5.1 Introduction

It has been largely recognized that infective processes have considerably different patient-to-patient behavior in such a way that some patients respond well to the treatment applied and some others end up developing a dysregulated immune response known as sepsis [44], organ failure, and some even die from this process. Infective endocarditis does not escape from this fact. Many variables, such as the virulence of the pathogen and the quality of the treatment applied, among many others, participate in an additive manner to conform the clinical outcomes of infections, and this helps to understand why a patient takes the road of success or failure regarding the control of the septic process. One of the most recent advances in the understanding of the pathophysiology of infective processes, including infective endocarditis, is the demonstration that genetically determined differences in the immune system of individuals are one of these many factors that determine the phenotypic behavior and outcomes. Therefore, the next chapter section is dedicated to explaining the existing evidence of the participation of immunogenetics in the development of infective endocarditis and sepsis.

Recently, the concept of sepsis has been redefined as the result of a better understanding of its pathophysiology, particularly regarding the early activation of pro- and anti-inflammatory immune responses. As the third international consensus definition of sepsis states, sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection [45]. Then, if sepsis is dependent on a dysregulated response, and this response is executed principally by the host immune system, then genetically defined differences between individuals immune system might play a role in the genesis of this syndrome and at least partially explain why some patients take the road of sepsis and some others do not. This hypothesis had long been existed, but it was until 1988 that the theory started gaining scientific evidence of its existence, when Sørensen et al. [46] published what is considered a landmark study with respect to this topic. In this article, the authors studied the genetical influences on the principal causes of nonviolent premature death in the Danish population; to separate them from the environmental influences, they studied a selected group of people that had been adopted early in life. This was extracted from the Danish Adoption Registry and included adoptees that were born between 1924 and 1926. They traced them up and demonstrated that the death of a biologic parent from an infection before the age of 50 resulted in a relative risk of death from infective causes in the adoptees of 4.5. Since this publication, a great number of studies have been conducted in an attempt to define the specific genetic variations that determine these differences in outcome. This task has resulted complex; as both pro- and anti-inflammatory responses contribute to the outcome of septic processes, all genes encoding effector proteins in the biochemical pathways of the inflammatory response to infection are potential candidates to determine the genetical background responsible for the interindividual differences aforementioned [47].

5.1.1 The study of single nucleotide polymorphism associations with sepsis and IE outcomes.

The most studied specific type of genetic anomaly regarding to sepsis susceptibility is the single nucleotide polymorphism (SNP); therefore, the largest body of evidence comes from the study of this type of genetic variations. SNPs are defined as frequent (occurring in >1% of the population) variations in the human DNA

sequence [48] and consist in the exchange of a single base pair for another in a specific location in the DNA sequence. They may occur within the exonic (coding) or intronic (noncoding) region of the gene and can have different consequences which include alteration of expression or structure of proteins and enzymes, introduction of an alternative translation initiation codon or stop codon, and destabilization of exonic mRNA [49]. Methodologically speaking, most studies are association studies (case/control and cohort type), and two approaches have been done. In the most common approach (which for purposes of this chapter section are going to be called specific SNP association studies), the frequency of one or more known SNPs present in genes coding defined molecular candidates involved in the pro- or anti-inflammatory responses (e.g., alpha tumoral necrosis factor gene) is compared between a specific phenotypically defined interest group (patients with a confirmed specific infectious scenario as sepsis or IE) and a control group, usually consisting of a group of healthy blood donors ideally with an ethnicity equal to the interest group. If there are statistically significant differences in the frequency of the SNPs between groups, authors take this as proof that such genetic differences are implicated in the specific way that the study population responds to infection. The other approach is a type of study called genome-wide association studies (GWAS). As the previously described type of study, GWAS are association studies (most frequently case–control studies) but differ in that the frequency of most known SNPs is measured in the whole genome of the cases (infected group) and controls (healthy blood donors). When a statistically significant difference is found, authors take this as proof that such genetic variability is responsible for the difference in outcomes and then hypothesize, based in the location of the SNPs, about the biological plausibility of the association given the gene that is affected.
