Hepatitis B virus persistent infection-related single nucleotide polymorphisms in HLA regions are associated with viral load in hepatoma families

doi:10.3748/wjg.v27.i37.6262

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World Journal of Gastroenterology

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Retrospective Cohort Study

World J Gastroenterol. Oct 7, 2021; 27(37): 6262-6276
Published online Oct 7, 2021. doi: 10.3748/wjg.v27.i37.6262

Table 1 Factors associated with persistent hepatitis B virus infection in the hepatocellular carcinoma family cohort

	HBsAg
Category	Positive	Negative	OR (95%CI)	Adjusted OR (95%CI)¹	P value	Adjusted P value²
Total family members, n	301	424
Age in yr, mean ± SD	44.23 ± 13.84	41.25 ± 14.97	1.018 (1.007-1.03)	1.017 (1.006-1.028)	0.0013	0.0030
Sex, n (%)
Male	182 (60.47)	203 (47.88)	1.641 (1.279-2.107)	1.57 (1.225-2.011)	0.0001	0.0004
Female	119 (39.53)	221 (52.12)	1	1
Index sex, n (%)
Male	226 (75.08)	309 (72.88)	1.207 (0.726-2.006)	1.147 (0.681-1.93)	0.4685	0.6061
Female	75 (24.92)	115 (27.12)	1	1
Relation to index, n (%)
Children and grandchildren	146 (48.50)	319 (75.24)	1	1
Parent generation	7 (2.33)	15 (3.54)	0.7 (0.302-1.622)	1.472 (0.533-4.065)	0.4059	0.4559
Index generation	148 (49.17)	90 (21.23)	3.203 (2.282-4.498)	4.861 (2.923-8.083)	< 0.0001	< 0.0001
Index status, n (%)
HBsAg-	70 (23.26)	257 (60.61)	1	1
HBsAg+	231 (76.74)	167 (39.39)	4.913 (3.209-7.522)	5.928 (3.747-9.377)	< 0.0001	< 0.0001
Mother’s status, n (%)
HBsAg-	85 (28.24)	239 (56.37)	1	1
HBsAg+	91 (30.23)	45 (10.61)	3.31 (1.894-5.783)	3.296 (1.891-5.746)	< 0.0001	< 0.0001
Unknown	125 (41.53)	140 (33.02)	2.305 (1.568-3.39)	1.87 (1.202-2.91)	<.0001	0.0055
SGPT, mean ± SD	49.98 ± 65.39	25.83 ± 24.92	1.017 (1.011-1.022)	1.015 (1.009-1.020)	< 0.0001	< 0.0001
rs477515 (MAF = 0.1552) Chr6: 32601914¹
TT (reference)	5 (1.66)	20 (4.72)
TC	59 (19.60)	116 (27.36)
CC	237 (78.74)	288 (67.92)	1.377 (1.036-1.831)	1.38 (1.034-1.842)	0.0274	0.0285
rs9272105 (MAF = 0.4282) Chr6: 32632222¹
GG (reference)	54 (17.94)	84 (19.86)
GA	137 (45.51)	207 (48.94)
AA	110 (36.54)	132 (31.21)	1.054 (0.859-1.293)	1.031 (0.844-1.261)	0.6126	0.7639
rs9276370 (MAF = 0.1159) Chr6: 32739518¹
GG (reference)	3 (1.00)	13 (3.07)
GT	39 (12.96)	97 (22.88)
TT	259 (86.05)	314 (74.06)	1.790 (1.258-2.547)	1.759 (1.228-2.519)	0.0012	0.0021
rs7756516 (MAF = 0.1166) Chr6: 32756140¹
CC (reference)	3 (1.00)	13 (3.07)
CT	42 (13.95)	95 (22.41)
TT	256 (85.05)	316 (74.53)	1.654 (1.166-2.346)	1.612 (1.123-2.313)	0.0048	0.0096
rs9277535 (MAF = 0.3234) Chr6: 33087084¹
AA (reference)	21 (6.98)	61 (14.39)
AG	114 (37.87)	191 (45.05)
GG	166 (55.15)	172 (40.57)	1.519 (1.204-1.916)	1.493 (1.182-1.886)	0.0004	0.0008

¹Genome build GRCH38.

²Adjusted for sex and age. HBsAg: Hepatitis B surface antigen; MAF: Minor allele frequency; SGPT: Serum glutamic pyruvic transaminase; CI: Confidence interval; OR: Odds ratio.

Table 2 Cumulative effect of the genetic-risk alleles associated with hepatitis B viral load or persistent hepatitis B virus infection

Study	WGRS quartile	OR (95%CI)	P value
Family first stage: Persistent HBV infection	Q1 (WGRS ≤ 6.166)	1
	Q2 (WGRS = 6.166-7.083)	1.878 (1.277-2.762)	0.0014
	Q3,4 (WGRS > 7.083)¹	2.538 (1.742-3.698)	< 0.0001
	Cochran-Armitage trend test		< 0.0001
Family second stage: Viral load	Q1 (WGRS ≤ 4.583)	1
	Q2 (WGRS = 4.583-5.291)	2.204 (1.253-3.878)	0.0061
	Q3,4 (WGRS > 5.291)²	3.156 (1.780-5.595)	< 0.0001
	Cochran-Armitage trend test		< 0.0001

¹The number of hepatitis B surface antigen negative individuals in Q4 was < 5, so Q3 and Q4 were combined.

²The number of individuals with hepatitis B virus DNA < 10⁵ cps/mL in Q4 was < 1, so Q3 and Q4 were combined. The cumulative effect was calculated from: Four single nucleotide polymorphisms (SNPs) (rs9272105, rs9276370, rs7756516, and s9277535) in unrelated male hepatitis B surface antigen (HBsAg) carriers; four SNPs (rs477515, rs9276370, rs7756516, and rs9277535) in the first-stage hepatocellular carcinoma (HCC) family cohort analysis; and three SNPs (rs477515, rs9272105, and rs7756516) in HBsAg-positive carriers in the second-stage HCC family cohort analysis. CI: Confidence interval; OR: Odds ratio; Q: Quartile; WGRS: Weighted genetic risk score; HBV: Hepatitis B virus.

Table 3 Multivariate generalized estimating equation and area under the curve for hepatitis B surface antigen status in the hepatocellular carcinoma family cohort

	Nongenetic model		Mixed model
Variable	OR (95%CI)	P value	OR (95%CI)	P value
Sex, male	1.458 (1.048-2.027)	0.0250	1.514 (1.075-2.133)¹/1.487 (1.063-2.081)²	0.0177¹/0.0205²
Index sex, male	0.915 (0.532-1.573)	0.7475	0.853 (0.496-1.466)¹/0.838 (0.488-1.442)²	0.5648¹/0.5238²
Age in yr	1.001 (0.984-1.018)	0.9392	1.000 (0.982-1.017)¹/0.998 (0.981-1.016)²	0.9608¹/0.8582²
Relation to index
Parent generation	0.523 (0.176-1.555)	0.2434	0.560 (0.182-1.719)¹/0.603 (0.198-1.833)²	0.3108¹/0.3726²
Index generation	3.385 (1.836-6.239)	< 0.0001	3.344 (1.766-6.331)¹/3.493 (1.860-6.559)²	0.0002¹/0.0001²
Index’s HBsAg+	5.077 (3.103-8.308)	< 0.0001	4.919 (2.980-8.119)¹/4.756 (2.912-7.766)²	< 0.0001¹/< 0.0001²
Mother’s status
HBsAg+	2.597 (1.332-5.064)	0.0051	2.459 (1.270-4.760)¹/2.517 (1.284-4.933)²	0.0076¹/0.0072²
Unknown	1.395 (0.788-2.469)	0.2538	1.412 (0.790-2.522)¹/1.413 (0.795-2.511)²	0.2444¹/0.2387²
AUC (95%CI)	0.786 (0.752-0.820)	< 0.0001
	Genetic model
rs477515	1.303 (0.969-1.753)	0.0802	1.121 (0.770-1.631)	0.5507
rs9276370	2.741 (0.766-9.812)	0.1211	3.040 (0.623-14.839)	0.1693
rs7756516	0.592 (0.171-2.042)	0.4064	0.516 (0.104-2.554)	0.4177
rs9277535	1.575 (1.244-1.995)	0.0002	1.535 (1.157-2.035)	0.0029
AUC (95%CI)	0.632 (0.593-0.671)	< 0.0001	0.798 (0.765-0.831)	< 0.0001
WGRS	1.322 (1.162-1.505)	< 0.0001	1.269 (1.099-1.465)	0.0012
AUC (95%CI)	0.620 (0.580-0.660)	< 0.0001	0.795 (0.762-0.829)	< 0.0001
IDI (95%CI)			0.017 (0.009-0.026)	< 0.0001
NRI (95%CI)			0.330 (0.192-0.467)	< 0.0001

¹Each single nucleotide polymorphism was included in the mixed model.

²The weighted genetic risk score was added in the mixed model. AUC: Area under the receiver operating characteristic curve; CI: Confidence interval; OR: Odds ratio; GEE: Generalized estimating equation; IDI: Integrated discrimination improvement; NRI: Net reclassification improvement; WGRS: Weighted genetic risk score.

Table 4 Factors associated with hepatitis B viral load in a hepatitis B surface antigen-positive hepatocellular carcinoma family cohort

	HBV DNA
Category	≥ 10⁵ cps/mL	< 10⁵ cps/mL	OR (95%CI)	Adjusted OR (95% CI)²		P value	Adjusted P value²
Total members	147	162
Age in yr, mean ± SD	45.03 ± 14.18	41.82 ± 14.21	1.017 (1-1.035)	1.017 (0.999-1.035)		0.0538	0.0668
Sex, n (%)
Male	100 (68.03)	88 (54.32)	1.922 (1.188-3.111)	1.914 (1.187-3.087)		0.0078	0.0078
Female	47 (31.97)	74 (45.68)	1	1
Relation to index, n (%)
Children and grandchildren generation	58 (39.46)	95 (58.64)	1	1
Parent generation	5 (3.4)	2 (1.23)	3.683 (0.866-15.656)	5.056 (1.259-20.3)		0.0775	0.0223
Index generation	84 (57.14)	65 (40.12)	2.033 (1.274-3.246)	1.845 (1.144-2.977)		0.0029	0.0121
Index’s status, n (%)
HBsAg-	21 (14.29)	49 (30.25)	1	1
HBsAg+	126 (85.71)	113 (69.75)	2.508 (1.351-4.657)	2.492 (1.324-4.692)		0.0036	0.0047
Mother’s status, n (%)
HBsAg-	43 (29.25)	43 (26.54)	1	1
HBsAg+	46 (31.29)	51 (31.48)	0.874 (0.467-1.634)	0.91 (0.485-1.707)		0.6724	0.7693
Unknown	58 (39.46)	68 (41.98)	0.855 (0.491-1.49)	0.857 (0.488-1.503)		0.5804	0.5898
HBV genotype (BGT230), n (%)
Unknown³	3 (2.05)	72 (44.44)	0.03 (0.009-0.104)	0.029 (0.008-0.1)		< 0.0001	< 0.0001
B	102 (69.86)	75 (46.3)	1	1
C	41 (28.08)	15 (9.26)	2.042 (1.023-4.079)	2.066 (0.995-4.288)		0.0431	0.0515
SGPT, mean ± SD	63.92 ± 79.63	37.02 ± 45.22	1.010 (1.002-1.018)	1.009 (1.001-1.017)		0.0105	0.0260
rs477515 (MAF = 0.1149) Chr6: 32601914¹
TT (reference)	1 (0.68)	4 (2.47)
TC	15 (10.2)	46 (28.4)
CC	131 (89.12)	112 (69.14)	3.107 (1.708-5.653)	3.195 (1.746-5.847)	0.0002	0.0002
rs9272105 (MAF = 0.4078) Chr6: 32632222¹
GG (reference)	20 (13.61)	36 (22.22)
GA	59 (40.14)	81 (50)
AA	68 (46.26)	45 (27.78)	1.747 (1.256-2.428)	1.75 (1.247-2.456)	0.0009	0.0012
rs9276370 (MAF = 0.07605) Chr6: 32739518¹
GG (reference)	1 (0.68)	3 (1.85)
GT	14 (9.52)	25 (15.43)
TT	132 (89.8)	134 (82.72)	1.747 (0.933-3.272)	1.679 (0.901-3.131)	0.0811	0.1029
rs7756516 (MAF = 0.08091) Chr6: 32756140¹
CC (reference)	0 (0)	4 (2.47)
CT	16 (10.88)	26 (16.05)
TT	131 (89.12)	132 (81.48)	1.951 (1.078-3.53)	1.875 (1.029-3.417)	0.0272	0.0400
rs9277535 (MAF = 0.2589) Chr6: 33087084¹
AA (reference)	13 (8.84)	8 (4.94)
AG	45 (30.61)	73 (45.06)
GG	89 (60.54)	81 (50)	1.235 (0.849-1.797)	1.303 (0.888-1.911)	0.2703	0.1767

¹Genome Build ARCH38.

²Adjusted by sex.

³Eight cases not tested. CI: Confidence interval; HBsAg: Hepatitis B surface antigen; OR: Odds ratio; HBV: Hepatitis B virus.

Table 5 Multivariate generalized estimating equation and area under the curve hepatitis B viral loads in a hepatocellular family cohort

	Nongenetic model		Mixed model
Variable	OR (95%CI)	P value	OR (95%CI)	P value
SNP
Sex, male	1.955 (1.132-3.376)	0.0162	1.918 (1.101-3.341)¹/1.911 (1.097-3.328)²	0.0214¹/0.0223²
Index sex, male	0.903 (0.481-1.699)	0.7527	0.914 (0.488-1.713)¹/0.912 (0.482-1.725)²	0.7786¹/0.7771²
Age in yr	1.012 (0.987-1.037)	0.3363	1.007 (0.983-1.032)¹/1.008 (0.983-1.033)²	0.5658¹/0.5426²
Relation to index
Parent generation	4.182 (0.68-25.731)	0.1228	4.343 (0.81-23.285)¹/4.091 (0.75-22.316)²	0.0866¹/0.1036²
Index generation	1.7 (0.844-3.423)	0.1372	1.851 (0.912-3.756)¹/1.797 (0.894-3.611)²	0.0881¹/0.0999²
Index HBsAg+	2.219 (1.142-4.31)	0.0187	1.734 (0.853-3.526)¹/1.816 (0.907-3.636)²	0.1283¹/0.0918²
Mother’s status
HBsAg+	0.828 (0.407-1.684)	0.6021	0.766 (0.361-1.623)¹/0.763 (0.360-1.619)²	0.4862¹/0.4814²
Unknown	0.537 (0.275-1.045)	0.0673	0.549 (0.272-1.107)¹/0.559 (0.278-1.125)²	0.094¹/0.1030²
AUC (95%CI)	0.674 (0.614-0.734)	< 0.0001
	Genetic model
rs477515	2.246 (1.164-4.333)	0.0159	2.242 (1.113-4.515)	0.0238
rs9272105	1.386 (0.965-1.991)	0.0775	1.266 (0.866-1.849)	0.2232
rs7756516	1.385 (0.765-2.509)	0.2826	1.379 (0.753-2.524)	0.2977
AUC (95%CI)	0.638 (0.579-0.698)	< 0.0001	0.705 (0.648-0.763)	< 0.0001
WGRS	1.644 (1.317-2.052)	< 0.0001	1.567 (1.250-1.965)	< 0.0001
AUC (95%CI)	0.632 (0.573-0.692)	< 0.0001	0.704 (0.646-0.761)	< 0.0001
IDI (95%CI)			0.042 (0.019-0.065)	0.0003
NRI (95%CI)			0.440 (0.236-0.644)	< 0.0001

¹Each single nucleotide polymorphism was added in the mixed model.

²The weighted genetic risk score was added in the mixed model. AUC: Area under the receiver operating characteristic curve; GEE: Generalized estimating equation; IDI: Integrated discrimination improvement; NRI: Net reclassification improvement; CI: Confidence interval; HBsAg: Hepatitis B surface antigen; OR: Odds ratio.

Citation: Hsieh AR, Fann CSJ, Lin HC, Tai J, Hsieh SY, Tai DI. Hepatitis B virus persistent infection-related single nucleotide polymorphisms in HLA regions are associated with viral load in hepatoma families. World J Gastroenterol 2021; 27(37): 6262-6276
URL: https://www.wjgnet.com/1007-9327/full/v27/i37/6262.htm
DOI: https://dx.doi.org/10.3748/wjg.v27.i37.6262