**4. Role of cytokine gene polymorphism in sepsis**

trauma has a multifactorial etiology, which can be divided in endogenous and exogenous factors [12]. The endogenous factors, such as genetic predisposition, form the basis of the patient's susceptibility for the development of organ failure. Recent studies have shown that genetic variations (e.g., TNF-α polymorphisms) are strongly associated with the development of organ failure [13]. The exogenous factors, such as injury itself (the "first hit" or "trauma load") and the resuscitation or surgical intervention (the "second hit" or "intervention load"), play a crucial role in the development of organ failure. Organ damage and subsequent organ

**3. Role of cytokines in development of sepsis-related complications**

Cytokines are low molecular weight polypeptides, and pharmacologically active molecules possess autocrine, paracrine, and juxtracrine effects [15]. These molecules are classified into several classes (i.e., interleukins, interferons, colony-stimulating factors, tumor necrosis factors,

**Figure 2.** The outcome of trauma patients depends on induced inflammatory response due to trauma such as migration of leukocytes, cellular activation, and effecter functions, which may subsequently depend on genetic background of

individuals.

failure are the result of dysfunctional immune system [11, 14].

44 Infectious Process and Sepsis

Cytokine gene polymorphism, therefore, is advocated as the underlying reason to distinguish individual specific immune responses. The cytokine gene polymorphism studies may be considered as powerful biomarkers for the identification of trauma patients who have higher risk to develop sepsis complications in the ICU [20, 21]. Therefore, understanding the associations between genetic polymorphisms and sepsis or MODS may lead to the better understanding of sepsis. Nowadays the significance of genetic variations [particularly single-nucleotide polymorphisms (SNPs)] as key determinants of inter-individual variations in both inflammatory responses and clinical outcome in trauma patients is advocated [13, 22]. Single-nucleotide polymorphisms are the key factors to regulate the expressional variation of human genes and found to be associated with the disease susceptibility and progression. To understand the importance of cytokine gene polymorphism (CGP) while predicting the occurrence of sepsis, the SNPs in the promoter, coding, and noncoding regions of 13 cytokine genes with 22 loci are commonly used. Single-nucleotide polymorphisms of 13 cytokine genes including interleukin IL-1-α (T/C-889), IL-1-β (-511 C/T, T/C + 3962), IL-1 RA (T/C mspal 1100), IL-4 RA (G/A + 1902), IL-4(T/G-1098, T/C-590, T/C-33), IL-6 (G/C-174, G/A nt560), IL-10 (G/C-1082, C/T-819, C/A-592), IL-12 (C/A-1188), γIFN (+874 A/T), TGF-β1(C/T codon 10, G/C codon 25), TNF α (G/A - 308, G/A-238), and IL-2(T/G-330 G/T + 166), to investigate the susceptibility towards sepsis in trauma patients, are commonly used. All the cytokine genes and their polymorphic loci which are commonly used to investigate the genetic basis of susceptibility towards disease are shown in **Table 1.** Various studies also showed the associations of these SNPs in the development of sepsis and outcomes. The polymorphic loci in the promoter region of TNF-α-308 and TNF-α-238 have been reported by various studies and showed susceptibility and resistance between populations [23, 24]. These two polymorphisms are well recognized and associated with susceptibility for tuberculosis, heart disease, and Graves' disease [25–27]. The interleukin 6 is an important cytokine and plays a very important role in the activation of T17 cells. The polymorphisms in the promoter region of IL-6 (174 G/C) and structural region (+560) are well characterized in various diseases. However, the polymorphism in the promoter regions (174G/C) showed significant association with celiac disease, bowel syndrome, cancer, and autoimmunity [28–31]. Interestingly, the polymorphism in the promoter region of IL-6 (174 G/C) influenced the immunopathogenesis of sepsis and associated with outcomes in European population of trauma [32, 33]. We have also reported the association of IL-6 (174 G/ C) polymorphism and susceptibility of sepsis in the Indian trauma patients [34]. IL-10 is an important anti-inflammatory cytokine and plays a very crucial role in the inflammation, autoimmunity, and tolerance. Many studies suggested that elevated level of IL-10 activates the transcription factor Fox P3 which may subsequently lead to the production T regulatory cells. Polymorphism in the promoter regions of IL-10 gene 1082(G/A), 819(C/T), and 592 (C/A) is well established and showed significant association with various infectious diseases, autoimmunity, cancer D, and diabetic retinopathy [35–37]. These IL-10 promoters, 1082(G/ A), 819(C/T), and 592(C/A) polymorphisms, are associated with resistance to sepsis in the Caucasian population [38, 39]. Interleukin (IL-1) gene complex consists of IL-1α, IL-1β, IL-1R, and IL-RA genes with five potent polymorphic loci in the structural and promoter regions [40]. These polymorphic loci are associated with susceptibility for sepsis in trauma patients of the Chinese population [41, 42] and also associated with other diseases, such as cancer and autoimmunity [43, 44]. In our study, we have reported the changes in alleles and genotype frequency at the promoter region of IL-1β (511) gene. We have also reported the significant association of this polymorphism with susceptibility for sepsis in Indian trauma patients. The recently published work by Gupta et al., 2016, showed that polymorphisms in the structural and promoter regions of TNF-α, IL-β, IL-6, and IL-10 are significantly associated with susceptibility to sepsis and outcomes in trauma patients [34] (**Figure 3**).


**Table 1.** Twenty-two single-nucleotide polymorphism in 13 cytokine genes including structural and coding regions.

Cytokine Gene Polymorphism and Sepsis http://dx.doi.org/10.5772/intechopen.90572 47

**Figure 3.** This figure shows the cytokine genes and its polymorphic loci present in the structural and promoter regions

which are significantly involved in susceptibility for sepsis, septic shock, and death.


populations [23, 24]. These two polymorphisms are well recognized and associated with susceptibility for tuberculosis, heart disease, and Graves' disease [25–27]. The interleukin 6 is an important cytokine and plays a very important role in the activation of T17 cells. The polymorphisms in the promoter region of IL-6 (174 G/C) and structural region (+560) are well characterized in various diseases. However, the polymorphism in the promoter regions (174G/C) showed significant association with celiac disease, bowel syndrome, cancer, and autoimmunity [28–31]. Interestingly, the polymorphism in the promoter region of IL-6 (174 G/C) influenced the immunopathogenesis of sepsis and associated with outcomes in European population of trauma [32, 33]. We have also reported the association of IL-6 (174 G/ C) polymorphism and susceptibility of sepsis in the Indian trauma patients [34]. IL-10 is an important anti-inflammatory cytokine and plays a very crucial role in the inflammation, autoimmunity, and tolerance. Many studies suggested that elevated level of IL-10 activates the transcription factor Fox P3 which may subsequently lead to the production T regulatory cells. Polymorphism in the promoter regions of IL-10 gene 1082(G/A), 819(C/T), and 592 (C/A) is well established and showed significant association with various infectious diseases, autoimmunity, cancer D, and diabetic retinopathy [35–37]. These IL-10 promoters, 1082(G/ A), 819(C/T), and 592(C/A) polymorphisms, are associated with resistance to sepsis in the Caucasian population [38, 39]. Interleukin (IL-1) gene complex consists of IL-1α, IL-1β, IL-1R, and IL-RA genes with five potent polymorphic loci in the structural and promoter regions [40]. These polymorphic loci are associated with susceptibility for sepsis in trauma patients of the Chinese population [41, 42] and also associated with other diseases, such as cancer and autoimmunity [43, 44]. In our study, we have reported the changes in alleles and genotype frequency at the promoter region of IL-1β (511) gene. We have also reported the significant association of this polymorphism with susceptibility for sepsis in Indian trauma patients. The recently published work by Gupta et al., 2016, showed that polymorphisms in the structural and promoter regions of TNF-α, IL-β, IL-6, and IL-10 are significantly associated with suscep-

46 Infectious Process and Sepsis

tibility to sepsis and outcomes in trauma patients [34] (**Figure 3**).

**Table 1.** Twenty-two single-nucleotide polymorphism in 13 cytokine genes including structural and coding regions.

**Figure 3.** This figure shows the cytokine genes and its polymorphic loci present in the structural and promoter regions which are significantly involved in susceptibility for sepsis, septic shock, and death.
