TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype

doi:10.3748/wjg.v22.i38.8509

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World J Gastroenterol. Oct 14, 2016; 22(38): 8509-8518
Published online Oct 14, 2016. doi: 10.3748/wjg.v22.i38.8509

Table 1 Initial characteristics of 167 patients with human immunodeficiency virus infection and chronic hepatitis C, according to the TM6SF variants

	TM6SF2 p. 167 E/K	TM6SF2 p. 167 E/E	P value
Patients, n	17	150
Age (yr)	42.6 (40.4-47.8)	40.3 (37.4-44.0)	0.04
Males	12 (70.6)	109 (72.7)	0.8
IVDU	8 (61.5)	95 (74.8)	0.2
BMI (kg/m²)	24.0 (22.0-25.0)	23.0 (21.3-25.0)	0.3
Glucose (mg/dL)	81.0 (75.0-87.0)	88.0 (81.0-98.0)	0.002
Bilirubin (mg/dL)	0.9 (0.7-1.2)	0.7 (0.5-1.0)	0.06
AST (IU/L)	108.0 (52.0-134.0)	59.0 (40.0-94.0)	0.02
ALT (IU/L)	141.0 (122.0-172)	81.5 (46.0-131.0)	0.02
Cholesterol (mg/dL)	144.0 (123.0-194.0)	164.0 (135.5-191.0)	0.4
Triglycerides (mg/dL)	136.0 (118.0-154.0)	125.5 (83.5-182.3)	0.6
GGT (IU/mL)	65.0 (46.0-95.0)	79.0 (39.0-165.0)	0.6
ALP (IU/mL)	192.0 (156.3-238.3)	186.5 (139.3-252.0)	0.9
HCV RNA (IU/mL), median	598679.0	601550.0	0.7
(IQR)	(140698.5-997750.0)	(202000.0-1432735.0)	0.7
Nadir of CD4⁺ cells/mm³	214.0 (153.0-380.0)	266.0 (176.3-413.3)	0.5
HIV RNA (cps/mL)	7638.0 (4112.5-19215.5)	10870.0 (3100.5-35374.4)	0.7
HIV RNA < 50 cps/mL	6 (35.3)	66 (44.0)	0.7
CD4⁺ cell/mmc	435.0 (380.0-650.0)	508.0 (399.3-670.0)	0.2
ART, treated	14 (82.3)	118 (78.7)	0.6
PI/r-NRTI-NNRTI	0	6 (5.3)
PI/r-NRTI	6 (46.1)	40 (35.1)
NRTI-NNRTI	2 (15.4)	30 (26.3)
PI-NRTI	0	7 (6.1)
NRTI	5 (38.5)	31 (27.2)
Therapy missing, n	1	4
Therapy-naïve	3 (17.6)	32 (21.3)
Duration of ART (yr)	7.7 (6.4-12.8)	8.0 (5.7-10.8)	0.3
Duration of HIV infection (yr)	17.4 (12.5-21.4)	14.0 (7.7-17.9)	0.05
HCV Genotype
1	5 (29.4)	57 (39.6)	0.3
2	1 (5.9)	7 (4.9)
3	6 (35.3)	62 (43.1)
4	5 (29.4)	18 (12.5)
Missing	0	6
HAI score	6.8 ± 2.9	5.8 ± 3.0	0.2
HAI: score 0-8	13 (76.5)	117 (78.0)	0.2
score 9-18	4 (23.5)	33 (22.0)	0.2
Fibrosis score	3.1 ± 2.0	2.3 ± 1.5	0.05
Degree of fibrosis
0	2 (11.8)	11 (7.3)	0.1
1	2 (11.8)	48 (32.0)
2	2 (11.8)	33 (22.0)
3	6 (35.3)	32 (21.3)
4	0	11 (7.3)
5	2 (11.8)	6 (4.0)
6	3 (17.6)	9 (6.0)
Steatosis score, mean ± SD	1.9 ± 1.2	1.7 ± 1.3	0.4
Degree of steatosis			0.8
0	3 (17.6)	45 (30.0)
1	3 (17.6)	19 (12.7)
2	4 (23.5)	37 (24.7)
3	6 (35.3)	40 (26.7)
4	1 (5.8)	9 (6.0)
PNPLA3
p. 148 I/I	9 (52.9)	79 (52.7)	0.7
p. 148 I/M	6 (35.3)	61 (40.7)
p. 148 M/M	2 (11.8)	10 (6.7)

Data represent as n (%), mean ± SD, or median (IQR). HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; BMI: Body mass index; HAI: Histological activity index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: γ glutamyl transferase; ART: Antiretroviral therapy; NRTIs: Nucleoside/nucleotide analogue reverse transcriptase inhibitors; NNRTIs: Non-nucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors; TM6SF2: Transmembrane 6 superfamily member 2; PNPLA3: Patatin-like phospholipase domain-containing 3 gene; IQR: Interquartile range.

Table 2 Initial characteristics of 167 patients with human immunodeficiency virus infection and chronic hepatitis C, according to the fibrosis score

	Fibrosis score 0-3	Fibrosis score 4-6	P value
Patients, n	136	31
Age (yr)	40.3 (37-44)	42.0 (39.5-46.7)	< 0.05
Males	96 (70.6)	25 (80.6)	0.1
BMI (kg/m²)	23 (21.2-24.9)	22.8 (21.7-26.5)	0.5
Glucose (mg/dL)	87.0 (80.0-95.0)	91.0 (81-102)	0.6
Bilirubin (mg/dL)	0.68 (0.4-1.0)	0.97 (0.7-1.5)	< 0.01
AST (IU/L)	55.0 (39-91)	96.0 (63.0-143.0)	0.0008
ALT (IU/L)	79.0 (44-131)	120.0 (67-180)	< 0.01
Cholesterol (mg/dL)	162 (137-194.0)	158 (116.8-177)	0.3
Triglycerides (mg/dL)	122.0 (84.0-164)	147.5 (55-227)	0.1
GGT (IU/mL)	70.0 (36.0-150)	108 (60.0-227.0)	0.2
ALP (IU/mL)	178.0 (136.0-239)	221 (182-269)	< 0.01
HCV RNA (IU/mL)	5.2e5 (1.8e5-1.4e6)	7e5 (2.3e5-1.7e6)	0.4
Nadir of CD4⁺ cells/mm³	271 (175.5-429.5)	238.0 (145.0-347.5)	0.1
HIV RNA (copies/mL)	10914.5	4500.0	0.1
HIV RNA (copies/mL)	(4402.3-31052.0)	(784.0-36959.0)	0.1
CD4⁺ cells/mm³	510.0 (403-708)	454.0 (338-586)	< 0.01
ART, Treated	105 (77.2)	27 (87.1)	0.4
PI/r-NRTI-NNRTI	6 (5.9)	0
PI/r-NRTI	35 (33.6)	11 (42.3)
PI-NRTI	6 (5.9)	1 (3.8)
NRTI-NNRTI	25 (24.8)	7 (26.9)
NRTI	29 (28.7)	7 (26.9)
Therapy missing, n	4	1
Therapy-naïve	31 (22.8)	4 (12.9)
Duration of ART (yr)	7.8 (5.4-10.9)	9.6 (6.3-12)	0.2
Duration of HIV infection (yr)	14.4 (7.5-18.1)	13.9 (8.4-17.4)	0.6
HCV Genotype
1	51 (38.9)	11 (3.7)	0.4
2	7 (5.3)	1 (0.4)
3	54 (41.2)	14 (46.7)
4	19 (14.5)	4 (13.4)
Missing, n	5	1
HAI score	5.0 ± 2.7	8.6 ± 2.3	< 0.0001
HAI
score 0-8	115 (84.6)	15 (48.4)	< 0.0001
score 9-18	21 (15.4)	16 (51.6)
Steatosis score	1.4 ± 1.2	1.9 ± 1.3	< 0.02
Degree of steatosis
0	44 (32.4)	4 (12.9)	0.0001
1	18 (13.2)	4 (12.9)
2	34 (25.0)	7 (22.6)
3	32 (23.55)	14 (45.2)
4	8 (5.9)	2 (6.5)
TM6SF
p. 167 E/K	12 (8.8)	5 (16.1)	< 0.03
p. 167 E/E	124 (91.2)	26 (83.9)
PNPLA3,
p. 148 I/I	75 (55.1)	13 (41.9)	0.2
p. 148 I/M	49 (36.1)	18 (58.6)
p. 148 M/M	12 (8.8)	0

Data represent as n (%), mean ± SD, or median (IQR). e: Elevated; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; BMI: Body mass index; HAI: Histological activity index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: γ glutamyl transferase; ART: Antiretroviral therapy; NRTIs: Nucleoside/nucleotide analogue reverse transcriptase inhibitors; NNRTIs: Non-nucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors; TM6SF2: Transmembrane 6 superfamily member 2; PNPLA3: Patatin-like phospholipase domain-containing 3 gene; IQR: Interquartile range.

Table 3 Initial characteristics of 167 patients with human immunodeficiency virus infection and chronic hepatitis C, according to the steatosis score

	Steatosis score 0-2	Steatosis score 3-4	P value
Patients, n	111	56
Age (yr)	40.3 (37.4-44.2)	41.8 (38.4-44.0)	0.3
Males	79 (71.2)	42 (75)	0.6
BMI (kg/m²)	22.8 (21.3-24.5)	23.9 (21.9-25.6)	0.03
Glucose (mg/dL)	85.5 (79.3-94.0)	92.5 (82.0-102.0)	0.004
Bilirubin (mg/dL)	0.6 (0.4-1.0)	0.8 (0.6-1.1)	0.01
AST (IU/L)	54.0 (38.3-79.0)	92.0 (55.8-142.3)	0.0004
ALT (IU/L)	67.0 (43.0-114.5)	129.0 (78.8-201.5)	0.00006
Cholesterol (mg/dL)	168.0 (141.0-196.5)	147.0 (120.0-174.0)	0.01
Triglycerides (mg/dL)	130.5 (84.0-188.5)	123.0 (87.0-156.0)	0.5
GGT (IU/mL)	70.0 (34.5-142.5)	97.0 (46.5-229.5)	0.04
ALP (IU/mL)	185.0 (138-240.3)	196.0 (147.5-265.0)	0.5
HCV RNA (IU/mL)	5.2e5 (1.5e5-1.4e6)	7.4e5 (2.4e5-1.4e6)	0.7
Nadir of CD4⁺ cells/mm³	272.0 (166.5-425.8)	257.5 (172.8-360.5)	0.2
HIV RNA copies/mL	7484.0 (2925.3-18994.0)	18918.0 (3991.0-37219.0)	0.1
HIV RNA < 50 copies/mL	61 (54.9)	25 (44.6)	0.1
CD4⁺ cell/ mm³	527.0 (425.3-720.5)	463.0 (373.0-542.8)	0.002
ART, Treated	88 (79.3)	44 (78.6)	0.91
PI/r-NRTI-NNRTI	5 (5.9)	1 (2.4)
PI/r-NRTI	33 (38.8)	13 (30.2)
PI-NRTI	3 (3.5)	4 (9.5)
NRTI-NNRTI	21 (24.7)	11 (26.2)
NRTI	23 (27.1)	13 (30.9)
Therapy missing, n	3	2
Therapy-naïve	23 (41.1)	12 (21.4)
Duration of HAART (yr)	8.2 (6.2-11.5)	7.6 (4.5-10.8)	0.3
Duration of HIV infection (yr)	14.1 (7.8-17.8)	14.2 (8.1-18.1)	0.8
HCV-genotype
1	44 (41.1)	18 (33.3)	0.04
2	5 (4.7)	3 (5.6)
3	38 (35.5)	30 (55.6)
4	20 (18.7)	3 (5.6)
Missing, n	4	2
HAI score	5.4 ± 2.9	6.9 ± 3.0	0.002
Degree of HAI
score 0-8	98 (88.3)	38 (67.8)	0.01
score 9-18	19 (17.1)	18 (32.1)
Fibrosis score	2.1 ± 1.6	2.9 ± 1.6	0.003
Degree of fibrosis
0	12 (10.8)	1 (1.8)	0.001
1	40 (36.0)	10 (17.9)
2	21 (18.9)	14 (25)
3	23 (20.7)	15 (26.3)
4	5 (4.5)	6 (10.7)
5	3 (2.7)	5 (8.9)
6	7 (6.3)	5 (8.9)
TM6SF
p. 167 E/K	10 (0.9)	7 (12.5)	0.48
p. 167 E/E	101 (90.9)	49 (87.5)
PNPLA3
p. 148 I/I	66 (59.4)	22 (39.3)	0.06
p. 148 I/M	38 (38.3)	29 (51.8)
p. 148 M/M	7 (6.3)	5 (8.9)

Table 4 Initial characteristics of 161 patients with human immunodeficiency virus infection and chronic hepatitis C, according to the hepatitis C virus genotype

	HCV genotype 3	non- 3 HCV genotype	P value
Patients, n	68	93
Age (yr)	40.6 (36.7-44.0)	40.8 (37.8-44.1)	0.3
Males	43 (63.2)	69 (74.2)	0.07
IVDU	44 (64.7)	57 (61.3)	0.8
BMI (kg/m²)	22.7 (21.2-25.2)	23.1 (21.7-24.9)	0.5
Glucose (mg/dL)	87.0 (79.0-94.0)	89.0 (82.0-98.0)	0.1
Bilirubin (mg/dL)	0.7 (0.6-1.0)	0.7 (0.5-1.0)	0.5
AST (IU/L)	77.5 (53.3-124.0)	55.0 (38.0-85.0)	0.004
ALT (IU/L)	120.5 (62.5-187.5)	66.0 (40.0-117.0)	0.0002
Cholesterol (mg/dL)	143.5 (115.3-173.0)	171.0 (147.5-197.0)	0.0006
Triglycerides (mg/dL)	99.0 (69.5-158.0)	139.0 (103.5-216.8)	0.003
GGT (IU/mL)	61.0 (32.8-106.0)	96.0 (49.5-226.5)	0.004
ALP (IU/mL)	196.0 (143.0-260.5)	192.0 (150.0-246.0)	0.9
HCV RNA (IU/mL)	477624.0	730500.0
HCV RNA (IU/mL)	(124539.0-1050000.0)	(233250.0-1941008.0)	0.07
Nadir of CD4⁺ cells/mm³	247.7 (155.3-380.0)	252.0 (175.0-404.0)	0.6
HIV RNA copies/mL	5607.5	12130.0	0.7
	(1972.3-18918.0)	(1806.8-37226.5)
HIV RNA < 50 copies/mL	30 (44.0)	42 (45.2)
CD4⁺ cell/mm³	506.5 (397.8-638.0)	494.0 (398.0-697.5)	0.7
ART, Treated	50 (73.5)	79 (84.9)	0.4
PI/r-NRTI-NNRTI	1 (2.0)	5 (6.6)
PI/r-NRTI	22 (44.9)	24 (31.6)
PI-NRTI	3 (6.1)	4 (5.3)
NRTI-NNRTI	13 (26.5)	18 (23.7)
NRTI	10 (20.4)	25 (32.9)
Therapy missing, n	1	3
Therapy-naïve	18 (26.47)	14 (15.0)
Duration of ART (yr)	9.0 (4.3-12.6)	7.7 (6.1-10.4)	0.4
Duration of HIV infection (yr)	14.0 (7.7-18.5)	14.1 (8.1-17.1)	0.8
HAI score	6.5 ± 3.1	5.5 ± 2.9	0.03
HAI
score 0-8	48 (70.6)	76 (81.7)	0.09
score 9-18	20 (14.7)	17 (18.3)
Fibrosis score	2.5 ± 1.6	2.2 ± 1.6	0.2
Degree of fibrosis
0	4 (5.9)	9 (9.7)	0.7
1	16 (23.5)	32 (34.4)
2	16 (23.5)	17 (18.3)
3	18 (26.5)	19 (20.4)
4	4 (5.9)	5 (5.3)
5	5 (7.3)	4 (4.3)
6	4 (5.9)	7 (7.5)
Steatosis score	2.0 ± 1.3	1.4 ± 1.2	0.002
Degree of steatosis
0	14 (20.6)	31 (33.3)	0.03
1	7 (10.3)	14 (15.0)
2	16 (23.5)	20 (21.5)
3	23 (33.8)	22 (23.7)
4	7 (10.1)	2 (2.1)
TM6SF
p. 167 E/K	6 (8.8)	11 (11.8)	0.5
p. 167 E/E	62 (91.2)	82 (88.2)
PNPLA3
p. 148 I/I	38 (55.9)	48 (51.6)	0.5
p. 148 I/M	24 (35.3)	40 (43.0)
p. 148 M/M	6 (8.8)	5 (5.4)

HCV genotype missing in 6 cases. Data represent as n (%), mean ± SD, or median (IQR). e: Elevated; HCV: Hepatitis C virus; HIV: Human immunodeficiency virus; BMI: Body mass index; HAI: Histological activity index; ALT: Alanine aminotransferase; AST: Aspartate aminotransferase; ALP: Alkaline phosphatase; GGT: γ glutamyl transferase; ART: Antiretroviral therapy; NRTIs: Nucleoside/nucleotide analogue reverse transcriptase inhibitors; NNRTIs: Non-nucleoside reverse transcriptase inhibitors; PIs: Protease inhibitors; TM6SF2: Transmembrane 6 superfamily member 2; PNPLA3: Patatin-like phospholipase domain-containing 3 gene; IQR: Interquartile range.

Citation: Sagnelli C, Merli M, Uberti-Foppa C, Hasson H, Grandone A, Cirillo G, Salpietro S, Minichini C, Starace M, Messina E, Morelli P, Miraglia Del Giudice E, Lazzarin A, Coppola N, Sagnelli E. TM6SF2 E167K variant predicts severe liver fibrosis for human immunodeficiency/hepatitis C virus co-infected patients, and severe steatosis only for a non-3 hepatitis C virus genotype. World J Gastroenterol 2016; 22(38): 8509-8518
URL: https://www.wjgnet.com/1007-9327/full/v22/i38/8509.htm
DOI: https://dx.doi.org/10.3748/wjg.v22.i38.8509