Genome-Wide Association Analysis of Protein-Coding Variants in IgA Nephropathy.

SIGNIFICANCE STATEMENT: Genome-wide association studies have identified nearly 20 IgA nephropathy susceptibility loci. However, most nonsynonymous coding variants, particularly ones that occur rarely or at a low frequency, have not been well investigated. The authors performed a chip-based association study of IgA nephropathy in 8529 patients with the disorder and 23,224 controls. They identified a rare variant in the gene encoding vascular endothelial growth factor A (VEGFA) that was significantly associated with a two-fold increased risk of IgA nephropathy, which was further confirmed by sequencing analysis. They also identified a novel common variant in PKD1L3 that was significantly associated with lower haptoglobin protein levels. This study, which was well-powered to detect low-frequency variants with moderate to large effect sizes, helps expand our understanding of the genetic basis of IgA nephropathy susceptibility. BACKGROUND: Genome-wide association studies have identified nearly 20 susceptibility loci for IgA nephropathy. However, most nonsynonymous coding variants, particularly those occurring rarely or at a low frequency, have not been well investigated. METHODS: We performed a three-stage exome chip-based association study of coding variants in 8529 patients with IgA nephropathy and 23,224 controls, all of Han Chinese ancestry. Sequencing analysis was conducted to investigate rare coding variants that were not covered by the exome chip. We used molecular dynamic simulation to characterize the effects of mutations of VEGFA on the protein's structure and function. We also explored the relationship between the identified variants and the risk of disease progression. RESULTS: We discovered a novel rare nonsynonymous risk variant in VEGFA (odds ratio, 1.97; 95% confidence interval [95% CI], 1.61 to 2.41; P = 3.61×10 -11 ). Further sequencing of VEGFA revealed twice as many carriers of other rare variants in 2148 cases compared with 2732 controls. We also identified a common nonsynonymous risk variant in PKD1L3 (odds ratio, 1.16; 95% CI, 1.11 to 1.21; P = 1.43×10 -11 ), which was associated with lower haptoglobin protein levels. The rare VEGFA mutation could cause a conformational change and increase the binding affinity of VEGFA to its receptors. Furthermore, this variant was associated with the increased risk of kidney disease progression in IgA nephropathy (hazard ratio, 2.99; 95% CI, 1.09 to 8.21; P = 0.03). CONCLUSIONS: Our study identified two novel risk variants for IgA nephropathy in VEGFA and PKD1L3 and helps expand our understanding of the genetic basis of IgA nephropathy susceptibility.

[Types and prognosis of human papillomavirus infection in the male urethra and skin lesions].

OBJECTIVE: To determine the types and investigate the distribution and prognosis of human papillomavirus (HPV) infection in different parts of the urethra and skin lesions in men. METHODS: Using real-time fluorescence quantitative (RT-qPCR), we determined and analyzed the genotypes of HPV in the urethra and skin lesions of 620 male patients. RESULTS: The results of HPV examination were comparable in the urethra and skin lesions of 53.39% of the patients (331/620) and different in 46.61% (289/620). HPV positive was detected in 36.61% (227/620) in the urethra and 44.84% (278/620) in skin lesions. Various HPV subtypes were identified in both the urethra and skin lesions, mostly of the low-risk type. High-risk types in the urethra included types 16, 52, 18 and 56, and those in the skin lesions included types 16, 51, 52 and 58 types. CONCLUSION: Analysis of HPV infection in different parts and its prognosis helps to predict the risk of morbidity. Attention should be paid to the early detection of high-risk HPV infection in males so as to give positive and effective intervention and take targeted preventive measures for the high-risk population.

Dataset of testicular germ cell tumors (TGCT) risk associated with serum polychlorinated biphenyl (PCB) by age at diagnosis and histologic types.

In a population-based case control study of testicular germ cell tumors (TGCT), we reported a strong positive association between serum levels of Wolff's Group 1 (potentially estrogenic) polychlorinated biphenyl (PCBs) and risk of TGCT, and the observed associations were similar for both seminoma and non-seminoma. While the observed specific associations between TGCT and Wolff's Group 1 PCBs cannot be easily explained by bias or confounding, a question can still be asked, that is, could the relationship between PCBs and TGCT differ by age at diagnosis? PCBs tend to bioaccumulate, with more heavily chlorinated PCB congeners tending to have longer half-lives. Half-lives of PCB congeners were reported ranging from 4.6 years for PCB-28 to 41.0 years for PCB-156. The half-life for the heavy PCB congeners (17.8 years) was found to be approximately twice that for the light PCBs (9.6 years) in early studies. Therefore, the same PCB concentration measured in a 20-year-old vs. a 55-year-old is unlikely to represent the same lifetime PCB exposure or type of PCB exposure. In this analysis, we stratified the data by median age of diagnosis of TGCT and further stratified by histologic type of TGCT (seminoma vs non-seminoma) to explore if the risk of TGCT associated with PCB exposures differs by age.

Serum polychlorinated biphenyl (PCB) levels and risk of testicular germ cell tumors: A population-based case-control study in Connecticut and Massachusetts.

The incidence rate of testicular germ cell tumors (TGCT) has continuously increased in Western countries over the last several decades. Some epidemiologic studies have reported that the endocrine disrupting polychlorinated biphenyls (PCBs) in serum may be associated with TGCT risk, but the evidence is inconsistent. Our goal was to investigate whether serum levels of PCBs are associated with the increase of TGCT risk. We conducted a population-based case-control study of 308 TGCT cases and 323 controls, all residents of Connecticut and Massachusetts. Serum levels of 56 PCBs congeners were measured using gas chromatography and unconditional logistic regression model was used to evaluate the risk of TGCT associated with total PCBs exposure, groups of PCBs categorized by Wolff's functional groups, and individual PCB congeners. The results showed that there was no association between total serum levels of PCBs and risk of TGCT overall (quartile 4 (Q4) vs. quartile 1 (Q1) odds ratio (OR) and 95% confidence interval (C.I.) = 1.0 (0.6-1.9), ρ trend = 0.9). However, strong positive association was observed between total serum levels of Wolff's Group 1 (potentially estrogenic) PCBs and risk of overall TGCT (Q4 vs. Q1 OR = 2.5, 95% CI = 1.3-4.7, ρ trend <0.05) as well as seminoma and non-seminoma subtypes. Wolff's Group 1 PCB congeners that showed an increased risk of TGCT included: 25, 44, 49, 52, 70, 101, 174, and 201/177. Considering the continuing increase of TGCT, these associations should be replicated in different populations with larger sample size.

Health-related quality of life of patients with colorectal neoplasms in China: A multicenter cross-sectional survey.

BACKGROUND AND AIM: This study aimed to clarify health-related quality of life (HRQoL) of patients with colorectal precancer and colorectal cancer (CRC) in China and to better understand related utility scores. METHODS: A hospital-based cross-sectional survey was conducted in precancer and CRC patients from 2012 to 2014, covering 12 provinces in China. HRQoL was assessed with EuroQol 5-Dimensions 3-Levels. Utility scores were derived using Chinese value set. A multivariate regression model was established to explore potential predictors of utility scores. RESULTS: A total of 376 precancer (mean age 58.7 years, 61.2% men) and 2470 CRC patients (mean age 58.6 years, 57.6% men) were included. In five dimensions, there was a certain percentage of problem reported among precancer (range: 12.0% to 36.7%) and CRC (range: 32.4% to 50.3%) patients, with pain/discomfort being the most serious dimension. Utility scores of precancer and CRC patients were 0.870 (95% confidence interval [CI], 0.855-0.886) and 0.751 (95% CI, 0.742-0.759), both of which were lower than those of general Chinese population (0.960 [95% CI, 0.960-0.960]). Utilities for patients at stage I to stage IV were 0.742 (95% CI, 0.715-0.769), 0.722 (95% CI, 0.705-0.740), 0.756 (95% CI, 0.741-0.772), and 0.745 (95% CI, 0.742-0.767), respectively. Multivariate analysis showed that therapeutic regimen, time point of the interview, education, occupation, annual household income, and geographic region were associated with utilities of CRC patients. CONCLUSION: Health-related quality of life of both precancer and CRC patients in China declined considerably. Utility scores differed by sociodemographic and clinical characteristics, and findings of these utilities may facilitate implementation of further cost-utility evaluations.

[Analysis of volatile organic compounds (VOCs) fingerprint of raw and honey-fried licorice based on headspace-gas-chromatography ion-mobility spectrometry (HS-GC-IMS)].

Licorice is one of the most commonly used traditional Chinese medicine. In clinic, raw licorice and honey-fried licorice are used in medicines, with the main effects in clearing away heat and detoxifying, moistening lungs and removing phlegm. Honey-fried licorice has effects in nourishing the spleen and stomach and replenishing Qi and pulse. Because traditional Chinese medicine exerts the effects through multiple components and multiple targets, the index components used in the quality evaluation of licorice are often difficult to reflect their real quality. In addition, most of studies for the quality standards have shown that honey-fried licorice are the same as licorice, with a lack of quality evaluation standards that can demonstrate their processing characteristics. The quality of medicine is directly related to its clinical efficacy, so it is necessary to establish a more effective quality control method. Licorice has a beany smell, which is one of the main quality identification characteristics. In this study, by taking advantage of the odor characteristics, a headspace-gas chromatography-ion migration mass spectrometry technology was used to establish a quality evaluation method. A total of 76 volatile components were identified. Through the dynamic principal component analysis, 7 kinds of volatile substances in raw licorice and 13 kinds of volatile substances in honey-fried licorice were statistically obtained, and could be taken as index components for the quality evaluation of raw and honey-fried licorice, respectively. This study could help realize the combination and unification of modern detection and traditional quality evaluation methods, and make a more realistic evaluation for the quality of licorice.

Effects of hepatitis B virus infection, alanine aminotransferase, aspartate aminotransferase and gamma-glutamyl transferase on prediabetes and diabetes mellitus: A cohort study.

INTRODUCTION AND OBJECTIVES: The purpose of this study was to confirm whether hepatitis B virus (HBV) infection and the levels of liver enzymes would increase the risk of prediabetes and diabetes mellitus (DM) in China. MATERIALS AND METHODS: A total of 10,741 individuals was enrolled in this prospective cohort study. Cox regression analysis was used to calculate the Hazard ratios (HRs) to evaluate the relationships between HBV infection and the risk of DM and prediabetes. Decision trees and dose response analysis were used to explore the effects of liver enzymes levels on DM and prediabetes. RESULTS: In baseline population, HBV infection ratio was 5.31%. In non-adjustment model, the HR of DM in HBV infection group was 1.312 (95% CI, 0.529-3.254). In model adjusted for gender, age and liver cirrhosis, the HR of DM in HBV infection group were 1.188 (95% CI, 0.478-2.951). In model adjusted for gender, age, liver cirrhosis, smoking, drinking, the HR of DM was 1.178 (95% CI, 0.473-2.934). In model further adjusted for education, family income and occupation, the HR of DM was 1.230 (95% CI, 0.493-3.067). With the increases of levels of Alanine aminotransferase (ALT), Aspartate aminotransferase (AST) and Gamma-glutamyl transferase (GGT), the risk of prediabetes was gradually increasing (Pnon-linearity<0.05). There were dose-response relationships between ALT, GGT and the risk of DM (Pnon-linearity<0.05). CONCLUSIONS: HBV infection was not associated with the risk of prediabetes and DM. The levels of liver enzymes increased the risk of prediabetes and DM.

The Relationship between Nkx2.1 and DNA Oxidative Damage Repair in Nickel Smelting Workers: Jinchang Cohort Study.

Background: Occupational nickel exposure can cause DNA oxidative damage and influence DNA repair. However, the underlying mechanism of nickel-induced high-risk of lung cancer has not been fully understood. Our study aims to evaluate whether the nickel-induced oxidative damage and DNA repair were correlated with the alterations in Smad2 phosphorylation status and Nkx2.1 expression levels, which has been considered as the lung cancer initiation gene. Methods: 140 nickel smelters and 140 age-matched administrative officers were randomly stratified by service length from Jinchang Cohort. Canonical regression, χ² test, Spearman correlation etc. were used to evaluate the association among service length, MDA, 8-OHdG, hOGG1, PARP, pSmad2, and Nkx2.1. Results: The concentrations of MDA, PARP, pSmad2, and Nkx2.1 significantly increased. Nkx2.1 (rs = 0.312, p < 0.001) and Smad2 phosphorylation levels (rs = 0.232, p = 0.006) were positively correlated with the employment length in nickel smelters, which was not observed in the administrative officer group. Also, elevation of Nkx2.1 expression was positively correlated with service length, 8-OHdG, PARP, hOGG1 and pSmad2 levels in nickel smelters. Conclusions: Occupational nickel exposure could increase the expression of Nkx2.1 and pSmad2, which correlated with the nickel-induced oxidative damage and DNA repair change.

Association of TNFSF13 polymorphisms with IgA nephropathy in a Chinese Han population.

BACKGROUND: Our previous genome-wide association study of IgA nephropathy (IgAN) in a Chinese Han population suggested that the TNFSF13 gene may be a novel susceptibility gene for IgAN. In the present study, we aimed to further evaluate the associations of single-nucleotide polymorphisms (SNPs) and expression level of the TNFSF13 gene with the risk and clinical parameters of IgAN. METHODS: Six candidate SNPs were selected for genotyping by Sequenom MassARRAY iPLEX in 1000 IgAN cases and 1000 controls. Unconditional logistic regression was used to calculate the odds ratio (OR) and 95% confidence interval (95% CI) with adjustment for age and sex. Serum APRIL (encoded by the TNFSF13 gene) level was detected by an enzyme-linked immunosorbent assay. RESULTS: We found that rs3803800 was significantly associated with the susceptibility of IgAN after Bonferroni correction [padditive  = 0.0009, OR (95% CI) = 1.25 (1.09-1.42); precessive  = 0.0006, OR (95% CI) = 1.54 (1.20-1.96)]; however, the association remained only in women after further sex-stratified analysis. Genotype-phenotype correlation analysis showed significant associations of rs3803800 with severe clinicopathological manifestations in IgAN patients after adjusting for age and sex, as well as the other two SNPs (rs4246413 and rs4968210) that were also associated with specific clinical phenotypes. Compared with healthy controls, serum APRIL levels were significantly higher in IgAN patients (p = 0.0001) and associated with severity of disease. CONCLUSIONS: The results of the present study indicate that the genetic variations and gene expression level of TNFSF13 are associated with the susceptibility and severity of IgAN in a Han Chinese population.

Expenditure and financial burden for the diagnosis and treatment of colorectal cancer in China: a hospital-based, multicenter, cross-sectional survey.

BACKGROUND: The increasing prevalence of colorectal cancer (CRC) in China and the paucity of information about relevant expenditure highlight the necessity of better understanding the financial burden and effect of CRC diagnosis and treatment. We performed a survey to quantify the direct medical and non-medical expenditure as well as the resulting financial burden of CRC patients in China. METHODS: We conducted a multicenter, cross-sectional survey in 37 tertiary hospitals in 13 provinces across China between 2012 and 2014. Each enrolled patient was interviewed using a structured questionnaire. All expenditure data were inflated to the 2014 Chinese Yuan (CNY; 1 CNY = 0.163 USD). We quantified the overall expenditure and financial burden and by subgroup (hospital type, age at diagnosis, sex, education, occupation, insurance type, household income, clinical stage, pathologic type, and therapeutic regimen). We then performed generalized linear modeling to determine the factors associated with overall expenditure. RESULTS: A total of 2356 patients with a mean age of 57.4 years were included, 57.1% of whom were men; 13.9% of patients had stage I cancer; and the average previous-year household income was 54,525 CNY. The overall average direct expenditure per patient was estimated to be 67,408 CNY, and the expenditures for stage I, II, III, and IV disease were 56,099 CNY, 59,952 CNY, 67,292 CNY, and 82,729 CNY, respectively. Non-medical expenditure accounted for 8.3% of the overall expenditure. The 1-year out-of-pocket expenditure of a newly diagnosed patient was 32,649 CNY, which accounted for 59.9% of their previous-year household income and caused 75.0% of families to suffer an unmanageable financial burden. Univariate analysis showed that financial burden and overall expenditure differed in almost all subgroups (P < 0.05), except for sex. Multivariate analysis showed that patients who were treated in specialized hospitals and those who were diagnosed with adenocarcinoma or diagnosed at a later stage were likely to spend more, whereas those with a lower household income and those who underwent surgery spent less (all P < 0.05). CONCLUSIONS: For patients in China, direct expenditure for the diagnosis and treatment of CRC seemed catastrophic, and non-medical expenditure was non-ignorable. The financial burden varied among subgroups, especially among patients with different clinical stages of disease, which suggests that, in China, CRC screening might be cost-effective.

Oncocytic carcinoma of the parotid gland.

OBJECTIVES/HYPOTHESIS: The incidence of oncocytic carcinoma of the parotid gland is low, so a systematic evaluation of treatment strategies is lacking. We aimed to describe our experiences in treating this malignancy. STUDY DESIGN: Retrospective study. METHODS: We reviewed the files for 18 patients (14 males) of oncocytic carcinoma of the parotid gland in our institution from 1991 to 2011. Four patients underwent surgery alone, four surgery and postoperative radiotherapy, nine surgery and postoperative brachytherapy, and one radiotherapy alone. Median follow-up was 36 months (range 2-108 months). RESULTS: The 5-year local control rate was 66.9%, overall survival 68.6%, disease progression-free survival 46.2%, and 5-year freedom from distant metastasis 61.0%. Clinical N category, local recurrence, and distant metastasis significantly influenced overall survival. CONCLUSIONS: Conservative parotidectomy is not radical enough to treat oncocytic carcinoma of the parotid gland. Elective neck dissection is recommended for patients with cancer stage T2 to 4. Surgery with postoperative (125) I brachytherapy leads to good local control for patients with advanced disease or with positive or close resection margins.

[A clinicopathologic study on oncocytoma and oncocytic carcinoma of the salivary glands].

OBJECTIVE: To investigate the clinicopathologic features, differential diagnosis, treatment and prognosis of oncocytoma and oncocytic carcinoma of the salivary glands. METHODS: The clinicopathologic features were studied in 23 cases of oncocytomas and 15 cases of oncocytic carcinomas, and immunohistochemical staining as well as electron microscopy were performed. RESULTS: Most oncocytomas occurred in the parotid gland (95.6%) with no recurrence. The diagnosis was made based on histopathological features. Oncocytic carcinomas were high-grade tumors, mainly occurring in the parotid gland. The diagnosis was based not only on histopathology but also on ultrastructural findings, phosphotungstic acid hematoxylin (PTAH), and immunohistochemistry. Of the 14 cases with follow-up information, 7 cases recurred. Regional or distant metastases were found in 7 and 4 cases, respectively. CONCLUSION: Oncocytoma is a rare tumor with well prognosis, whereas oncocytic carcinoma of the salivary glands is a high-grade tumor, with frequent local recurrence, regional or distant metastasis, the diagnosis of which should be based on a combination of clinical and histopathological features. Immunohistochemistry for mitochondria is considered as a practical and helpful adjuvant for diagnosis.

Primary oncocytic carcinoma of the salivary glands: a clinicopathologic and immunohistochemical study of 12 cases.

Oncocytic carcinoma (OC) of salivary gland origin is an extremely rare proliferation of malignant oncocytes with adenocarcinomatous architectural phenotypes, including infiltrative qualities. To help clarify the clinicopathologic and prognostic features of this tumor group, herein, we report 12 OC cases arising from the salivary glands, together with follow-up data and immunohistochemical observations. There were 10 males and 2 females with an age range of 41 to 86 years (median age: 61.3 years). Most occurred in the parotid gland (10/12) with one in the palate and one in the retromolar gland. The tumors were unencapsulated and often invaded into the nearby gland, lymphatic tissues and nerves. The neoplastic cells had eosinophilic granular cytoplasm and round vesicular nuclei with prominent red nucleoli. Ultrastructural study, PTAH, and immunohistochemistry staining confirmed the presence of numerous mitochondria in the cytoplasm of oncocytes. Cellular atypia and pleomorphism varied in the current series. Double nuclei and mitoses were observed in some cases, while one case that showed mild cellular pleomorphism but had local invasion following local recurrence was also identified as an OC. Of the 11 cases with follow-up information, 7 cases had local recurrence. Regional or distant metastases were found in 6 and 4 cases, respectively. Five-year disease-specific survivals were 54.9%. In summary, OC of salivary gland origin is a high-grade tumor, often with local recurrence, regional or distant metastasis, diagnosis of which based on a combination of clinical and histopathological features. Immunohistochemistry for mitochondria is considered as a practical and helpful adjuvant diagnosis. Complete surgical excision is the treatment of choice while the role of radiotherapy or chemotherapy is controversial, and careful follow-up is necessary.