Objective To explore the clinical significance of serum cytokine expression in the hepatitis B surface antigen(HBsAg)sero-clearance in patients with severe hepatitis B.Methods A nested case-control trial was conducted on 14 inpatients with severe hepatitis B admitted in our hospital from 2006 to 2020.Of them,7 patients(aged 36.57±3.15 years)achieved HBsAg sero-clearance within 1 year after the onset of hepatitis B flares(with abrupt rise of ALT level to＞5 times the upper limit of normal during HBV infection)and were assigned into HBsAg clearance group,while the other 7 patients(aged 34.14±2.97 years)only obtained HBsAg decreased less than 1 g within 1 year after the onset(HBsAg non-clearance group).Then,multiplex liquid-chip assay based on Luminex xMAP was used to detect the expression levels of 48 cytokines such as IFN-γ and IL-2 in serum samples of these 14 patients.Results The serum levels IFN-γ,IL-2Ra and SDF-1α were significantly lower in the HBsAg clearance group than the HBsAg non-clearance group(P＜0.05),but no statistical differences were observed in other 39 cytokines between the 2 groups.And there were 5 cytokines having no mutual expression in both groups.The copy number of HBV DNA was positively correlated with serum HGF(r=0.675,P=0.008)and SDF-1α levels(r=0.587,P=0.027),while negatively with IP-10(r=-0.600,P=0.023)and MIG level(r=-0.640,P=0.014).Meanwhile,a positive correlation was found between HBsAg titer and IL12-p70 level(r=0.593,P=0.025),and a negative correlation between HBsAg titer and TNF-α level(r=-0.609,P=0.021).In addition,the serum total bilirubin level was positively correlated with the expression of SCGF-β(r=0.543,P=0.045).Conclusion Three differentially expressed cytokines and some cytokines related to HBV DNA level and HBsAg titer are found,which may provide new insights into the underlying immunological mechanism of HBV virus clearance caused by hepatitis flares.Meanwhile,it also provides potential biomarkers for HBsAg serological clearance in patients with severe hepatitis B.

Objective:To investigate the clinical and gene variant characteristics of PCDH19 gene related epilepsy, and improve the ability of clinicians in early disease identification. Methods:The clinical data of 3 PCDH19 gene related epilepsy patients admitted to Children′s Hospital Affiliated to Zhengzhou University from October 2018 to August 2023 diagnosed by gene detection were reviewed and analyzed. Results:All the patients are female, and the onset age of seizure ranged in their infancy. Seizures in clusters and fever sensitivity were observed in all patients, and were very hard to control by single-drug treatment. Proband 1 was seizure-free after 2 kinds of anti-epileptic drug treatment, but with mild degree of intellectual disability. Proband 2 had refractory epilepsy with severe degree of intellectual disability. Proband 3 was seizure-free after 2 kinds of anti-epileptic drug treatment and without intellectual disability. In the first family, the proband carried heterozygous c.369C>G variant in the PCDH19 gene which was identified as de novo after parental validation. In the second family, the proband carried c.1652T>A variant inherited from her mother. In the third family, the proband carried c.278G>A variant inherited from her father. The 3 mutations had not been reported in the Human Gene Mutation Database. Conclusions:PCDH19 gene related epilepsy is one special kind of X-linked inherited epilepsy syndrome characterized by seizures in clusters and sensitivity to fever. And gene detection can help with early diagnosis and make rational clinical strategies in time. The variants c.369C>G, c.1652T>A and c.278G>A have enriched the gene variant spectrum of PCDH19.

Crigler-Najjar syndrome (CNS) is an autosomal recessive disorder in which the content of plasma unconjugated bilirubin is increased due to the reduction or complete deficiency of the activity of bilirubin uridine diphosphate glucuronosyl transferase 1A1 (UGT1A1), classified as CNS type Ⅰ and Ⅱ. CNS type Ⅰ is the most severe, which will develop into kernicterus, damage the brain nervous system, and even threaten the life of patients. This article introduces six CNS treatment techniques, including phototherapy, plasma exchange, drug therapy, liver transplantation, hepatocyte transplantation and gene therapy. The applicable patient types, treatment effects and existing deficiencies of each technique were summarized. Phototherapy, plasma exchange, drug therapy and hepatocyte transplantation can temporarily control serum levels and reduce the risk of jaundice, but cannot completely restore UGT1A1 enzyme activity; liver transplantation is currently the only treatment option for CNS type Ⅰ patients, but is limited by suitable liver donors and post-operative immune rejection. Gene therapy has the most promising application in the treatment of genetic disorders such as CNS, which can provide more viable therapeutic techniques for CNS patients.

We report a case of type A insulin resistance syndrome. A 16-year-old girl with BMI of 19.1 kg/m 2 presented with primary amenorrhea and hyperglycemia for two years. Baseline HbA 1C was 10.8%, along with severe hyperinsulinemia, increased total testosterone and free androgen index(FAI). Ultrasonography showed polycystic ovaries. Next generation sequencing identified a novel and de novo heterozygous missense mutation of Trp1220Gly in the insulin receptor gene. Short-term intensive insulin pump treatment was initiated, followed by insulin glargine, pioglitazone and acarbose combination regiment. Fasting blood glucose and insulin levels decreased significantly, but post-load hyperglycemia and hyperinsulinemia remained unsatisfactory. HbA 1C dropped to 7.6% at 1-year follow up. Patients with polycystic ovarian syndrome who are adolescent-onset and with lean body type should be taken into account of type A insulin resistance syndrome. Currently, there is no standardized treatment protocol, and therapy should be individualized based on the specific gene mutation of each patient.

Objective:To examine the heritability of body mass index (BMI) and coronary heart disease (CHD), and to explore whether genetic factors can explain their correlation.Methods:Participants were from 11 provinces/municipalities reqistered in the Chinese National Twin Registry (CNTR) from 2010 to 2018. Participants data were collected from face-to-face questionnaire survey. Bivariate structure equation model was used to estimate the heritability and the genetic correlation of BMI and CHD.Results:A total of 20 340 pairs of same-sex twins aged ≥25 years were included in this study. After adjusting for age and gender, the heritability of BMI and CHD was 0.52 (95% CI: 0.49-0.55) and 0.76 (95% CI: 0.69-0.81), respectively. Further, a genetic correlation was identified between BMI and CHD ( rA=0.10, 95% CI:0.02-0.17). Conclusion:In Chinese adult twin population, BMI and CHD are affected by genetic factors, and their correlation can be attributed to the common genetic basis.

Objective:To examine the heritability of body mass index (BMI) and coronary heart disease (CHD), and to explore whether genetic factors can explain their correlation.Methods:Participants were from 11 provinces/municipalities reqistered in the Chinese National Twin Registry (CNTR) from 2010 to 2018. Participants data were collected from face-to-face questionnaire survey. Bivariate structure equation model was used to estimate the heritability and the genetic correlation of BMI and CHD.Results:A total of 20 340 pairs of same-sex twins aged ≥25 years were included in this study. After adjusting for age and gender, the heritability of BMI and CHD was 0.52 (95% CI: 0.49-0.55) and 0.76 (95% CI: 0.69-0.81), respectively. Further, a genetic correlation was identified between BMI and CHD ( rA=0.10, 95% CI:0.02-0.17). Conclusion:In Chinese adult twin population, BMI and CHD are affected by genetic factors, and their correlation can be attributed to the common genetic basis.

Objective:To report four male COL4A5 mutation mosaicism patients with X-linked Alport syndrome, and to provide evidence for diagnosis, genetic counseling, and reproduction in the respective families and improve our knowledge of mosaicism in Alport syndrome. Methods:Suspected male mosaic patients for COL4A5 who met the following criteria: clinical diagnosis of Alport syndrome, harbored COL4A5 mutations detected using next generation sequencing or Sanger sequencing, heterozygosity for the mutant and normal COL4A5 alleles in the DNA demonstrated by Sanger sequencing, registered in the on-line registry of hereditary kidney diseases, and admitted to Peking University First Hospital during the period of April 2018 to April 2019 were enrolled. Clinical data and karyotypes were retrospectively analyzed. Genetic DNA isolated from multiple tissues was analyzed for COL4A5 gene mutations by using PCR and Sanger sequencing. Related literatures published in PubMed, CNKI and Wanfang databases were reviewed. Results:Four COL4A5 somatic and germline mosaic male patients with Alport syndrome were included in the study. Patient 1 was characterized by hematuria and proteinuria. His karyotype of peripheral blood was normal. COL4A5 c.3455-1G>A mosaicism was detected in multiple tissues (peripheral blood, saliva and urine). Patient 2 presented with hematuria and microalbuminuria. His karyotype of peripheral blood was normal. COL4A5 c.4994+1G>A mosaicism was detected in multiple tissues (peripheral blood, saliva and skin fibroblasts). Patients 3 showed hematuria without proteinuria. COL4A5 c.3535G>A mosaicism was found in genomic DNA of peripheral blood and hair. Laboratory and physical examinations of patient 4 showed hematuria and normal renal function, without proteinuria, megasoma or small testes. COL4A5 c.3106G>A mosaicism was detected in genomic DNA of skin fibroblasts. Although without karyotype analysis due to unavailable specimens, 47,XXY or 46,XY/47,XXY mosaicism was not considered according to the reproductive history and lack of clinical manifestations of megasoma and small testes in patients 3 and 4. Renal disease in 8 published male cases with mosaicism for COL4A5 was affected by mutant allelic fractions and genotype. Conclusions:Compared with hemizygous males with X-linked Alport syndrome, the renal phenotype of mosaic males was milder, and associated with mutant allelic fractions and mutation type.

Objective:To describe the differences in body mass index (BMI) distribution in adult twins registered in Chinese National Twin Registry (CNTR), and provide evidence for the risk factor analysis and prevention and control of overweight or obesity.Methods:A total of 32 725 twin pairs aged 18 years and above who completed the questionnaire survey during 2010-2018 and had complete registered information in CNTR and normal body weight and length were included in the analysis on the population and region specific distributions of BMI of twin pairs and the difference in BMI in twin pairs.Results:The twin pairs included in the analysis were aged (34.6±12.4) years, the twin pairs of same gender accounted for 79.7%. The average BMI was 22.5 kg/m 2. The overall prevalence of obesity and overweight was 4.9% and 23.7%, respectively. Participants who were men, 50-59 years old, married, had lower education level, and lived in northern China had higher overweight rate and obesity rate ( P<0.001). The difference in overweight or obesity prevalence between monozygotic (MZ) twin pars and dizygotic (DZ) twin pairs was not significant, but firstborn twin pairs had slightly higher rates of overweight and obesity than later-born twin pairs ( P<0.05). The analysis in same gender-twin pairs indicated that the difference in BMI was associated with age (trend test: P<0.001), and the difference was more obvious in DZ twin pair in MZ pair and this difference increased with age. The concordant rate of BMI was higher in MZ twin pairs than DZ twin pairs ( P<0.05). Conclusion:The distribution of BMI of twin pairs varied with population and region and BMI varied with age due to its genetic nature.

Objective:To explore the modification effect of physical activity on the genetic effects of type 2 diabetes mellitus (T2DM).Methods:The univariate moderation model was fitted to calculate the modifying effect of physical activity on the genetic effects of T2DM based on the data of 12 107 pairs of same gender twins aged 30 years and older enrolled by the Chinese National Twin Registry in 11 provinces/cities in China.Results:After adjusting for age and gender, the heritability of T2DM was 0.56 (0.31-0.84). Qualified physical activity could attenuate the genetic effects of T2DM. The heritability of T2DM in twin pairs with qualified physical activity was 0.46 (0.06-0.88), which was lower than that in twin pairs without qualified physical activity during the same model [0.68(0.36-0.94)].Conclusion:T2DM is a moderate genetic disease, physical activity can modify the genetic effects of T2DM.

Objective:To explore the gene-body mass index (BMI) interaction on coronary heart disease (CHD) in the Chinese adult twins.Methods:A total of 20 340 same-sex twin pairs registered in the Chinese National Twin Registry (CNTR) were enrolled in this study. Classical twin structure equation model was used to estimate the gene-BMI interaction on CHD.Results:After adjusting for age, we found that genetic variance of CHD differed as the function of BMI in male twins, which indicated the presence of a gene-BMI interaction on CHD ( P=0.008).The genetic moderating effect ( βa) was -0.14 (95% CI: -0.22--0.04), indicating that for each logarithmic transformation value of BMI increase, genetic path parameters would decrease by 0.14, which would result in the decrease of genetic variance of CHD. And the heritability of CHD was 0.77 (95% CI: 0.65-0.86) among the male twins with lower BMI (<24.0 kg/m 2), but 0.56 (95% CI: 0.33-0.74) among the male twins with high BMI (≥24.0 kg/m 2). However, there was no evidence suggesting that BMI could moderate genetic variants of CHD in female. Conclusion:We found a significant gene-BMI interaction on CHD in the Chinese male adult twins in China, and the heritability of CHD was higher among the twins whose BMI was <24.0 kg/m 2.