Tae-Hwi Schwantes-An

Background and Aims: The genetic susceptibility to MASLD histological severity remains incompletely defined. We assessed the associations between recently developed genome‐wide association studies–derived polygenic risk scores (PRSs) and advanced fibrosis in MASLD. We also evaluated PRSs' associations with histological activity and selected PRSs' predictive ability for advanced fibrosis. Methods: We analysed 2149 adults and 900 children with biopsy‐proven MASLD from the NASH Clinical Research Network studies. Genotyping was performed by the Regeneron Genetics Center using whole‐exome sequencing with targeted genotyping. Associations between seven published PRSs (Chen, Emdin, Whitfield, Schwantes‐An, Vujkovic, and Ghouse) and MASLD histological features were examined using linear and logistic regression models. Penalized regression models were used to select top PRSs associated with MASLD traits. Results: The Schwantes‐An PRS in adults (OR 1.29, 95% CI 1.17–1.42, p < 0.01) and the Chen PRS in children (OR 1.46, 95% CI 1.17–1.82, p < 0.01) were associated with higher risk of advanced fibrosis versus other PRSs. The Chen PRS in adults (OR 1.29, 95% CI 1.18–1.41, p < 0.01) and Schwantes‐An PRS in children (OR 1.39, 95% CI 1.20–1.61, p < 0.05) were associated with higher risk with MASLD activity. Although highest PRSs quartiles were associated with advanced fibrosis risk versus bottom quartiles, neither PRS had good diagnostic discrimination for advanced fibrosis (AUROC < 60%). Conclusions: In this large biopsy‐proven MASLD cohort, two distinct PRSs were associated with disease histological severity and activity in adults versus children. Findings suggest current PRSs may improve personalized risk stratification for advanced fibrosis but not its diagnosis.

BACKGROUND: Although pulmonary arterial hypertension (PAH) is a rare and fatal disease that is well-characterized, vasodilator-responsive PAH accounts for a minority of cases, with little mechanistic knowledge, but with dramatically improved survival. METHODS: By assembling national cohorts, we evaluated genetic influences on acute vasodilator drug response, a key determinant of the presence of vasodilator-responsive PAH. Differences between hemodynamics at rest and after a PAH-specific vasodilator were tested in a genome-wide association study. Validated loci were functionally tested in cell culture and in a hypoxic mouse model of pulmonary hypertension. RESULTS: Rs8057488 in the sorting nexin 29 ( SNX29 ) gene reached genome-wide significance in the discovery cohort ( P =4.00×10 ⁻⁸ ) and was nominally replicated ( P =0.027). Consistent with its predicted function, SNX29 demonstrated an endosomal distribution in PA smooth muscle cells. Silencing SNX29 redistributed stromal interaction molecule proteins to the cell membrane and enhanced store-operated calcium entry. Over-expression of SNX29, in vivo, attenuated hypoxic vasoconstriction in isolated perfused murine lung models. CONCLUSIONS: The data cumulatively suggest SNX29 may contribute to vasodilation partly through reduced store-operated calcium entry and endosomal trafficking of store-operated calcium entry proteins, advancing our understanding of vasodilator-responsive PAH.

Background and Aims: Dyslipidemia is common in patients with MASLD, but the frequency and significance of inherited disorders of dyslipidemia are unclear. We investigated the prevalence and significance of pathogenic variants associated with selected monogenic disorders of dyslipidemia in 3358 patients with well‐characterised MASLD. Approach: We identified clinically relevant variants in APOB , MTTP , PCSK9 , ANGPTL3 , LDLR and LDLRAP1 genes which can cause hypobetalipoproteinemia (HBL) and familial hypercholesterolemia (FH). Using ClinVar annotations as initial variant selection, we identified 2027 variants in those 6 genes which are reported as ‘pathogenic’ or ‘likely pathogenic’ (P/LP). We first assessed for the presence of P/LP variants in the study cohort and then investigated the effect of carrying P/LP variants on liver histology, by comparing ~4 matched controls for each APOB and LDLR carrier. As interpretative analyses, we also looked at the difference between liver enzymes, lipid measures and outcomes between the carriers and matched controls. Results: Twenty‐two variants among these 2027 P/LP variants were present in 24 out of 3358 patients (12 ApoB , 10 LDLR , 1 ANGPTL3 and 1 MTTP variant carriers). Compared to controls, APOB carriers had higher steatosis grade (2.4 vs. 1.7, p ‐value 0.0028), higher NAFLD activity score (NAS) (4.9 vs. 3.8, p ‐value 0.04), and numerically higher but statistically not significant fibrosis stage (1.2 vs. 1.1, p ‐value 0.75) and ALT (87.4 vs. 58.1 U/L, p ‐value 0.06). Their LDL‐c (51 vs. 147.8 mg/dL, p ‐value 6.1E‐09) and triglycerides (91.5 vs. 160.6 mg/dL, p ‐value 2.8E‐03) were significantly lower. Compared to controls, LDLR carriers had numerically higher steatosis grade, NAS, fibrosis stage and LDL‐c levels, but these were not statistically different. Conclusions: Monogenic disorders of dyslipidemia are rarely present in patients with MASLD and are sometimes associated with worse liver histology. Testing for these conditions may be considered on a case‐by‐case basis.

Substance use disorders (SUDs, including alcohol, cannabis, opioids, and tobacco) represent significant public health challenges. The estimated heritability of SUDs is ~50% and many individuals experience multiple SUDs concurrently. Studies have demonstrated the existence of genes shared across multiple SUDs, and identifying these SUD-shared genes is critical to developing novel prevention and treatment strategies. Here, we conducted the largest cross SUD meta-analysis to date to identify SUD-shared genes using samples genetically similar to 1000 Genomes Project European (1kg-EUR-like), African (1kg-AFR-like), and American mixed (1kg-AMR-like) populations. We defined variants that had the same direction of effects across different SUDs (i.e., concordant variants) as SUD-shared. In total, we identified 220 loci, including 40 novel loci that were not reported as SUD-associated in previous genome-wide association studies. Through gene-based analyses, gene mapping, and gene prioritization, we identified 785 SUD-shared genes. These genes are highly expressed in the amygdala, cortex, hippocampus, hypothalamus, and thalamus; and are primarily highly expressed in neuronal cells, suggesting that more brain regions may be involved in SUDs than previously reported. Concordant variants explained 56–96% of the SNP-heritability of each SUD in the 1kg-EUR-like sample. Furthermore, the top 10% of individuals in the 1kg-EUR-like and 1kg-AMR-like samples with the highest polygenic scores had odds ratios ranging from 1.95–2.87 to develop SUDs, and these polygenic scores could potentially be used to identify high-risk individuals. Lastly, using a real-world dataset, we identified seven SUD-shared genes targeting drugs that may be repurposed for treating SUDs, particularly in those suffering from comorbid SUDs.

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=2×10⁻⁶⁸) and of cirrhosis progressing to HCC (HR=1.65, P=7×10⁻⁰⁸). 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.

Background: There is a substantial heritable component to metabolic dysfunction–associated steatotic liver disease (MASLD), and several genetic variants that promote MASLD development or associate with its severity have been reported. These associations vary in terms of their effect size and degree of replication. Methods: We developed a framework to classify previously identified MASLD genetic polymorphisms into 4 tiers based on effect size and extent of replication in the literature. We tested the association between “tier 1” single-nucleotide polymorphisms (OR ≥1.5, replicated in >2 independent studies) and biopsy measures of MASLD severity in a large, well-characterized histologic cohort of MASLD patients (n=3094). Results: Across 19 “tier 1” variants reflecting 11 genetic loci, only those in the PNPLA3-SAMM50-PARVB locus showed significant associations with biopsy-proven fibrosis severity and NAFLD activity score; the highest risk was for the rs738409 p.I148M variant in PNPLA3. A genetic risk score based on “tier 1” variants, as well as a previously developed genetic risk score based on variants in PNPLA3, TM6SF2, and HSD17B13, were both associated with fibrosis and NAFLD activity score, but these results were driven entirely by PNPLA3 rs738409. Conclusions: Our study provides a framework to prioritize evaluation of genetic polymorphisms for future replication efforts and demonstrates that in a large case-only cohort, histologic severity of MASLD is only robustly associated with the presence of variation in PNPLA3 among known candidate genes. These findings may have implications for patient risk stratification based on the presence of PNPLA3 rs738409.

Fetal alcohol spectrum disorders (FASD) describe ethanol-induced developmental defects including craniofacial malformations. While ethanol-sensitive genetic mutations contribute to facial malformations, the impacted cellular mechanisms remain unknown. Signaling via bone morphogenetic protein (Bmp) is a key regulatory step of epithelial morphogenesis driving facial development, providing a possible ethanol-sensitive mechanism. We found that zebrafish carrying mutants for Bmp signaling components are ethanol-sensitive and affect anterior pharyngeal endoderm shape and gene expression, indicating that ethanol-induced malformations of the anterior pharyngeal endoderm cause facial malformations. By integrating FASD patient data, we provide the first evidence that variants of the human Bmp receptor gene BMPR1B associate with ethanol-related differences in jaw volume. Our results show that ethanol exposure disrupts proper morphogenesis of, and tissue interactions between, facial epithelia that mirror overall viscerocranial shape changes and are predictive for Bmp−ethanol associations in human jaw development. Our data provide a mechanistic paradigm linking ethanol to disrupted epithelial cell behaviors that underlie facial defects in FASD.

Acute kidney injury (AKI) is common and predicts mortality in severe malaria. Studies have reported an increased incidence of AKI in males with hemolytic features of severe malaria. Glucose-6-phosphate dehydrogenase (G6PD) deficiency, an X-linked enzymopathy, can induce hemolysis. We evaluated whether the G6PD African allele (A−) was associated with AKI in children with severe malaria. The prevalence of G6PD deficiency was 16.7% among hemizygous male children and 2.4% in female children. G6PD deficiency was associated with 2.56-fold odds of AKI (95% confidence interval, 1.33–4.93; P = .005), adjusting for age, sex, site, nutritional status, and features of hemolysis.

Vascular inflammation regulates endothelial pathophenotypes, particularly in pulmonary arterial hypertension (PAH). Dysregulated lysosomal activity and cholesterol metabolism activate pathogenic inflammation, but their relevance to PAH is unclear. Nuclear receptor coactivator 7 ( NCOA7 ) deficiency in endothelium produced an oxysterol and bile acid signature through lysosomal dysregulation, promoting endothelial pathophenotypes. This oxysterol signature overlapped with a plasma metabolite signature associated with human PAH mortality. Mice deficient for endothelial Ncoa7 or exposed to an inflammatory bile acid developed worsened PAH. Genetic predisposition to NCOA7 deficiency was driven by single-nucleotide polymorphism rs11154337, which alters endothelial immunoactivation and is associated with human PAH mortality. An NCOA7-activating agent reversed endothelial immunoactivation and rodent PAH. Thus, we established a genetic and metabolic paradigm that links lysosomal biology and oxysterol processes to endothelial inflammation and PAH.