Given that African Americans and Latinos have increased risk of ALI mortality, significant interest exists for the identification of genetic and non-genetic factors potentially contributing to ARDS susceptibility and prognosis [26]. Individual genetic variation may be responsible for conferring differing risks with respect to ALI outcomes among different racial groups.

In the era of personalized medicine, study of the human genome is providing increasing insight into the role of race and ethnic variations in multiple complex disorders including the influence of single nucleotide polymorphisms (SNPs) on susceptibility and severity of sepsis and sepsis-associated ARDS [27–35]. Due to the increasing number of epidemiologic studies that implicate race may play a role in the large heterogeneity associated with ARDS outcomes, several strategies have been developed to identify race-specific candidate genes. Using a candidate gene-based case-control association study, sampling distinct individuals from the population of patients and controls was performed to assess differences in the frequency of variants in genes of interest. Candidate gene variants were identified by analyzing publicly known SNPs or via gene sequencing [36] and SNPs associated with human ARDS were determined, with unique variants observed specifically in African Americans. Highly differentially regulated genes between the apex and base regions included several genes commonly associated with ARDS: vascular endothelial growth factor (VEGF), thrombospondin 1 (THBS1), plasminogen activator inhibitor 1 (PAI-1), transforming growth factor β (TGF-β), and pre-B cell colony-enhancing factor (PBEF) [37]. Several variants of genes involved in inflammatory and innate responses to infection showed different allelic frequencies by race and gender in ARDS and sepsis, suggesting that race and gender may have variable inherent response to infection [38]. Studies, however, suggest that genetic variation alone does not fully explain the differences in outcomes with respect to common acute critical illness. Immunologic and inflammatory diseases are associated with a large number of genetic markers with a large variance among different ethnic populations. Examples of this variation have been associated with individuals of African descent and individuals of non-African descent with either the presence of diseases associated with the inflammatory and/or infection pathways, or for which the susceptibility allele occurs at a larger frequency. Examples include the 237G allele of the beta chain of the high-affinity IgE receptor [FCER1B]; the -589T allele of interleukin (IL)-4 receptor alpha; the P46L (c.224C>T) variant in the gene encoding member 1A of tumor necrosis factor receptor superfamily (TNFRSF1A); the -174G/G genotype in the pro-inflammatory cytokine IL-6 gene; and the -401A allele of RANTES [35, 39]. Moreover, there are gene variants that have been associated with sepsis development and ARDS. For example, Saleh et al. identified CGA (Arg) codon resulting in a full-length caspase polypeptide (Csp12-L) associated with severe sepsis and a higher mortality due to sepsis; this variant confers hypo-responsiveness to LPS-stimulated cytokine production and is present in approximately 20 % of African descent but is absent in Europeans and Asians [40]. Tumor necrosis factor alpha has also been associated with ARDS. Similarly, the functional rs2814778 SNP in the gene encoding Duffy antigen/receptor for chemokines is associated with worse clinical outcomes among African Americans with ARDS, possibly via an increase in circulating IL-8 [41].

Candidate gene-based studies from our laboratory utilizing preclinical models of sepsis and ARDS identified a number of genes that have been shown to be associated with features of ARDS pathobiology [28, 30, 35, 36, 42, 43]. For example, two genes associated with ARDS susceptibility include NAMPT/PBEF (NAMPT) and myosin light chain kinase (MYLK). PBEF was identified from high-throughput expression profiling in animal models of ARDS and in human patients following ALI [35, 43]. PBEF protein levels were elevated in human bronchoalveolar lavage and serum samples from patients with ARDS, and also DNA sequencing identified two SNPs in the PBEF promoter that were overrepresented in patients with sepsis-induced ARDS [26]. Variants in the promoter region of PBEF were shown to confer a 7.7-fold higher risk of sepsis-associated ALI (p < 0.001) compared with both individuals with severe sepsis and healthy control subjects. Additionally, functional studies have further validated PBEF as a novel biomarker in ARDS [30, 39]. PBEF is not only an essential participant in ventilator-induced lung injury (VILI), but also a key regulator of cellular apoptosis and vascular barrier regulation.

MYLK is a multifunctional Ca²⁺/calmodulin (CaM)-dependent kinase in endothelium that contributes to endothelial contraction and barrier dysfunction. The human MYLK encodes three proteins including non-muscle and smooth muscle myosin light chain involved in cell motility, vascular regulation of inflammation, permeability, and apoptosis [36, 42, 43], with an important role in endothelial/epithelial barrier dysfunction and vascular leak, trademarks of ARDS. Direct sequencing of MYLK in individuals of European and African descent with sepsis, sepsis-associated ARDS, and healthy controls identified 57 genetic variations and 51 polymorphic base substitutions. Five of ten MYLK SNPs conferred an amino acid change and four novel polymorphisms. Genotyping studies showed several MYLK SNPs to be overrepresented in Caucasians as well as several SNPs overrepresented in African Americans. These observations implicate a variety of potential contributors that may influence ARDS incidence and mortality. Recent reports support a genetic/epigenetic predisposition to ARDS, with several studies highlighting individual genetic variation as a contributor to ALI susceptibility with increased frequency of ARDS-associated variants in individuals with African descent. For example, the coding SNPs in MYLK, rare in European descendants but frequent in those of African descent, confer susceptibility to ARDS as well as severe asthma in African Americans [36].

African American and Hispanic/Latino populations exhibit decreased life expectancy and disproportionately higher morbidity and mortality from preventable diseases [38, 44]. These include the burden of acute and chronic lung diseases, conditions well established to be significant and distributed unevenly across gender, ethnic, and social groups, including African Americans and Latinos [44]. A well-established Index of comorbidity, the Charlson Comorbidity Index (CCI), has been used to assess the comorbidities in ARDS patients. CCI has been statistically significantly correlated with the acute physiology and chronic health evaluation score, also known as APACHE II, and sequential organ failure assessment (SOFA) score (r = 0.387, p < 0.01 and r = 0.288, p < 0.05, respectively) [45]. The CCI score is determined through the sum of an already established point value for categories of comorbidities, where each condition category is scored from 1 to 6 (Table 7.1). Examination of the CCI list of comorbidities indicates there are several which are more common among racial and ethnic minorities. Chronic untreated conditions such as diabetes are more often seen in minorities and some of these conditions, such as diabetes, predispose to sepsis development [14]. African American septic patients are more likely to have diabetes, chronic renal failure, obesity, and HIV compared to whites (Table 7.3 ).

A retrospective cohort study analyzing 47 patients over 198.2 days (6.6 months) using CCI showed that the prognosis of ARDS was affected more by comorbidity than by age [45].

It has been estimated that the overall chronic disease prevalence will increase 42 % by 2023 and the projected economic burden will be about $4.2 trillion; that includes the economic cost associated with obesity, diabetes, and hypertension, conditions with higher prevalence among blacks and Hispanics [46]. Increasing access to interventions that enhance outcomes and care of individuals with chronic preexisting conditions may decrease ARDS incidence and improve its prognosis (Table 7.4).