Association of MBOAT7 rs641738 polymorphism with hepatocellular carcinoma susceptibility: A systematic review and meta-analysis

Table 1 Systematic review of MBOAT7 rs641738 and hepatocellular carcinoma susceptibility

Ref.	Country	Cohort characteristics	Study design	Genotyping method	Genetic model(s)	Main results	Conclusion
Thabet et al[8], 2016	Multi-countries	HCV-related HCC	1706 with chronic HCV infection, divided into two cohorts: Discovery cohort (n = 931) and validation cohort (n = 775)	TaqMan	Dominant model	No significant association was observed with HCC (OR: 0.96; 95%CI: 0.58-1.57)	The role of rs641738 is limited to the early stages of liver disease, but not to further progression or occurrence of HCC
Donati et al[9], 2017	Multi-countries	NAFLD, HCV, and alcohol-related HCC	Italian (n = 765) and United Kingdom (n = 358) NAFLD patients; combined cohort of chronic hepatitis C (n = 597) or alcoholic liver disease (n = 524)	TaqMan	Additive models	In Italian NAFLD patients, the T allele was associated with NAFLD-HCC (OR: 1.65, 95%CI: 1.08-2.55; n = 765). In United Kingdom & Italian NAFLD cohort with non-cirrhotic NAFLD, the T allele remained associated with HCC (OR: 2.10, 95%CI: 1.33-3.31; n = 913). In combined cohort of chronic hepatitis C or alcoholic liver disease, the T allele was independently associated with HCC risk (OR: 1.93, 95%CI: 1.07-3.58; n = 1121)	The MBOAT7 rs641738 T allele may predispose to HCC in patients without cirrhosis
Stickel et al[11], 2018	Multi-countries	Alcohol-related cirrhotic HCC	751 cases with alcohol-related cirrhosis and HCC and 1165 controls with alcohol-related cirrhosis without HCC	TaqMan	Additive models	The risk associated with carriage of MBOAT7 rs641738 was not significant (OR: 1.04, 95%CI: 0.88-1.24)	Neither heterozygous nor homozygous carriage of the MBOAT7 rs641738 T allele was associated with HCC risk
Raksayot et al[14], 2019	Thailand	HBV, HCV, and NBNC-related HCC	Healthy controls (n = 105), HBV-related HCC (n = 270), HCV-related HCC (n = 131), and NBNC-related HCC (n = 129)	TaqMan	NA	The genotype distribution and T allele frequencies of MBOAT7 rs641738 were similar between groups (NBNC-HCC vs NBNC-cirrhosis OR: 0.86, 95%CI: 0.51-1.46)	The data did not reveal any association between MBOAT7 rs641738 and the development of NBNC-HCC
Wang et al[16], 2021	China	Unspecified	779 HCC cases and 1412 cancer-free controls (controls consist of 678 persistent HBV carriers and 734 spontaneously recovered subjects)	MassARRAY	Dominant, additive, recessive, and allelic models	The results suggested no association between MBOAT7-TMC4 rs641738 and HCC risk in most genetic models	The work highlights that MBOAT7-TMC4 rs641738 is not associated with the risk of HCC
Bianco et al[12], 2021	Multi-countries	NAFLD-related HCC	At-risk individuals (NAFLD cohort, n = 2566 and a replication cohort of 427 German patients with NAFLD). The general population (UKBB cohort, n = 364048).	TaqMan & United Kingdom BiLEVE and UKBB Axiom array	NA	In NAFLD cohort, OR: 1.0, 95%CI: 0.7-1.5; in overall UKBB, OR: 1.3, 95%CI: 0.9-1.8; in non-viral UKBB, OR: 1.3, 95%CI 0.9-1.9	Variants in PNPLA3-TM6SF2-GCKR-MBOAT7 were combined in a hepatic fat PRS and PRS predicted HCC more robustly than single variants
Liu et al[13], 2022	United Kingdom	MAFLD-related HCC	160979 participants were diagnosed as having MAFLD	United Kingdom BiLEVE and UKBB Axiom array	NA	Model 2: Adjusted for gender, age, assessment center, genotyping chip, smoking status, physical activity level, overall health rating, average household income, and alcohol consumption. CT vs CC: OR: 1.16, 95%CI: 0.84-1.62; TT vs CC: OR: 1.36, 95%CI: 0.95-1.95	MAFLD is independently associated with an increased risk of both intrahepatic and extrahepatic events. The impact of MAFLD on hepatic health events was amplified by variants in fatty liver disease related genes, among which the genetic variations in PNPLA3, TM6SF2, and MBOAT7 play prominent roles
Nahon et al[15], 2023	French	Compensated cirrhosis (HCV or alcohol)-related HCC	Cohort 1 (n = 659): Compensated cirrhosis with HCV sustained virologic response. Cohort 2 (n = 486): Compensated alcohol-related cirrhosis	TaqMan	NA	In HCV-cured cohort, CT/TT vs CC: Subhazard ratio: 1.43, 95%CI: 0.68-3.01; In alcohol cohort, CT/TT vs CC: Subhazard ratio: 1.83, 95%CI: 0.85-3.94 (Fine-Gray regression modelling)	A 7-SNP genetic risk score was established, which contains PNPLA3, TM6SF2, HSD17B13, APOE, MBOAT7, and WNT3A-WNT9A variants

HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; NAFLD: Nonalcoholic fatty liver disease; HBV: Hepatitis B virus; NBNC: Non-hepatitis B and non-hepatitis C; MAFLD: Metabolic dysfunction-associated fatty liver disease; PRS: Polygenic risk score; OR: Odds ratio; 95%CI: 95% confidence interval; UKBB: United Kingdom Biobank; SNP: Single-nucleotide polymorphism; NA: Not available.

Table 2 Studies included in meta-analysis

Ref.	Country	Cohort characteristics	Cases	Controls	Genotype (CC/CT/TT)		Allele (C/T)		Minor allele frequency		Adjustment	HWE of control (P value)
					Case	Control	Case	Control	Case	Control
Thabet et al[8], 2016	Multi	HCV-related HCC	75	1706	24/35/16	531/822/353	83/67	1884/1528	0.45 (T)	0.45 (T)	Age, gender, BMI, and Child-Pugh score	0.305
Donati et al[9], 2017	Italian	NAFLD-related HCC	132	633	26/69/37	213/285/135	121/143	711/555	0.46 (C)	0.44 (T)	Age, gender, obesity, T2DM, and presence of advanced fibrosis	0.036
Donati et al[9], 2017	Italian & United Kingdom	Non-cirrhotic NAFLD-related HCC	41	872	5/21/15	280/422/170	31/51	982/762	0.38 (C)	0.44 (T)	NA	0.664
Donati et al[9], 2017	Italian	HCV-related HCC	13	584	1/7/5	177/259/148	9/17	613/555	0.35 (C)	0.48 (T)	Age, gender, and genetic variants	0.009
Donati et al[9], 2017	Italian	Alcohol-related HCC	12	512	1/8/3	150/251/111	10/14	551/473	0.42 (C)	0.46 (T)	Age, gender, and genetic variants	0.805
Stickel et al[11], 2018	Switzerland, Germany & United Kingdom	Alcohol-related cirrhotic HCC	751	1165	203/363/185	314/583/268	769/733	1211/1119	0.49 (T)	0.48 (T)	Age, gender, BMI, and T2DM	0.967
Raksayot et al[14], 2019	Thailand	HBV-related HCC	270	105	140/114/16	66/34/5	394/146	166/44	0.27 (T)	0.21 (T)	NA	0.943
Raksayot et al[14], 2019	Thailand	HCV-related HCC	131	105	71/53/7	66/34/5	195/67	166/44	0.26 (T)	0.21 (T)	NA	0.943
Raksayot et al[14], 2019	Thailand	NBNC-related HCC (containing NAFLD and alcoholic liver disease)	129	105	68/46/15	66/34/5	182/76	166/44	0.30 (T)	0.21 (T)	NA	0.943
Wang et al[16], 2021	China	Unspecified	779	1405	426/295/58	800/528/77	1147/411	2128/682	0.26 (T)	0.24 (T)	Age, gender, smoking status, and drinking status	0.437
Bianco et al[12], 2021	Italian & United Kingdom	NAFLD-related HCC	226	2338	NA	NA	NA	NA	NA	NA	Age, gender, BMI, and T2DM	NA
Bianco et al[12], 2021	United Kingdom	UKBB (Non-viral)	202	363,846	NA	NA	NA	NA	NA	NA	Age, gender, BMI, T2DM, ethnicity, array batch, and assessment center	NA

HCV: Hepatitis C virus; HCC: Hepatocellular carcinoma; HWE: Hardy-Weinberg equilibrium; NAFLD: Nonalcoholic fatty liver disease; HBV: Hepatitis B virus; T2DM: Type 2 diabetes mellitus; BMI: Body mass index; UKBB: United Kingdom BioBank; NBNC: Non-hepatitis B and non-hepatitis C; NA: Not available.