GSTP, GSTT1, XRCC1 and CASP8 Genetic Variations are Associated with Human Papillomavirus in Women with Cervical Cancer From Zimbabwe

Figures & data

Figure 1. Overall schematic of the research protocol.

FFPE: Formalin-fixed paraffin-embedded; HR-HPV: High-risk human papillomavirus.

Table 1. Loci of interest in the current analysis.

Study (year)	Gene	Relationship to HPV	Loci of interest	Functional significance	Characterization method	Ref.
Rigalli et al. (2018)	ABCC2	HPV E6 and E7 oncoproteins stabilize ABCC2 resulting in upregulation	rs717620	↓	Sanger sequencing	[72]
Yuan et al. (2012)	CASP8	Direct target of HPV E6 to promote evasion of apoptosis	rs3834129	↑	PCR-RFLP	[57]
Bajpai et al. (2013); Du et al. (2022)	ERCC1	Impaired DNA repair increases risk of HPV persistence	rs11615	↑	Sanger sequencing	[17]
Chatterjee et al. (2011); Filippova et al. (2004)	FASL	Direct target for HPV16 E6 to protect infected cells from apoptosis	rs763110	↑	PCR-RFLP	[52]
Bortolli et al. (2022)	GSTM1	Xenobiotic metabolism	Whole gene deletion	0	Multiplex PCR	[15]
Phuthong et al. (2018)	GSTP1	Direct target for HPV E7 to activate transcription of infected cells	rs1695 rs1138272	↓	Sanger sequencing	[24]
Bortolli et al. (2022)	GSTT1	Xenobiotic metabolism	Whole gene deletion	0	Multiplex PCR	[15]
AlBosale et al. (2022)	p53	Direct target for HPV E6 oncoprotein	rs1042522	↓	PCR-RFLP	[71]
Ma et al. (2014)	NQO1	Reduced cytotoxicity of HPV	rs1800566	↑	Sanger sequencing	[68]
Bahramabadi et al. (2019)	TLR4	Aberrant HPV recognition to facilitate immune evasion	rs4986790 rs4986791	↑	Sanger sequencing	[70]
Iftner et al. (2002)	XRCC1	Direct target for HPV16 E6	rs179978 rs25487	↓	Sanger sequencing	[48]

↓: Decreased protein expression; ↑: Increased protein expression; 0: Loss of function; HPV: Human papillomavirus; PCR-RFLP: Polymerase chain reaction-restriction fragment length polymorphism.

Table 2. Description of the clinicopathologic characteristics (n = 238).

Parameter	Value
Mean age ± SD (years)	51.6 ± 12
HIV positive serostatus, n (freq)	115 (0.48)
BMI in kg/m^2, n (freq)
Normal (18.5–25)	83 (0.35)
Underweight (<18.49)	15 (0.06)
Overweight (25.1–29.99)	78 (0.33)
Obese (>30.0)	9 (0.04)
Marital status
Married	100 (0.42)
Single (never married)	9 (0.04)
Divorced	14 (0.06)
Widow	49 (0.21)
Unknown	66 (0.28)
Tumor histology
Squamous cell carcinoma	196 (0.82)
Adenocarcinoma	19 (0.08)
Adenosquamous	8 (0.034)
Other	13 (0.06)
Positive history of alcohol consumption	29 (0.12)
Positive history of smoking	8 (0.03)
Positive STI history	71 (0.30)

STI: Sexually transmitted infection; SD: Standard deviation.

Table 3. Genotype and allele frequencies (n = 238).

Genetic polymorphism	Genotype	Frequency, n (proportion)	HWE
ABCC2 rs717620	AA	222 (0.93)	0.299
	AG	15 (0.06)
	GG	1 (0.00)
CASP8 rs3834129	ins/ins	212 (0.89)	<0.001
	ins/del	24 (0.10)
	del/del	2 (0.01)
ERCC1 rs11615	GG	140 (0.59)	<0.001
	GT	98 (0.41)
	TT	1 (0.000)
FASL rs763110	TT	174 (0.73)	<0.001
	TC	52 (0.22)
	CC	12 (0.05)
GSTM1 whole gene deletion	ins/ins	195 (0.81)	NA
	del/del	44 (0.19)
GSTT1 whole gene deletion	ins/ins	206 (0.86)	NA
	del/del	32 (0.14)
GSTP rs1695	AA	67 (0.24)	0.636
	AG	121 (0.51)
	GG	50 (0.21)
GSTP rs1138272	CC	238 (1.00)	NA
NQO1 rs1800566	CC	171 (0.720)	0.100
	CT	64 (0.270)
	TT	3 (0.001)
p53 rs1042522	CC	117 (0.49)	0.020
	CG	109 (0.46)
	GG	12 (0.05)
TLR4 rs4986790	AA	117 (0.49)	<0.001
	AG	40 (0.17)
	GG	2 (0.01)
TLR4 rs4986791	CC	230 (0.97)	<0.010
	CT	5 (0.02)
	TT	3 (0.01)
XRCC1 rs1799782	CC	181 (0.76)	0.010
	CT	57 (0.24)
XRCC1 rs25487	GG	190 (0.80)	0.140
	AG	48 (0.20)
	AA	1 (0.00)

p-value in bold: adherence to HWE.

HWE: Hardy–Weinberg equilibrium; Ins/del: Insertion or deletion.

Table 4. Association analyzes between genetic variants and human papillomavirus genotypes.

Predictor	Variable	OR (95% CI)	p-value
HPV positivity	ABCC2 rs717620	0.6 (0.1–4.5)	0.637
	ERCC1 rs11615	1.4 (0.3–5.6)	0.637
	FASL rs763110	0.7 (0.3–2.0)	0.527
	GSTM1 whole gene deletion	1.9 (0.2–15.1)	0.564
	GSTT1 whole gene deletion	1.3 (0.2–10.4)	0.828
	GSTP rs1695	1.8 (0.7–5.0)	0.249
	P53 rs1052522	2.2 (0.6–8.2)	0.236
	TLR4 rs4986791	0.8 (0.2–3.7)	0.806
	XRCC1 rs25487	0.9 (0.2–4.4)	0.918
HPV16/18	ABCC2 rs717620	0.5 (0.2–1.2)	0.134
	CASP8 rs3834129	1.2 (1.1–6.0)	0.014
	ERCC1 rs11615	0.9 (0.6–1.4)	0.663
	FASL rs763110	1.1 (0.8–1.7)	0.550
	GSTM1 whole gene deletion	0.9 (0.5–1.6)	0.701
	GSTT1 whole gene deletion	1.1 (0.5–2.1)	0.853
	GSTP rs1695	0.8 (0.6–1.1)	0.181
	P53 rs1052522	1.0 (0.7–1.5)	0.999
	TLR4 rs4986791	2.2 (0.5–11.1)	0.313
	TLR4 rs4986790	1.1 (0.6–1.9)	0.737
	XRCC1 rs25487	1.3 (0.7–2.3)	0.344
	XRCC1 rs1799782	1.0 (0.6–1.8)	0.864

CI: Confidence interval; HPV: Human papillomavirus; OR: Odds ratio.

Figure 2. Heatmap showing the association of high-risk human papillomavirus genotypes with host genetic polymorphisms in a univariate model.

HPV: Human papillomavirus.

Table 5. Multivariate association of host genetic polymorphisms with distinct high-risk human papillomavirus genotypes using regression modeling.

Predictor	Covariates	OR (95% CI)	p-value
HPV16	Age	1.0 (1.0–1.0)	0.440
	HIV	1.0 (0.5–1.7)	0.842
	NQO1 rs1800566GG	1.8 (1.0–3.1)	0.050
HPV51	Age	1.0 (0.9–1.0)	0.194
	HIV	1.8 (0.4–8.2)	0.429
	FasL rs763110CC	1.7 (0.6–4.8)	0.303
	GSTP rs1695GG	3.9 (1.3–11.7)	0.017^†
HPV58	Age	1.0 (1.0–1.0)	0.687
	HIV	1.7 (0.7–4.1)	0.251
	XRCC1 rs1799782TT	2.4 (1.2–5.8)	0.048^†
HPV59	Age	1.00 (0.9–1.1)	0.848
	HIV	4.3 (0.4–46.9)	0.234
	GSTT1 null/null	8.2 (1.1–63.2)	0.043^†
Single HPV infection	Age	1.0 (0.97–1.0)	0.396
	HIV	0.9 (0.5–1.5)	0.664
	Other histology	5.9 (1.8–19.3)	0.006^†
	CASP8 rs3834129del/del	2.3 (1.2–4.4)	0.008^†
	GSTP rs1695GG	0.7 (0.5–0.9)	0.042^†
Multiple HPV infections	Age	1.0 (1.0–1.0)	0.556
	HIV	1.3 (0.9–2.2)	0.369
	Squamous cell carcinoma	2.4 (1.3–4.3)	0.010^†
	CASP8 rs3834129del/del	0.5 (0.3–1.0)	0.057
	GSTP rs1695GG	1.5 (1.1–2.1)	0.035^†
HPV 16/18	Age	1.0 (1.0–1.0)	0.940
	HIV	1.2 (0.7–1.9)	0.545
	CASP8 rs3834129del/del	2.7 (1.2–6.0)	0.017^†
	STI history	0.8 (0.5–1.3)	0.337
	Other tumor histology	1.1 (0.5–2.4)	0.849

† p: indicate statistical significant p-values even after adjusting using the Bonferroni correction.

CI: Confidence interval; HPV: Human papillomavirus; OR: Odds ratio; STI: Sexually transmitted infection.

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