Genetic Variation in the Inflammatory Response

Inflammation drives the development or severity of a large number of diseases (e.g., atherosclerosis, asthma, ulcerative colitis, postmenopausal osteoporosis, sleep disorders). Variation in genes that encode proteins regulating inflammation may underlie a large proportion of interindividual variation in susceptibility to numerous diseases. Furthermore, variation in the production or function of cytokines can cause variation in inflammatory responses that in turn influences the progression of inflammatory disease.

Examples of genetic variation in inflammation are abundant. For example, a single nucleotide polymorphism in the human caspase-12 proenzyme confers hyporesponsiveness to LPS-stimulated cytokine production that manifests clinically as increased susceptibility to severe sepsis and mortality (Saleh et al. 2004). Similarly, a polymorphism in TNF-a promoter region is associated with increased TNF-a production in response to LPS and increased risk of sepsis-related morbidity and mortality (Bessler, Osovsky, and Sirota 2004; Hartel, von Puttkamer, Gallner, Strunk, and Schultz 2004; Lorenz, Mira, Frees, and Schwartz 2002; Strunk and Burgner 2006), an IL-6 polymorphism is associated with higher risk of bacterial sepsis (Heesen, Kunz, Bachmann-Mennenga, Merk, and Bloemeke 2003), and certain IL-1ß polymorphisms correlate with susceptibility to Helicobacter pylori infection and gastric cancer, Alzheimer's disease, and possibly rheumatoid arthritis (Cantagrel et al. 1999; El Omar, Chow, Mccoll, Fraumeni, and Rabkin 2000; Hamajima et al. 2001; Mcgeer and Mcgeer 2001). Receptors for inflammatory mediators also show genetic variation. For example, toll-like receptor 4 (TLR4), which mediates the effects of LPS, has two missense single nucleotide polymorphisms are associated with differences in susceptibility to sepsis (Agnese et al. 2002; Barber, Aragaki, Rivera-Chavez, Purdue, Hunt, and Horton 2004; Child et al. 2003).

The impact of genetic variation on the inflammatory response is perhaps best illustrated in mice. C3H/HeJ mice, for example, are hyporesponsive to Escherichia coli LPS because they bear a mutation in the TLR4 gene that is not present in related strains (e.g., C3H/HeOuJ and C3H/HeN) (Qureshi et al. 1996; Vallance, Deng, Jacobson, and Finlay 2003). The cytokine responses (TNF-a, IL-1, IL-6) of C3H/HeJ mice treated with LPS are similar those of in humans with TLR4 mutations (Kuhns, Priel, and Gallin 1997; Poltorak et al. 1998). As a second example, C57BL/6J and A/J mice injected with LPS demonstrate different numbers of infiltrating polymorphonuclear leucocytes (PMN) in liver and lungs, serum levels of IL-1P and IL-6 are higher in C57BL/6J mice than in A/J mice, A/J mice have higher levels of TNF-a, and mortality is higher in the C57BL/6J strain (De Maio, Mooney, Matesic, Paidas, and Reeves 1998). In contrast to LPS, A/J mice are far more susceptible to infection with C. albicans than are C57BL/6J mice (Marquis, Montplaisir, Pelletier, Auger, and Lapp 1988; Tuite, Elias, Picard, Mullick, and Gros 2005). Genetic variation in the sensitivity and immune responses of different mouse strains to microbial challenge is a likely factor in the changes in vigilance associated with infectious and inflammatory disease.

In considering the genetics of inflammation and its relationship to disease, three questions warrant attention: (a) will identified polymorphisms significantly impact the inflammatory process, (b) will the impact on inflammation be clinically relevant, and (c) does genetic information suggest therapeutic measures that may reduce clinical morbidity and mortality (Kornman 2006). Functional genetic polymorphisms in the cytokine response both under normal conditions and after inflammation may influence both the disease process and the sleep.

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