Annual Review of Medicine - Volume 54, 2003

This review focuses on the functional genomics of the human paraoxonase (PON1) polymorphisms. Levels and genetic variability of the PON1 position 192 isoforms (Gln/Arg) influence sensitivity to specific insecticides or nerve agents and risk for cardiovascular disease. A more recent area of investigation, the role of PON1 in drug metabolism, is also discussed. We emphasize the importance of considering both PON1 isoforms and PON1 levels in disease/sensitivity association studies.

During the past 10 years, the number of genetic tests performed more than tripled, and public concern about genetic privacy emerged. The majority of states and the U.S. government have passed regulations protecting genetic information. However, research has shown that concerns about genetic privacy are disproportionate to known instances of information misuse. Beliefs in genetic determinacy explain some of the heightened concern about genetic privacy. Discussion of the debate over genetic testing within families illustrates the most recent response to genetic privacy concerns.

The antiphospholipid (aPL) antibody syndrome is an autoimmune condition in which vascular thrombosis and/or recurrent pregnancy losses occur in patients with laboratory evidence for antibodies that bind to phospholipids. There have been significant advances in the recognition of the role of phospholipid-binding cofactors, primarily β2GPI, as the true immunologic targets of the antibodies. Recent evidence suggests that the antibodies disrupt phospholipid-dependent anticoagulant mechanisms and/or that aPL antibodies induce the expression of procoagulant and proadhesive molecules on endothelial cells. Current diagnosis is based on clinical findings and empirically derived tests, such as assays for antibodies that bind to phospholipids or putative cofactors and coagulation assays that detect inhibition of phospholipid-dependent coagulation reactions. Current treatment relies primarily on anticoagulant therapy. Research advances are expected to bring mechanistically based diagnostic tests and improved therapy that target the roots of the disease process.

The glycoprotein IIb/IIIa integrin receptor binds fibrinogen and is therefore a final common pathway responsible for platelet aggregation. One antibody (abciximab) and two synthetic compounds (tirofiban and eptifibatide) are clinically available to antagonize the function of this receptor. Several large-scale studies have documented the benefit of these compounds in acute coronary syndromes and during percutaneous interventions. Current data suggest that abciximab is the preferred drug in the catheterization laboratory, whereas the other compounds reduce risk for patients with unstable angina before coronary interventions are performed. The highest benefit is achieved in diabetic patients and in patients with elevated troponins. Adverse reactions are rare, and bleeding complications are minor when weight-adjusted heparin is given. Oral compounds have been associated with excess mortality, precluding their clinical use.

Interindividual variability in the efficacy and toxicity of drug therapy is associated with polymorphisms in genes encoding drug-metabolizing enzymes, transporters, or drug targets. Pharmacogenetics aims to identify individuals predisposed to high risk of toxicity from conventional doses of cancer chemotherapeutic agents. We review the role of genetic polymorphisms in UGT1A1 and TPMT, as well as mutations in DPD, in influencing drug disposition and toxicity. Recent studies show that pharmacogenetic determinants may also influence treatment outcomes. We discuss the clinical significance of polymorphisms in TS, MTHFR, and FCGR3A, as well as the polymorphic DNA repair genes XPD and XRCC1, in influencing reponse to chemotherapy and survival outcomes. Finally, the potential implications of transporter pharmacogenetics in influencing drug bioavailability are addressed.

Obesity has become a leading public health concern. Over 1 billion people are now overweight or obese, and the prevalence of these conditions is rising rapidly. Remarkable new insights into the mechanisms that control body weight are providing an increasingly detailed framework for a better understanding of obesity pathogenesis. Key peripheral signals, such as leptin, insulin, and ghrelin, have been linked to hypothalamic neuropeptide systems, and the anatomic and functional networks that integrate these systems have begun to be elucidated. This article highlights some of these recent findings and their implications for the future of obesity treatment.

“Banish plump Jack, and banish all the world.”

William Shakespeare, King Henry IV Part 1

Under the impetus of the Human Genome Project, new disease-associated genes are being discovered at a rapid pace. Mutations in many of these genes are present in a high enough proportion of the general population, or of particular ethnic groups, that global or targeted population screening can be contemplated. If performed early enough, identification of these mutations by molecular genetic testing can be used not merely to diagnose disease but to predict risk of future disease, either in the individual being tested or in his or her offspring. In some cases this knowledge can be the rationale for heightened surveillance and/or preventive or therapeutic interventions. Mass screening has already commenced for cystic fibrosis mutations and has been discussed for such diverse diseases as hereditary hemochromatosis, thrombophilias, familial cancer predispositions, and pharmacogenetic risk factors. However, implementation of such programs is often impeded by the complexity of the gene mutations, by incomplete penetrance, and by thorny ethical and social issues. This chapter reviews the basic criteria to be considered before embarking on population genetic risk screening, and examines multiple disease-screening examples representing a variety of modes of inheritance and technical challenges.

Hematopoietic cell transplantation is the preferred therapy for a substantial proportion of patients with life-threatening diseases of the lymphohematopoietic system. Recent advances in donor identification, disease eradication, and supportive care measures have broadened the application of transplantation and improved outcomes. This article provides a brief review of the major clinical principles of transplantation and results achieved to date.

Growth hormone (GH) is classically linked with linear growth in childhood but continues to have important metabolic actions throughout life. GH deficiency in adulthood causes a distinct syndrome with significant morbidities. These include increased total and visceral fat, decreased muscle mass and aerobic capacity, affective disturbances, abnormal lipids, and increased vascular mortality, all of which are ameliorated with GH replacement. The possibility of adult GH deficiency (AGHD) should always be considered in individuals with a history of childhood GH deficiency or significant hypothalamic-pituitary damage, and the diagnosis should then be confirmed by biochemical testing. Adult GH dosing is much lower than that in pediatric practice, as appropriate for physiologic reconstitution. Hormonal side effects are minimized by stepwise dose titration. Lingering concerns remain regarding the possibility of increased cancer risk with long-term treatment, but this hazard has not been unequivocally demonstrated. Compared with AGHD, there is much less information about GH replacement in other diseases or in normal aging, or about the use of supraphysiologic GH doses to treat catabolic states. In critical illness, high-dose GH therapy has proven clearly harmful, and the balance of risks and benefits of GH administration in most adult contexts other than AGHD has not been defined.

Genetic resistance to infectious diseases is likely to involve a complex array of immune-response and other genes with variants that impose subtle but significant consequences on gene expression or protein function. We have gained considerable insight into the genetic determinants of HIV-1 disease, and the HLA class I genes appear to be highly influential in this regard. Numerous reports have identified a role for HLA genotype in AIDS outcomes, implicating many HLA alleles in various aspects of HIV disease. Here we review the HLA associations with progression to AIDS that have been consistently affirmed and discuss the underlying mechanisms behind some of these associations based on functional studies of immune cell recognition.