Host genetic factors affecting hepatitis B infection outcomes: Insights from genome-wide association studies

Table 1 Results of genome-wide association studies for persistence of hepatitis B virus infection

Ref.	Studypopulation	SNPID	Minor/major alleles	Riskallele	P	OR	Location	Nearestgene	Functional class
Kamatani et al[22]	Japanese, Thai (n = 6387)1	rs3077	A/G	G	2.31 × 10-38	0.56	6p21.32	HLA-DPA1	3'UTR
		rs9277535	A/G	G	6.34 × 10-39	0.57	6p21.32	HLA-DPB1	3'UTR
Mbarek et al[23]	Japanese (n = 9163)1	rs3077	A/G	G	1.57 × 10-61	1.87	6p21.32	HLA-DPA1	3'UTR
		rs9277535	A/G	G	2.55 × 10-54	1.77	6p21.32	HLA-DPB1	3'UTR
		rs2856718	A/G	A	3.99 × 10-37	1.56	6p21.32	HLA-DQB1, HLA-DQA2	Intergenic
		rs7453920	A/G	G	5.98 × 10-28	1.81	6p21.32	HLA-DQB2	Intron
Nishida et al[25]	Japanese (n = 1793)2	rs3077	A/G	G	4.40 × 10-19	0.46	6p21.32	HLA-DPA1	3'UTR
		rs9277542	A/G	G	1.28 × 10-15	0.5	6p21.32	HLA-DPB1	Exon
Kim et al[26]	Korean (n = 4309)2	rs3077	A/G	G	3.74 × 10-40	0.53	6p21.32	HLA-DPA1	3'UTR
		rs9277535	A/G	G	5.25 × 10-39	0.53	6p21.32	HLA-DPB1	3'UTR
		rs2856718	A/G	A	1.78 × 10-24	1.6	6p21.32	HLA-DQB1, HLA-DQA2	Intergenic
		rs7453920	A/G	G	6.71 × 10-26	0.5	6p21.32	HLA-DQB2	Intron
		rs652888	G/A	G	7.07 × 10-13	1.38	6p21.33	EHMT2	Intron
		rs1419881	G/A	A	1.26 × 10-18	0.73	6p21.33	TCF19	3'UTR
Hu et al[28]	Chinese (n = 11791)3	rs7453920	A/G	G	4.93 × 10-37	0.53	6p21.32	HLA-DQB2	Intron
		rs3130542	A/G	A	9.49 × 10-14	1.33	6p21.33	HLA-C	Intergenic
		rs4821116	A/G	G	1.71 × 10-12	0.82	22q11.21	UBE2L3	Intron
		rs3077	A/G	G	6.50 × 10-14	0.75	6p21.32	HLA-DPA1	3'UTR
Chang et al[27]	Han Taiwanese (n = 2688)2	rs9277535	A/G	G	4.87 × 10-14	1.59	6p21.32	HLA-DPB1	3'UTR
		rs7453920	A/G	G	6.66 × 10-15	2.31	6p21.32	HLA-DQB2	Intron
Jiang et al[29]	Chinese (n = 18371)1	rs12614	T/C	C	1.28 × 10-34	1.89	6p21.33	CFB	Exon
		rs422951	G/A	A	5.33 × 10-16	1.27	6p21.32	NOTCH4	Exon
		rs378352	T/C	T	1.04 × 10-23	1.26	6p21.32	HLA-DOA	Exon
		rs2853953	A/G	G	5.06 × 10-20	1.47	6p21.33	HLA-C	Intergenic
		rs1883832	T/C	T	2.95 × 10-15	1.19	20q13.12	CD40	5'UTR
		rs2856718	G/A	A	7.35 × 10-28	1.28	6p21.32	HLA-DQB1, HLA-DQA2	Intergenic
		rs7453920	A/G	G	1.28 × 10-60	2	6p21.32	HLA-DQB2	Intron
		rs9277535	A/G	G	9.84 × 10-71	1.52	6p21.32	HLA-DPB1	3'UTR
		rs3077	A/G	G	1.15 × 10-53	1.45	6p21.32	HLA-DPA1	3'UTR
Li et al[30]	Chinese (n = 9569)3	rs7000921	C/T	T	3.20 × 10-12	0.78	8p21.3	INTS10	Intergenic
		rs7453920	A/G	G			6p21.32	HLA-DQB2	Intron
		rs9277535	A/G	G			6p21.32	HLA-DPB1	3'UTR

Participant phenotypes:

¹CHB vs Non-infected;

²Chronic HBV carriers vs Non-infected;

³Chronic HBV carriers vs Spontaneously recovered. OR: Odds ratio.

Table 2 Human leukocyte antigen classical alleles associated with hepatitis B virus persistence in more than one study

HLA gene	Associated alleles	Effect on HBV persistence	Study population	Ref.
HLA-C	*07:02	Protective	Chinese	[24,28,29]
HLA-DPA1	*01:03	Protective	Japanese, Korean, Chinese, Thai	[22,24,58]
	*02:02	Susceptible	Japanese, Korean, Chinese	[22,24,58]
HLA-DPB1	*04:01	Protective	Japanese, Chinese	[22,28,58]
	*04:02	Protective	Japanese, Korean	[22,58]
	*02:01	Protective	Chinese, Japanese	[28,58]
	*05:01	Susceptible	Japanese, Korean, Chinese	[22,24,58,59]
	*09:01	Susceptible	Japanese, Chinese	[22,24,58,59]
HLA-DQA1	*06:01	Susceptible	Chinese	[24,28,30]
HLA-DQB1	*03:02	Protective	Japanese, Chinese	[24,28,30,59]
	*03:01	Susceptible	African American, Chinese	[18,28,30]
	*06:01	Susceptible	Japanese	[23,59]
HLA-DRB1	*13:02	Protective	Japanese, Chinese, Gambian, Korean, Germany, European Americans	[24,59,68]

Table 3 Results of genome-wide association studies for non-response to hepatitis B vaccine

Ref.	Study population	SNPID	Minor/major alleles	Riskallele	P	OR	Location	Nearest gene	Functional class
Png et al[73]	Indonesian (n = 3614)1	rs3135363	C/T	C	6.53 × 10-22	1.53	6p21.32	BTNL2, HLA-DRA	Intergenic
		rs9277535	A/G	G	2.91 × 10-12	0.72	6p21.32	HLA-DPB1	3'UTR
		rs9267665	T/C	T	1.24 × 10-17	2.05	6p21.33	STK19	Intron
Pan et al[76]	Chinese (n = 1944)2	rs477515	T/C	T	2.63 × 10-19	2.05	6p21.32	HLA-DRB1	Intergenic
Wu et al[81]	Taiwanese (n = 285)3	rs7770370	A/G	G	1.20 × 10-08	0.33	6p21.32	HLA-DPB1	Intergenic

Participant phenotypes:

¹Low, intermediate and high responders to primary vaccine (ordinal groups);

²High responders to primary vaccine vs non-responders to booster vaccine;

³Non-responders vs responders to booster vaccine.

Table 4 Results of genome-wide association studies for hepatitis B virus-related advanced liver diseases

Ref.	Study population	Participant phenotypes	SNPID	Minor/major alleles	Risk allele	P	OR	Location	Nearestgene	Functional class
Al-Qahtani et al[85]	Saudi Arabian (n = 693)	LC/HCC vs Inactive1	rs2724432	T/C	T	4.29 × 10-08	3.01	11q22.3	FDX1	Intergenic
Zhang et al[88]	Chinese (n = 4107)	HCC vs Non-HCC2	rs17401966	G/A	A	3.40 × 10-19	0.62	1p36.22	KIF1B	Intron
Chan et al[91]	Chinese (n = 1420)	HCC vs Non-HCC2	rs12682266	A/G	G	3.76 × 10-05	1.38	8p12	Expressed sequenced tag	Intergenic
Li et al[89]	Chinese (n = 12159)	HCC vs Non-HCC2	rs9272105	A/G	A	5.24 × 10-22	1.28	6p21.32	HLA-DQA1, HLA-DRB1	Intergenic
			rs455804	A/C	C	5.24 × 10-10	0.84	21q21.3	GRIK1	Intron
Jiang et al[90]	Chinese (n = 11799)	HCC vs Non-HCC2	rs7574865	T/G	G	2.48 × 10-10	1.21	2q32.2-2q32.3	STAT4	Intron
			rs9275319	G/A	A	2.72 × 10-17	1.49	6p21.32	HLA-DQB1, HLA-DQA2	Intergenic
Tan et al[86]	Chinese (n = 3387)	ACLF vs Inactive3	rs3129859	C/G	C	2.64 × 10-20	1.83	6p21.32	HLA-DQB1, HLA-DRA	Intergenic

¹HBV carriers with LC or HCC vs inactive chronic carriers;

²Chronic HBV carriers with HCC vs chronic HBV carriers without HCC;

³Acute-on-chronic liver failure vs inactive chronic HBV carriers. LC: Liver cirrhosis; HCC: Hepatocellular carcinoma; HBV: Hepatitis B virus.