Genetic analysis of haptoglobin polymorphisms with cardiovascular disease and type 2 diabetes in the diabetes heart study

Adams, Jeremy N.; Cox, Amanda J.; Freedman, Barry I.; Langefeld, Carl D.; Bowden, Donald W.

doi:10.1186/1475-2840-12-31

Cited by 51 publications

(38 citation statements)

References 37 publications

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“…Our study used a candidate gene approach, and an accompanying editorial (2) suggested that the recently completed genome wide association (GWA) studies of millions of single nucleotide polymorphisms (SNPs) should identify the same genetic predictor of CHD, to confirm our findings. However, the Hp CNV is not a SNP; it is a 1.7 kb replication, and as detailed in the following text, our investigations and the work of 2 different groups (3,4) show that currently available GWA studies cannot tag Hp CNV or identify the association between this variant and risk of disease.…”

mentioning

confidence: 62%

Currently Available Versions of Genome-Wide Association Studies Cannot Be Used to Query the Common Haptoglobin Copy Number Variant

Cahill¹,

Jensen²,

Chasman³

et al. 2013

Journal of the American College of Cardiology

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mentioning

confidence: 62%

Currently Available Versions of Genome-Wide Association Studies Cannot Be Used to Query the Common Haptoglobin Copy Number Variant

Cahill¹,

Jensen²,

Chasman³

et al. 2013

Journal of the American College of Cardiology

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“…Taken together, genetic studies strongly support the theory that high concentrations of TG-rich lipoproteins or remnant cholesterol are causal risk factors for cardiovascular disease and all-cause mortality [2, [131][132][133][134][135][136][137][138], and that low HDL cholesterol is probably an innocent bystander. Low HDL cholesterol might merely be a long-term marker of raised TG and remnant cholesterol.…”

Section: Tg and Hdlmentioning

confidence: 94%

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

Tenenbaum

Klempfner

Fisman

2014

Cardiovasc Diabetol

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The existence of an independent association between elevated triglyceride (TG) levels, cardiovascular (CV) risk and mortality has been largely controversial. The main difficulty in isolating the effect of hypertriglyceridemia on CV risk is the fact that elevated triglyceride levels are commonly associated with concomitant changes in high density lipoprotein (HDL), low density lipoprotein (LDL) and other lipoproteins. As a result of this problem and in disregard of the real biological role of TG, its significance as a plausible therapeutic target was unfoundedly underestimated for many years. However, taking epidemiological data together, both moderate and severe hypertriglyceridaemia are associated with a substantially increased long term total mortality and CV risk. Plasma TG levels partially reflect the concentration of the triglyceride-carrying lipoproteins (TRL): very low density lipoprotein (VLDL), chylomicrons and their remnants. Furthermore, hypertriglyceridemia commonly leads to reduction in HDL and increase in atherogenic small dense LDL levels. TG may also stimulate atherogenesis by mechanisms, such excessive free fatty acids (FFA) release, production of proinflammatory cytokines, fibrinogen, coagulation factors and impairment of fibrinolysis. Genetic studies strongly support hypertriglyceridemia and high concentrations of TRL as causal risk factors for CV disease. The most common forms of hypertriglyceridemia are related to overweight and sedentary life style, which in turn lead to insulin resistance, metabolic syndrome (MS) and type 2 diabetes mellitus (T2DM). Intensive lifestyle therapy is the main initial treatment of hypertriglyceridemia. Statins are a cornerstone of the modern lipids-modifying therapy. If the primary goal is to lower TG levels, fibrates (bezafibrate and fenofibrate for monotherapy, and in combination with statin; gemfibrozil only for monotherapy) could be the preferable drugs. Also ezetimibe has mild positive effects in lowering TG. Initial experience with en ezetimibe/fibrates combination seems promising. The recently released IMPROVE-IT Trial is the first to prove that adding a non-statin drug (ezetimibe) to a statin lowers the risk of future CV events. In conclusion, the classical clinical paradigm of lipids-modifying treatment should be changed and high TG should be recognized as an important target for therapy in their own right. Hypertriglyceridemia should be treated.

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“…Ten independent longitudinal studies have demonstrated that individuals homozygous for the Hp 2 allele (Hp 2-2 genotype), present in 36% of all DM individuals, have a several fold increased risk of atherothrombosis (i.e., myocardial infarction) in the setting of DM as compared to individuals without the Hp 2-2 genotype and DM [12–21]. We have proposed that this Hp genotype and CVD interaction may be due to Hp genotype differences in the response to intraplaque hemorrhage and in the ability to protect against extracorpuscular Hb in the atherosclerotic plaque [22–26].…”

mentioning

confidence: 99%

Pharmacogenomic interaction between the Haptoglobin genotype and vitamin E on atherosclerotic plaque progression and stability

Viener¹,

Gorbatov²,

Vardi³

et al. 2015

Atherosclerosis

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Structured Abstract Objective Homozygosity for a 1.7kb intragenic duplication of the Haptoglobin (Hp) gene (Hp 2-2 genotype), present in 36% of the population, has been associated with a 2–3 fold increased incidence of atherothrombosis in individuals with Diabetes (DM) in 10 longitudinal studies compared to DM individuals not homozygous for this duplication (Hp 1-1/2-1). The increased CVD risk associated with the Hp 2-2 genotype has been shown to be prevented with vitamin E supplementation in man. We sought to determine if there was an interaction between the Hp genotype and vitamin E on atherosclerotic plaque growth and stability in a transgenic model of the Hp polymorphism. Methods and Results Brachiocephalic artery atherosclerotic plaque volume was serially assessed by high resolution ultrasound in 28 Hp 1-1 and 26 Hp 2-2 mice in a C57Bl/6 ApoE−/− background. Hp 2-2 mice had more rapid plaque growth and an increased incidence of plaque hemorrhage and rupture. Vitamin E significantly reduced plaque growth in Hp 2-2 but not in Hp 1-1 mice with a significant pharmacogenomic interaction between the Hp genotype and vitamin E on plaque growth. Conclusions These results may help explain why vitamin E supplementation in man can prevent CVD in Hp 2-2 DM but not in non Hp 2-2 DM individuals.

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Genetic analysis of haptoglobin polymorphisms with cardiovascular disease and type 2 diabetes in the diabetes heart study

Cited by 51 publications

References 37 publications

Currently Available Versions of Genome-Wide Association Studies Cannot Be Used to Query the Common Haptoglobin Copy Number Variant

Currently Available Versions of Genome-Wide Association Studies Cannot Be Used to Query the Common Haptoglobin Copy Number Variant

Hypertriglyceridemia: a too long unfairly neglected major cardiovascular risk factor

Pharmacogenomic interaction between the Haptoglobin genotype and vitamin E on atherosclerotic plaque progression and stability

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