Serum Uric Acid Levels and Their Association with Renal Function Decline and Kidney Disease Progression in Middle-Aged and Elderly Populations: A Retrospective Cohort Study.

Objective: To evaluate the associations between serum uric acid (SUA) levels and estimated glomerular filtration rate (eGFR) and chronic kidney disease (CKD), with a focus on gender differences, and variations among women pre-and post-menopausal stages. Design: A retrospective cohort study. Setting: A large community-based survey was conducted every two years from 2010 to 2018 in Hangzhou, Zhejiang Province, Southeastern China. Participants: 10,218 participants (40 years or above) without CKD at baseline who underwent three physical examinations were enrolled. CKD was defined as an eGFR of less than 60 mL/min/1.73m2. Methods: Participants with SUA levels were divided into four groups (Q1-Q4) based on baseline SUA quartiles. The Q1 was the reference. By stratifying participants by gender, the relationships between SUA levels and eGFR were investigated using the generalized additive mixture model. The associations of SUA and the risk of incident CKD were examined using multivariate logistic regression models in the generalized estimating equation. Results: After adjusting for confounding variables, a nonlinear association between SUA and eGFR was observed in females, while an approximately linear relationship was observed in males, suggesting that elevated SUA levels are associated with renal function decline. Furthermore, the highest quartile of SUA was associated with a 2.16-fold (95% CI: 1.31-3.58) increased risk of CKD in males and a 2.76-fold (95% CI: 1.59-4.78) increased risk in females, compared with the lowest quartile. And the spline curves demonstrated a U-shaped pattern, suggesting a potential threshold effect of SUA on the risk of CKD. Additionally, Subgroup analyses revealed significant associations between elevated SUA levels with CKD in postmenopausal women, but not in premenopausal women. Conclusion: Elevated SUA levels are associated with an increased risk of CKD development and renal function decline in middle-aged and elderly individuals, particularly in postmenopausal women.

Role of serum ceruloplasmin in the diagnosis of Wilson's disease: A large Chinese study.

Background: Conventionally, serum ceruloplasmin levels below the lower reference limit (0. 20 g/L) is considered a diagnostic cutoff point for Wilson's disease (WD). However, the lower reference limit varies with assay methodologies and the individuals in the included studies. The objective of this study was to determine the optimal cutoff value of serum ceruloplasmin levels for the diagnosis of WD in a large Chinese cohort and to identify factors associated with serum ceruloplasmin. Methods: The cutoff value of ceruloplasmin levels was developed based on a retrospective derivation cohort of 3,548 subjects (1,278 patients with WD and 2,270 controls) and was validated in a separate validation cohort of 313 subjects (203 patients with WD and 110 controls). The performance of immunoassay was tested by receiver operating characteristic curve (ROC) analysis, and differences among the groups were analyzed by using the Mann-Whitney U-test and the Kruskal-Wallis test. Results: The conventional cutoff of serum ceruloplasmin levels of <0.2 g/L had an accuracy of 81.9%, which led to a false-positive rate of 30.5%. The optimal cutoff of the serum ceruloplasmin level for separating patients with WD from other participants was 0.13 g/L, as determined by ROC analysis. This cutoff value had the highest AUC value (0.99), a sensitivity of 97.0%, and a specificity of 96.1%. Moreover, it prevented unnecessary further investigations and treatments for 492 false-positive patients. By determining the correlation between serum ceruloplasmin and phenotypes/genotypes in patients with WD, we found that the serum ceruloplasmin level was lower in early-onset patients and higher in late-onset patients. Interestingly, patients with the R778L/R919G genotype had higher serum ceruloplasmin levels than patients with other hot spot mutation combinations. Conclusion: Our work determined the optimal cutoff value of serum ceruloplasmin levels for the diagnosis of WD and identified differences in serum ceruloplasmin levels with respect to the age of symptom onset and ATP7B mutations, which may provide some valuable insights into the diagnosis and counsel of patients with WD.

Myositis-specific autoantibodies and their clinical associations in idiopathic inflammatory myopathies: results from a cohort from China.

OBJECTIVES: The purpose of this study was to determine the incidence of myositis-specific autoantibodies (MSAs) in a cohort of Chinese patients with idiopathic inflammatory myopathies (IIMs) and to examine their associations with clinical characteristics and long-term prognosis. METHODS: Adult patients with confirmed IIMs (n = 515) were studied using the EUROLINE Autoimmune Inflammatory Myopathies 16 Ag (IgG) commercial line blot test to detect MSAs/myositis-associated autoantibodies. We collected the laboratory data and clinical features. The frequencies of MSAs and their associations with clinical phenotypes were evaluated using SPSS 25.0 software. RESULTS: At least one MSA was found in 88.2% of the 515 IIM patients studied. The most frequently detected MSAs were anti-MDA5 (25.4%), anti-Jo-1(15.1%), and anti-EJ (9.5%). Autoantibodies against MDA5, TIF1-γ, and NXP2 were significantly correlated with cutaneous involvement (P < 0.001 or P < 0.01). Anti-TIF1-γ-positive patients had an enhanced risk of malignancy (OR = 3.51). Rapidly progressive interstitial lung disease (RP-ILD) was significantly correlated with anti-MDA5 (P < 0.0001). Anti-MDA5-positive patients had increased risks of elevated ferritin and decreased lymphocyte counts (OR = 5.65 and OR = 5.74, respectively). Kaplan-Meier survival revealed that individuals positive for anti-MDA5, especially anti-MDA5 combined with anti-Ro52, had the worst prognosis (P = 0.03). Male, old age, RP-ILD, and elevated ferritin were identified as predictors of poor prognosis in IIM patients. CONCLUSIONS: MSAs were present in the majority of the IIM patients. Numerous MSAs were independent factors for identifying exceptional clinical phenotypes. Key Points • This is a large Chinese cohort of IIM patients to analyze possible associations of MSA profiles with clinical characteristics, aiming to provide valuable data for clinical work. • MSAs were present in approximately 90% of IIM patients with distinct clinical subsets. Patients with anti-Jo-1 and non-anti-Jo-1 ASAs exhibited similar characteristics. • The association of anti-TIF1-γ with malignancy was confirmed in adult patients. Patients with IIMs who were positive for both anti-Ro52 and anti-MDA5 had a worse prognosis. • Male, RP-ILD, and heliotrope rash were independent risk factors for a poor prognosis in patients with IIMs.

Genotype-Phenotype Relationship and Follow-up Analysis of a Chinese Cohort With Osteogenesis Imperfecta.

OBJECTIVE: To evaluate the genotype-phenotype relationship and the effect of treatment on the clinical course of osteogenesis imperfecta (OI). METHODS: We established a Chinese hospitalized cohort with OI and followed them up for an average of 6 years. All patients were confirmed as having OI using whole-exome sequencing. We analyzed the genotype-phenotype relationship based on different types, pathogenic mechanisms, and gene inheritance patterns of OI. Additionally, we assessed whether there was a difference in treatment efficacy based on genotype. RESULTS: One hundred sixteen mutations in 6 pathogenic genes (COL1A1, COL1A2, IFITM5, SERPINF1, FKBP10, and WNT1) were identified in 116 patients with type I, III, IV, V, VI, XI, or XV OI. Compared with patients with COL1A1 mutations, patients with COL1A2 mutations were younger at the time of the first fracture, whereas other phenotypes were similar. When 3 groups (helical, haploinsufficiency, and non-collagen I gene mutations) were compared, patients with helical mutations were the shortest and most prone to dentinogenesis imperfecta. Patients with haploinsufficiency mutations were the oldest at the time of the first fracture. Moreover, patients with non-collagen I gene mutations were least susceptible to blue sclerae and had the highest fracture frequency. Furthermore, there were some minor phenotypic differences among non-collagen I gene mutations. Interestingly, pamidronate achieved excellent results in the treatment of patients with OI, and the treatment effect appeared to be unrelated to their genotypes. CONCLUSION: Our findings indicated a genotype-phenotype relationship and a similar effect of pamidronate treatment in patients with OI, which could provide a basis for guiding clinical treatment and predicting OI prognosis.

Genotype-phenotype correlation and natural history analyses in a Chinese cohort with pelizaeus-merzbacher disease.

BACKGROUND: The natural history and genotype-phenotype correlation of Pelizaeus-Merzbacher disease (PMD) of Chinese patients has been rarely reported. METHOD: Patients who met the criteria for PMD were enrolled in our study. Genomic analysis was conducted by multiplex ligation probe amplification (MLPA) and Sanger or whole-exome sequencing (WES). Natural history differences and genotype-phenotype correlations were analyzed. RESULT: A total of 111 patients were enrolled in our follow-up study. The median follow-up interval was 53 m (1185). Among PMD patients, developmental delay was the most common sign, and nystagmus and hypotonia were the most common initial symptoms observed. A total of 78.4% of the patients were able to control their head, and 72.1% could speak words. However, few of the patients could stand (9.0%) or walk (4.5%) by themselves. Nystagmus improved in more than half of the patients, and hypotonia sometimes deteriorated to movement disorders. More PLP1 point mutations patients were categorized into severe group, while more patients with PLP1 duplications were categorized into mild group (p < 0.001). Compared to patients in mild groups, those in the severe group had earlier disease onset and had acquired fewer skills at a later age. CONCLUSION: PMD patients have early disease onset with nystagmus and hypotonia followed by decreased nystagmus and movement disorders, such as spasticit. Patients with PLP1 duplication were more likely to be categorized into the mild group, whereas patients with point mutations were more likely to be categorized into the severe group.

Can Active Surveillance Management be Developed for Patients With Low-Risk Papillary Thyroid Microcarcinoma? A Preliminary Investigation in a Chinese Population.

OBJECTIVE: Active surveillance (AS) has been shown to be a safe approach that can effectively block transition from overdiagnosis to overtreatment in patients with low-risk papillary thyroid microcarcinoma (PTMC). This study aimed to determine whether the AS approach can be implemented in China and investigate the population characteristics of Chinese patients who underwent AS. METHODS: The epidemiologic and clinical characteristics as well as patient adherence were evaluated in 115 patients who underwent AS management as an alternative to immediate surgery for low-risk (or highly suspected) PTMC. RESULTS: The mean patient age was 41.8 ± 10.3 years, with 41.7% and 4.4% of the patients aged <40 and ≥60 years, respectively. The median baseline diameter of index tumors was 4 (range, 3-6) mm, with 73.0% of the tumors being ≤5 mm. A total of 84.4% of the patients had a junior college, college, or graduate degree, and 83.5% were employed by the government, public institutions, companies, or technical posts. After a median 25-month follow-up, a tumor growth of ≥3 mm occurred in 3 patients (2.6%), and no new lymph node metastasis occurred. Surgery was performed in 4 patients because of patient preferences rather than because of disease progression. There was satisfactory adherence in 109 patients (94.8%) in a simulated ideal medical environment. CONCLUSION: The AS approach can be used as an alternative to low-risk PTMC management in China. Given the difference in epidemiologic and clinical characteristics, Chinese institutions should fully consider the features of the Chinese population while developing candidate criteria, surveillance intervals, and follow-up strategies for AS.

The prevalence of hereditary angioedema in a Chinese cohort with decreased complement 4 levels.

OBJECTIVE: Hereditary angioedema (HAE) is a rare, life-threatening autosomal dominant disorder. We aimed to investigate the prevalence of HAE in a Chinese population with a decreased Complement 4 (C4) level. METHODS: All the patients present in Tongji Hospital with C4 below lower normal range were included from January 2019 to June 2020. The individual data were extracted from the database and categorized by diagnosis. Patients suspected of HAE were further evaluated by C1 inhibitor level and function test to confirm the HAE diagnosis. RESULTS: A total of 8226 patients were enrolled in our study, among whom 18 had symptoms similar to HAE and received C1 inhibitor level and function tests. Two (1 male and 1 female) of the 18 patients were identified as HAE patients. This means the prevalence of HAE was 2.43/10 000 among the C4-decreased population and 10.1/10 000 in the C4-decreased population with etiology undetermined. The 2 HAE patients had experienced skin and oropharynx edema attack and received tracheotomy. The female patient had a family history. Laboratory tests showed significant decrease of C4 and C1 inhibitor levels in the 2 patients, both of whom were diagnosed as type 1 HAE. CONCLUSION: The prevalence of HAE is low in C4-decreased patients. In a large cohort, C4 level can serve as a practical indicator to screen the HAE patients, but further testing of C1 inhibitor activity and levels is needed to confirm the diagnosis of HAE.

Association of the programmed death ligand-1 combined positive score in tumors and clinicopathological features in esophageal cancer.

BACKGROUND: The combined positive score (CPS) of the programmed death ligand-1 (PD-L1) 22C3 assay is a predictive marker of pembrolizumab monotherapy for advanced esophageal cancer (EC) patients. However, little is known about the association of the PD-L1 22C3 CPS with the clinicopathological features and heterogeneity of PD-L1 expression in EC in the Chinese population in a real-world setting. METHODS: We examined the association of the PD-L1 22C3 CPS with clinicopathological characteristics in 533 EC specimens. Further, we compared 37 cases' different blocks of the same specimen and 50 paired primary/metastatic lymph node lesions to investigate the heterogeneity of PD-L1 expression. RESULTS: PD-L1 positive expression was observed in 45.0% of 533 EC patients, including 46.8% with squamous cell carcinoma, 15.4% with adenocarcinoma, 28.6% with basaloid squamous carcinoma, 42.9% with spindle cell carcinoma, and 33.3% with neuroendocrine tumors. PD-L1 positive expression was positively associated with lymph node metastasis (59.2% chance, p = 0.021) and venous/lymphatic invasion (66.3% chance, p = 0.029). PD-L1 expression was highly consistent in different paraffin blocks of the same surgically resected specimen (concordance rate: 86.5%, p = 0.000016) and a moderate consistency (concordance rate: 78.0%, p = 0.000373) for the primary and metastatic lymph node lesion comparison. CONCLUSIONS: This is a novel study which demonstrated a positive correlation between a high PD-L1 22C3 CPS and invasion/metastasis risk in EC surgical specimens. Both paired blocks and paired primary/metastatic lymph node lesions showed significant concordance. PD-L1 heterogeneity was inferred to be mainly related to positive mononuclear inflammatory cells (MICs), which might have substantial implications for clinical practice.

Genetic analysis and prenatal diagnosis of 76 Chinese families with X-linked adrenoleukodystrophy.

BACKGROUND: Variants in the ATP binding cassette protein subfamily D member 1 (ABCD1) gene are known to cause X-linked adrenoleukodystrophy (X-ALD). This study focused on the characteristics of ABCD1 variants in Chinese X-ALD families and elucidated the value of genetic approaches for X-ALD. METHODS: 68 male probands diagnosed as X-ALD were screened for ABCD1 variants by the Sanger sequencing of polymerase chain reaction (PCR) products and multiplex ligation-dependent probe amplification (MLPA) combined with long-range PCR. Prenatal diagnosis was performed in 20 foetuses of 17 probands' mothers. Descriptive statistics were used to summarise the gene variants and prenatal diagnosis characteristics and outcomes. RESULTS: This study allowed the identification of 61 variants occurring in 68 families, including 58 single nucleotide variants or small deletion/insertion variants and 3 large deletions. Three probands with no variants detected by next-generation sequencing were found to have variants by PCR-sequencing. Prenatal diagnosis found that 10 of the 20 foetuses had no variants in ABCD1. CONCLUSION: PCR primers that do not amplify the pseudogenes must be used for PCR-sequencing. MLPA combined with long-range PCR can detect large deletions and insertions, which are usually undetectable by PCR-sequencing. Prenatal diagnosis could help to prevent the birth of infants with X-ALD.

A Predictive Model of Metabolic Syndrome by Medical Examination: Evidence from an 8-Year Chinese Cohort.

PURPOSE: To develop a predictive model for the risk of metabolic syndrome (MetS). PATIENTS AND METHODS: Totally, 1556 residents without MetS were finally included in 2006 and they were observed for 8 years to check who developed MetS. Univariate and multivariate logistic regression analyses was adopted to explore the risk factors of MetS and develop the predictive model that used the medical examination information of MetS risk after 8 years. The receiver operating characteristic (ROC) curve was drawn to assess the predictive capacity of the model. RESULTS: The risk of MetS in overweight, prehypertension, hypertension subjects were 4.610 [95% confidence interval (CI): 2.415 to 8.800], 2.759 (95% CI: 1.519 to 5.011) and 3.589 (95% CI: 1.672 to 7.706) times higher than that in controls, respectively. The risk of MetS in people with high-density lipoprotein (HDL) <1.10 mmol/L was 3.716-fold in comparison with HDL ≥1.55 mmol/L [odds risk (OR) = 3.716, 95% CI: 1.483 to 9.313]. Individuals with fatty liver had a higher risk of MetS (OR = 2.577, 95% CI: 1.472 to 4.512). The AUC of the predictive model was 0.831 (95% CI: 0.798 to 0.865), with the sensitivity of 0.898 (95% CI: 0.831 to 0.941) and the specificity of 0.676 (95% CI: 0.651 to 0.700). CONCLUSION: The model performed well predictive power for the risk of MetS, which may provide a reference for clinicians to identify high-risk groups early.

Report of the Largest Chinese Cohort With SLC19A3 Gene Defect and Literature Review.

Thiamine metabolism dysfunction syndrome 2 (THMD2) is a rare metabolic disorder caused by SLC19A3 mutations, inherited in autosomal recessive pattern. As a treatable disease, early diagnosis and therapy with vitamin supplementation is important to improve the prognosis. So far, the reported cases were mainly from Saudi Arab regions, and presented with relatively simple clinical course because of the hot spot mutation (T422A). Rare Chinese cases were described until now. In this study, we investigated 18 Chinese THMD2 patients with variable phenotypes, and identified 23 novel SLC19A3 mutations, which expanded the genetic and clinical spectrum of the disorder. Meanwhile, we reviewed all 146 reported patients from different countries. Approximately 2/3 of patients presented with classical BTBGD, while 1/3 of patients manifested as much earlier onset and poor prognosis, including infantile Leigh-like syndrome, infantile spasms, neonatal lactic acidosis and infantile BTBGD. Literature review showed that elevated lactate in blood and CSF, as well as abnormal OXPHOS activities of muscle or skin usually correlated with infantile phenotypes, which indicated poor outcome. Brainstem involvement on MRI was more common in deceased cases. Thiamine supplementation is indispensable in the treatment of THMD2, whereas combination of biotin and thiamine is not superior to thiamine alone. But biotin supplementation does work in some patients. Genotypic-phenotypic correlation remains unclear which needs further investigation, and biallelic truncated mutations usually led to more severe phenotype.

Genomic Association vs. Serological Determination of ABO Blood Types in a Chinese Cohort, with Application in Mendelian Randomization.

ABO blood system is an inborn trait determined by the ABO gene. The genetic-phenotypic mechanism underneath the four mutually exclusive and collectively exhaustive types of O, A, B and AB could theoretically be elucidated. However, genetic polymorphisms in the human populations render the link elusive, and importantly, past studies using genetically determined rather than biochemically determined ABO types were not and could not be evaluated for the inference errors. Upon both blood-typing and genotyping a cohort of 1008 people of the Han Chinese population, we conducted a genome-wide association study in parallel with both binomial and multinomial log-linear models. Significant genetic variants are all mapped to the ABO gene, and are quantitatively evaluated for binary and multi-class classification performances. Three single nucleotide polymorphisms of rs8176719, rs635634 and rs7030248 would together be sufficient to establish a multinomial predictive model that achieves high accuracy (0.98) and F1 scores (micro 0.99 and macro 0.97). Using the set of identified ABO-associated genetic variants as instrumental variables, we demonstrate the application in causal analysis by Mendelian randomization (MR) studies on blood pressures (one-sample MR) and severe COVID-19 with respiratory failure (two-sample MR).

Probiotic Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14 as an Adjunctive Treatment for Bacterial Vaginosis Do Not Increase the Cure Rate in a Chinese Cohort: A Prospective, Parallel-Group, Randomized, Controlled Study.

The purpose of this study was to evaluate the effectiveness of metronidazole and oral probiotics adjunct to metronidazole in the treatment of bacterial vaginosis (BV). One hundred and twenty-six Chinese women with BV were enrolled in this parallel, controlled trial, and were randomly assigned into two study arms: the metronidazole group, which was prescribed metronidazole vaginal suppositories for 7 days, and the adjunctive probiotic group, which received Lacticaseibacillus rhamnosus GR-1 and Limosilactobacillus reuteri RC-14 orally for 30 days as an adjunct to metronidazole. Clinical symptoms and Nugent scores at the initial visit, 30 days and 90 days were compared. There was no significant difference of the 30-day total cure rate between the adjunctive probiotic group (57.69%) and the metronidazole group (59.57%), with an odds ratio (OR) of 0.97 (95% confidence interval (CI), 0.70 to 1.35, p-value = 0.04), or of the 90-day total cure rate (36.54% vs. 48.94%, OR, 0.75; 95% CI, 0.47 to 1.19; p-value = 0.213). Also, no significant difference of the vaginal and faecal microbial diversity and structure between the two groups at 0, 30 or 90 days were shown based on 16S rRNA sequences. The probiotic species were rarely detected in either the vaginal microbiota or the faecal microbiota after administration which may revealed the cause of noneffective of oral probiotics. No serious adverse effects were reported in the trial. The study indicated that oral probiotic adjunctive treatment did not increase the cure rate of Chinese BV patients compared to metronidazole.

Chinese Glioma Genome Atlas (CGGA): A Comprehensive Resource with Functional Genomic Data from Chinese Glioma Patients.

Gliomas are the most common and malignant intracranial tumors in adults. Recent studies have revealed the significance of functional genomics for glioma pathophysiological studies and treatments. However, access to comprehensive genomic data and analytical platforms is often limited. Here, we developed the Chinese Glioma Genome Atlas (CGGA), a user-friendly data portal for the storage and interactive exploration of cross-omics data, including nearly 2000 primary and recurrent glioma samples from Chinese cohort. Currently, open access is provided to whole-exome sequencing data (286 samples), mRNA sequencing (1018 samples) and microarray data (301 samples), DNA methylation microarray data (159 samples), and microRNA microarray data (198 samples), and to detailed clinical information (age, gender, chemoradiotherapy status, WHO grade, histological type, critical molecular pathological information, and survival data). In addition, we have developed several tools for users to analyze the mutation profiles, mRNA/microRNA expression, and DNA methylation profiles, and to perform survival and gene correlation analyses of specific glioma subtypes. This database removes the barriers for researchers, providing rapid and convenient access to high-quality functional genomic data resources for biological studies and clinical applications. CGGA is available at http://www.cgga.org.cn.

Genomic Profiling of Chinese Cervical Cancer Patients Reveals Prevalence of DNA Damage Repair Gene Alterations and Related Hypoxia Feature.

BACKGROUND: Cervical cancer is responsible for 10-15% of cancer-related deaths in women worldwide. In China, it is the most common cancer in the female genital tract. However, the genomic profiles of Chinese cervical cancer patients remain unclear. MATERIALS AND METHODS: A total of 129 cervical cancer patients were enrolled in this study (113 squamous, 12 adenocarcinoma, 2 adenosquamous, and 2 neuroendocrine carcinoma). To classify the clinical features and molecular characteristics of cervical cancer, the genomic alterations of 618 selected genes were analyzed in the samples of these patients, utilizing target next-generation sequencing (NGS) technology. Furthermore, the findings from the Chinese cohort were then compared with the data of Western patients downloaded from The Cancer Genome Atlas (TCGA) database, in terms of gene expression files, mutation data, and clinical information. RESULTS: All studied patients had valid somatic gene alterations, and the most frequently altered genes were PIK3C, TP53, FBXW7, ARID1A, ERBB2, and PTEN. Comparison of genomic profiling showed significantly different prevalence of genes, including TP53, KMT2C, and RET, between the Chinese and the TCGA cohorts. Moreover, 57 patients (44.19%) with 83 actionable alterations were identified in our cohort, especially in PI3K and DNA damage repair (DDR) pathways. After an in-depth analysis of cervical cancer data from the TCGA cohort, DDR alteration was found to be associated with extremely higher tumor mutation burden (TMB) (median mutation count: 149.5 vs 66, p <0.0001), and advanced stages (p <0.05). Additionally, DDR alteration, regardless of its function, was positively correlated with hypoxia feature and score. Moreover, patients with a high hypoxia score were positively correlated with a high abundance of mast cell resting, but lower abundance of CD8+ T cells and activated mast cell. Finally, CDHR5 was identified as the hub gene to be involved in the DDR-hypoxia network, which was negatively correlated with both the DDR alteration and hypoxia score. CONCLUSIONS: Overall, a unique genomic profiling of Chinese patients with cervical cancer was uncovered. Besides, the prevalent actionable variants, especially in PI3K and DDR pathways, would help promote the clinical management. Moreover, DDR alteration exerted the significant influence on the tumor microenvironment in cervical cancer, which could guide the clinical decisions for the treatment. CDHR5 was the first identified hub gene to be negatively correlated with DDR or hypoxia in cervical cancer, which had potential effects on the treatment of immune checkpoint inhibitors (ICIs).

Genotypic and Phenotypic Analysis in Chinese Cohort With Autosomal Recessive Osteogenesis Imperfecta.

Osteogenesis imperfecta (OI) is a rare heritable skeletal disorder which is mainly caused by defected type I collagen. Autosomal recessive OI (AR-OI) is caused by mutations of genes that are responsible for type I collagen modification and folding, and is often associated with more severe phenotypes. Due to the limited number of recessive OI patients, it has been difficult to study the mutation spectrum as well as the correlation of genotype and phenotype. This study recruited a Chinese cohort of 74 AR-OI families, aiming to establish the mutation spectrum and to examine the genotypic and phenotypic correlation. We identified 82 variants including 25 novel variants and 57 HGMD reported variants in these AR-OI patients, using whole exome sequencing/panel sequencing combined with Sanger sequencing. Pathogenic mutations were found at WNT1 (n = 30, 40.54%), SERPINF1 (n = 22, 29.73%), FKBP10 (n = 10, 13.51%), CRTAP (n = 3, 4.05%), P3H1 (n = 3, 4.05%), SERPINH1 (n = 2, 2.70%), SEC24D (n = 3, 4.05%), and PLOD2 (n = 1, 1.35%) respectively. Thus, WNT1 represents the most frequent pathogenic gene of AR-OI in Chinese population. The most common clinical manifestations of AR-OI patients include walking problem (72.86%), scoliosis (65.28%) and frequent fractures (fractures ≥2/year) (54.05%). Interestingly, ptosis represents a unique phenotype of patients carrying WNT1 variants, and it was rare in patients harboring other pathogenic genes. Our study expanded the mutation spectrum of AR-OI and enriched the knowledge of genotypic and phenotypic correlation in Chinese cohort with AR-OI.

POLE Mutation Characteristics in a Chinese Cohort with Endometrial Carcinoma.

OBJECTIVE: To study the characteristics of polymerase epsilon (POLE) exonuclease domain mutations in Chinese patients with endometrial carcinoma (EC). METHODS: This study analyzed data from 529 patients with EC in The Cancer Genome Atlas (TCGA) and 467 EC patients evaluated at the Shanghai First Maternity and Infant Hospital (SFMIH). POLE mutation heterogeneity was analyzed in paired curettage and hysterectomy samples from 120 SFMIH patients. Sanger sequencing identified mutations in the POLE exonuclease domain, and correlations between POLE mutation status and various clinicopathological features were determined by chi-squared testing and Cohen's kappa analysis, with Kaplan-Meier survival curves generated to assess correlations between POLE mutation status and overall survival (OS). RESULTS: Thirty-five mutations were identified in 467 samples (7.5%), and novel mutations were detected in the SFMIH cohort. Compared to the TCGA cohort, the SFMIH cohort had fewer POLE mutations when matched by age (<60) and histology (endometrioid) (p < 0.001 and p = 0.010, respectively). In our study cohort, POLE mutations were significantly associated with adjuvant treatment (p = 0.029), and patients with POLE mutations who underwent chemoradiotherapy had a poor OS (p < 0.0001). Notably, shorter OS was significantly associated with POLE mutations in hysterectomy samples from patients aged >60 years or with stage I disease in the paired curettage-hysterectomy group. CONCLUSION: The significant difference in POLE mutation profiles between the TCGA and SFMIH cohorts, as well as the poor consistency between the curettage and hysterectomy samples, suggests that different parameters need to be applied to determine the prognosis of patients with EC in China.

MECP2 mutation spectrum and its clinical characteristics in a Chinese cohort.

The dysfunction of methyl-CpG-binding protein 2 (MeCP2) is associated with several neurological disorders, of which Rett syndrome (RTT) is the most prominent. This study focused on a Chinese patient cohort with MECP2 mutations, and analyzed the characteristics of these mutations and their clinical manifestations. In total, 666 patients were identified with 126 different MECP2 mutations, including 22 novel mutations. Over 80% of patients carried an MECP2 mutation on exon 4. Nonsense and missense mutations were the most commonly reported types. Missense mutations were mainly located on methyl-CpG-binding domain (MBD), and nonsense mutations predominantly occurred on transcription repression domain (TRD) and inter domain. The predilection site of large deletion was exon 3 and/or exon 4. Patients with p.R133C, p.R294*, p.R306C, and C-terminal domain (CTD) deletions were less severely affected. Significant differences were found in ambulation ability, hand function, and language among different mutation groups. Three female patients with MECP2 mutations (1 with p.R306P and 2 with p.R309W) only presented with intellectual disability/developmental delay (ID/DD), and no obvious RTT symptoms were reported. Eight male individuals with MECP2 mutations were also identified in this study, including 2 diagnosed with typical RTT, 3 with atypical RTT and 3 with ID/DD.

Genetic Study in a Large Cohort Supported Different Pathogenesis of Graves' Disease and Hashimoto's Hypothyroidism.

CONTEXT: Hashimoto's thyroiditis (HT) and Graves' disease (GD) are the 2 main autoimmune thyroid diseases that have both similarities and differences. Determining the genetic basis that distinguishes HT from GD is key for a better understanding of the differences between these closely related diseases. OBJECTS: To identify the susceptibility genes for HT in the Chinese cohort and compare susceptibility genes between GD and HT. DESIGN: In the current study, 18 SNPs from 18 established GD risk loci were selected and then genotyped in 2682 patients with HT, 4980 patients with GD, and 3892 controls. The association analysis between HT and controls and heterogeneity analysis between HT and GD were performed on SPSS, with the logistic regression analysis adjusted for sex and age. RESULTS: We identified 11 susceptibility loci for HT in the Chinese Han population, with 4 loci, including the rs1265883 in SLAMF6 locus, rs1024161 in CTLA4, rs1521 in HLA-B, and rs5912838 in GPR174/ ITM2A at X chromosome, reaching genome-wide significance of 5 × 10-8. Five loci were reported to be associated with HT for the first time. We also identified 6 susceptibility loci with heterogeneity between GD and HT. Out of them, 4 loci were associated with GD but not with HT, including HLA-DPB1, CD40, TSHR, and TG; the association of HLA-B with GD was stronger than that with HT, but the association of SLAMF6 was reversed. CONCLUSION: Our findings suggested that the pathogenesis of HT and GD was different.

Prediagnostic blood levels of organochlorines and risk of non-Hodgkin lymphoma in three prospective cohorts in China and Singapore.

Specific organochlorines (OCs) have been associated with non-Hodgkin lymphoma (NHL) with varying degrees of evidence. These associations have not been evaluated in Asia, where the high exposure and historical environmental contamination of certain OC pesticides (e.g., dichlorodiphenyltrichloroethane [DDT], hexachlorocyclohexane [HCH]) are different from Western populations. We evaluated NHL risk and prediagnostic blood levels of OC pesticides/metabolites and polychlorinated biphenyl congeners in a case-control study of 167 NHL cases and 167 controls nested within three prospective cohorts in Shanghai and Singapore. Conditional logistic regression was used to analyze lipid-adjusted OC levels and NHL risk. Median levels of p,p'-dichlorodiphenyldichloroethylene (p,p'-DDE), the primary DDT metabolite, and ß-HCH were up to 12 and 65 times higher, respectively, in samples from the Asian cohorts compared to several cohorts in the United States and Norway. An increased risk of NHL was observed among those with higher ß-HCH levels both overall (3rd vs. 1st tertile OR = 1.8, 95%CI = 1.0-3.2; ptrend = 0.049) and after excluding cases diagnosed within 2 years of blood collection (3rd vs. 1st tertile OR = 2.0, 95%CI = 1.1-3.9; ptrend = 0.03), and the association was highly consistent across the three cohorts. No significant associations were observed for other OCs, including p,p'-DDE. Our findings provide support for an association between ß-HCH blood levels and NHL risk. This is a concern because substantial quantities of persistent, toxic residues of HCH are present in the environment worldwide. Although there is some evidence that DDT is associated with NHL, our findings for p,p'-DDE do not support an association.