Summary The R644C variant of lamin A is controversial, as it has been linked to multiple phenotypes in familial studies, but has also been identified in apparently healthy volunteers. Here we present data from a large midwestern US cohort showing that this variant associates genetically with hepatic steatosis, and with related traits in additional publicly available datasets, while in vitro testing demonstrated that this variant increased cellular lipid droplet accumulation. Taken together, these data support this LMNA variant’s potential pathogenicity in lipodystrophy and metabolic liver disease.

Background Insulin resistance and the G allele of rs738409 interact to create a greater risk of metabolic dysfunction–associated steatotic liver disease. Objective This study aims to confirm that one promising way to reduce insulin resistance is by following a very low–carbohydrate (VLC) dietary pattern. Methods Adults with rs738409-GG or -CG with liver steatosis and elevated liver function tests, were taught an ad libitum VLC diet, positive affect and mindful eating skills, goal setting, and self-monitoring and given feedback and coaching for 4 months. We measured liver steatosis, anthropometric, serum metabolic diet adherence, and quality of life measures. Results In this small pilot trial, of the 11 participants enrolled, 9 (82%) participants completed outcomes. All 11 participants viewed at least 1 session of the intervention, and 8 (73%) participants viewed at least half of the sessions. Among the 9 participants who provided 4-month self-report information, intervention satisfaction was high (mean 6.22, 95% CI 5.58-6.85), with 5 (56%) participants rating the intervention the top score, and 4 (44%) participants reporting they did not plan to stop following the VLC diet. Across participants with a 4-month hepatic liver fat percent measurement, the percent change in liver fat was −33.17% (95% CI −86.48 to 20.14), and in only the participants who were adherent to the eating pattern, the percent change in liver fat was −53.12% (95% CI −71.25 to −34.99). Amongst participants with a 4-month hepatic liver fat percent measurement, 6 out of 8 (75%) participants were considered responders, with a relative decline in liver fat ≥30%, and of the 9 participants with a 4-month body weight, 9 (100%) participants lost ≥5% of their body weight. There were no serious adverse events. Conclusions Results suggest the feasibility, acceptability, and preliminary efficacy of the VLC intervention in adults with higher genetic risk for metabolic dysfunction–associated steatotic liver disease, although there is a need for further studies given the small sample size and the high risk of substantial biases in this small pilot study.

BACKGROUND/AIMS:As the primary anthropometric measure in metabolic dysfunction-associated steatotic liver disease (MASLD), waist circumference (WC) may more accurately reflect the visceral fat distribution than body mass index (BMI). This study aimed to compare the prognostic value of BMI, WC and WC-related indices including waist-hip ratio (WHR), body shape index (BSI) and weight-adjusted-waist index (WWI) in individuals with MASLD. METHODS:The study population was derived from four large-scale cohorts: the National Health and Nutrition Examination Survey (NHANES 2017-2020 and NHANES III), the Kailuan Cohort and the UK Biobank Cohort. We evaluated the mortality risk across these measures using multivariate Cox proportional hazards regression and restrictive cubic spline. RESULTS:The Pearson correlation coefficient of WC with hepatic steatosis and fibrosis was better than that of BMI. WC [Quartile 4 vs. Quartile 1: HR (hazard ratio) = 1.48 (95% confidence interval (CI) 1.13-1.93)] and WC-related indices [Quartile 4 vs. Quartile 1: WHR HR = 3.21 (95% CI 2.36-4.37); BSI HR = 3.22 (95% CI 2.48-4.17); WWI HR = 4.72 (95% CI 3.36-6.62)], but not BMI [obesity vs. lean: HR = 0.90 (95% CI 0.72-1.12)], indicated a significant mortality risk gradient among individuals with MASLD. The finding was consistent across sex and racial/ethnic subgroups, with external validation supporting the WC-related indices. MASLD and fibrosis prevalence showed a dose-dependent pattern across WC-related index quartiles. Notably, low BMI and high WC-related indices portended the highest mortality risk. CONCLUSIONS:WC and WC-related indices are better parameters in prognosticating MASLD than BMI. The BMI-related 'obesity paradox' may be a misnomer resulting from the use of an incorrect metric. WC should be measured more routinely among individuals with MASLD.

Cirrhosis and hepatocellular carcinoma (HCC) are long-term complications of chronic liver disease (CLD). In this large multi-ancestry genome-wide association study of all-cause cirrhosis (35,481 cases, 2.36M controls) and HCC (6,680 cases, 1.76M controls), we identified 27 loci associated with cirrhosis (10 novel) and 11 with HCC (three novel). Three novel cirrhosis loci were replicated in independent cohorts (e.g. FGF21, RPTOR, and IFNL3/4). Fifteen cirrhosis loci exhibited differential effects on cirrhosis risk via underlying etiologies, and six HCC loci influenced HCC risk indirectly via cirrhosis. In a gene-burden analysis of rare variants from whole-genome sequencing data in the VA Million Veteran Program (n=102,677), we identified GSTA5 as a novel cirrhosis-associated gene, while APOB and ATP9B were associated with and replicated for HCC. A high genetic risk score for cirrhosis was associated with a nearly doubled risk of CLD progressing to cirrhosis (HR=1.94, P=2x10-68) and of cirrhosis progressing to HCC (HR=1.65, P=7x10-08). Finally, among individuals with chronic hepatitis C who underwent antiviral therapy, cirrhosis risk was modified by variants in PNPLA3, IFNL3/4, and CD81 following pegylated interferon-α therapy, and by APOE lead variant following direct-acting antiviral therapy. These findings provide new insights into the complex genetic architecture of CLD progression with potential clinical and therapeutic implications.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is characterized by increased hepatic steatosis with cardiometabolic disease and is a leading cause of advanced liver disease. We review here the genetic basis of MASLD. The genetic variants most consistently associated with hepatic steatosis implicate genes involved in lipoprotein input or output, glucose metabolism, adiposity/fat distribution, insulin resistance, or mitochondrial/ER biology. The distinct mechanisms by which these variants promote hepatic steatosis result in distinct effects on cardiometabolic disease that may be best suited to precision medicine. Recent work on gene-environment interactions has shown that genetic risk is not fixed and may be exacerbated or attenuated by modifiable (diet, exercise, alcohol intake) and nonmodifiable environmental risk factors. Some steatosis-associated variants, notably those in patatin-like phospholipase domain-containing 3 (PNPLA3) and transmembrane 6 superfamily member 2 (TM6SF2), are associated with risk of developing adverse liver-related outcomes and provide information beyond clinical risk stratification tools, especially in individuals at intermediate to high risk for disease. Future work to better characterize disease heterogeneity by combining genetics with clinical risk factors to holistically predict risk and develop therapies based on genetic risk is required.

BACKGROUND AND AIMS:An elevated level of lipoprotein(a), or Lp(a), in the bloodstream has been causally linked to the development of atherosclerotic cardiovascular disease and calcific aortic valve stenosis. Steady state levels of circulating lipoproteins are modulated by their rate of clearance, but the identity of the Lp(a) uptake receptor(s) has been controversial. METHODS:We performed a genome-scale CRISPR screen to functionally interrogate all potential Lp(a) uptake regulators in HuH7 cells. Screen validation was performed by single gene disruption and overexpression. Direct binding between purified lipoproteins and recombinant protein was tested using biolayer interferometry. An association between human genetic variants and circulating Lp(a) levels was analyzed in the UK Biobank cohort. RESULTS:The top positive and negative regulators of Lp(a) uptake in our screen were LDLR and MYLIP, encoding the LDL receptor and its ubiquitin ligase IDOL, respectively. We also found a significant correlation for other genes with established roles in LDLR regulation. No other gene products, including those previously proposed as Lp(a) receptors, exhibited a significant effect on Lp(a) uptake in our screen. We validated the functional influence of LDLR expression on HuH7 Lp(a) uptake, confirmed in vitro binding between the LDLR extracellular domain and purified Lp(a), and detected an association between loss-of-function LDLR variants and increased circulating Lp(a) levels in the UK Biobank cohort. CONCLUSIONS:Our findings support a central role for the LDL receptor in mediating Lp(a) uptake by hepatocytes.

Glucagon-like peptide 1 receptor agonists (GLP-1RAs) are approved for treatment of type 2 diabetes mellitus (T2DM) and weight loss in people with overweight, and semaglutide is in phase 3 clinical trials for treatment of nonalcoholic fatty liver disease (NAFLD). GLP-1RAs reduce alanine aminotransferase (ALT) levels, and in phase 2 trials, semaglutide resulted in histologic improvement in steatohepatitis.1,2

Patients with inflammatory bowel disease (IBD) are at increased risk of Clostridioides difficile infection (CDI). Herein, we aimed to determine if genetic risk contributes to this observed association. We carried out a genome-wide association study (GWAS) analysis in the Michigan Genomics Initiative and the United Kingdom Biobank for CDI based on ICD codes and meta-analyzed these results with similar publicly accessible GWAS summary statistics from Finngen. Conditional and joint multi-SNP analyses were used to identify independent associations. Imputation of the human leukocyte antigen (HLA) region with fine mapping was used to try to identify causal HLA allele groups. Two-sample bidirectional Mendelian randomization (MR) was implemented to determine causal relationships between IBD and CDI. A total of 3,500 cases of CDI and 674,323 controls were meta-analyzed, revealing one genome-wide significant variant for CDI, HLA-C;LINC02571-rs3134745-C (P = 4.27E-08), which annotated to the major histocompatibility complex on chromosome 6. While fine mapping did not identify a statistically significant HLA allele group, there was a suggestive signal for HLA-B*35:01 (P = 4.74e-04). Using two-sample MR, genetically predicted IBD was associated with increased risk of CDI (MR Egger [odds ratio {OR} 1.16, 95% confidence interval {CI} 1.02-1.31]). Subset analysis revealed that risk was primarily driven by genetically predicted ulcerative colitis (MR Egger [OR 1.22, 95% CI 1.05-1.41]). These results highlight the importance of the host immune response in CDI pathogenesis, help explain the observed relationship between IBD and CDI, and open new avenues for targeted treatment of CDI in IBD.IMPORTANCEData from this paper (i) provide reproducible evidence that susceptibility CDI is genetically mediated, (ii) highlight genetic risk as a mechanism for the increased risk of CDI in patients with inflammatory bowel disease, and (iii) point toward anti-interleukin-23 therapy as a common therapeutic strategy.

Insulin resistance (IR) is a well-established risk factor for metabolic disease. The ratio of triglycerides to high-density lipoprotein cholesterol (TG:HDL-C) is a surrogate marker of IR. We conducted a genome-wide association study of the TG:HDL-C ratio in 402,398 Europeans within the UK Biobank. We identified 369 independent SNPs, of which 114 had a false discovery rate-adjusted P value < 0.05 in other genome-wide studies of IR making them high-confidence IR-associated loci. Seventy-two of these 114 loci have not been previously associated with IR. These 114 loci cluster into five groups upon phenome-wide analysis and are enriched for candidate genes important in insulin signaling, adipocyte physiology and protein metabolism. We created a polygenic-risk score from the high-confidence IR-associated loci using 51,550 European individuals in the Michigan Genomics Initiative. We identified associations with diabetes, hyperglyceridemia, hypertension, nonalcoholic fatty liver disease and ischemic heart disease. Collectively, this study provides insight into the genes, pathways, tissues and subtypes critical in IR.

Introduction and Objective: Steatotic liver disease, formerly called non-alcoholic fatty liver disease (NAFLD), is the most common cause of chronic liver disease worldwide; yet, few effective methods for prevention/treatment exist making it one of the biggest unmet public health needs of our time. To date, genetic studies have been limited to identifying common variants in predominantly European-ancestry populations or focused on surrogate phenotypes, e.g. liver enzymes, identifying association with comorbidities. Here we present a multi-ancestry whole genome sequencing (WGS) association study to discover rare variants associated with imaging-measured hepatic steatosis. Methods: Study-, ancestry- and sex-stratified association analyses were conducted using SAIGEgds in nine studies with imaging-measured hepatic steatosis adjusted for age, sex, alcoholic drinks per week and principal component estimates of admixture. Stratified results were meta-analyzed using a fixed-effects model. Cochran’s Q-test and the I2 metric were used to estimate heterogeneity. Results: Meta-analyses included 23,156 European, African, Hispanic and Chinese ancestry individuals and identified five significant loci (P<5x10-08): PNPLA3, PPP1R3B, HAPLN4, intergenic region on chr14 and F11-AS1. Nine additional variants trended toward association (P<5x10-07). Sex-stratified meta-analyses revealed additional associations in an intergenic region on chr10, RP11-115J16.1 and UBE3B. Variants in RP11-115J16.1 remained significant in European ancestry samples. Significantly associated variants in SLC2A1-AS1 and LINC01684 were novel loci in African Americans. Conclusion: Taken together, multi-ancestry analysis of imaging-measured hepatic steatosis using WGS replicated previously associated loci and identified novel sex- and ancestry-specific loci. Functional studies are underway to determine the biological impact of these findings. Disclosure N. Allred: None. C. Raut: None. Y. Chen: None. A. Oliveri: None. J. O'Connell: None. K. Ryan: None. J.I. Rotter: None. S.S. Rich: None. A. Hakim: None. P. Peyser: None. L.F. Bielak: None. C. Liu: None. J.G. Terry: None. M. Fornage: None. L.E. Wagenknecht: None. E.K. Speliotes: Other Relationship; University of Michigan. Funding National Institute of Diabetes and Digestive Kidney Disease (R01 DK128871)

INTRODUCTION:TM6SF2-rs58542926-T is associated with increased cirrhosis and modestly decreased coronary artery disease prevalence. However, relative effects of TM6SF2 genotype on major adverse cardiovascular events (MACE) vs liver-related events (LRE) are not known. METHODS:We used the UK Biobank, a prospective cohort with genetic and inpatient diagnosis data. The primary predictor was TM6SF2-rs58542926 genotype, and the primary outcomes were MACE and LRE. Effects were reported as subhazard ratios (sHRs) and 10-year cumulative incidence by Fine-Gray competing risk analyses. RESULTS:More than 430,000 individuals met inclusion criteria. TM6SF2-rs58542926-TT genotype (vs CC) was associated with higher incidence of LRE (adjusted sHR 3.16, 95% confidence interval 1.86-5.37) and lower incidence of MACE (adjusted sHR for TT vs CC genotype 0.76, 95% confidence interval 0.63-0.91). In individuals with fibrosis-4 (FIB4) < 1.3, 1.3-2.67, and > 2.67, 10-year LRE incidence in TM6SF2-rs58542926-TT vs CC individuals was 0.08% vs 0.06% (P > 0.05), 0.81% vs 0.20% (P < 0.0001), and 10.5% vs 3.4% (P = 0.00094), respectively. The corresponding values for MACE were 3.8% vs 5.1% (P = 0.032), 6.4% vs 8.2% (P = 0.040), and 17.1% vs 12.4% (P > 0.05). The absolute decrease in MACE with rs58542926-TT (vs CC) genotype exceeded the absolute increase in LRE in all groups but FIB4 > 2.67. Associations of TM6SF2 genotype with LRE/MACE were significant in men but not women. TM6SF2-rs58542926-T allele was also associated with increased hepatic steatosis and corrected T1 time by magnetic resonance imaging, with greater effect sizes in men than women.D ISCUSSION:TM6SF2 genotype has opposite effects on LRE vs MACE incidence, and absolute effects on MACE were greater except in those with highest FIB4 scores. Effects were strongest in men. These findings clarify implications of TM6SF2 genotype based on personalized clinical risk.