Haptoglobin genotype and the iron hypothesis of atherosclerosis

Jerome Sullivan first proposed 30 years ago that iron deficiency ay be protective against the development of ischemic heart disase [1]. Enthusiasm for this hypothesis was dampened by a series f studieswhich failed to show that conventionalmeasurements of otal body iron status were associated with increased atheroscleosis in man. However, one potential reason for the failure to emonstrate an association between iron and atherosclerosis in hese studies may have been due to a failure to focus on themoleclar form of iron which is most likely responsible for inducing therosclerosis. Iron is a reasonable candidate for carrying out the xidative modifications which are believed to be paramount in he atherosclerotic process [2]. Iron is capable of generating highly eactive label oxygen free radicals such as superoxide radical and ydroxyl radical under physiological conditions. However, most of he iron in our bodies is stored bound to professional iron binding roteins – transferrin or ferritin – in which the iron is redox inacive and not capable of inducing oxidation of substrates. Over the ast 10 years it has become appreciated that there exists a small ut tightly regulated pool of iron which is not bound to transferrin r ferritin and which is redox active (referred to as labile plasma on-transferrin bound iron or NTBI) [3,4]. NTBI represents a numer of molecular species very few of which have been identified. ne type of NTBI which has been identified is the iron contained ithin the haptoglobin–hemoglobin complex [5]. Haptoglobin (Hp) is an abundant plasma protein which binds ith high affinity to hemoglobin [6]. While the heme iron in emoglobin is a very potent oxidant, the binding of Hp to emoglobin serves to decrease the ability of iron derived from emoglobin from carrying out oxidative reactions [7]. In man their xists two possible alleles at the Hp genetic locus, denoted 1 and . The protein product of the Hp 2 allele is defective in its ability o block oxidative reactions mediated by iron derived hemoglobin. herefore, while the Hp 1–Hb complex is relatively redox inert,