
  • K.P. Burdon et al.

    Association analysis of genes in the renin-angiotensin system with subclinical cardiovascular disease in families with Type 2 diabetes mellitus: the Diabetes Heart Study

    Diabet Med

    (2006)
  • D.R. Gable et al.

    Common adiponectin gene variants show different effects on risk of cardiovascular disease and type 2 diabetes in European subjects

    Ann Hum Genet

    (2007)
  • S.L. Prior et al.

    Association between the adiponectin promoter rs266729 gene variant and oxidative stress in patients with diabetes mellitus

    Eur Heart J

    (2009)
  • C. Lacquemant et al.

    The adiponectin gene SNP+45 is associated with coronary artery disease in Type 2 (non-insulin-dependent) diabetes mellitus

    Diabet Med

    (2004)
  • L. Qi et al.

    Adiponectin genetic variability, plasma adiponectin, and cardiovascular risk in patients with type 2 diabetes

    Diabetes

    (2006)
  • S. Bacci et al.

    The +276 G/T single nucleotide polymorphism of the adiponectin gene is associated with coronary artery disease in type 2 diabetic patients

    Diabetes Care

    (2004)
  • T. Soccio et al.

    Common haplotypes at the adiponectin receptor 1 (ADIPOR1) locus are associated with increased risk of coronary artery disease in type 2 diabetes

    Diabetes

    (2006)
  • J. Lin et al.

    Genetic polymorphisms of angiotensin-2 type 1 receptor and angiotensinogen and risk of renal dysfunction and coronary heart disease in type 2 diabetes mellitus

    BMC Nephrol

    (2009)
  • G. Tuncman et al.

    A genetic variant at the fatty acid-binding protein aP2 locus reduces the risk for hypertriglyceridemia, type 2 diabetes, and cardiovascular disease

    Proc Natl Acad Sci U S A

    (2006)
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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.

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