Genetic Polymorphisms and Posttraumatic Complications

Table 1

Effects of gene polymorphisms on sepsis or MODS.

Gene	Chrome location	Variation	Study size	Functional effects	Clinical effects on sepsis or MODS	Reference
Pattern-recognition receptors
TLR1	4p14	−7202A/G (rs5743551)	999	Cytokine production and TLR1 expression	Sepsis, organ dysfunction and death (ODD), sepsis related acute lung injury (ALI)	[24]
		I602S		IL-6 production and NF-κB signalling		[25]
TLR2	4q32	−16933T/A	252		increased prevalence of sepsis and with Gram-positive bacteria	[15]
		Arg753Thr	91	staphylococcal infections	Association with Gram-positive infection	[14, 15]
		19216T/C (rs3804099)	410	Cytokine production	Association with sepsis	[16]
TLR4	9q33. 1	896A/G	598		Association with decreased risk of complicated sepsis	[26]
		Asp299Gly, Thr399Ile	307/319/116		sepsis; Gram-negative septic shock; Conflicting results	[27–29]
		−2242T/C	303	Cytokine production and promoter activity	Association with sepsis and MODS	[17]
		11367G/C	132	gene expression	Association with sepsis and MODS	[18, 19]
LBP	20q11.23	Cys98Gly, Pro436Leu and 1683T/C	454/1215	higher median basal serum LBP levels	Gender-specific association with sepsis. Bacteraemia after stem cell transplantation and death from Gram-negative bacteraemia	[22, 23]
CD14	5q31.1	−159C/T(−260C/T), −1145G/A	293/85/319/; 116/252/430	higher monocyte mCD14, but not sCD14 expression	higher mortality; higher sepsis morbidity. Conflicting results	[15, 21, 28–32]
MD-2	8q21.11	103G/A; (Thr35Ala)	20		Decreased cytokine release. No influence on sepsis studied	[33]
		−1625C/G	105	MD-2 promoter activity, MD-2 expression	Association with sepsis and MODS after trauma	[20]
Signal transduction
IRAK-4	12q12	877C/T, 620-621/AC deletion	1	IRAK-1 kinase activity	Severe infections in childhood	[34]
IRAK-1	Xq28	1595T/C (haplotype)	155	nuclear levels of NF-κB	Increased mortality in sepsis	[35]
TIRAP/Mal	11q24.2	Ser180Leu (rs8177374)	6106		Heterozygous carriers associated with infectious disease	[36]
IκB	14q13	rs3138053, rs2233406	1060		Association with invasive pneumococcal	[37]
Cytokines
IL-1α	2q14	46 bp VNTR			No association with sepsis	[38]
IL-1β	2q14	−31C/T, −511C/T	60/276/238	Higher production of IL-1β	Association with sepsis; Higher mortality in homozygous carriers with meningococcal sepsis. Conflicting results	[38–41]
IL-1RN	2q14.2	intron 2, VNTR	78		Higher mortality in homozygous carriers	[38, 42]
IL-6	7p21	−174G/C	69/288/293	Baseline of C-reactive protein	C-allele confers increased risk of shock	[30, 43–45]
		−572C/G	453	IL-6 production from leukocytes after LPS ex vivo	Sepsis in major trauma patients	[46]
IL-10	1q31-32	−592C/734G/3367G, −1082G/A	550/33	interleukin-10 production	Association with sepsis from pneumonia, increased mortality in severe sepsis	[47–51]
TNFα	6p21.3	−308G/A	1321/197		Association not clear. Early studies suggest higher risk when homozygous	[52–60]
TNFβ	6p21.3				Association not clear	[56]
IFN-γ	12q14	CA repeat	61		Association with sepsis	[61]
MIF	22q11.23	−173G/C, −794 CATT repeat		MIF RNA and protein levels from mononuclear cells stimulated with bacteria	Influence on sepsis in African–Americans	[62]
Coagulation system
PAI-1	7q21.3-q22	4G/5G	50	Increased gene transcription in cell lines in vitro and with increased PAI-1 concentrations in carriers in vivo	Higher rate of septic shock in meningitis	[63]
TAFI	13q14.11	Thr325Ile	50		Higher risk of death in meningitis	[64]
Factor V	1q23	R506Q	3894		Smaller risk of sepsis (heterozygous)	[65]
Fibrinogen	4q28	−854G/A, −455G/A, and +9006G/A. −148C/T	631/73	higher fibrinogen levels	Haplotype GAA was associated with a significantly lower 28-day mortality	[66, 67]