Haptoglobin is a hemoglobin-binding protein expressed by a genetic polymorphism as three major phenotypes: 1-1, 2-1, and 2-2. Most attention has been paid to determining haptoglobin phenotype as a genetic fingerprint used in forensic medicine. More recently, several functional differences between haptoglobin phenotypes have been demonstrated that appear to have important biological and clinical consequences. Haptoglobin polymorphism is associated with the prevalence and clinical evolution of many inflammatory diseases, including infections, atherosclerosis, and autoimmune disorders. These effects are explained by a phenotype-dependent modulation of oxidative stress and prostaglandin synthesis. Recent evidence is growing that haptoglobin is involved in the immune response as well. The strong genetic pressure favoring the 2-2 phenotype suggests an important role of haptoglobin in human pathology.

Biological and clinical significance of haptoglobin polymorphism in humans.

There is some evidence that major depression is characterized by systemic immune activation with involvement of phagocytic cells, T cell activation, B cell proliferation and increased autoantibody production This paper reviews that major depression may be accompanied by higher concentrations of positive and lower concentrations of negative acute phase proteins (APPs) The most prominent abnormalities of APPs in major depression are increased haptoglobin (Hp) plasma levels The latter are significantly and positively correlated with interleukin (IL)-6 production, various indices of systemic immune activation (eg monocytosis, neutrophilia, T cell activation) and with the vegetative symptoms of depression (eg anorexia, weight loss, psychomotor retardation, sleep disorders, anergy) Major depression is characterized by an altered distribution of Hp phenotypes and genes suggesting that genetic variation on chromosome 16 may be associated with this illness It is concluded that increased production of IL-6 and IL-1 in major depression may underlie both immune activation and the "acute" phase response in that illness, and that disorders in Hp may be related to the pathophysiology and pathogenesis of major depression

A review on the acute phase response in major depression.

There are many lines of evidence illustrating that iron plays a pivotal role in modulating the battle for survival between mammalian hosts and their pathogens. Each displays considerable genetic investment in a wide range of mechanisms for acquiring and maintaining iron. These competitive mechanisms are highly complex, existing within an interacting matrix of absorption, transport, storage and detoxification systems, each of which are iron-responsive and thus able to adapt to the different phases of infection. Considerable genetic polymorphism in some of these systems, with signals of geographic selection in the hosts, and niche selection in the pathogens, indicates that they are critical for species survival. In this review we briefly summarize the role of iron in host immune function before reviewing the available evidence that iron modulates susceptibility and disease outcomes in HIV and TB (tuberculosis). We then examine the putative role of iron-related host genes by focussing on two candidate genes, haptoglobin and NRAMP1, for which there are common polymorphic variants in humans with strong evidence of functionally distinct biochemical phenotypes that would be predicted to influence the course of HIV and TB infections. Finally, we examine the limited evidence so far available that nutrient-gene interactions are likely to influence the way in which gene variants can protect against infection. We conclude that there is a wealth of evidence associating alterations in iron balance and in iron-regulatory systems with disease progression, but that many issues related to the direction of causality, mechanisms of action and sensitivity to pharmacological intervention remain to be elucidated. Since iron is probably the most widely prescribed compound throughout the world, used in both preventative and treatment regimens, a deeper understanding of the host-pathogen interactions relating to iron constitutes an important area for both basic and clinical research.

Iron and infection: effects of host iron status and the iron-regulatory genes haptoglobin and NRAMP1 (SLC11A1) on host-pathogen interactions in tuberculosis and HIV.

Haptoglobin (Hp) is a plasma glycoprotein, the main biological function of which is to bind free hemoglobin (Hb) and prevent the loss of iron and subsequent kidney damage following intravascular hemolysis. Haptoglobin is also a positive acute-phase protein with immunomodulatory properties. In humans, the HP locus is polymorphic, with two codominant alleles (HP1 and HP2) that yield three distinct genotypes/phenotypes (Hp1-1, Hp2-1 and Hp2-2). The corresponding proteins have structural and functional differences that may influence the susceptibility and/or outcome in several diseases. This article summarizes the available data on the structure and functions of Hp and the possible effects of Hp polymorphism in a number of important human disorders.

/pdf/polymorphism-of-human-haptoglobin-and-its-clinical-i9muh8cc5s.pdf

Polymorphism of human haptoglobin and its clinical importance

In Brief Prospective identification of individuals with diabetes who are at greatest risk for developing complications would have considerable public health importance by allowing appropriate resources to be focused on those who would benefit most from aggressive intervention. Haptoglobin (Hp) is an acute-phase protein that is crucial for the elimination of free hemoglobin and the neutralization of oxidative damage. In the past two decades, associations have been made between polymorphisms in Hp and complications arising from diabetes. Individuals with polymorphism in Hp have been shown to have significantly higher risk of developing cardiovascular disease. This review summarizes the current literature on the role of Hp in health and disease, with a focus on diabetes.

https://clinical.diabetesjournals.org/content/diaclin/34/3/148.full.pdf

H E Sutton

Papers

Association between response to typhoid vaccination and known genetic markers.