Haptoglobin Phenotype and Gestational Diabetes

Abstract

OBJECTIVE -Haptoglobin (Hp), an Hb-binding plasma protein, exists in two major allelic variants. Hp1 has higher Hb binding and antioxidant capacity compared with Hp2. Individuals with Hp1 exhibit a lower incidence of angiopathies. Gestational diabetes mellitus (GDM) is an early manifestation of type 2 diabetes in pregnant women. It is usually confined to the time of gestation, but carries an increased risk to develop type 2 diabetes later in life.RESEARCH DESIGN AND METHODS -From consecutive Caucasian pregnant women (n ϭ 250) referred for oral glucose tolerance testing, the Hp phenotype was determined. Significance of distribution and odds ratios (ORs) associated with Hp phenotype were calculated for women with GDM (n ϭ 110) and women with normal glucose tolerance (n ϭ 140).RESULTS -Frequency of GDM in Hp phenotype classes increased with the number of Hp2 alleles (P Ͻ 0.001). ORs for GDM in women heterozygous and homozygous for Hp2 were 2.7 (95% CI 1.06 -6.84) and 4.2 (1.67-10.55), respectively. CONCLUSIONS -Hp phenotype is an apparent risk factor for the development of GDM in our study population. This might be due to the low antioxidative potential of Hp2 compared with Hp1. Diabetes Care 27:2103-2107, 2004H aptoglobin (Hp) is an acute-phase protein synthesized in the liver and, to some extent, in fat tissue (1) in response to interleukin 6 -type cytokines. The Hp gene is located on the long arm of chromosome 16 (16q22.3) (2). The two major Hp alleles (Hp1 and Hp2) are coding for proteins with one (Hp1) or two (Hp2) SH groups used in multimerization. The Hp1 molecule forms only dimers with a molecular weight of 86 kDa, whereas the Hp2 molecule forms multimers with a molecular weight between 170 and 900 kDa. A mixture of Hp1 and Hp2, as present in heterozygous individuals, exhibits dimeric Hp as well as oligomeric Hp, but the latter with a lower degree of polymerization than in Hp2 homozygotes. The Hp phenotype is inherited in a Mendelian pattern.Hp forms complexes with free Hb that are rapidly cleared by the liver and by macrophages. Rapid complexation of free Hb, stemming from common, low-grade intravascular hemolysis (3), is important because free Hb catalyzes the generation of reactive oxygen species, like the extremely reactive hydroxyl radical, by the so-called Fenton reaction. Reactive oxygen species promote endothelial activation and inflammation and play a crucial role in the development of endothelial dysfunction (4), which is also observed in gestational diabetes mellitus (GDM) (5). Thus Hp functions as an antioxidant and an essential vascular endothelial protector. However, the Hb-binding capacity (6) and antioxidant capacity of Hp1 is higher compared with Hp2 (7-9). The increased antioxidant function of Hp1 is thought to confer protection from angiopathies. This has been reported for coronary (10) and peripheral (11) atherosclerotic lesions, cardiac transplant vasculopathy (12), diabetic nephropathy (13), mortality in coronary heart disease (14), restenosis after peripheral and coronary angioplasty ...

Haptoglobin 2-2 Genotype Is Associated with Increased Risk of Type 2 Diabetes Mellitus in Northern Chinese

“…The dysfunction of endothelial cells is one of the characteristic of early stage type 2 diabetes mellitus (T2DM) (Sjoholm and Nystrom, 2005;Quaye et al, 2006). Thus, Hp functions as an antioxidant and an important vascular endothelial protector by binding Hb and preventing LDL oxidation (Mustafa et al, 2004;Asleh et al, 2005Asleh et al, , 2006Levy et al, 2007Levy et al, , 2010.…”

“…The best known function of Hp is to bind and aid in clearance of free Hb, stemming from common, low-grade intravascular hemolysis (Bowman and Kurosky, 1982;Mustafa et al, 2004;Levy et al, 2010). This can prevent kidney damage by free Hb in the circulation passed through the glomeruler filter.…”

“…Hp is characterized by its strong binding affinity for free hemoglobin (Hb) released after hemolysis (Bowman and Kurosky, 1982). In humans, the Hp gene is located on chromosome 16q22.3 (Bowman and Kurosky, 1982;Mustafa et al, 2004). The two common alleles for Hp1 and Hp2 result in three major genotypes: Hp1-1, Hp2-1, and Hp2-2 (Bowman and Kurosky, 1982).…”

“…H aptoglobin (Hp), an acute-phase plasma protein, is synthesized mainly in the liver (Mustafa et al, 2004;Levy et al, 2010). Hp is characterized by its strong binding affinity for free hemoglobin (Hb) released after hemolysis (Bowman and Kurosky, 1982).…”

“…At the protein level, there are three major phenotypes: Hp1-1, Hp2-1, and Hp2-2. The Hp phenotype is inherited in a Mendelian pattern (Langlois and Delanghe, 1996;Mustafa et al, 2004).…”