WHY should we be interested in the genetics of risk of sepsis? Astute clinicians have observed for years quite variable interpersonal risk of infection despite similar environments and exposure to pathogens. If one could fast forward to a day when a clinician could assess (by genotyping a patient) the degree of risk of infection, what would be the clinical utility of such knowledge? Such individual patient risk stratification could be used to supplement clinical information to select individuals for different—patient-specific—preventive strategies before surgery that has increased risk of infection, before chemotherapy, before use of immunosuppressive agents for inflammatory diseases, and before use of other devices and drugs that increase risk of infection. Defensins are antimicrobial, cytotoxic peptides stored in azurophilic granules of neutrophils. The α-defensin genes (denoted DEFA1-3
) code for human neutrophil peptides 1–3 (HNP1–3) and have great genetic variability. In this issue of Anesthesiology, Chen et al
report their case–control study of genetic variability (copy number variants [CNVs]) of DEFA1-3
and the risk of severe sepsis. Patients who had severe sepsis had greater copy number (median 9) of DEFA1-3
compared with controls (median 7, odds ratio 2.77, 95% CI 1.84–4.16) in a discovery cohort of 179 severe sepsis (cases) and 233 healthy blood donors (controls). The results were replicated in a second replication case–control study (copy number of DEFA1-3
was nine in severe sepsis cases vs.
seven in controls). Biologic plausibility was assessed by comparing the genotype to circulating levels of HNP1–3: patients who had greater than eight copies of DEFA1-3
had lower HNP1–3 than did patients who had less than or equal to eight copies of DEFA1-3
. Furthermore, patients who had greater than eight copies of DEFA1-3
had lower plasma levels of tumor necrosis factor-α, interleukin-6, and interleukin-10. Chen et al.1
concluded that patients having greater than eight copies of DEFA1-3
are at risk for severe sepsis.
How clear is the evidence that risk of infection and death from infection could be heritable? Sorensen et al
provided a sound foundation to this insight. They studied adopted humans in a large Danish registry to examine how risk of disease of persons was correlated (or not) with the diseases that caused death of first, the biologic parents and second, the parents who raised the person in essence to compare “genes” with “environment.” Ironically, if one of the biologic parents died of infection before the age of 50 yr, then the person had a 5.8 increased relative risk of dying of infection. In contrast, there was no correlation of the risk of death from infection between the child-raising parents and the person. Thus, Sorensen et al
suggested that the risk of dying of infection may be highly heritable. Accordingly, it is plausible that variations in genes of the host response to infection, such as innate immunity genes, inflammatory genes, and perhaps even coagulation pathway genes, could explain the heritability of risk of infection and of risk of death from infection.
How do defensins relate to this risk of infection? Neutrophils are key components of the innate immune response to infection and direct and respond to a complex orchestra of signals and mediators. The neutrophil response is scaled according to variables, such as organism load, site of infection, and even type of organism. One instrument section that the conductor of the response to infection calls upon early from the orchestra is the defensins.3
Defensins are the fundamental components of innate immunity. Defensins are classified as α and β. The α, or classic, defensins (denoted DEFA1-3
) are antimicrobial peptides of neutrophils, macrophages, and mucosal crypt cells. DEFA1-3
also enhances phagocytosis by macrophages (so increasing microorganism killing), recruits additional neutrophils (thus escalating the scale of the neutrophil response), regulates complement activation (also enhancing microorganism killing) and is chemotactic for T cells4
and dendritic cells. The α defensins seem to enhance the serum immunoglobulin G response and induce CD4+ cells proliferation and cytokine responses.5
code for HNP1–3 has great variability of copy number (CNV). It is known that the protein levels of HNP1–3 increase in sepsis. It has also been shown that genetic variation of β defensin1 (DEFB1) has been associated with risk of and death from sepsis.6
Therefore, it is reasonable to hypothesize that there is an association between CNV of DEFA1-3
and risk of sepsis.
CNVs usually alter the risk of disease by altering the gene expression and may be an underevaluated source of genetic variability. Aldred et al
found that normal humans had 4–11 copies of DEFA1-3
, an unusually high variability of copy number. Furthermore, there is evolutionary conservation at work: apes, chimpanzees, gorillas, and humans all show marked variability of copy number of DEFA1-3
Chen et al
found that patients who had greater than eight copies of DEFA1-3
had lower levels of HNP1–3 (as well as lower tumor necrosis factor-α and interleukin-6) and had significantly increased risk of severe sepsis. Other authors have assessed the relationship between CNV of DEFA1-3
and levels of HNP1–3 and found conflicting results. Indeed, Aldred et al.7
noted that there was no relationship between the copy number of DEFA1-3
and total DEFA1-3
mRNA, suggesting that there are superimposed trans
-acting factors. Therefore, it is uncertain how to reconcile the lack of relationship of CNV of DEFA1-3
expression in normal humans,7
with the strong inverse relationship between CNV of DEFA1-3
and serum HNP1–3 levels in septic patients.1
Chen et al
speculate that sepsis causes neutrophil dysfunction, which somehow “dysregulates the release of HNP1–3 into the circulation,” but this is unproven.
Some of the strengths of the study by Chen et al. are that there is a discovery case–control study and a replication case–control study that the main genotype/clinical phenotype association findings did replicate, that there was measurement of intermediate phenotypes (HNP1–3) to assess the biologic plausibility, that all patients and controls were one ethnicity (decreasing risk of population admixture), and that the odds ratios were relatively high (2.77 in discovery study, 1.90 in replication study). Issues for consideration are the relatively small sample sizes, the unusual relationship of CNV of DEFA1-3 with plasma levels of HNP1–3, that the study is single center, and that the results may not apply (until further studied) to other settings or diseases.
Thus, we are left with a replicated case–control genetic association study between CNV of DEFA1-3
and risk of sepsis in which there was a higher CNV (median 9) of DEFA1-3
in severe sepsis compared with healthy controls (median 7) in a Chinese Han population.1
It will be interesting to see whether these provocative findings are replicated by other investigators in other geographic locations (because genetic expression may vary according to the geographic location8
), in other ethnicities, and in other infections. If the findings of Chen et al
are true, then copy number variation of DEFA1-3
may be an important but highly variable instrument section in the orchestrated response to infection that explains at least in part the heritability of infection.
James A. Russell, M.D.
University of British Columbia, Vancouver, British Columbia, Canada, and Department of Medicine, Critical Care Medicine, St. Paul's Hospital, Vancouver, British Columbia, Canada. email@example.com
1. Chen Q, Hakimi M, Wu S, Jin Y, Cheng B, Wang H, Xie G, Ganz T, Linzmeier RM, Fang X: Increased genomic copy number of DEFA1/DEFA3 is associated with susceptibility to severe sepsis in Chinese Han population. Anesthesiology 2010; 112:1428–34
2. Sorensen TI, Nielsen GG, Andersen PK, Teasdale TW: Genetic and environmental influences on premature death in adult adoptees. N Engl J Med 1988; 318:727–32
3. Zhang H, Porro G, Orzech N, Mullen B, Liu M, Slutsky AS: Neutrophil defensins mediate acute inflammatory response and lung dysfunction in dose-related fashion. Am J Physiol Lung Cell Mol Physiol 2001; 280:L947–54
4. Chertov O, Michiel DF, Xu L, Wang JM, Tani K, Murphy WJ, Longo DL, Taub DD, Oppenheim JJ: Identification of defensin-1, defensin-2, and CAP37/azurocidin as T-cell chemoattractant proteins released from interleukin-8-stimulated neutrophils. J Biol Chem 1996; 271:2935–40
5. Lillard JW Jr, Boyaka PN, Chertov O, Oppenheim JJ, McGhee JR: Mechanisms for induction of acquired host immunity by neutrophil peptide defensins. Proc Natl Acad Sci U S A 1999; 96:651–6
6. Chen QX, Lv C, Huang LX, Cheng BL, Xie GH, Wu SJ, Fang XM: Genomic variations within DEFB1 are associated with the susceptibility to and the fatal outcome of severe sepsis in Chinese Han population. Genes Immun 2007; 8:439–43
7. Aldred PM, Hollox EJ, Armour JA: Copy number polymorphism and expression level variation of the human α-defensin genes DEFA1 and DEFA3. Hum Mol Genet 2005; 14:2045–52
8. Idaghdour Y, Czika W, Shianna KV, LeeSH, Visscher PM, Marin HC, Miclaus K, Jadallah SJ, Goldstein DB, Wolfinger RD, Gibson G: Geographical genomics of human leukocyte gene expression variation in southern Morocco. Nat Genet 2010; 42:62–7
© 2010 American Society of Anesthesiologists, Inc.