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Translating the Genome

National Jewish Health
Denver, Colorado

The Toll-like receptors (TLRs) are the primary receptors that recognize molecules released by microorganisms. This fundamental responsibility in immunosurveillance may explain why this family of receptors has proven to play such a critical role in a broad array of immune and autoimmune diseases. The findings of Wurfel and colleagues (1), reported in this issue of the AJRCCM (pp. 710–720), demonstrate the vital role that TLR1 plays in sepsis and septic shock. Moreover, these results illustrate the potential clinical utility of specific sequence changes in TLR1 that can identify individuals at increased risk of gram-positive sepsis and its ensuing complications. Their findings add to the growing list of polymorphisms in innate immune genes (TLR2_Arg753Gln, TLR4_Asp299Gly, TLR5_Arg392STOP, TIRAP_Ser180Leu, and IRAK4_Glu293STOP) that have been found to alter the risk of developing a number of different diseases and conditions (2–6). On the basis of this body of research, one could develop a personalized innate single-nucleotide polymorphism (SNP) profile that would prove useful in risk-stratifying patients, especially those more prone to infections and their complications (e.g., the elderly, diabetics, and alcoholics). Because the scientific and clinical consequences of Wurfel and colleagues' findings have been comprehensively considered in their DISCUSSION (1), I will focus this editorial on a few more general questions.

Why were these investigators successful?
Bill Clinton's response to this question would probably be "It's the phenotype, stupid." And he'd probably be right. While 275 healthy subjects seem like a large group of individuals to screen for innate immune phenotypes, these numbers are small compared with most genetic studies. Despite these small numbers, the investigators were able to confirm the phenotypes of other innate immune polymorphisms (TLR4_Asp299Gly, TLR5_Arg392Ter, and TIRAP_Ser180Leu) and discover a highly significant (P < 10^–20) relationship between TLR1_{–720 g} and an enhanced response to pam₃CSK₄. I believe that this was only possible because the investigators were exploiting an exposure–response relationship by probing specific biological pathways with unique stimuli. In fact, one could argue that, if they evaluated more proximal indices of TLR activation (rather than the downstream cytokines), additional significant polymorphisms would have been identified. The point here is that the more narrowly a phenotype can be defined (especially in terms of basic biology), the more likely one will be able to identify the genetic etiology. Moreover, specific exposures (in this case, microbial peptides) can (and should) be used to narrow the pathophysiologic phenotype to enhance the discovery of genes and gene variants that drive these basic biological responses. After all, such basic biological processes cause disease, so let's exploit them to understand genetic susceptibility.

Why are these detrimental polymorphisms preserved in the genome?
The answer to this is in part related to the multifunctional nature of TLRs. These receptors have evolved in response to the unique challenges presented by the diversity of microorganisms and their negative consequences. However, to ensure their own future (7), these receptors have assumed additional responsibilities and, in a polygamous fashion, now serve as the critical link between the cell and a broad range of endogenous and exogenous ligands, including fibronectin, oxidized low-density lipoprotein, and hyaluronin. While many of these innate immune polymorphisms were discovered because of their adverse effects on host defense, one could reasonably hypothesize that their preservation in human evolution was based on survival advantages that were realized through other receptor–ligand interactions. These trade-offs and evolutionary pressures are best illustrated for TLR4, in which the prevalence of the TLR4_Asp299Gly in Africa, Asia, and Europe appears to be directly related to the type of microbial stress (8). However, this is also likely to be valid for other TLRs and may prove relevant to the discovery made by Wurfel and colleagues (1). On the basis of this line of reasoning, one can imagine that the TLR1 polymorphisms shown to be detrimental in gram-positive sepsis may prove advantageous in other diseases or populations.

Why is this body of work so special?
While the scientific findings offered by Wurfel and associates substantially advance our understanding of innate immunity, the approach used by these investigators should be carefully considered by those interested in genomic research. This one article illustrates all of the important tenants of rigorous translational genomic research, and particularly using the genome to integrate basic biology with the clinical sciences to address a problem that is profoundly important to our patients and their families. The special feature of this study is the interdisciplinary approaches used to develop a biology-driven phenotype and identify an associated innate immune SNP (broad-based screening of peripheral blood innate immune responsiveness), the discovery of associated amino acid changing polymorphisms in TLR1 (bioinformatics), the biological consequences of these polymorphisms (cloning, site-directed mutagenesis, transfection, and cell surface receptor detection of TLR1), and evaluation of the clinical relevance of these TLR1 SNPs in two independent populations (clinical relevance through collaboration). The interdisciplinary approaches represented in this article are independent approaches that all intersect on TLR1 to demonstrate its importance in determining who becomes septic from gram-positive organisms and how sick they become. These are the types of approaches we need to incorporate into our research to effectively translate the genome into clinically meaningful advances at the bedside.

The research tools and collaborations that are available to us at this point in time are unprecedented. But, like the double-edged sword of innate immunity, these tools and opportunities raise the scientific bar and require that our genetic and genomic studies move beyond mere association, and include fundamental approaches that shed light on the biology and the phenotypes that underlie such associations. I applaud the authors for showing us the path forward.

FOOTNOTES

Conflict of Interest Statement: D.A.S. has a patent on TLR4 variants and has received royalties from MedImmune.

REFERENCES

1. Wurfel MM, Gordon AC, Holden TD, Radella F, Strout J, Kajikawa O, Ruzinski J, Rona G, Black RA, Stratton S, et al. Toll-like receptor 1 polymorphisms affect innate immune responses outcomes in sepsis. Am J Respir Crit Care Med 2008;178:710–720.[Abstract/Free Full Text]
2. Lorenz E, Mira J, Cornish K, Arbour N, Schwartz D. A novel polymorphism in the toll-like receptor 2 gene and its potential association with staphylococcal infection. Infect Immun 2000;68:6398–6401.[Abstract/Free Full Text]
3. Arbour NC, Lorenz E, Schutte B, Zabner J, Kline J, Jones M, Frees K, Watt JL, Schwartz DA. Tlr4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet 2000;25:187–191.[CrossRef][Medline]
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5. Khor CC, Chapman SJ, Vannberg FO, Dunne A, Murphy C, Ling EY, Frodsham AJ, Walley AJ, Kyrieleis O, Khan A, et al. A mal functional variant is associated with protection against invasive pneumococcal disease, bacteremia, malaria and tuberculosis. Nat Genet 2007;39:523–528.[CrossRef][Medline]
6. Picard C, Puel A, Bonnet M, Ku CL, Bustamante J, Yang K, Soudais C, Dupuis S, Feinberg J, Fieschi C, et al. Pyogenic bacterial infections in humans with IRAK-4 deficiency. Science 2003;299:2076–2079.[Abstract/Free Full Text]
7. Dawkins R. The selfish gene. New York: Oxford University Press; 2006.
8. Ferwerda B, McCall MB, Alonso S, Giamarellos-Bourboulis EJ, Mouktaroudi M, Izagirre N, Syafruddin D, Kibiki G, Cristea T, Hijmans A, et al. Tlr4 polymorphisms, infectious diseases, and evolutionary pressure during migration of modern humans. Proc Natl Acad Sci USA 2007;104:16645–16650.[Abstract/Free Full Text]

Related articles in AJRCCM:

Toll-like Receptor 1 Polymorphisms Affect Innate Immune Responses and Outcomes in Sepsis

Mark M. Wurfel, Anthony C. Gordon, Tarah D. Holden, Frank Radella, Jeanna Strout, Osamu Kajikawa, John T. Ruzinski, Gail Rona, R. Anthony Black, Seth Stratton, Gail P. Jarvik, Adeline M. Hajjar, Deborah A. Nickerson, Mark Rieder, Jonathan Sevransky, James P. Maloney, Marc Moss, Greg Martin, Carl Shanholtz, Joe G. N. Garcia, Li Gao, Roy Brower, Kathleen C. Barnes, Keith R. Walley, James A. Russell, and Thomas R. Martin
AJRCCM 2008 178: 710-720. [Abstract] [Full Text]  

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