Chronic hepatitis B (CHB) is a major global health issue. The role of rare genetic variants in CHB has not been elucidated. We aimed to identify rare allelic variants predisposing to CHB. We performed exome sequencing in 50 CHB patients who had no identifiable risk factors for CHB and 40 controls who were healthy and hepatitis B surface antibody-positive, but had never received hepatitis B vaccination. We selected six rare variant alleles and followed up their association with disease status by Sanger sequencing in a case-control study comprising 1,728 CHB patients and 1,636 healthy controls. The latter had either not been immunized with hepatitis B vaccine or had uncertain vaccination status. Our results showed that transmembrane protein 2 p.Ser1254Asn, interferon alpha 2 p.Ala120Thr, its regulator NLR family member X1 p.Arg707Cys, and complement component 2 p.Glu318Asp were associated with CHB, with P values of <1.0 × 10−7, 2.76 × 10−5, 5.08 × 10−5, 2.78 × 10−4 and odds ratios (ORs) of 2.45, 4.08, 2.34, and 1.97, respectively. The combined P value was <2.0 × 10−16. As there has been no indication of immunological functions for the associated gene, transmembrane protein 2 , we further studied its expression by immunohistochemistry, real-time polymerase chain reaction, and western blotting. Our results showed that it was strongly expressed by healthy hepatocytes, but its expression was reduced in liver tissues with CHB, hepatitis B viral (HBV) genome-containing HepG2.2.15 cells, as compared with healthy liver tissues and non-HBV genome-containing HepG2 cells ( P = 0.022 and 0.0036, respectively). Conclusion : We identified four missense mutations associated with CHB, our results providing evidence for rare inborn genetic defects that contribute to increased host susceptibility to CHB.

Background. Acute kidney injury (AKI) was a common and serious complication in patients with acute myocardial infarction (AMI). Novel biomarkers and therapies were deficient and imperative for AKI’s early diagnosis and therapy after AMI. α-Klotho was considered as an early biomarker and potential therapy for AKI recently. Previous studies reported that the expression of α-Klotho was decreased in AKI rodents, and supplement of α-Klotho alleviated kidney injury. Nevertheless, its effect has not been studied in patients presenting with AMI. Methods. A total of 155 consecutive diagnosed with AMI at emergency department whose eGFR >60 ml/min 1.73 m² were enrolled in this prospective observational cohort study which conducted between May 2016 and April 2019 in Peking University People’s Hospital. AKI was defined according to the KDIGO criteria in 2012. At admission, the clinical data of patients were collected and serum α-Klotho was tested by ELISA. The relationship between α-Klotho, serum creatinine, eGFR, systolic pressure, BNP, LVEF, and Hgb of AKI were analyzed and their discrimination performances were compared. The association variables were calculated (adjusted odds ratio) with a confidence interval (CI) of 95% by binary logistic regression. And, we followed up the incidence of CKD and rehospitalization after patients’ discharge in one year. Our study was approved by the ethics committee (no. 2016PHB042-01). Results. AKI incidence was 17.4% (27/155) during hospitalization. Compared to patients without AKI, the AKI group had obviously higher mortality and was more female and had higher incidence of chronic kidney disease, worse cardiac function, more cardiac complications, larger doses of diuretics, and less use of angiotensin-converting enzyme inhibitors/angiotensin receptor blocker. By contrary to previous animal experiments, we found serum α-Klotho levels were increased significantly in AKI patients (740.2 ± 306.8 vs. 419.0 ± 272.6 pg/mL, ). And, the areas under the receiver operating curves indicated serum α-Klotho levels had a superior discriminative power for predicting AKI after AMI compared with other risk factors (0.792, 95% CI, 0.706–0.878, ). Meanwhile, logistic regression model indicates extensive anterior myocardial infarction, Killip classification ≥2 grade, α-Klotho ≥516.9 pg/mL, eGFR (decrease per 10 ml/min 1.73 m²), Hgb, and nonuse of ACEI/ARB were the risk factors of AKI after AMI. Moreover, one-year follow-up presented AMI patients developed CKD had higher α-Klotho levels (739.7 ± 315.2 vs. 443.8 ± 292.5 pg/mL, ), but no significant difference in rehospitalization. And, patients with -Klotho ≥516.9 pg/ml was 6.699 times more likely to develop CKD than those with α-Klotho <516.9 pg/ml (relative risk 6.699, 95% CI 1.631–27.519, ). Conclusion. Compared with traditional cardiac and renal biomarkers, serum α-Klotho could be a more appropriate predict biomarker for AKI after AMI in patients’ eGFR >60 ml/min 1.73 m². Higher α-Klotho levels are related to the development of AKI during hospitalization and suggest a higher prevalence of CKD after discharge. By contrary to animal experiments, whether the increased expression of α-Klotho could be a protective factor secreted by AKI after AMI, is remained to be further studied.

Macrophage activation syndrome (MAS) represents a subtype of hemophagocytic lymphohistiocytosis (HLH) associated with autoimmune diseases. Systemic lupus erythematosus (SLE) is one of the most common autoimmune diseases that induce MAS. The overlapping systemic symptoms of SLE and clinical manifestations of HLH pose challenges in clinical diagnosis, contributing to significant rates of underdiagnosis and misdiagnosis, warranting further investigation. Identifying early diagnostic biomarkers with high sensitivity and specificity for MAS in SLE holds significant clinical importance. Active SLE (SLEDAI 2k score≥5) patients were recruited from January 2022 to January 2024, from Peking University People's Hospital. MAS was diagnosed according to HLH-2004 criteria or HScore≥ 169. RNA sequencing was utilized to conduct a preliminary examination of the differences in mRNA expression profiles among peripheral blood mononuclear cells (PBMC) derived from healthy controls (HC), patients with moderately active SLE, and those with SLE-MAS. Subsequently, key differentially expressed mRNA candidates were selected to verify their accuracy in predicting MAS within the active SLE population by stratifying SLE patients into groups with or without MAS through using Real-time PCR method. Meanwhile, clinical baseline data were collected for further analysis. Overall, 50 active SLE patients were enrolled eventually, 28 % developed MAS. In this study, RNA-seq of PBMCs from active SLE patients revealed KLRG1, KLRC3, and ULK2 as key mRNA predictors of SLE-MAS. Clinically, SLE-MAS patients showed higher rates of fever, cytopenia, lymphadenopathy, acute liver injury, and thrombotic microangiopathy, and with obvious abnormal HLH-related laboratory tests in comparison with active SLE group. Among the three transcripts, KLRG1 achieved the best performance (AUC 0.927, sensitivity 88.9 %, specificity 92.9 %), KLRC3 and ULK2 all have to been shown good identification ability, with an AUC of 0.885 and 0.843 respectively, all outperforming traditional diagnostic indicators including Fer, FIB, and TG. KLRG1, KLRC3, and ULK2 are potential biomarkers for predicting MAS in SLE patients. Among them, KLRG1 has the highest sensitivity (0.889) and specificity (0.929) for predicting SLE induced MAS, which is considered the optimal biomarker for diagnosing MAS in SLE. These findings position KLRG1 as a minimally invasive, early-warning biomarker that could promptly predict MAS and might guide timely MAS-directed therapy in SLE.