Th1/Th2 cytokines and their genotypes as predictors of hepatitis B virus related hepatocellular carcinoma

Table 1 Cytokines involved in hepatitis B virus - hepatocellular carcinoma risk

Cytokine genes	Physiological function	Role in viral clearance/persistence	SNP analyzed	Disease association
IL-1	Proinflammatory	Viral clearance	IL-1B (-511 C > T)	NS[28,29,31]; risk[30]
			IL-1RN (VNTR)	Risk[28]; protection[29];
			Intron 2	NS[30,31]
			IL-1 haplotypes	Protection[28]
IL-6	Pro- as well as anti-inflammatory	Both	-572 C > G	Protection[38]; NS[39]
			-597 G > A	Protection[38]
			IL-6 haplotypes	Risk[38]
IFN-γ	Proinflammatory	Viral clearance	+874 T > A	Protection[42]; NS[43]
IL-10	Anti-inflammatory	Viral persistence	-819 C > T/-592 C > A	Risk[49]; NS[50]
			IL-10 haplotypes	NS[49,51]
IL-12B	Proinflammatory	Viral clearance	+1188 A > C 3’UTR	NS[50,54,55]
TNF-α	Proinflammatory	Viral clearance	-308 G > A	NS[42,60]; risk[59]
TGF-β1	Pro- as well as anti-inflammatory	Both	-509 C > T	Risk[54]; protection[54,70,71]
IL-2	Proinflammatory	Viral clearance	-330 T > G	NS[50,54,77]; risk[78]
IL-4	Anti-inflammatory	Viral persistence	-590 C > T	Protection[54]; NS[50]

NS: Non-significant; TNF-α: Tumor necrosis factor-α; IL: Interleukin; TGF-β: Transforming growth factor-β; VNTR: Variable number tandem repeat; IFN-γ: Interferon-γ; 3’UTR: 3’ untranslated region.

Table 2 Association of various cytokine genotypes in progression of hepatitis B infection

Cytokine genes	OR (95%CI)					Ref.
	Control	Inactive HBV-carrier	Chronic-active HBV	HBV-cirrhotic	HBV-HCC
IL-1RN (VNTR) 1/2	1 (REF)	0.45a (0.2-1)	2.70b (1.3-5.3)	2 (1-4)	1.90 (1-4)	[28]
	-	1 (REF)	5.80h (2.5-13.4)	4.20f (1.8-10)	4.12f (1.7-10)
IL-6 (-572 G > C) GC	1 (REF)	3.98b (1.5-10.2)	2.50a (1.1-6)	0.94 (0.4-2)	0.75 (0.3-1.7)	[38]
	-	1 (REF)	0.63 (0.2-2)	0.24f (0.1-0.7)	0.20f (0.06-0.6)
CC	1 (REF)	1.8 (0.6-5.6)	2.54a (1.05-6.2)	0.40a (0.16-1)	1.50 (0.6-3.8)
	-	1 (REF)	1.30 (0.3-5)	0.20c (0.01-0.6)	0.83 (0.2-3.2)
IL-6 (-597 G > A) GA	1 (REF)	8.65d (3-25)	0.52 (0.2-1.2)	0.63 (0.3-1.5)	2.1 (0.7-6.4)
	-	1 (REF)	0.06h (0.02-0.2)	0.07h (0.03-0.2)	0.22c (0.06-0.8)
IFN-γ(+874 T > A) TA	1 (REF)	2.20 (0.6-8)	0.34b (0.14-0.8)	0.56 (0.24-1.3)	0.39a (0.17-0.85)	[42]
AA	1 (REF)	0.65 (0.26-1.7)	0.78 (0.34-1.8)	0.62 (0.26-1.5)	0.31b (0.13-0.72)
IL-10 (-819 C > T/-592 C > A)	1 (REF)	4.34d (1.83-10.3)	ND	2.02a (1-4.1)	2.20a (1.05-4.5)	[49]
IL-12B (+1188 A > C 3’UTR) CC	1 (REF)	1.44 (0.5-4.1)	3.30b (1.3-8)	1.3 (0.5-3.8)	1.80 (0.6-5.3)	[54]
TGF-β1 (-509 C > T) CT	1 (REF)	4.70d (1.8-12)	2.20a (1-4.5)	2.81b (1.3-5.8)	2.10a (1-4.2)
TT	1 (REF)	15.42d (5-47.6)	5.87d (2.2-15.7)	1.50 (0.4-4.8)	3.72b (1.4-10)
	-	1 (REF)	0.38 (0.13-1.1)	0.10h (0.03-0.3)	0.24f (0.1-0.7)
IL-4 (-590 C > T)	1 (REF)	2.26b (1.2-4.2)	0.40b (0.2-0.7)	0.70 (0.38-1.27)	1.65 (0.9-3)

OR: Odd ratio adjusted with age, sex, bilirubin, total protein, A/G, aspartate transaminase, alanine transaminase, alkaline phosphatase; ND: Not determined due to a single subject having this genotype.

^aP < 0.05,

^bP < 0.01,

^dP < 0.001 with respect to control;

^cP < 0.05,

^fP < 0.01,

^hP < 0.001 with respect to inactive HBV-carrier. HBV: Hepatitis B virus; IFN-γ: Interferon-γ; IL: Interleukin; TGF-β: Transforming growth factor-β; HCC: Hepatocellular carcinoma.