Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis

doi:10.3748/wjg.v27.i11.1064

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World Journal of Gastroenterology

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World J Gastroenterol. Mar 21, 2021; 27(11): 1064-1075
Published online Mar 21, 2021. doi: 10.3748/wjg.v27.i11.1064

Table 1 Demographic and clinical profile of all candidate patients for liver transplant according to E2, E3 and E4 allele stratification

Variables	*APOE*2	*APOE*3	*APOE*4	P value
Age (yr) (mean ± SD)	60.8 ± 7.26	60.3 ± 7.19	60.3 ± 7.44	0.956
BMI (mean ± SD)	27.6 ± 4.36	26.4 ± 5.01	27.0 ± 4.81	0.167
Gender (n¹= 179; n²= 358), n²(%)
Male (n¹= 145; n²= 290)	52 (17.9)	193 (66.6)	45 (15.5)	0.650
Female (n¹= 34; n²= 68)	9 (13.2)	48 (70.6)	11 (16.2)	0.650
BMI (n¹= 179; n²= 358), n²(%)
Non-obese (n¹= 137; n²= 274)	49 (17.9)	185 (67.5)	40 (14.6)	0.519
Obese (n¹= 42; n²= 84)	12 (14.3)	56 (66.7)	16 (19.0)	0.519
Etiology (n¹= 179; n²= 358), n²(%)
HCV (n¹= 74; n²= 148)	24 (16.2)	96 (64.9)	28 (18.9)	0.357
HCV + HCC (n¹= 105; n²= 210)	37 (17.6)	145 (69.0)	28 (13.3)	0.357
HCC Milan (n¹= 105; n²= 210), n²(%)
Within the criteria (n¹= 83; n²= 166)	29 (17.5)	115 (69.3)	22 (13.2)	0.885
Outside the criteria (n¹= 22; n²= 44)	8 (18.2)	29 (65.9)	7 (15.9)	0.885

Of 105 patients complicated with hepatocellular carcinoma. n¹: Number of subjects; n²: Number of alleles; APOE: Apolipoprotein E gene; BMI: Body mass index; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma.

Table 2 Genotypic and allele distribution of apolipoprotein E according to group, hepatitis C virus serology/viral load and severity of liver inflammation by the METAVIR score of the total population

*APOE* genotype		Group		HCV-RNA		METAVIR		METAVIR
	All	HCV	HCV + HCC	Positive	Negative	≤ A2F4	A3F4	A1F4	A3F4
	n¹ (179)	n¹(74)	n¹(105)	n¹(33)	n¹(146)	n¹(80)	n¹(11)	n¹(27)	n¹(11)
E2/E2	15 (8.4)	6 (8.1)	9 (8.6)	7 (21.2)	8 (5.5)	9 (11.2)	1 (9.1)	4 (14.8)	1 (9.1)
E2/E3	25 (14.0)	9 (12.2)	16 (15.2)	3 (9.1)	22 (15.1)	11 (13.8)	2 (18.2)	4 (14.8)	2 (18.2)
E2/E4	6 (3.3)	3 (4.1)	3 (2.9)	0 (0.0)	6 (4.1)	2 (2.5)	0 (0.0)	1 (3.7)	0 (0.0)
E3/E3	92 (51.4)	36 (48.6)	56 (53.3)	16 (48.5)	76 (52.0)	39 (48.8)	8 (72.7)	12 (44.5)	8 (72.7)
E3/E4	32 (17.9)	15 (20.3)	17 (16.2)	5 (15.1)	27 (18.5)	14 (17.5)	0 (0.0)	3 (11.1)	0 (0.0)
E4/E4	9 (5.0)	5 (6.7)	4 (3.8)	2 (6.1)	7 (4.8)	5 (6.2)	0 (0.0)	3 (11.1)	0 (0.0)
*APOE* alleles	n²(%)	n²(%)	n²(%)	n²(%)	n²(%)	n²(%)	n²(%)	n²(%)	n²(%)
E2	61 (17.1)	24 (16.2)	37 (17.6)	17 (25.8)	44 (15.1)	31 (19.4)	4 (18.2)	13 (24.1)	4 (18.2)
E3	241 (67.3)	96 (64.9)	145 (69.1)	40 (60.6)	201 (68.8)	103 (64.4)	18 (81.8)	31 (57.4)	18 (81.8)
E4	56 (15.6)	28 (18.9)	28 (13.3)	9 (13.6)	47 (16.1)	26 (16.2)	0(0.0)	10 (18.5)	0 (0.0)
All	358	148	210	66	292	160	22	54	22

METAVIR score of biopsies liver explants from 89 patients and from 2 patients in pre-transplant. n¹: Number of subjects; n²: Number of alleles; APOE: Apolipoprotein E gene; HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma.

Table 3 METAVIR scores for liver inflammation in pre-orthotopic liver transplantation patients according to E2, E3 and E4 alleles stratification

METAVIR score	*APOE*2			*APOE*3			*APOE*4
	Yes	No		Yes	No		Yes	No
	n²(%)	n²(%)	P value	n²(%)	n²(%)	*P value*	n²(%)	n²(%)	P value
METAVIR (n¹= 38; n²= 76)
A1F4 (n¹= 27; n²= 54)	13 (24.1)	41 (75.9)	0.764	31 (57.4)³	23 (42.6)	0.064	10 (18.5)	44 (81.5)	0.055
A3F4 (n¹= 11; n²= 22)	4 (18.2)	18 (81.8)	0.764	18 (81.8)	4 (18.2)	0.064	0 (0.0)¹	22 (100.0)	0.055
METAVIR (n¹= 91; n²= 182)
≤ A2F4 (n¹= 80; n²= 160)	31 (19.4)	129 (80.6)	1.000	103 (64.4)⁴	57 (35.6)	0.148	26 (16.2)	134 (83.8)	0.048^a
A3F4 (n¹= 11; n²= 22)	4 (18.2)	18 (81.8)	1.000	18 (81.8)	4 (18.2)	0.148	0 (0.0)²	22 (100.0)	0.048^a

n¹: Number of subjects; n²: Number of alleles.

³APOE3 vs APOE4 allele frequency, P = 0.024.

⁴APOE3 vs APOE4 allele frequency, P = 0.043.

^aP < 0.05. METAVIR A1: Minimal degree of inflammation; METAVIR A1A2: Minimal and moderate degree of inflammation; METAVIR A3: High degree of inflammation; APOE: Apolipoprotein E gene.

Table 4 Association of the models for end-stage liver disease score and variables in pre-orthotopic liver transplantation patients according to E2, E3 and E4 allele stratification

Variables	MELD≤ 25				MELD> 25				MELD≤ 25			MELD> 25
	*APOE*2	*APOE*3	*APOE*4		*APOE*2	*APOE*3	*APOE*4		*APOE4*			*APOE*4
	*APOE*2	*APOE*3	*APOE*4		*APOE*2	*APOE*3	*APOE*4		(Yes)	(No)		(Yes)	(No)
	n²(%)	n²(%)	n²(%)	P value	n²(%)	n²(%)	n²(%)	P value	n²(%)	n²(%)	P value	n²(%)	n²(%)	P value
METAVIR (n¹= 38; n²= 76)
A1F4 (n¹= 27; n²= 54)	9 (20.4)	27 (61.4)³	8 (18.2)	0.085	4 (40.0)	4 (40.0)	2 (20.0)	NA	8 (18.2)	36 (81.8)	0.044^a	2 (20.0)	4 (80.0)	NA
A3F4 (n¹= 11; n²= 22)	4 (18.2)	18 (81.8)	0 (0.0)³	0.085	0 (0.0)	0 (0.0)	0 (0.0)	NA	0 (0.0)	22 (100.0)	0.044^a	0 (0.0)	0 (0.0)	NA
METAVIR (n¹= 91; n²= 182)
≤ A2F4 (n¹= 80; n²= 160)	26 (18.6)	92 (65.7)⁴	22 (15.7)	0.123	5 (25.0)	11 (55.0)	4 (20.0)	NA	22 (15.7)	118 (84.3)	0.046^a	4 (20.0)	16 (80.0)	NA
A3F4 (n¹= 11; n²= 22)	4 (18.2)	18 (81.8)	0 (0.0)⁴	0.123	0 (0.0)	0 (0.0)	0 (0.0)	NA	0 (0.0)	22 (100.0)	0.046^a	0 (0.0)	0 (0.0)	NA

n¹: Number of subjects; n²: Number of alleles.

³APOE3 vs APOE4 allele frequency, P = 0.040.

⁴APOE3 vs APOE4 allele frequency, P = 0.042.

^aP < 0.05. METAVIR F4: Cirrhosis; METAVIR A1: Minimal degree of inflammation; METAVIR A1A2: Minimal and moderate degree of inflammation; METAVIR A3: High degree of inflammation; APOE: Apolipoprotein E gene; MELD: Model for end-stage liver disease; NA: Not applicable.

Table 5 Logistic regression model predicting moderate and severe (A2A3) degree of liver inflammation

Variables	Odds ratio	95%CI	P value
Alcohol consumption	0.636	0.188-2.148	0.466
Gender–male	7.609	1.195-48.447	0.032^a
Mean MELD	0.932	0.829-1.049	0.244
Mean age	0.969	0.893-1.051	0.446
Mean BMI	0.874	0.782-0.976	0.017^a
APOE2	1.519	0.059-39.334	0.801
APOE3	2.850	0.121-66.917	0.516
APOE4	2.868	0.112-73.560	0.524

^aP < 0.05. MELD: Model for end-stage liver disease; BMI: Body mass index; APOE: Apolipoprotein E gene; CI: Confidence interval.

Citation: Nascimento JCR, Pereira LC, Rêgo JMC, Dias RP, Silva PGB, Sobrinho SAC, Coelho GR, Brasil IRC, Oliveira-Filho EF, Owen JS, Toniutto P, Oriá RB. Apolipoprotein E polymorphism influences orthotopic liver transplantation outcomes in patients with hepatitis C virus-induced liver cirrhosis. World J Gastroenterol 2021; 27(11): 1064-1075
URL: https://www.wjgnet.com/1007-9327/full/v27/i11/1064.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i11.1064