Mendelian and complex traits

There is considerable interest in understanding genetic determinants of critical illness to improve current risk stratification models, provide individualized therapies, and improve our current understanding of disease mechanisms. This review provides a broad overview of genetic nomenclature, different study designs, and problems unique to each of these study designs in critical illnesses. Well designed genetic studies with careful attention to these issues during the planning phase, use of rigorous statistical methods during analysis, and replication of these results in different cohorts will lead to more robust results and improved understanding of genetics of critical care. The completion of the Human Genome draft in 2000 has been accompanied by an explosion of studies examining genetic determinants of disease [1,2]. In critical care, current prediction models based on socio-demographic and clinical risk factors fail to explain fully why a particular patient either develops or succumbs to disease. Consequently, physicians have tried to understand if genetic variation affects susceptibility and outcome of critical illnesses. Genetics may also provide insights into biological mechanisms and allow more precise use of interventions. Using targeted therapy based on an individual’s genetic makeup, rather than using it on all patients, is an appealing strategy. But conflicting results from early studies in genetics of critical illness have led the scientific community to view these results with skepticism [3]. For example, there has been little consensus regarding genetic markers associated with a tumor necrosis factor (TNF) hypersecretor response. In particular, contradictory reports have been published for the association between the -308 guanine to adenine transition within the promoter region of the TNF gene and its expression and severe sepsis susceptibility [4,5]. This article will provide a broad outline of study designs to ascertain the role of genetic variation in critical care and focus on gene association studies, the most common study design in critical care. The article also addresses both problems generic to genetic studies and those unique to genetics of critical illness. Mendelian and complex traits Mendelian traits or diseases, such as sickle cell disease or cystic fibrosis, are influenced by a single gene. In contrast, most critical illnesses are multifactorial diseases, and called ‘complex traits’ in genetic parlance. Severe sepsis, an example of a complex trait, results from multiple etiologies, such as Gram-positive and Gram-negative bacteria, or fungal infections. The progression to severe sepsis is often mediated by a common biological pathway, with variations unique to specific infectious agents. Therefore, genetic variations within inflammatory mediators involved in the sepsis pathway have been hypothesized to play a role [4,6,7]. However, in addition to genetic factors, host characteristics and pathogen load also influence the phenotype. The relative contribution of host genetic factors in complex traits like severe sepsis would be modest. Focusing only on the contribution of genetic variation to disease, the exact pattern of genetic variation influencing complex traits is still unclear and several theories have been proposed [8]. One model, termed the common disease-rare variant model, suggests that phenotypic variation in complex traits is due to numerous rare genetic variants at multiple loci, with each variant single handedly causing disease. Although the frequency of each rare variant is low, populations may have several such variants. An example of the common disease-rare variant model includes mutations in the BRCA1 and BRCA2 genes, which have been implicated in the susceptibility to breast and ovarian cancer [9]. The frequency Review Bench-to-bedside review: Genetics and proteomics: deciphering gene association studies in critical illness Sachin Yende1, Candace M Kammerer2 and Derek C Angus1 1The CRISMA (Clinical Research, Investigation, and Systems Modeling of Acute Illness) Laboratory, Department of Critical Care Medicine, University of Pittsburgh, Pittsburgh, PA, USA 2Department of Human Genetics, University of Pittsburgh, PA, USA Corresponding author: Sachin Yende, [email protected] Published: 24 August 2006 Critical Care 2006, 10:227 (doi:10.1186/cc5015) This article is online at http://ccforum.com/content/10/4/227 © 2006 BioMed Central Ltd ARDS = adult respiratory distress syndrome; IL = interleukin; LD = linkage disequilibrium; SNP = single nucleotide polymorphism; TNF = tumor necrosis factor.