Role of genetic polymorphisms in hepatitis C virus chronic infection

Table 1 Studies on the role of the rs738409PNPLA3 polymorphisms in hepatitis C virus chronic infection

Ref.	No. of	Country	Type of study	Liver disease	Outcome (GG vs GC + CC)
	patients				Steatosis	Severe steatosis	Cirrhosis	SVR	HCC
Cai et al[98]	626	Switzerland	Cross-sectional	Chronic liver disease	OR = 1.880 (95%CI: 1.571-2.250)1	OR = 1.578 (95%CI: 1.331-1.870)12
Clark et al[101]	972	United States	Cross-sectional	Chronic liver disease	OR = 1.62 (95%CI: 1.22-2.14)3	OR = 1.78 (95%CI: 1.40-2.27)34		No association (P = 0.294)3
Dunn et al[103]	101	United States	Cohort	Liver transplantation recipients and donors			HR = 2.53, (95%CI: 1.28-5.02)56
Guyot et al[105]	253	France	Cohort	Cirrhosis				No association (P = 0.5)7	No association (P = 0.5)
Nakamura et al[102]	260	Japan	Cross-sectional	37 Cirrhosis 223 Chronic hepatitis	No association (P = 0.935)8		No association (P = 0.876)8
Nischalke et al[104]	162	Germany	Case-control	Cirrhosis					No association (P = 0.386)
Trépo et al[96]	537	Belgium, Germany, France	Cross-sectional	Chronic liver disease		OR = 2.84 (95%CI: 1.22-6.60)2	OR = 2.43 (95%CI: 1.24-4.78)9
Valenti et al[97]	819	Italy	Cross-sectional/case-control	548 Chronic hepatitis 215 Cirrhosis 56 HCC	OR = 1.90 (95%CI: 1.39-2.73)	OR = 2.09 (95%CI: 1.62-2.67)4	OR = 1.47 (95%CI: 1.15-1.87)	OR = 0.63 (95%CI: 0.44-0.86)10	OR = 2.16 (95%CI: 1.33-3.59)11
Zampino et al[99]	166	Italy	Cross-sectional	Chronic hepatitis	Mean steatosis score GG: 1.94 ± 1.6, CG: 1.25 ± 1.2, CC: 1 ± 1.1, P < 0.05

¹GG + GC vs CC non-genotype 3;

²Steatosis > 5%;

³Rs2896019 GG + GT vs TT genotype 1;

⁴Steatosis > 32%;

⁵GG + GC vs CC donors;

⁶Occurrence of Ishak staging ≥ 3, acute cellular rejection, chronic rejection or fibrosing cholestatic hepatitis during a 620-d (IQR 317-975) follow-up;

⁷226 patients;

⁸GG+GC vs CC, United States diagnosis of steatosis and cirrhosis;

⁹F3 or F4;

¹⁰470 patients;

¹¹325 patients. SVR: Sustained viral response; HCC: Hepatocellular carcinoma.

Table 2 Studies on the role of inosine triphosphate pyrophosphatase polymorphisms in hepatitis C virus chronic infection

Ref.	No. ofpatients	Country	Type of study	SNPs	Liver disease/HCV genotype	Therapy	Outcome
Thompson et al[30]	304	United States	Retrospective	rs1127354 rs7270101	CHC/1	Peg-IFN-α-2a + RBV	Hb reduction > 3 g/dL at week 4 ITPase deficiency (both SNPs): OR = 0.26, 95%CI: 0.15-0.4; P = 2.7 × 10-7
Eskesen et al[128]	457	Norway	Retrospective	rs1127354 rs7270101	CHC/2/3	Peg-IFN-α-2b + RBV	Patients with any degree of reduced ITPAase activity were less likely to have their RBV dose reduced: OR = 0.39, 95%CI: 0.16-0.96, P = 0.040
Seto et al[129]	60	Hong Kong	Prospective	rs1127354	CHC/6	Peg-IFN + RBV	ITPA rs1127354 CA vs CC genotype: lesser degree of anemia throughout therapy P < 0.05 for all time points
Hai et al[122]	66	Japan	Retrospective	rs1127354	CHC/1	Peg-IFN + RBV	At multiple regression analysis, age < 60 yr, ITPA CA/AA genotype and serum RBV concentration were significant independent predictive factors for SVR
Thompson et al[116]	238	United States	Retrospective	rs1127354 rs7270101	CHC/2/3	PegIFN-α-2b + RBV	Hb reduction at week 4 ITPase deficiency (both SNPs): P = 10(-11) There was no association between the ITPA variants and SVR
Ahmed et al[123]	102	Egypt	Prospective	rs1127354	CHC 1/4	Peg-IFN + RBV	CC patients had more frequently Hb decline > 3 g/dL than non-CC patients at weeks 8 and 12 (P = 0.024 and 0.038, respectively) Reduction of the amount of the planned RBV dose was significantly higher for CC patients than non-CC patients during the first 12 wk (18% ± 12.1% vs 8.5% ± 10.2%, P = 0.021)
Azakami et al[124]	830	Japan	Retrospective	rs1127354	CHC/1	Peg-IFN + RBV	Cumulative reduction of ribavirin was significantly more frequent in genotype CC patients than non-CC patients (OR = 1.928, P = 8.6 × 10-8)
Kurosaki et al[125]	446	Japan	Prospective	rs1127354	CHC/1	Peg-IFN + RBV	ITPA AA/CA had the lowest incidence of anemia (17%)
Matsuura et al[126]	309	Japan	Retrospective	rs1127354	CHC/1	Peg-IFN + RBV	The incidence of severe anemia, ≥ 3 g/dL reduction or < 10 g/dL of Hb up to week 12 was more frequent in patients with CC (65% and 33%) than in those with CA/AA (25%, 6%); P < 0.0001)
Rau et al[130]	216	Switzerland	Retrospective	rs1127354 rs7270101	CHC Mixed genotype	Peg-IFN + RBV	ITPA SNP rs1127354 was associated with Hb drop ≥ 3 g/dL during treatment (RR = 2.1, 95%CI: 1.3-3.5)
Clark et al[131]	193	Australia	Retrospective	rs1127354 rs7270101	CHC Mixed genotype	Peg-IFN + RBV	More severe ITPA deficiency was associated with a lesser reduction in Hb level (P < 0.001), lesser ribavirin dose reduction (P = 0.005), lesser EPO use (P = 0.029) ITPA deficiency was associated with SVR (P = 0.041)
Rembeck et al[132]	354	Sweden	Prospective	rs1127354 rs7270101	CHC/2/3	Peg-IFN + RBV	Reduced ITPase activity was associated with a decreased risk of anemia (P < 0.0001), increased risk of thrombocytopenia (P = 0.007), and lower ribavirin concentrations (P = 0.02)
D'Avolio et al[127]	167	Italy	Retrospective	rs1127354 rs7270101	CHC/1	Peg-IFN + RBV	Both SNPs were associated with Hb decrease. The carrier of at least one variant in the ITPA was associated with a lower decrease of Hb (-1.1 g/dL), compared to patients without (-2.75 g/dL; P = 4.09 × 10)
Suzuki et al[133]	61	Japan	Retrospective cohort study	rs1127354	CHC/1	Peg-IFN + RBV + telaprevir	Decreases in Hb levels were greater in patients with CC than CA/AA genotypes at week 2 (-1.63 ± 0.92 g/dL vs -0.48 ± 0.75 g/dL, P = 0.001), week 4 (-3.5 ± 1.1 vs -2.2 ± 0.96, P = 0.001) and at the end of treatment (-2.9 ± 1.1 vs -2.0 ± 0.86, P = 0.013)
Ogawa et al[134]	292	Japan	Prospective, multicenter study	rs1127354	CHC/1	Peg-IFN + RBV + telaprevir	Pretreatment predictors of the development of severe anemia: baseline Hb < 135 g/L (HR = 2.53; P = 0.0013), estimated glomerular filtration rate < 80 mL/min per 1.73 m2 (HR = 1.83; P = 0.0265), ITPA CC genotype (rs1127354) (HR = 2.91; P = 0.0024)
Aghemo et al[135]	69	Italy	Retrospective cohort study	rs1127354 rs7270101	CHC/1	Peg-IFN + RBV + telaprevir	During the first 12 wk of TPV triple therapy: grade 3-4 anemia developed in 81% non-ITPA deficient patients vs 67% mildly deficient and 55% moderately deficient patients (P = NS); RBV dose reduction in 60% with no deficiency, 58% with mild, 67% with moderate deficiency (P = NS); Erythropoietin use in 65% with no deficiency, 58% with mild, 56% with moderate (P = NS); need for blood transfusion in 27% with no deficiency, 17% with mild, 33% with moderate (P = NS)

CHC: Chronic hepatitis C; Hb: Hemoglobin; RBV: Ribavirin; Peg-IFN: Peg-Interferon; SNP: Single nucleotide polymorphism; NS: Not significant.

Table 3 Studies on the role of the polymorphisms influencing the vitamin D metabolism in hepatitis C virus chronic infection

Ref.	No. of	Country	Type of	Liver disease	Polymorphism	Outcome
	patients		study			Cirrhosis	SVR	HCC
Baur et al[142]	155	Switzerland	Cross-sectional	Chronic hepatitis	rs7975232		OR = 2.67 (95%CI: 1.24-5.70)14
					rs731236		OR = 6.05 (95%CI: 1.71-21.43)24
					rs1544410		No association (P = 0.085)
					CC/CC/AA3		OR = 2.50 (95%CI: 1.07-5.87)4
Baur et al[143]	223	Switzerland	Cross-sectional	185 chronic hepatitis	rs7975232	2.67 (95%CI: 1.29-5.51)1
				38 cirrhosis	rs731236	No association
					rs1544410	No association
					CC/CC/AA3	2.54 (95%CI: 1.07-6.01)
Falleti et al[141]	206	Italy	Cross-sectional	Chronic liver disease	rs7041 rs4588		OR = 0.164 (95%CI: 0.056-0.482)5
Falleti et al[140]	206	Italy	Cross-sectional	Chronic liver disease	rs10741657		1.778 (95%CI: 1.135-2.788)6
					rs7041		No association (P = 0.679)
					rs4588		No association(P = 0.458)
					rs10877012		No association (P = 0.422)
					VDPFA7		OR = 2.30 (95%CI: 1.02-5.22)8
García-Martín et al[144]	238	Spain	Cross-sectional	169 chronic hepatitis	rs2228570		0.438 (95%CI: 0.204-0.882)49
				33 cirrhosis	CC/CC/AA3		2.743 (95%CI: 1.313-5.731)4
				36 not assessed
Lange et al[139]	110	Germany	Case-control	Chronic liver disease	rs10877012		10/13 AA vs 27/41 AC and 24/56 CC (P < 0.05)
Lange et al[162]	5604	Germany, Switzerland, Japan	Case-control/retrospective cohort	1279 HCC	rs2282679			OR = 1.56 (95%CI: 1.12-2.15)10
				4325 chronic liver disease	rs7944926			OR = 1.56 (95%CI: 1.13-1.78)11
					rs1993116			No association (P = 0.07)12
								HR = 1.81 (95%CI: 1.03-3.13)13

¹CC vs CA + AA;

²AA + AG vs GG;

³CCA haplotype comprises rs1544410 (BsmI) C, rs7975232 (ApaI) C and rs731236 (TaqI) A alleles of VDR gene;

⁴OR for non-SVR;

⁵OR for non-SVR in WT vs non-WT; WT were patients carrying ≥ 3 major alleles (GG/CC, GT/CC and GG/CA);

⁶GG + GC vs CC;

⁷VDPFA (Vitamin D Pathway Functional Alleles) was constructed giving a value of 1 to the functional allele of each gene and a value of 0 to the other alleles. Thus, for each patient a VDPFA value ranging from 0 to 8 was obtained;

⁸VPDFA > 5 vs≤ 5;

⁹TT + TC vs CC;

¹⁰TT + TG vs GG, 2534 patients;

¹¹TT vs TC + CC, 2420 patients;

¹²5591 patients;

¹³GG vs GA + AA, 1657 patients. SVR: Sustained viral response; HCC: Hepatocellular carcinoma.

Table 4 Role of other single nucleotide polymorphisms in hepatitis C virus infection

Ref.	Gene	SNPs/haplotypes	Important results
	CRS (7 genes):
Huang et al[145]	AZIN1	rs62522600	The Cirrhosis Risk Score was evaluated both in retrospective and prospective studies and appeared to be a useful predictor of fibrosis progression in patients with mild chronic hepatitis C, even in special populations (i.e., liver transplant recipients or HIV-HCV coinfected patients)
Marcolongo et al[146]	TLR4	rs4986791
Trépo et al[148]	TRMP5	rs886277
Curto et al[147]	AP3S2	rs2290351
do O et al[150]	B008027	rs4290029
Fernández-Rodríguez et al[149]	AQP2	rs2878771
	STXBP5	rs17740066
Nattermann et al[152]	IL-6	rs1800795	The CC genotype was associated with lower plasma levels of IL-6 and seemed to correlate with higher SVR rate and lower grading and staging, although the data from the literature are discordant, probably due to the heterogeneity of the study populations (i.e., different virological and clinical characteristics, HIV-coinfection, etc.)
Yee et al[151]
Falleti et al[153]
Cussigh et al[154]
Khakoo et al[156]	KIR-HLA	KIR2DL3/HLAC1	The association between KIR2DL3 and HLAC1 appeared to be related to both a spontaneous and treatment-induced resolution of HCV infection
Knapp et al[157]
Huang et al[145]	IFNγ	rs2069707	The C764G polymorphism seemed to be associated with a higher SVR rate and a more frequent spontaneous viral clearance
Hellier et al[163]	CCR5	CCR5Δ32	The CCR5Δ32 deletion, which was associated with resistance to HIV infection, seemed to correlate with lower spontaneous clearance of HCV and milder inflammation and fibrosis, although the data from the literature are discordant
Nattermann et al[164]
Goulding et al[165]
Coppola et al[158]	CNR2	rs35761398	The CB2-65 QQ genotype was associated with the PNALT status in chronic HCV infection, but also with a higher HAI
Coppola et al[159]

PNALT: Persistently normal alanine-amino-transferase; HAI: Histological activity index; SVR: Sustained viral response; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; IL- 6: Interleukin-6; SNPs: Single nucleotide polymorphisms.