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CLINICAL STUDY

Haptoglobin phenotype is an independent risk factor for cardiovascular disease in individuals with diabetes

the strong heart study

Andrew P. Levy, MD, PhD, FACC^*,*, Irit Hochberg, MD^*, Kathleen Jablonski, PhD, Helaine E. Resnick, PhD, Elisa T. Lee, PhD, Lyle Best, MD and Barbara V. Howard, PhD

^* Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, Haifa, Israel;
MedStar Research Institute and Washington Hospital Center, Washington, DC, USA
Center for American Indian Health Research, University of Oklahoma Health Sciences Center, Oklahoma City, Oklahoma, USA
Missouri Breaks Industries Research Inc., Timber Lake, South Dakota, USA

Manuscript received April 25, 2002; revised manuscript received July 31, 2002, accepted August 26, 2002.

^* Reprint requests and correspondence: Dr. Andrew Levy, Rappaport Faculty of Medicine, Technion-Israel Institute of Technology, POB 9649, Haifa 31096, Israel.
alevy{at}tx.technion.ac.il

	Abstract

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OBJECTIVES: The goal of this study was to determine if the haptoglobin phenotype was predictive of cardiovascular disease (CVD) in diabetic mellitus (DM).

BACKGROUND: Cardiovascular disease is the most frequent, severe, and costly complication of type 2 DM. There are clear geographic and ethnic differences in the risk of CVD among diabetic patients that cannot be fully explained by differences in conventional CVD risk factors. We have demonstrated that a functional allelic polymorphism in the haptoglobin gene acts as a major determinant of susceptibility for the development of diabetic microvascular complications.

METHODS: We sought to determine if this paradigm concerning the haptoglobin gene could be extended to CVD in DM. We tested this hypothesis in a case-control sample from the Strong Heart study, a population-based longitudinal study of CVD in American Indians. Haptoglobin phenotype was determined by polyacrylamide gel electrophoresis in 206 CVD cases and 206 matched controls age 45 to 74 years. Median follow-up was six years.

RESULTS: In multivariate analyses controlling for conventional CVD risk factors, haptoglobin phenotype was a highly statistically significant, independent predictor of CVD in DM. The odds ratio of having CVD in DM with the haptoglobin 2-2 phenotype was 5.0 times greater than in DM with the haptoglobin 1-1 phenotype (p = 0.002). An intermediate risk of CVD was associated with the haptoglobin 2-1 phenotype.

CONCLUSIONS: This study suggests that determination of haptoglobin phenotype may contribute to the algorithm used in CVD risk stratification, and in evaluation of new therapies to prevent CVD in the diabetic patient.

Abbreviations and Acronyms   BP   blood pressure   BMI   body mass index   CI   confidence intervals   CVD   cardiovascular disease   DM   diabetes mellitus   HDL   high-density lipoprotein   Hp 1-1   individuals who are homozygous for the 1 allele   Hp 2-2   individuals who are homozygous for the 2 allele   Hp 2-1   individuals who are heterozygous at the haptoglobin locus   LCAT   lecithin-cholesterol acyl transferase   LDL   low-density lipoprotein   SHS   Strong Heart Study

Although the incidence of CVD is higher in DM compared with non-DM in all populations studied, there are geographic and ethnic differences in the risk of CVD among DM patients that cannot be fully explained by differences in conventional CVD risk factors between these groups (4). These studies suggest that genetic factors could contribute to differences in susceptibility to CVD among individuals with DM. One such factor is a functional allelic polymorphism in the haptoglobin gene. In man, there are two general classes of alleles for the haptoglobin gene, designated 1 and 2 (5,6). The haptoglobin 2 allele appears to have arisen from the 1 allele early in human evolution and to have spread in the world population as a result of selective pressures related to resistance to infectious agents (7,8). Haptoglobin alleles differ dramatically in their relative frequency among different ethnic groups (9). The protein products of the two haptoglobin alleles differ both in biophysical and biochemical properties. A key difference between the alleles is that the protein product of the 1 allele is a more potent antioxidant compared with that produced by the 2 allele (10).

We have demonstrated that haptoglobin phenotype is predictive of development of microvascular complications in DM (11–13). Specifically, we have shown that patients who are homozygous for the haptoglobin 1 allele are at decreased risk for developing retinopathy and nephropathy. This effect, at least for nephropathy, has been observed in both type 1 and type 2 DM and the relevance strengthened by the finding of a gradient effect with respect to the number of haptoglobin 2 alleles and the development of nephropathy (13). Furthermore, the haptoglobin phenotype may be predictive of development of macrovascular complications in DM. We have shown that development of restenosis after percutaneous coronary angioplasty is significantly decreased in DM patients with the 1-1 haptoglobin phenotype (11–14). Previous retrospective and cross-sectional studies examining haptoglobin phenotype and coronary artery disease in the general population have yielded conflicting results (15–17). The role of haptoglobin phenotype in the development of atherosclerotic coronary artery disease in DM has not been studied.

American Indians, previously thought to be resistant to developing coronary artery disease, are presently experiencing CVD in epidemic proportions (18). The increased incidence of CVD has been attributed to the sharp increase in type 2 DM in this population (1,2). The Strong Heart Study (SHS) has examined the incidence, prevalence, and risk factors of CVD in American Indian populations in three geographic areas since 1988 with continued surveillance to the present time (18). The relative genetic homogeneity of this population, along with the high prevalence of DM, permits a unique opportunity for identification of genetic factors that may contribute to CVD in DM. Accordingly, we aimed to determine the relative risk of CVD in DM according to haptoglobin phenotype in a case-control sample from the SHS.

	Methods

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Detailed descriptions of the SHS study design, survey methods, and laboratory techniques and the participating Indian communities have been published (18–20). All SHS participants gave consent for utilization of their blood samples in genetic studies. In addition, institutional review boards of individual tribes and of the tribal communities approved use of stored blood samples for the determination of haptoglobin phenotype.

The SHS study cohort consists of 4,549 individuals ages 45 to 74 years who were seen at the first examination conducted between July, 1989 and January, 1992. Participation rates of all eligible tribe members averaged 64%. Nonparticipants were similar to participants in age and self-reported frequency of DM. Reexamination rates for those alive at the second examination (July 1993 to December 1995) averaged 89% and at the third examination (July 1997 to December 1999) averaged 88%. However, surveillance for cardiovascular events by review of hospital records and tribal records was also performed on participants who did not attend the second and third examinations such that greater than 99% of all cardiovascular events occurring in the SHS cohort were detected (20).

Blood samples were collected in the presence of EDTA, and the plasma was stored at –80°C. Standardized blood pressure (BP) measurements were obtained, and electrocardiograms were recorded and coded as previously described (19,20). Participants were classified as diabetic according to WHO criteria (21).

Deaths in the SHS cohort between 1988 and the present were identified through tribal and hospital records and by direct contact by study personnel with participants and their families. Copies of death certificates were obtained from state health departments and ICD-9 coded centrally by a nosologist. Possible CVD deaths were initially identified from death certificates as described previously (22). Cause of death was investigated through autopsy reports, medical records abstractions, and informant interviews as described previously (22).

Medical records were reviewed at each examination to identify nonfatal cardiovascular events, definite myocardial infarction, and definite CVD (18,23) that had occurred since the previous examination. Records of those who did not participate in the second or third examination were also reviewed to maximize event ascertainment. For all potential CVD events or interventions, medical records were reviewed by trained medical record abstractors. Blinded review of abstracted records by other physician members of the Morbidity Review Committee showed >90% concordance in diagnosis.

Definition of case-control sample.   This case-control sample was designed to examine the relationship between CVD and haptoglobin phenotype. A total of 206 CVD cases and 206 controls (matched for age, gender, and geographic area) were included in the analysis. Incident cases of fatal and nonfatal CVD were ascertained during ongoing surveillance between 1989 and 1998 (18). Cases in this report consisted of one-half of all CVD cases identified during this surveillance period. These cases were selected at random. Controls were selected at random from all age, gender, and center-matched individuals without CVD at the time of case ascertainment.

Haptoglobin phenotyping.   The haptoglobin gene on chromosome 16 exists as two allelic variants (5,6). The haptoglobin phenotype refers to the distinct set of polymeric haptoglobin molecules produced from the two classes of haptoglobin alleles. The polymeric nature of the haptoglobin molecule (dimer, linear, or cyclic polymer) is dependent on the haptoglobin alleles because the protein product of the 1 allele is monovalent, combining with only one other haptoglobin monomer, while the protein product of the 2 allele is bivalent, combining with two other haptoglobin monomers (6). A signature pattern of polymeric species is, therefore, obtained from individuals who are homozygous for the 1 allele (Hp 1-1), homozygous for the 2 allele (Hp 2-2), or are heterozygous at the haptoglobin locus (Hp 2-1). This unique pattern of polymeric species first demonstrated over 45 years ago by Smithies (24) by gel electrophoresis remains the most common method used today for phenotyping haptoglobin. Accordingly, we phenotyped haptoglobin from 10 µl of plasma by polyacrylamide gel electrophoresis according to established methods (25). Haptoglobin phenotyping was performed without knowledge concerning participant case/control status.

Because diabetes is associated with posttranslational modification of serum proteins, there was concern whether the haptoglobin phenotype of diabetic patients would accurately reflect the correct haptoglobin allele. We observed the same three unambiguous banding patterns in nondiabetic and diabetic patients. Furthermore, proof of coincidence in diabetic patients of the haptoglobin phenotype and the haptoglobin genotype was demonstrated by 100% concordance in over 300 diabetic and nondiabetic patients in which we have typed haptoglobin both from the plasma and from DNA by polymerase chain reaction.

Statistical analysis.   Cardiovascular disease risk factors including age, gender, low-density lipoprotein (LDL) cholesterol, high-density lipoprotein (HDL) cholesterol, triglycerides, systolic BP, body mass index (BMI), diabetes, smoking status, family history of CVD, and geographic area were compared between cases and controls as well as between the three haptoglobin phenotypes. In addition, DM-associated characteristics including fasting glucose and insulin levels, HbA1c, DM duration, and family history of DM were compared between cases and controls as well as between the three haptoglobin phenotypes. Univariate and multinomial logistic regression modeling was performed to determine if these CVD risk factors and DM characteristics were related to phenotype. The likelihood ratio test was used to evaluate individual model parameters.

Consistent with the case-control design, conditional logistic regression was used to model the probability of having a CVD event for diabetic and nondiabetic patients by the three haptoglobin phenotypes. A diabetes-haptoglobin phenotype interaction term was coded using two indicator variables, one for patients with diabetes and another for patients without diabetes. Nested models were constructed, first with only the DM-haptoglobin variables, then adjusted for DM characteristics (fasting glucose and insulin levels, HbA1c, and family history of DM), and then for DM characteristics and CVD risk factors (LDL cholesterol, HDL cholesterol, triglycerides, systolic BP, BMI, smoking status, and family history of CVD). Adjustment was designed to account for known and postulated biological relationships among specific factors in the disease pathway. Adjustment for known CVD risk factors in the presence of haptoglobin permits testing of the hypothesis that haptoglobin is related to CVD independently of known CVD risk factors, and whether this relationship is similar in diabetic and nondiabetic participants. Model fit was assessed by an analysis of residuals. We report odds ratios and 95% confidence intervals (CI) for the probability of a CVD event for each haptoglobin phenotype in diabetic and nondiabetic individuals.

	Results

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Table 1 shows the clinical characteristics of the case-control sample according to CVD risk factors and DM characteristics. Cases and controls were matched for age, gender, and geographic area. These data are consistent with our previous finding in this population that DM, LDL cholesterol, triglycerides, and hypertension are all independent predictors of CVD (18).

	Discussion

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Our findings are inconsistent with a recently reported prospective study from Belgium demonstrating increased cardiac mortality in patients with the Hp 1-1 phenotype (17). Three differences between the two studies may explain the apparently inconsistent results. First, only 7% of the Belgian cohort had DM as opposed to nearly 60% of the SHS cohort. The DM subgroup in the Belgian cohort was too small to be able to determine relative risk by haptoglobin phenotype in DM. The interaction of DM and haptoglobin phenotype on risk of CVD is a key finding in our study. Second, the Belgian study examined a single cardiovascular end point, CVD mortality; our report includes both fatal and nonfatal cardiovascular events and may, therefore, provide greater insight into the relationship between haptoglobin and CVD (20). Finally, only 35% of eligible patients were enrolled in the Belgian study (17), potentially leading to selection bias in that study. In contrast, the SHS enrollment was approximately twice that of the Belgian study, suggesting a greater degree of generalizability of the findings (20). Because our study cohort includes a significant percentage of individuals of advanced age, we cannot rule out the effect of selection bias in this study due to survivorship. Selective mortality may have introduced a bias if DM carriers of the haptoglobin 1 allele were more likely to die before they entered the study and could be phenotyped. Thus, DM patients with Hp 1-1 who were most susceptible to CVD may have self-selected out of the study due to early mortality. The Belgian study cited above appears to support this idea, but this is not the case (17). Although the number of DM patients in the Belgian study was too small to permit meaningful statistical analysis, the cardiovascular mortality rate in DM patients with Hp 2-2 or Hp 2-1 was double that in Hp 1-1. Furthermore, population-based analysis of haptoglobin type stratified by age has failed to show an increased mortality rate among carriers of the 1 allele (26).

We cannot rule out the possibility that our findings are not due to a polymorphism in haptoglobin but rather could be explained by linkage disequilibrium with another gene that is in close proximity to the haptoglobin gene. One gene of interest is the LCAT (lecithin-cholesterol acyl transferase) gene, which is found in close proximity to the haptoglobin gene on chromosome 16 (27). Deficiency of the LCAT gene product, a rare recessive condition, has been associated with premature atherosclerosis (27). It is important to note that our results suggest an association between functionally distinct phenotypes of the haptoglobin gene product and CVD. This is distinct from linkage disequilibrium, which is the result not only of physical proximity of loci, but also of many other factors related to the evolutionary history of nucleotide diversity in the region. In order for the association we have reported to reflect an association based on linkage disequilibrium with LCAT or any other gene, it would be necessary to define the relevant polymorphisms in the LCAT gene and/or establish the pattern of linkage disequilibrium across the whole region based on the generation of haplotypes.

Several functions have been assigned to the haptoglobin protein that may impact on development of atherosclerotic CVD. It has been appreciated for over 60 years that a major function of serum haptoglobin is to bind free hemoglobin (5). This interaction is thought to help scavenge iron, and prevent its loss in the urine, and to serve as an antioxidant, thereby protecting tissues against hemoglobin-mediated tissue oxidation (6). The antioxidant capacity of the different haptoglobin phenotypes has been shown to differ, with the Hp 1-1 protein appearing to confer superior antioxidant protection as compared with the other forms of the protein (6,10). Such an antioxidant hypothesis is particularly intriguing given the apparent important role of oxidative stress in the development of diabetic vascular complications (28). Potentially further amplifying differences in the oxidative protection afforded by the different types of haptoglobin are gross differences in the size of the haptoglobin protein present in individuals with the different phenotypes. Haptoglobin 1-1 is markedly smaller than Hp 2-2 and may, thus, be better able to sieve into the extravascular compartment and prevent hemoglobin-mediated tissue damage at sites of vascular injury (6). Haptoglobin has also been demonstrated to play a role as an immunomodulator that may not be unrelated to its role in hemoglobin metabolism (6).

The SHS population is a distinct ethnic group with unique metabolic characteristics associated with a high degree of obesity and other components of the metabolic syndrome, including diabetes. However, DM has not been shown to have unique physiology in American Indians. Indeed, current American Diabetes Association and WHO definitions of DM are largely based on data collected in American Indian communities. The fact that fundamental clinical practice guidelines are based on data from American Indians indicates that data from these communities are generalizable to other populations. In support of the generalizability of findings in this report are previous studies in which we demonstrated that the haptoglobin phenotype is predictive of the development of diabetic microvascular complications in a Semitic population of diabetics (11–13). Furthermore, we have recently found in a one-year follow-up study after coronary artery stent placement of over 900 diabetic patients in Germany that patients with the 1-1 Hp phenotype have significantly less myocardial infarction and less need for target vessel revascularization as compared with patients with the Hp 2-1 or Hp 2-2 phenotypes (Roguin A, Koch W, Kastrati A, Schomig A, Levy AP, unpublished data). Thus, although the anthropometric and metabolic profiles of American Indians are unique, the role of DM in CVD and the potentially modifying role of haptoglobin in this pathway are similar across ethnicity.

Haptoglobin phenotype appears to be less predictive of CVD in the non-DM population as compared with the DM population. This may be due to differences in the relative importance of antioxidant protection between DM and non-DM patients. While oxidative modification of proteins has been implicated in the pathogenesis of atherosclerotic disease in the non-DM as well as in the DM patient, the individual with DM is under considerably more oxidative stress than the individual without DM (28). Genetic differences in the endogenous antioxidant status, as determined by the haptoglobin phenotype, may be, therefore, of considerable importance in DM.

	Acknowledgments

 
This manuscript is dedicated to the memory of Dr. Robert I. Levy who served as an inspiration for these studies and proposed over 20 years ago the existence of a genetic factor responsible for susceptibility to cardiovascular disease in diabetic patients. The authors acknowledge the cooperation of the AkChin Tohono O’Odham (Papago)/Pima, Apache, Caddo, Cheyenne River Sioux, Comanche, Delaware, Spirit Lake Sioux, Fort Sill Apache, Gila River Pima/Maricopa, Kiowa, Oglala Sioux, Salt River Pima/Maricopa, and Wichita Indian communities, without whose support this study would not have been possible.

	Footnotes

 
Supported by NHLBI RO1 HL-66195, the Kennedy Leigh Trust (A.P.L.), and cooperative grants for Strong Heart (NHLBI U01-HL-41642, 41652, 41654).

	References

Top Abstract Methods Results Discussion References

 
1. Howard BV, Magee MF. Diabetes and cardiovascular disease. Curr Atheroscler Rep. 2000;2:476–481[Medline]

2. Aronson D, Rayfield EJ. Diabetes. Topol EJ. Textbook of Cardiovascular Medicine. Philadelphia, PA: Lippincott-Raven; 1998. p. 171–194

3. Hammoud T, Tanguay JF, Bourassa MG. Management of coronary artery disease: therapeutic options in patients with diabetes. J Am Coll Card. 2000;36:355–365[Abstract/Free Full Text]

4. UK Prospective Diabetes Study Group. Ethnicity and cardiovascular disease: the incidence of myocardial infarction in white, south Asian and afro-Caribbean patients with type 2 diabetes. Diabetes Care. 1998;21:1271–1277[Abstract]

5. Bowman BH, Kurosky A. Haptoglobin: the evolutionary product of duplication, unequal crossing over, and point mutation. Adv Hum Genetics. 1982;12:189–261

6. Langlois MR, Delanghe JR. Biological and clinical significance of haptoglobin polymorphism in humans. Clin Chem. 1996;42:1589–1600[Abstract/Free Full Text]

7. Maeda N, Smithies O. The evolution of multigene families: human haptoglobin genes. Ann Rev Genetics. 1986;20:81–108[CrossRef][Medline]

8. Delanghe J, Langlois M, Ouyang J, Claeys G, De Buyzere M, Wuyts B. Effect of haptoglobin phenotypes on growth of Streptococcus pyogenes. Clin Chem Lab Med. 1998;36:691–696[CrossRef][Medline]

9. Giblett ER. Genetic Markers in Human Blood. Oxford: Blackwell Scientific; 1969. p. 63–125

10. Melamed-Frank M, Lache O, Enav BI, Rickliss R, Levy AP. Structure/function analysis of the anti-oxidant properties of haptoglobin. Blood. 2001;98:3693–3698[Abstract/Free Full Text]

11. Levy AP, Roguin A, Hochberg I, et al. Haptoglobin phenotype and vascular complications in diabetes. N Eng J Med. 2000;343:969–970[Free Full Text]

12. Nakhoul F, Marsh S, Hochberg I, Leibu R, Miller BP, Levy AP. Haptoglobin phenotype and diabetic retinopathy. JAMA. 2000;284:1244–1245[Free Full Text]

13. Nakhoul F, Zoabi R, Kantor Y, et al. Haptoglobin phenotype and diabetic nephropathy. Diabetologia. 2001;44:602–604[CrossRef][Medline]

14. Roguin A, Hochberg I, Nikolsky E, et al. Haptoglobin phenotype as a predictor of restenosis after percutaneous transluminal coronary angioplasty. Am J Cardiol. 2001;87:330–332[CrossRef][Medline]

15. Delanghe J, Cambier B, Langlois M, De Buyzere ML, Bernard DR, Ouyang J. Haptoglobin polymorphism, a genetic risk factor in coronary artery bypass surgery. Atherosclerosis. 1997;132:215–219[CrossRef][Medline]

16. Chapelle JP, Albert A, Smeets JP, Marechal JP, Heusghem C, Kulbertus HE. Effect of the haptoglobin phenotype on the size of a myocardial infarct. N Engl J Med. 1982;307:457–463[Abstract]

17. DeBacquer D, DeBacker G, Langlois M, Delanghe J, Kesteloot H, Kornitzer M. Haptoglobin polymorphism as a risk factor for coronary heart disease mortality. Atherosclerosis. 2001;157:161–166[CrossRef][Medline]

18. Howard BV, Lee ET, Cowan LD, et al. Rising tide of cardiovascular disease in American Indians: the Strong Heart study. Circ. 1999;99:2389–2395[Abstract/Free Full Text]

19. Lee ET, Welty TK, Fabsitz R, et al. The Strong Heart study: design and methods. Am J Epidemiol. 1990;132:1141–1155[Abstract/Free Full Text]

20. Howard BV, Welty TK, Fabsitz R, et al. Risk factors for coronary heart disease in diabetic and nondiabetic North Americans: the Strong Heart study. Diabetes. 1992;41:4–11

21. WHO Expert Committee on Diabetes Mellitus. Second Report (technical report series 646). Geneva: World Health Organization; 1980.

22. Lee ET, Cowan LD, Welty TK, et al. All cause mortality and cardiovascular disease mortality in 3 American Indian populations aged 45 to 74 years, 1984 to 88: the Strong Heart study. Am J Epidemiol. 1998;147:995–1008[Abstract/Free Full Text]

23. Howard BV, Lee ET, Cowan LD, et al. Coronary heart disease prevalence and its relation to risk factors in American Indians: the Strong Heart study. Am J Epidemiol. 1995;142:254–268[Abstract/Free Full Text]

24. Smithies O. Zone electrophoresis in starch gels: group variations in the serum proteins of normal human adults. Biochemistry. 1955;61:629–641

25. Hochberg I, Roguin A, Nikolsky E, Chanderaskekhar PV, Cohen S, Levy AP. Haptoglobin phenotype and coronary artery collaterals in diabetic patients. Atherosclerosis. 2002;161:441–446[CrossRef][Medline]

26. Hamad M, Awadallah S. Age group associated variations in the pattern of Hp type distribution in Jordan. Clin Chim Acta. 2000;300:75–81[CrossRef][Medline]

27. Teisberg P, Gjone E, Olaisen B. Genetics of lecithin:cholesterol acyltransferase deficiency. Ann Hum Genetics. 1975;38:327–340[Medline]

28. Guigliano D, Ceriello A, Paolisso G. Oxidative stress and diabetic vascular complications. Diabetes Care. 1996;19:257–267[Abstract]

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				A. Roguin, J. R. Resar, J. Koerselman, Y. van der Graaf, P. P.T. de Jaegere, and D. E. Grobbee Genetics and Susceptibility of Coronary Collateral Formation * Response Circulation, November 25, 2003; 108 (21): e149 - e149. [Full Text] [PDF]

				A. Roguin, W. Koch, A. Kastrati, D. Aronson, A. Schomig, and A. P. Levy Haptoglobin Genotype Is Predictive of Major Adverse Cardiac Events in the 1-Year Period After Percutaneous Transluminal Coronary Angioplasty in Individuals With Diabetes Diabetes Care, September 1, 2003; 26(9): 2628 - 2631. [Abstract] [Full Text] [PDF]

				M. Suleiman, M. R. Kapeliovich, A. Roguin, D. Aronson, S. R. Meisel, M. Shochat, S. A. Reisner, H. Hammerman, R. Lotan, N. S. Levy, et al. Haptoglobin Type and 30-Day Mortality in Diabetic Individuals Presenting With Acute Myocardial Infarction Diabetes Care, September 1, 2003; 26(9): 2699 - 2700. [Full Text] [PDF]

				R. Asleh, S. Marsh, M. Shilkrut, O. Binah, J. Guetta, F. Lejbkowicz, B. Enav, N. Shehadeh, Y. Kanter, O. Lache, et al. Genetically Determined Heterogeneity in Hemoglobin Scavenging and Susceptibility to Diabetic Cardiovascular Disease Circ. Res., June 13, 2003; 92(11): 1193 - 1200. [Abstract] [Full Text] [PDF]

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