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• W2016365602 abstract "PharmacogenomicsVol. 9, No. 8 EditorialFree AccessPharmacogenomic application of the haptoglobin genotype in the prevention of diabetic cardiovascular diseaseShany Blum, Uzi Milman, Chen Shapira & Andrew P LevyShany BlumDepartment of Anatomy and Cell Biology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa, Israel. Search for more papers by this authorEmail the corresponding author at alevy@tx.technion.ac.il, Uzi MilmanClinical Research Unit, Clalit Health Services, Haifa and Western Galilee, and the Department of Family Medicine, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, IsraelSearch for more papers by this author, Chen ShapiraClalit Health Services, Haifa and Western Galilee, and the Lady Davis Carmel Medical Center, Haifa, IsraelSearch for more papers by this author & Andrew P Levy† Author for correspondenceDepartment of Anatomy and Cell Biology, Bruce Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa, Israel. Search for more papers by this authorEmail the corresponding author at alevy@tx.technion.ac.ilPublished Online:5 Aug 2008https://doi.org/10.2217/14622416.9.8.989AboutSectionsPDF/EPUB ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareShare onFacebookTwitterLinkedInReddit The public health and economic burdens from diabetes mellitus (DM) are presently staggering and are becoming more severe. Morbidity and mortality from DM is due to the effect of DM on the cardiovascular system. Accelerated atherosclerosis and its sequalae are by far the most severe and important complication of DM. Over 75% of all DM individuals die due to atherosclerotic cardiovascular disease (CVD) [1]. The incidence of myocardial infarction (MI) is 3–4-times higher in DM individuals. DM individuals are more likely to have larger MIs and to develop heart failure after MI. Presently, medical costs of treating cardiovascular complications of DM are well over US$100 billion per year in the USA alone [2].Prevention of cardiovascular complications of DM has focused on aggressively reducing conventional cardiovascular risk factors (cholesterol, high blood pressure and smoking) and it is clear that drug therapy to reduce low-density lipoprotein (LDL) cholesterol in DM individuals reduces CVD. While these conventional risk factors clearly are important for determining cardiovascular risk, they cannot account for the dramatically increased burden in individuals with DM. While tight glycemic control has been shown to be associated with a lower incidence of microvascular complications of DM, the role of aggressive blood glucose lowering in reducing cardiovascular risk is currently unclear.Over the past several years, we and others have identified a new risk factor that determines which individuals with DM (Type I and II) will develop CVD. The haptoglobin (Hp) gene at chromosomal locus 16q22 is polymorphic, with two common alleles denoted 1 and 2. The prevalence of the Hp 1-1, Hp 2-1 and Hp 2-2 genotypes is approximately 16, 48 and 36%, respectively, in the western world. A total of five independent longitudinal studies have demonstrated that DM individuals with the Hp 2-2 genotype have a two- to five-fold increased risk of CVD as compared with DM individuals without the Hp 2-2 genotype [3–7]. Hp genotype does not appear to be a determinant of risk in individuals without DM.The pathophysiological mechanism underlying the increased susceptibility of Hp 2-2 DM individuals to CVD is the result of functional differences in the protein products of the Hp 1 and Hp 2 alleles. The function of the Hp protein is to bind free extracorpuscular hemoglobin (Hb) [8], thereby preventing the iron in the Hb molecule from mediating oxidative tissue damage, and accelerating clearance of the Hp–Hb complex via the Hp–Hb scavenger receptor CD163 [9]. We and others have shown that the Hp 2-2 protein is inferior to the Hp 1-1 in being able to neutralize the oxidative activity of Hb [10,11]. Furthermore, we have shown that the Hp 1-1–Hb complex is taken up by the process of receptor mediated endocytosis much more rapidly than the Hp 2-2–Hb complex [12]. In vivo studies have demonstrated that the Hp 2-2-Hb complex is cleared much slower from the plasmatic compartment as compared with the Hp 1-1-Hb complex [13]. These differences are exaggerated in the setting of DM owing to downregulation of the CD163 receptor in DM, particularly in Hp 2-2 DM individuals [14]. We have recently demonstrated an important consequence of the impaired clearance of Hp 2-2–Hb in Hp 2-2 DM individuals. We have found that Hp binds directly to ApoA1 on the high-density lipoprotein (HDL) particle and can thereby tether Hb to HDL [13]. We have found that Hb is associated with the HDL of all Hp 2-2 DM individuals [13]. The functional consequences of the association of Hb with HDL are that the HDL in Hp 2-2 DM individuals appears to be dysfunctional with regards to its ability to stimulate the reverse transfer or efflux of cholesterol from the macrophage to HDL [13]. We believe that the dysfunctional nature of HDL in Hp 2-2 DM individuals is owing to its oxidative modification.These mechanistic studies would suggest that antioxidant therapy might provide benefit to Hp 2-2 DM individuals. However, antioxidant therapy, particularly with vitamin E, has failed to show benefit in numerous clinical trials [15]. We proposed that there may be a pharmacogenomic effect whereby vitamin E might be effective in individuals with DM and the Hp 2-2 genotype but not in other types. In the Heart Outcomes Prevention Evaluation (HOPE) study, we assessed, retrospectively, whether vitamin E might have provided benefit to individuals with DM. While benefit could not be demonstrated when all individuals with DM were pooled together, we found a 50% reduction in CVD death and 40% reduction in MI in Hp 2-2 DM individuals who received vitamin E [16]. In the Israel Cardiovascular Vitamin E (ICARE) study, we assessed, in a prospective, double-blinded, randomized study, whether vitamin E could prevent CVD in Hp 2-2 DM individuals. We found that vitamin E resulted in a greater than 50% reduction in the primary composite end point of MI, stroke and cardiovascular death [17]. These clinical studies are supported by mechanistic studies showing that vitamin E improved HDL function and reduced HDL oxidation in Hp 2-2 DM individuals [13].ICARE was a real-life study in which the primary-care physician was given total discretion on how he managed his patients. While statins appear to be indicated in nearly all DM individuals, in ICARE only approximately 60% of the population was actively taking statins. We therefore asked whether the beneficial effect of vitamin E would still be seen in those individuals who were taking statins. As would be expected from the different pathophysiological mechanisms that are targeted by statins and vitamin E, we found that dual therapy was superior to therapy with statins or vitamin E alone [17].Clearly, these studies will require validation in an additional clinical trial before Hp typing of all DM individuals to determine whether or not they should or should not take vitamin E can be recommended as a treatment guideline. Such a pharmacogenomic approach appears warranted based on the finding in several meta-analyses that indiscriminate use of vitamin E supplements in all individuals is associated with a 5–10% increase in overall mortality [15].The potential public health and economic benefits from this pharmacogenomic paradigm are enormous. Hp genotyping may allow a personalized approach to medical care, enabling identification of individuals who will benefit from vitamin E supplementation and dramatically reducing the burden of CVD in this population. DM prevalence is increasing at an alarming rate, primarily due to poor nutrition, among individuals of lower socioeconomic status, both in the USA and in the developing world. Tragically, the medications to prevent diabetes-induced cardiovascular complications (statins, angiotensin-converting enzyme inhibitors) are neither accessible nor affordable to these populations. Vitamin E, however, is so inexpensive that it can be expected to be made available to all populations worldwide. Furthermore, the technological requirements for Hp typing (which only needs to be performed once in a lifetime) are extremely simple, and it is expected that a diagnostic kit will become available for Hp typing within the coming year.Financial & competing interest disclosure.Dr Levy is a consultant for Synvista Therapeutics which owns the rights to use of a diagnostic test to determine the Hp genotype for the prediction of cardiovascular disease risk in diabetes mellitus. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.Bibliography1 Moreno P, Fuster V: New aspects in the pathogenesis of diabetic atherosclerosis. J. Am. Coll. Cardiol.44,2293–2300 (2004).Crossref, Medline, CAS, Google Scholar2 American Diabetes Association: Economic costs of diabetes in the US in 2007. Diabetes Care31,1–20 (2008).Crossref, Google Scholar3 Levy AP, Hochberg I, Jablonski K et al.: Haptoglobin phenotype and the risk of cardiovascular disease in individuals with diabetes: The Strong Heart Study. J. Am. Coll. Cardiol.40,1984–1990 (2002).Crossref, Medline, Google Scholar4 Roguin A, Koch W, Kastrati A, Aronson D, Schomig A, Levy AP: Haptoglobin genotype is predictive of major adverse cardiac events in the one year period after PTCA in individuals with diabetes. Diabetes Care26,2628–2631 (2003).Crossref, Medline, Google Scholar5 Suleiman M, Aronson D, Asleh R et al.: Haptoglobin polymorphism predicts 30-day mortality and heart failure in patients with diabetes and acute myocardial infarction. Diabetes19,2802–2806 (2005).Crossref, Google Scholar6 Milman U, Blum S, Shapira C et al.: Vitamin E supplementation reduces cardiovascular events in a subgroup of middle-aged individuals with both Type 2 diabetes mellitus and the haptoglobin 2-2 genotype: a prospective, double-blinded clinical trial. Arterioscler. Thromb. Vasc. Biol.28,341–347 (2008).Crossref, Medline, CAS, Google Scholar7 Costacou T, Ferrell RE, Orchard TJ: Haptoglobin genotype: a determinant of cardiovascular complication risk in Type I diabetes. Diabetes57(6),1702–1706 (2008).Crossref, Medline, CAS, Google Scholar8 Bowman BH, Kurosky A: Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation. Adv. Hum. Genet.12,189–261 (1982).Crossref, Medline, CAS, Google Scholar9 Kristiansen M, Graversen JH, Jacobsen C et al.: Identification of the hemoglobin scavenger receptor. Nature409,198–201 (2001).Crossref, Medline, CAS, Google Scholar10 Bamm VV, Tsemakhovich VA, Shaklai M, Shaklai N: Haptoglobin phenotypes differ in their ability to inhibit heme transfer from hemoglobin to LDL. Biochemistry43,3899–3906 (2004).Crossref, Medline, CAS, Google Scholar11 Frank M, Lache O, Enav B et al.: Structure/function analysis of the anti-oxidant properties of haptoglobin. Blood98,3693–3698 (2001).Crossref, Medline, Google Scholar12 Asleh R, Marsh S, Shiltruck M et al.: Genetically determined heterogeneity in hemoglobin scavenging and susceptibility to diabetic cardiovascular disease. Circ. Res.92,1193–1200 (2003).Crossref, Medline, CAS, Google Scholar13 Asleh R, Blum S, Kalet-Litman S et al.: Correction of HDL dysfunction in individuals with diabetes and the haptoglobin 2-2 genotype. Diabetes (2008) (Epub ahead of print).Medline, Google Scholar14 Levy AP, Purushothaman KR, Levy NS et al.: Downregulation of the hemoglobin scavenger receptor in individuals with diabetes and the Hp 2-2 genotype: implications for the response to intraplaque hemorrhage and plaque vulnerability. Circ. Res.101,106–110 (2007).Crossref, Medline, CAS, Google Scholar15 Miller ER, Barriuso RP, Dalal D, Riemersma RA, Appel LJ, Guallar E: Meta-analysis: high dosage vitamin E supplementation may increase all cause mortality. Ann. Intern. Med.142,37–46 (2005).Crossref, Medline, CAS, Google Scholar16 Levy AP, Gerstein H, Lotan R et al.: The effect of vitamin E supplementation on cardiovascular risk in diabetic individuals with different haptoglobin phenotypes. Diabetes Care27,2767 (2004).Crossref, Medline, Google Scholar17 Blum S, Milman U, Shapira C et al.: Dual therapy with statins and and antioxidants is superior to statins alone in decreasing the risk of cardiovascular disease in a subgroup of middle-aged individuals with both diabetes mellitus and the haptoglobin 2-2 genotype. Arterioscler. Thromb. Vasc. Biol.28,e18–e20 (2008).Crossref, Medline, CAS, Google ScholarFiguresReferencesRelatedDetailsCited ByGut Microbiota Ecology and Inferred Functions in Children With ASD Compared to Neurotypical Subjects9 June 2022 | Frontiers in Microbiology, Vol. 13Serum vitamin E as a significant prognostic factor in patients with dyslipidemia disordersDiabetes & Metabolic Syndrome: Clinical Research & Reviews, Vol. 13, No. 1Differential immune responses and microbiota profiles in children with autism spectrum disorders and co-morbid gastrointestinal symptomsBrain, Behavior, and Immunity, Vol. 70Vitamin E in the prevention of cardiovascular disease: the importance of proper patient selectionJournal of Lipid Research, Vol. 54, No. 9Is the Hp 2-2 diabetic mouse model a good model to study diabetic nephropathy?Diabetes Research and Clinical Practice, Vol. 100, No. 3Zonulin, regulation of tight junctions, and autoimmune diseases25 June 2012 | Annals of the New York Academy of Sciences, Vol. 1258, No. 1Is It Time to Screen for the Haptoglobin Genotype to Assess the Cardiovascular Risk Profile and Vitamin E Therapy Responsiveness in Patients with Diabetes?18 March 2012 | Current Diabetes Reports, Vol. 12, No. 3Haptoglobin: Basic and Clinical AspectsAntioxidants & Redox Signaling, Vol. 12, No. 2Divergent Effects of α -Tocopherol and Vitamin C on the Generation of Dysfunctional HDL Associated with Diabetes and the Hp 2-2 GenotypeAntioxidants & Redox Signaling, Vol. 12, No. 2Modification of HDL structure and function in individuals with diabetes and the haptoglobin 2-2 genotypeClinical Lipidology, Vol. 4, No. 1 Vol. 9, No. 8 Follow us on social media for the latest updates Metrics History Published online 5 August 2008 Published in print August 2008 Information© Future Medicine LtdFinancial & competing interest disclosure.Dr Levy is a consultant for Synvista Therapeutics which owns the rights to use of a diagnostic test to determine the Hp genotype for the prediction of cardiovascular disease risk in diabetes mellitus. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.No writing assistance was utilized in the production of this manuscript.PDF download" @default.
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