East Asian-specific and cross-ancestry genome-wide meta-analyses provide mechanistic insights into peptic ulcer disease.

Peptic ulcer disease (PUD) refers to acid-induced injury of the digestive tract, occurring mainly in the stomach (gastric ulcer (GU)) or duodenum (duodenal ulcer (DU)). In the present study, we conducted a large-scale, cross-ancestry meta-analysis of PUD combining genome-wide association studies with Japanese and European studies (52,032 cases and 905,344 controls), and discovered 25 new loci highly concordant across ancestries. An examination of GU and DU genetic architecture demonstrated that GUs shared the same risk loci as DUs, although with smaller genetic effect sizes and higher polygenicity than DUs, indicating higher heterogeneity of GUs. Helicobacter pylori (HP)-stratified analysis found an HP-related host genetic locus. Integrative analyses using bulk and single-cell transcriptome profiles highlighted the genetic factors of PUD being enriched in the highly expressed genes in stomach tissues, especially in somatostatin-producing D cells. Our results provide genetic evidence that gastrointestinal cell differentiations and hormone regulations are critical in PUD etiology.

Genetically proxied HTRA1 protease activity and circulating levels independently predict risk of ischemic stroke and coronary artery disease.

HTRA1 has emerged as a major risk gene for stroke and cerebral small vessel disease with both rare and common variants contributing to disease risk. However, the precise mechanisms mediating this risk remain largely unknown as does the full spectrum of phenotypes associated with genetic variation in HTRA1 in the general population. Using a family-history informed approach, we first show that rare variants in HTRA1 are linked to ischemic stroke in 425,338 European individuals from the UK Biobank with replication in 143,149 individuals from the Biobank Japan. Integrating data from biochemical experiments on 76 mutations occurring in the UK Biobank, we next show that rare variants causing loss of protease function in vitro associate with ischemic stroke, coronary artery disease, and skeletal traits. In addition, a common causal variant (rs2672592) modulating circulating HTRA1 mRNA and protein levels enhances the risk of ischemic stroke, small vessel stroke, and coronary artery disease while lowering the risk of migraine and age-related macular dystrophy in GWAS and UK Biobank data from > 2,000,000 individuals. There was no evidence of an interaction between genetically proxied HTRA1 activity and levels. Our findings demonstrate a central role of HTRA1 for human disease including stroke and coronary artery disease and identify two independent mechanisms that might qualify as targets for future therapeutic interventions.

Stroke genetics informs drug discovery and risk prediction across ancestries.

Previous genome-wide association studies (GWASs) of stroke - the second leading cause of death worldwide - were conducted predominantly in populations of European ancestry1,2. Here, in cross-ancestry GWAS meta-analyses of 110,182 patients who have had a stroke (five ancestries, 33% non-European) and 1,503,898 control individuals, we identify association signals for stroke and its subtypes at 89 (61 new) independent loci: 60 in primary inverse-variance-weighted analyses and 29 in secondary meta-regression and multitrait analyses. On the basis of internal cross-ancestry validation and an independent follow-up in 89,084 additional cases of stroke (30% non-European) and 1,013,843 control individuals, 87% of the primary stroke risk loci and 60% of the secondary stroke risk loci were replicated (P < 0.05). Effect sizes were highly correlated across ancestries. Cross-ancestry fine-mapping, in silico mutagenesis analysis3, and transcriptome-wide and proteome-wide association analyses revealed putative causal genes (such as SH3PXD2A and FURIN) and variants (such as at GRK5 and NOS3). Using a three-pronged approach4, we provide genetic evidence for putative drug effects, highlighting F11, KLKB1, PROC, GP1BA, LAMC2 and VCAM1 as possible targets, with drugs already under investigation for stroke for F11 and PROC. A polygenic score integrating cross-ancestry and ancestry-specific stroke GWASs with vascular-risk factor GWASs (integrative polygenic scores) strongly predicted ischaemic stroke in populations of European, East Asian and African ancestry5. Stroke genetic risk scores were predictive of ischaemic stroke independent of clinical risk factors in 52,600 clinical-trial participants with cardiometabolic disease. Our results provide insights to inform biology, reveal potential drug targets and derive genetic risk prediction tools across ancestries.

Transmission of a Novel Genotype of Hepatitis E Virus from Bactrian Camels to Cynomolgus Macaques.

Hepatitis E virus (HEV) is zoonotic and a major cause of acute viral hepatitis worldwide. Recently, we identified a novel HEV genotype 8 (HEV8) in Bactrian camels in Xinjiang, China. However, the epidemiology, pathogenicity, and zoonotic potential of HEV8 are unclear. Here, we present the prevalence of HEV8 in China and investigate its pathogenicity and cross-species transmission in cynomolgus macaques. Fresh fecal and milk samples from Bactrian camels collected from four provinces/regions in China were screened for HEV RNA by reverse transcriptase PCR (RT-PCR). An HEV8-positive sample was used to inoculate two cynomolgus macaques to examine the potential for cross-species infection. The pathogenicity of HEV8 was analyzed by testing HEV markers and liver function during the study period and histopathology of liver biopsy specimens at 3, 13, and 25 weeks postinoculation. Extrahepatic replication was tested by using reverse transcriptase quantitative PCR (RT-qPCR) and immunofluorescence assays. The overall prevalence of HEV8 RNA in Chinese Bactrian camels was 1.4% (4/295), and positive samples were found in three different provinces/regions in China. Histopathology confirmed acute and chronic HEV8 infections in the two monkeys. Multiple tissues were positive for HEV RNA and ORF2 proteins. Renal pathology was observed in the monkey with chronic hepatitis. Whole-genome sequencing showed only 1 to 3 mutations in the HEV8 in the fecal samples from the two monkeys compared to that from the camel. HEV8 is circulating in multiple regions in China. Infection of two monkeys with HEV8 induced chronic and systemic infections, demonstrating the high potential zoonotic risk of HEV8.IMPORTANCE It is estimated that one-third of the world population have been exposed to hepatitis E virus (HEV). In developed countries and China, zoonotic HEV strains are responsible for almost all acute and chronic HEV infection cases. It is always of immediate interest to investigate the zoonotic potential of novel HEV strains. In 2016, we discovered a novel HEV genotype, HEV8, in Bactrian camels, but the epidemiology, zoonotic potential, and pathogenicity of the virus were unknown. In the present study, we demonstrated that HEV8 was circulating in multiple regions in China and was capable of infecting cynomolgus macaques, a surrogate for humans, posing high risk of zoonosis. Chronic hepatitis, systemic infection, and renal pathology were observed. Collectively, these data indicate that HEV8 exhibits a high potential for zoonotic transmission. Considering the importance of Bactrian camels as livestock animals, risk groups, such as camelid meat and milk consumers, should be screened for HEV8 infection.