Table 1.
Human studies linking MBOAT7 function to diverse human disease
| Disease etiology | Study information | Major findings | References |
|---|---|---|---|
| ALD | GWAS for alcohol-related cirrhosis in individuals of European descent (712 cases and 1,426 controls) with subsequent validation in two independent European cohorts (1,148 cases and 922 controls) | rs641738 variant near MBOAT7 is associated with alcohol-related cirrhosis | Buch et al. (1) |
| ALD | Genetic association study for HCC (765 Italian liver disease patients) | rs641738 variant is not significantly associated with alcohol-related HCC | Stickel et al. (3) |
| ALD | Large case-control multicenter study for SNP in association with ALD (507 ALD patients and 645 ethnically matched healthy controls—Han Chinese population) | rs641738 variant is not associated with indices of liver damage in alcohol users | Zhang et al. (2) |
| ALD | Effect of MBOAT7 rs641738 variant on AH and severity (211 patients with AH and 176 heavy drinking controls) | rs641738 variant did not show significant relationships with AH | Beaudoin et al. (4) |
| NAFLD | Population based (first stage); cases only (second stage) associated with steatosis, NASH, fibrosis stage (3,854 participants from the Dallas Heart Study [first stage]; 1,149 cases from LBC [second stage] from European descent) | rs641738 variant was associated with an increased hepatic fat content, more severe liver damage, and increased risk of hepatic fibrosis | Mancina et al. (8) |
| NAFLD | Genetic variation in MBOAT7 associated with steatosis, NASH, fibrosis stage (125 cases) | rs641738 variant associates with histologic liver damage, particularly significant fibrosis | Luukkonen et al. (9) |
| NAFLD | Hospital-based prospective cohort investigating relationship between MBOAT7 and outcomes of bariatric surgery (84 obese individuals) | MBOAT7 might regulate not only hepatic fat accumulation but also the whole-body adiposity | Krawczyk et al. (10) |
| NAFLD | Investigating rs641738 near MBOAT7 modulate both steatosis and fibrosis in NAFLD patients (multicenter biopsy-based study—515 patients with NAFLD) | rs641738 variant was linked with increased hepatic fat content, severe liver disease, and increased risk of fibrosis | Krawczyk et al. (11) |
| NAFLD | MBOAT7 variant in association with NAFLD and liver injury | rs641738 variant was more frequently associated with severe hepatic steatosis and to a lesser extent with NAFLD risk and liver injury modulation | Krawczyk et al. (12) |
| NAFLD/HCC | rs626283 polymorphism in the MBOAT7 associated with increased risk of MAFLD-HCC and alcohol-related or HCV-related HCC (765 noncirrhotic MAFLD cases [HCC, n = 132]); 1,121 noncirrhotic patients affected by ALD or HCV (HCC, n = 25) | MBOAT7 loss of function is independently associated with HCC risk | Donati et al. (13) |
| NAFLD | A Mendelian randomization approach to examine whether hepatic fat causally determines liver damage and metabolic comorbidities (liver biopsy cohort involving 1,515 individuals, the Swedish Obese Subjects Study involving 3,329 subjects, and the Dallas Heart Study with 4,570 participants) | rs641738 variant exerted significant effects on hepatic fat, liver damage, and metabolic traits | Dongiovanni et al. (14) |
| NAFLD | GWAS for NAFLD; resequencing strategy by next-generation sequencing in a cohort of 218 NAFLD subjects and 227 controls | rs641738 variant is associated with NAFLD and possibly influencing its severity | Di Costanzo et al. (15) |
| NAFLD | To explore the effect derived from silybin-phospholipid complex, oral administration in NAFLD patients carrying MBOAT7-rs641738 variant (92 biopsy-proven NAFLD patients were grouped in 30 NAFLD wild-type controls, 30 wild-type-treated patients, and 32 mutated treated ones) | The assessed mutations are independently associated with no response to a silybin-based therapeutic regimen and could be considered as useful predictive markers | Dallio et al. (16) |
| ALD/NAFLD | Polygenic risk score on genetic variants in MBOAT7 associated with severe liver disease (266,687 individuals in the UK Biobank) | rs641738 variant was causally related to liver injury and strongly associated with severe liver disease | De Vincentis et al. (17) |
| NAFLD/HCC | Learning NAFLD cohort, n = 2,566; 226 with HCC; and a replication cohort of 427 German patients with NAFLD and the general population (UK Biobank [UKBB] cohort, n = 364,048; 202 with HCC) | rs641738 variant is associated with hepatic fat, and hepatic fat is causally related to HCC | Bianco et al. (18) |
| Pediatric NAFLD | Longitudinal follow up in 467 Caucasian children aged 6–9 years old | rs641738 T allele had higher plasma ALT levels | Viitasalo et al. (19) |
| Pediatric NAFLD | rs641738 variant near MBOAT7 associated with NAFLD (1,002 Italian obese children and adolescents) | The rs641738 variant in obese children showed elevated serum level of ALT. This is the first pediatric association of the MBOAT7 polymorphism with indirect markers of liver fibrosis | Di Sessa et al. (22) |
| Pediatric NAFLD | Multiethnic cohort of obese children and adolescents, we genotyped the rs626283 polymorphism in the MBOAT7 gene | The rs626283 variant is associated with NAFLD and altered glucose metabolism | Umano et al. (23) |
| NAFLD | Case-control hospital-based cohort study on NAFLD (634 individuals; 372 patients with NAFLD diagnosed by liver biopsy and 262 control subjects) | The rs641738 variant is not associated with NAFLD or the histological disease severity | Sookoian et al. (24) |
| NAFLD | Case-control hospital-based cohort to study the MBOAT7 association with NAFLD (416 cases and 109 controls) | No association between the rs641738 variant and any of the histological severity markers of NAFLD | Koo et at. (25) |
| NAFLD | To study the effect of MBOAT7 rs626283 variant on renal function and NAFLD (prospective Asian cohort from NAFLD registry) | Rs641738 variant is associated with CKD mediated by increased systemic inflammation | Koo et al. (26) |
| NAFLD | 453 patients with biopsy-proven NAFLD with sufficient clinical data for calculating scores (n = 302; discovery cohort; n = 151; validation cohort) | rs641738 variant is not associated with NAFLD or NASH phenotypes | Koo et al. (27) |
| NAFLD/cirrhosis | Study of an Eastern European population that assessed the impact of MBOAT7 rs641738 on developing liver injury (1,012 individuals) | rs641738 variant was not linked to hepatic fibrosis, alcohol, or hepatitis C virus-induced liver cirrhosis in an Eastern European population | Basyte-Bacevice et al. (28) |
| NAFLD | 958 middle-aged Finns, 249 with NAFLD, were followed for 21 years | rs641738 variant not associated with overall mortality associated with the metabolic syndrome | Karajamki et al. (29) |
| NAFLD | 294 patients (63% women) with a mean age of 53 (±17) years and 31% Hispanic ethnicity with genotyping | rs641738 variant was not associated with advanced fibrosis | Ajmera et al. (30) |
| NAFLD | GWAS involved 1,483 biopsied NAFLD cases and 17,781 controls | rs641738 variant was not associated with NAFLD | Anstee et al. (31) |
| Pediatric NAFLD | Genetic variant, demographic, and biochemical data analysis on the effects on NAFLD (126 enrolled subjects, 84 in the case group and 42 in the control group) | rs641738 variant is not a risk factor for NAFLD in obese US children of Hispanic ethnicity | Mansoor et al. (32) |
| Pediatric NAFLD | Association of MBOAT7 rs641738 variant and NAFLD in the pediatric population (1,760 overweight or obese children) | No significant contribution of the rs641738 variant to the risk of NAFLD/NASH in a large hospital-based cohort of Italian overweight/obese children | Zusi et al. (33) |
| Pediatric NAFLD | rs641738 genotyping in 232 children with obesity and NAFLD | No significant contribution of the rs641738 variant to the risk of NAFLD | Di Costanzo et al. (34) |
| Pediatric NAFLD | 831 obese children aged 7–15 were genotyped for the rs641738 variant | rs641738 variant was not associated with hepatic steatosis or CK-18 fragment in obese Taiwanese children | Lin et al. (35) |
| NAFLD | Meta-analysis of MBOAT7 associated with steatosis, MAFLD severity, fibrosis stage, and HCC (42 studies, including 1,047,265 participants [including 4,174 children], out of which 7,692 had liver biopsy and 45,419 had minor T allele of rs641738 C>T) | rs641738 variant was associated with elevated hepatic steatosis and is linked to more severe fatty liver disease | Teo et al. (36) |
| HCV | Study associated with severe hepatic inflammation and increased risk of fibrosis (2,051 Caucasian consecutive subjects, including 1,706 with CHC, 931 in the discovery cohort, and 775 in the validation cohort; 270 healthy controls and 75 with HCV-related HCC) | rs641738 variant is a novel risk variant for liver inflammation in hepatitis C and thereby for liver fibrosis | Thabet et al. (44) |
| HBV | Functional analysis associated with hepatic inflammation and fibrosis in chronic hepatitis B (1,101 HBV cases) | rs641738 variant associated with hepatic inflammation and fibrosis in patients with HBV | Thabet et al. (45) |
| HBV/HCV | Association between the MBOAT7 rs641738 polymorphism and disease progression of HCV and HBV infection (971 consecutive Moroccan subjects [288 with CHC, 98 formerly HCV-infected patients, 268 with CHB, 126 HBV, and 191 healthy controls]) | rs641738 variant is not associated with progression of liver disease in chronic HBV or HCV | Ezzikouri et al. (46) |
| HBV/HCV/HCC | rs641738 was genotyped in 105 healthy controls and 530 patients with HCC (270 with HBV, 131 with HCV) and 129 with no virus detected matched for age and gender | rs641738 variant was not associated with HCV- or HBV-associated HCC | Raksayot et al. (47) |
| HCV/HCC | About 56 patients with HCV-associated cirrhosis who underwent antiviral therapy | ra641738 variant was not associated with HCV associate with response to therapy | Dunn et al. (48) |
| HCV/HCC | A total of 171 patients who received direct acting antiviral therapy | rs641738 variant was not associated with response to therapy | Kang et al. (49) |
| HBV/HCC | Case-control study for MBOAT7 rs641738 in the risk of HCC and persistent HBV infection (779 HCC cases and 1,412 cancer-free controls) | rs641738 variant is not associated with the risk of HCC or persistent HBV infection | Wang et al. (50) |
| PSC | Case study of two MBOAT7 variant alleles (TT and CT) on PSC patients (262 PSC cases from Freund 2020 study and 252 patients with PSC from Rahal 2020 study) | Liver transplant-free survival was significantly prolonged in carriers of two rs641738 variant allele | Freund et al. (51), Rahal et al. (52) |
| Hemochromatosis | rs641738 was genotyped in 1,319 C282Y homozygotes, from six European countries, of whom 171 (13.0%) had cirrhosis | rs641738 variant was not associated with hemochromatosis outcome | Buch et al. (53) |
| CVD | GWAS of 141 lipid species (n = 2,181 individuals), phenome-wide scans with 25 CVD-related phenotypes (n = 511,700 individuals) | MBOAT7 rs8736 variant not associated with CVD mortality, and TT carriers showed significantly reduced levels of PI (18:0;0–20:4;0) | Tabassum et al. (54) |
| CVD | Meta-analysis of 48 GWAS studies for CAD (60,801 CAD cases; 123,504 controls) | rs641738 variant had neutral effects in coronary artery disease | Simons et al. (55), Brouwers et al. (56) |
| Gastric cancer | A fine-mapping association study in 1,926 gastric cancer patients and 2,012 controls of European descent | Downregulation of MBOAT7 expression is associated with gastric cancer risk | Heinrichs et al. (57) |
| Lung cancer | Study of MBOAT7 function non-small-cell lung cancer cell lines | MBOAT7 is necessary for proliferation and in vivo tumor formation in mice | Saliakoura et al. (58) |
| Kidney cancer | Study of MBOAT7 function in clear cell renal carcinoma (ccRCC) cell lines | MBOAT7 is overexpressed in ccRCC, and MBOAT7 knockout prevents in vivo tumor formation | Neumann et al. (59) |
| Intellectual disability | Sequencing on individuals with intellectual disability and other neurological conditions | Inactivating variants in MBOAT7 lead to intellectual disability accompanied by epilepsy and autistic features in patients | Johansen et al. (60), Jacher et al. (61), Khan et al. (62), Heidari et al. (63), Yalnizoglu et al. (64) |
| COVID-19 | Prospectively analyzed a cohort of 44 patients with COVID-19 | rs641738 genotype: only n = 8 were wild-type CC, and the remaining n = 36 were carrying the variant allele (19 heterozygous and 17 homozygous carriers) | Machill et al. (65) |
AH, alcoholic hepatitis; ALT, alanine aminotransferase; CHC, combined hepatocellular cholangiocarcinoma; CKD, chronic kidney disease; CVD, cardiovascular disease; MAFLD, metabolic-associated fatty liver disease; PSC, primary sclerosis cholangitis.