A genome-first approach to variants in MLXIPL and their association with hepatic steatosis and plasma lipids.

BACKGROUND: Common variants of the max-like protein X (MLX)-interacting protein-like (MLXIPL) gene, encoding the transcription factor carbohydrate-responsive element-binding protein, have been shown to be associated with plasma triglyceride levels. However, the role of these variants in steatotic liver disease (SLD) is unclear. METHODS: We used a genome-first approach to analyze a variety of metabolic phenotypes and clinical outcomes associated with a common missense variant in MLXIPL, Gln241His, in 2 large biobanks: the UK Biobank and the Penn Medicine Biobank. RESULTS: Carriers of MLXIPL Gln241His were associated with significantly lower serum levels of triglycerides, apolipoprotein-B, gamma-glutamyl transferase, and alkaline phosphatase. Additionally, MLXIPL Gln241His carriers were associated with significantly higher serum levels of HDL cholesterol and alanine aminotransferase. Carriers homozygous for MLXIPL Gln241His showed a higher risk of SLD in 2 unrelated cohorts. Carriers of MLXIPL Gln241His were especially more likely to be diagnosed with SLD if they were female, obese, and/or also carried the PNPLA3 I148M variant. Furthermore, the heterozygous carriage of MLXIPL Gln241His was associated with significantly higher all-cause, liver-related, and cardiovascular mortality rates. Nuclear magnetic resonance metabolomics data indicated that carriage of MLXIPL Gln241His was significantly associated with lower serum levels of VLDL and increased serum levels of HDL cholesterol. CONCLUSIONS: Analyses of the MLXIPL Gln241His polymorphism showed a significant association with a higher risk of SLD diagnosis and elevated serum alanine aminotransferase as well as significantly lower serum triglycerides and apolipoprotein-B levels. MLXIPL might, therefore, be a potential pharmacological target for the treatment of SLD and hyperlipidemia, notably for patients at risk. More mechanistic studies are needed to better understand the role of MLXIPL Gln241His on lipid metabolism and steatosis development.

The common p.Ile291Val variant of ERLIN1 enhances TM6SF2 function and is associated with protection against MASLD.

BACKGROUND: The ERLIN1 p.Ile291Val single-nucleotide polymorphism (rs2862954) is associated with protection from steatotic liver disease (SLD), but effects of this variant on metabolic phenotypes remain uncertain. METHODS: Metabolic phenotypes and outcomes associated with ERLIN1 p.Ile291Val were analyzed by using a genome-first approach in the UK Biobank (UKB), Penn Medicine BioBank (PMBB), and All of Us cohort. FINDINGS: ERLIN1 p.Ile291Val carriers exhibited significantly lower serum levels of alanine aminotransferase and aspartate aminotransferase as well as higher levels of triglycerides, low-density lipoprotein cholesterol, Apolipoprotein B, high-density lipoprotein cholesterol, and Apolipoprotein A1 in UKB, and these values were affected by ERLIN1 p.Ile291Val in an allele-dose-dependent manner. Homozygous ERLIN1 p.Ile291Val carriers had a significantly reduced risk of developing metabolic dysfunction-associated SLD (MASLD, adjusted odds ratio [aOR] = 0.92, 95% confidence interval [CI], 0.88-0.96). The protective effect of this variant was enhanced in patients with alcoholic liver disease. Our results were replicated in PMBB and the All of Us cohort. Strikingly, the protective effects of ERLIN1 p.Ile291Val were not apparent in individuals carrying the TM6SF2 p.Glu167Lys variant associated with increased risk of SLD. We analyzed the effects of predicted loss-of-function ERLIN1 variants and found that they had opposite effects, namely reduced plasma lipids, suggesting that ERLIN1 p.Ile291Val may be a gain-of-function variant. CONCLUSION: Our study contributes to a better understanding of ERLIN1 by investigating a coding variant that has emerged as a potential gain-of-function mutation with protective effects against MASLD development.

Omega-3 intake is associated with liver disease protection.

Background: Non-alcoholic fatty liver disease (NAFLD) and alcoholic liver disease are among the most common liver diseases worldwide, and there are currently no Food and Drug Administration (FDA)-approved treatments. Recent studies have focused on lifestyle changes to prevent and treat NAFLD. Omega-3 supplementation is associated with improved outcomes in patients with chronic liver disease. However, it is unclear whether Omega-3 supplementation can prevent the development of liver disease, particularly in individuals at an increased (genetic) risk. Methods: In this UK Biobank cohort study, we established a multivariate cox proportional hazards model for the risk of incident liver disease during an 11 year follow up time. We adjusted the model for diabetes, prevalent cardiovascular disorders, socioeconomic status, diet, alcohol consumption, physical activity, medication intake (insulin, biguanides, statins and aspirin), and baseline characteristics. Results: Omega-3 supplementation reduced the risk of incident liver disease (HR = 0.716; 95% CI: 0.639, 0.802; p = 7.6 × 10-9). This protective association was particularly evident for alcoholic liver disease (HR = 0.559; 95% CI: 0.347, 0.833; p = 4.3 × 10-3), liver failure (HR = 0.548; 95% CI: 0.343, 0.875; p = 1.2 × 10-2), and non-alcoholic liver disease (HR = 0.784; 95% CI: 0.650, 0.944; p = 1.0 × 10-2). Interestingly, we were able to replicate the association with reduced risk of NAFLD in a subset with liver MRIs (HR = 0.846; 95% CI: 0.777, 0.921; p = 1.1 × 10-4). In particular, women benefited from Omega-3 supplementation as well as heterozygous allele carriers of the liver-damaging variant PNPLA3 rs738409. Conclusions: Omega-3 supplementation may reduce the incidence of liver disease. Our study highlights the potential of personalized treatment strategies for individuals at risk of metabolic liver disease. Further evaluation in clinical trials is warranted before Omega-3 can be recommended for the prevention of liver disease.

Comorbidities, biomarkers and cause specific mortality in patients with irritable bowel syndrome: A phenome-wide association study.

BACKGROUND: Irritable bowel syndrome (IBS) is one of the most common functional digestive disorders. Our understanding about its comorbidities, biomarkers, or long-term risks is still incomplete. OBJECTIVE: To characterize comorbidities and biomarkers for IBS and establish the effect of IBS on overall- and cause specific mortality. METHODS: We analyzed data from the population-based cohort of the UK Biobank (UKB) with 493,974 participants, including self-reported physician-diagnosed (n = 20,603) and ICD-10 diagnosed (n = 7656) IBS patients, with a mean follow-up of 11 years. We performed a phenome-wide association study (PheWAS) and competing risk analysis to characterize common clinical features in IBS patients. RESULTS: In PheWAS analyses, 260 PheCodes were significantly overrepresented in self-reported physician-diagnosed IBS patients, 633 in patients with ICD-10 diagnosed IBS (ICD-10-IBS), with 221 (40%) overlapping. In addition to gastrointestinal diseases, psychiatric, musculoskeletal, and endocrine/metabolic disorders represented the most strongly associated PheCodes in IBS patients. Self-reported physician-diagnosed IBS was not associated with increased overall mortality and the risk of death from cancer was decreased (hazard ratio [HR] = 0.78 [95% CI = 0.7-0.9]). Lastly, we evaluated changes in serum metabolites in IBS patients and identified glycoprotein acetyls (GlycA) as a potential biomarker in IBS. One standard deviation increase in GlycA raised the risk of self-reported IBS/ICD-10 coded by 9%-20% (odds ratio [OR] = 1.09 [95% CI = 1.1-1.1]/OR = 1.20 [95% CI = 1.1-1.3]) and the risk of overall mortality in ICD-10-IBS patients by 28% (HR = 1.28 [95% CI = 1.1-1.5]). CONCLUSION: Our large-scale association study determined IBS patients having an increased risk of several different comorbidities and that GlycA was increased in IBS patients.

Association of Statin Use With Risk of Liver Disease, Hepatocellular Carcinoma, and Liver-Related Mortality.

Importance: Given the burden of chronic liver disease on the health care system, more information on the hepatoprotective association of statins in the general population is needed. Objective: To examine whether regular statin use is associated with a reduction in liver disease, particularly hepatocellular carcinoma (HCC) and liver-related deaths, in the general population. Design, Setting, and Participants: This cohort study used data from the UK Biobank (UKB) (individuals aged 37-73 years) collected from baseline (2006-2010) to the end of follow-up in May 2021, from the TriNetX cohort (individuals aged 18-90 years) enrolled from baseline (2011-2020) until end of follow-up in September 2022, and from the Penn Medicine Biobank (PMBB) (individuals aged 18-102 years) with ongoing enrollment starting in 2013 to the end of follow-up in December 2020. Individuals were matched using propensity score matching according to the following criteria: age, sex, body mass index, ethnicity, diabetes with or without insulin or biguanide use, hypertension, ischemic heart disease, dyslipidemia, aspirin use, and number of medications taken (UKB only). Data analysis was performed from April 2021 to April 2023. Exposure: Regular statin use. Main Outcomes and Measures: Primary outcomes were liver disease and HCC development as well as liver-associated death. Results: A total of 1 785 491 individuals were evaluated after matching (aged 55 to 61 years on average, up to 56% men, and up to 49% women). A total of 581 cases of liver-associated death, 472 cases of incident HCC, and 98 497 new liver diseases were registered during the follow-up period. Individuals were aged 55-61 years on average, with a slightly higher proportion of men (up to 56%). In UKB individuals (n = 205 057) without previously diagnosed liver disease, statin users (n = 56 109) had a 15% lower hazard ratio (HR) for the association of developing a new liver disease (HR, 0.85; 95% CI, 0.78-0.92; P < .001). In addition, statin users demonstrated a 28% lower HR for the association with liver-related death (HR, 0.72; 95% CI, 0.59-0.88; P = .001) and a 42% lower HR for the development of HCC (HR, 0.58; 95% CI, 0.35-0.96; P = .04). In TriNetX individuals (n = 1 568 794), the HR for the association of HCC was reduced even further for statin users (HR, 0.26; 95% CI, 0.22-0.31; P = .003). The hepatoprotective association of statins was time and dose dependent, with a significant association in PMBB individuals (n = 11 640) for incident liver diseases after 1 year of statin use (HR, 0.76; 95% CI, 0.59-0.98; P = .03). Taking statins was particularly beneficial in men, individuals with diabetes, and individuals with a high Fibrosis-4 index at baseline. Carriers of the heterozygous minor allele of PNPLA3 rs738409 benefited from statin use and had a 69% lower HR for the association with HCC (UKB HR, 0.31; 95% CI, 0.11-0.85; P = .02). Conclusions and Relevance: This cohort study indicates substantial preventive associations of statins against liver disease, with an association with duration and dose of intake.

Large-scale identification of undiagnosed hepatic steatosis using natural language processing.

Background: Nonalcoholic fatty liver disease (NAFLD) is a major cause of liver-related morbidity in people with and without diabetes, but it is underdiagnosed, posing challenges for research and clinical management. Here, we determine if natural language processing (NLP) of data in the electronic health record (EHR) could identify undiagnosed patients with hepatic steatosis based on pathology and radiology reports. Methods: A rule-based NLP algorithm was built using a Linguamatics literature text mining tool to search 2.15 million pathology report and 2.7 million imaging reports in the Penn Medicine EHR from November 2014, through December 2020, for evidence of hepatic steatosis. For quality control, two independent physicians manually reviewed randomly chosen biopsy and imaging reports (n = 353, PPV 99.7%). Findings: After exclusion of individuals with other causes of hepatic steatosis, 3007 patients with biopsy-proven NAFLD and 42,083 patients with imaging-proven NAFLD were identified. Interestingly, elevated ALT was not a sensitive predictor of the presence of steatosis, and only half of the biopsied patients with steatosis ever received an ICD diagnosis code for the presence of NAFLD/NASH. There was a robust association for PNPLA3 and TM6SF2 risk alleles and steatosis identified by NLP. We identified 234 disorders that were significantly over- or underrepresented in all subjects with steatosis and identified changes in serum markers (e.g., GGT) associated with presence of steatosis. Interpretation: This study demonstrates clear feasibility of NLP-based approaches to identify patients whose steatosis was indicated in imaging and pathology reports within a large healthcare system and uncovers undercoding of NAFLD in the general population. Identification of patients at risk could link them to improved care and outcomes. Funding: The study was funded by US and German funding sources that did provide financial support only and had no influence or control over the research process.

Aspirin is associated with a reduced incidence of liver disease in men.

BACKGROUND: The hepatoprotective effects of aspirin have been observed in individuals with viral hepatitis; however, its impact on the general population remains uncertain. Understanding the association between aspirin use and the development of liver diseases is crucial for optimizing preventive strategies. METHODS: We identified individuals with aspirin use in the UK Biobank and the Penn Medicine Biobank, as well as propensity-score-matched controls. Outcome measures included new liver disease development, diagnosed by MRI or "International Classification of Diseases and Related Health Problems" coding, and incidences of gastrointestinal bleeding and ulcers. RESULTS: In the UK Biobank cohort, regular aspirin use was associated with an 11.2% reduction in the risk of developing new liver diseases during the average 11.84 ± 2.01-year follow-up period (HR=0.888, 95% CI = 0.819-0.963; p = 4.1 × 10-3). Notably, the risk of metabolic dysfunction-associated steatotic liver disease (ICD-10 K76.0) and MRI-diagnosed steatosis was significantly lower among aspirin users (HR = 0.882-0.911), whereas no increased risk of gastrointestinal bleeding or ulcers was observed. These findings were replicated in the Penn Medicine Biobank cohort, in which the protective effect of aspirin appeared to be dependent on the duration of intake. The greatest risk reduction for new liver disease development was observed after at least 1 year of aspirin use (HR = 0.569, 95% CI = 0.425-0.762; p = 1.6 × 10-4). Intriguingly, when considering general risk factors, only men exhibited a lower risk of MRI-confirmed or ICD-coded steatosis with aspirin use (HRs = 0.806-0.906), while no significant protective effect of aspirin was observed in females. CONCLUSION: This cohort study demonstrated that regular aspirin use was associated with a reduced risk of liver disease in men without an elevated risk of gastrointestinal bleeding or ulcers. Further investigation is warranted to elucidate potential sex-related differences in the effects of aspirin and to inform tailored preventive strategies for liver diseases.

A coding variant in the microsomal triglyceride transfer protein reduces both hepatic steatosis and plasma lipids.

BACKGROUND: Genetic inactivation and pharmacologic inhibition of the microsomal triglyceride transfer protein (MTP; gene name MTTP) inhibits hepatic secretion of VLDL, thereby reducing serum lipids and apoB at the expense of increasing hepatic steatosis. AIM: To examine the effects of missense variants in MTTP on hepatic and circulating lipids. METHODS: We analysed the association of MTTP missense variants with metabolic, hepatic and clinical phenotypes in the Penn Medicine Biobank (PMBB; n = 37,960) and the UKBiobank (UKB; n = 451,444). RESULTS: We analysed 24 missense variants in MTTP in PMBB for association with biopsy-proven hepatic steatosis and found that an isoleucine 128 to threonine variant (I128T: rs3816873-A, frequency 26%) was associated with reduced steatosis (p < 0.001). PMBB subjects with imaging-proven steatosis also revealed significantly fewer carriers of MTTP I128T compared to controls. Analysis in UKB also showed that MTTP I128T was associated with reduced risk of hepatic steatosis. Unexpectedly, MTTP I128T was found to be associated with reduced plasma levels of LDL-cholesterol and apoB (all p < 0.001). Functional studies indicated that MTTP I128T is neither a classic loss nor gain of function allele. CONCLUSIONS: MTTP I128T is associated with reduced hepatic steatosis as well as reduced plasma lipids and apoB. This paradoxical profile is not consistent with a simple gain or loss of function in MTP activity and suggests a more complex effect on MTP function. Further investigation of MTTP I128T will provide insight into the structure-function of MTP and potentially new approaches to modulate MTP activity that could both reduce hepatic and circulating lipids.