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      Haptoglobin Polymorphism in Individuals with Type 2 Diabetic Microangiopathy

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          Abstract

          Background:

          Haptoglobin is an acute phase protein with antioxidant and immunomodulatory properties. Gene polymorphism may be a risk factor for diabetic vascular disease in Iranian population.

          Aims:

          The study investigates the existence or not of an association between haptoglobin genotypes and prevalence of diabetic microangiopathy in individuals with type 2 diabetic microangiopathy.

          Materials and Methods:

          We included 206 type 2 diabetic patients (<5 years duration) categorized into two groups according to the presence or absence of diabetic microvascular complications. The cases of interest were diabetic neuropathy, retinopathy, and nephropathy identified during clinical and or laboratory examination. In addition, 114 age- and sex-matched individuals were selected to serve as a control group. Haptoglobin genotyping was done using an amplification gel electrophoresis.

          Results:

          The frequency of haptoglobin phenotype 2-1 in diabetic patients was 70/206 (33.9%) as compared with 54/114 (47.3%) in nondiabetics ( P = 0.01). However, the frequency of haptoglobin phenotype 2-2 was greater in diabetics (126/114, 61.1%) than in those without diabetes (56/114, 49.1%; P = 0.02). Patients with diabetic microangiopathy; however, did not differ significantly between haptoglobin phenotype groups.

          Conclusions:

          Haptoglobin phenotype 2-2 is considered to be a major susceptibility gene for type 2 diabetic patients. Moreover, haptoglobin phenotype 2-1may be good prognostic factors for the development of diabetes mellitus.

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          Most cited references41

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          Haptoglobin: a review of the major allele frequencies worldwide and their association with diseases.

          Haptoglobin (Hp) is a plasma alpha(2)-glycoprotein which binds free haemoglobin, thus preventing oxidative damage. The complex is rapidly removed from the circulation by a specific receptor (CD163) found on macrophages. Three major subtypes, Hp1-1, Hp2-1 and Hp2-2 are the product of two closely related genes HP(1) and HP(2). The frequency of the HP(1) and HP(2) genes varies worldwide depending on racial origin: the HP(1)frequency varying from about 0.07 in parts of India to over 0.7 in parts of West Africa and South America. Both HP(1) and HP(2) have been linked to susceptibility to various diseases. Such associations may be explained by functional differences between the subtypes in the binding of Hb and its rate of clearance from the plasma. However, there are also corresponding negative reports for disease associations. The conflicting evidence on disease association and the lack of association between disease and particular populations, despite the wide range of HP(1) and HP(2) gene frequencies across the world, may indicate that any associations are marginal.
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            Genotyping of the common haptoglobin Hp 1/2 polymorphism based on PCR.

            A genetically defined molecular heterogeneity of haptoglobin, characterized by the major phenotypic forms Hp 1-1, Hp 2-1, and Hp 2-2, has been associated with distinct clinical manifestations. To enable the use of DNA samples for the study of this polymorphism, we established a haptoglobin genotyping method based on PCR. Taking advantage of the selectivity of PCR, we amplified DNA segments specifically representing haptoglobin alleles Hp 1 and Hp 2 from genomic DNA. The products were analyzed by agarose gel electrophoresis. Haptoglobin phenotyping of plasma samples was performed by polyacrylamide gel electrophoresis and peroxidase staining. Exploiting the known size difference between Hp 1 and Hp 2, we amplified allele-specific DNA molecules with one pair of oligonucleotide primers. As an alternative, we used separate primer pairs to generate amplification products indicative of alleles Hp 1 and Hp 2. Because of the primer design, genotype determination was not compromised by sequence variations specifying haptoglobin allele subtypes S and F. For the same reason, the sequence similarity between the haptoglobin gene and the haptoglobin-related gene did not interfere with the accuracy of genotyping. Analysis with restriction enzymes demonstrated the authenticity of the allele-specific DNA products. Haptoglobin DNA genotyping and protein phenotyping, performed in parallel, yielded fully corresponding results. In a group of 249 individuals, the haptoglobin genotype distribution was as follows: 14.5% Hp 1-1, 48.2% Hp 2-1, and 37.3% Hp 2-2. The new method can be used for genotyping of a common haptoglobin polymorphism.
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              Biological functions of haptoglobin--new pieces to an old puzzle.

              Haptoglobin, an "acute phase" protein, has different functions, which display genetic polymorphism. The complex of haptoglobin with haemoglobin is metabolized in the heptic reticuloendothelial system. Biosynthesis of haptoglobin occurs not only in the liver, but also in adipose tissue and in lung; providing antioxidant and antimicrobial activity. Changes in the measured concentrations of haptoglobin in serum may help to assess the disease status of patients with inflammations, infections, malignancy etc. (increases) as well as in haemolytic conditions (decreases). Haptoglobin plays a role in stimulation of angiogenesis and has highly potent cholesterolcrystallization-promoting activity. Probably the most important biological function of haptoglobin consists in the host defence responses to infection and inflammation, acting as a natural antagonist for receptor-ligand activation of the immune system.
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                Author and article information

                Journal
                N Am J Med Sci
                N Am J Med Sci
                NAJMS
                North American Journal of Medical Sciences
                Medknow Publications & Media Pvt Ltd (India )
                2250-1541
                1947-2714
                September 2013
                : 5
                : 9
                : 529-535
                Affiliations
                [1 ] Department of Ophthalmology, Mazandaran University of Medical Sciences, Mazandaran, Iran
                [2 ] Molecular and Cell Biology Research Center and Medical Faculty, Mazandaran University of Medical Sciences, Mazandaran, Iran
                [3 ] Department of Microbiology, Molecular Cell-Biology Research Center, Faculty of Medicine, Mazandaran University of Medical Sciences, Sari, Iran
                [4 ] General Medicine, Research Committee, Faculty of Health, Tehran University of Medical Sciences, Tehran, Iran
                [5 ] General Medicines, Student Research Committee, Faculty of Medicine, Mazandaran University of Medical Sciences, Mazandaran, Iran
                Author notes
                Address for correspondence: Dr. Mohammad Bagher Hashemi-Soteh, Molecular and Cell Biology Research Center and Medical Faculty, Mazandaran University of Medical Sciences, Mazandaran, Iran. E-mail: hashemisoteh@ 123456gmail.com
                Article
                NAJMS-5-529
                10.4103/1947-2714.118929
                3818825
                24251270
                961bcc8a-65e4-424d-800b-b86cb5e2494f
                Copyright: © North American Journal of Medical Sciences

                This is an open-access article distributed under the terms of the Creative Commons Attribution-Noncommercial-Share Alike 3.0 Unported, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                Categories
                Original Article

                Medicine
                diabetes mellitus,diabetic microvascular complications,genetic polymorphisms,haptoglobin genotypes

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