Glucocorticoid receptor (NR3C1) genetic polymorphisms and the outcomes of sudden sensorineural hearing loss.

BACKGROUND: The glucocorticoid receptor gene (NR3C1) encodes the receptor to which cortisol and other glucocorticoids bind. Steroids in either oral, intratympanic, or intravascular forms are the treatment of choice for sudden sensorineural hearing loss (SSNHL), but the outcome varies. The outcomes of SSNHL have been investigated for related factors, including age, initial hearing loss severity and pattern, vertigo, genetic variations, and the time between onset and treatment. The objective of the present study was to analyze the association of genetic polymorphisms of NR3C1 with the outcomes of SSNHL. MATERIALS AND METHODS: We conducted a comparison study of 93 cases with a poor outcome (control) and 100 cases with a good outcome (case) in SSNHL patients. Six single nucleotide polymorphisms (SNPs) were selected. The genotypes were determined using TaqMan technology. RESULTS: The heterozygous AT genotype of rs17100289 was associated with a poor outcome in comparison with the major homozygous AA genotype after adjustments for age and sex (OR = 0.50; 95% CI 0.26-0.95; P = 0.035) in SSNHL patients. The CT genotype of rs4912912 was also associated with a poor outcome compared with the major homozygous TT genotype after the adjustments (OR = 0.47; 95% CI 0.24-0.92; P = 0.026). CONCLUSION: These results suggest that NR3C1 genetic polymorphisms may influence the outcomes of SSNHL.

Facial canal dehiscence, dural exposure, and labyrinthine fistula in middle ear cholesteatoma and mastoiditis.

PURPOSE: To analyze the prevalence and associations of facial canal dehiscence (FCD), dural exposure, and labyrinthine fistula in chronic otitis media (COM) with and without cholesteatoma. METHODS: This was a retrospective study performed in an academic medical center. Patients who received tympanoplasty with mastoidectomy for COM with and without cholesteatoma were included. The prevalence of FCD, dural exposure, and labyrinthine fistula in COM with and without cholesteatoma (mastoiditis) and their relationships were analyzed. RESULTS: A total of 189 patients, including 107 (56.6%) females and 82 (43.4%) males, with 191 ears were included. There were 149 cases (78.0%) of cholesteatoma and 42 patients (22.0%) with mastoiditis. FCD was noted in 27.5% of patients with cholesteatoma and 9.5% of patients with mastoiditis. Dural exposure was found in 21 patients (14.1%) with cholesteatoma and 4 patients (9.5%) with mastoiditis. Eleven patients (7.4%) with cholesteatoma and 1 patient (2.4%) with mastoiditis had labyrinthine fistula. Patients with a labyrinthine fistula had nearly a fivefold greater chance (OR = 4.924, 95% CI = 1.355-17.896, p = 0.015) of having FCD than those without a fistula. There was a positive correlation between dural exposure and labyrinthine fistula (P = 0.011, Fisher's exact test). CONCLUSION: FCD, dural exposure, and labyrinthine fistula are common complications in COM. These complications are more frequently observed in patients with cholesteatoma than in patients with mastoiditis. Surgeons should pay more attention to the treatment of COM.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with sudden sensorineural hearing loss in a Taiwanese population: a case control study.

BACKGROUND: Sudden sensorineural hearing loss (SSNHL) is a disease with an unknown etiology; damage to the auditory nerve from inflammation due to viral infection or vascular incidents has been implicated. According to several studies, cytokines, including interleukins, are associated with SSNHL in terms of serum expression and genetic polymorphisms. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with SSNHL. This study analyzed the association of single nucleotide polymorphisms (SNPs) of IL-1 receptor (IL-1R) genes with SSNHL in Taiwan. METHODS: We conducted a case-control study involving 401 patients with SSNHL and 730 healthy controls. Four SNPs (IL-1R type 1 gene [IL1R1] [rs3917225 and rs2234650] and IL-1R type 2 gene [IL1R2] [rs4141134 and rs2071008]) were selected. The genotypes were determined using the TaqMan assay. The Hardy-Weinberg equilibrium (HWE) was tested for each SNP, and genetic effects were evaluated. RESULTS: The TT genotype of rs2234650 had an adjusted odds ratio (OR) of 2.988 (95% confidence interval [95% CI] 1.27-6.82) (P = 0.012) compared with the CC genotype in patients with SSNHL. The SNP rs2234650 was associated with SSNHL in the recessive model (TT vs. CC + CT, P = 0.0206, OR = 2.681). The CT genotype of rs4141134 had an adjusted OR of 3.860 (95% CI 2.01-7.44; P < 0.0001) compared with the TT genotype, in patients with SSNHL. The SNP rs4141134 was associated with SSNHL under the dominant model (CC + CT vs. TT, P < 0.0001, OR = 4.087). CONCLUSION: These findings suggest that IL1R1 and IL1R2 gene polymorphisms may contribute to an increased risk of SSNHL in Taiwan.

The association of heat shock protein genetic polymorphisms with age-related hearing impairment in Taiwan.

BACKGROUND: Age-related hearing impairment (ARHI) is a major disability among the elderly population. Heat shock proteins (HSPs) were found to be associated with ARHI in animal studies. The aim of this study was to analyze the associations of single nucleotide polymorphisms (SNPs) of HSP genes with ARHI in an elderly population in Taiwan. METHODS: Participants ≥65 years of age were recruited for audiometric tests and genetic analyses. The pure tone average (PTA) of the better hearing ear was calculated for ARHI evaluation. The associations of HSPA1L (rs2075800 and rs2227956), HSPA1A (rs1043618) and HSPA1B (rs2763979) with ARHI were analyzed in 146 ARHI-susceptible (cases) and 146 ARHI-resistant (controls) participants. RESULTS: The "T" allele of HSPA1B rs2763979 showed a decreased risk of ARHI. The "TT" genotype of rs2763979 also showed a decreased risk of ARHI in the dominant hereditary model. For HSPA1L (rs2075800 and rs2227956) and HSPA1A (rs1043618), the haplotype "CAG" was related to a decreased risk of ARHI. CONCLUSION: These findings suggest that HSP70 polymorphisms are associated with susceptibility to ARHI in the elderly population.

The association of genetic polymorphisms in interleukin-1 receptors type 1 and type 2 with age-related hearing impairment in a Taiwanese population: a case control study.

BACKGROUND: Age-related hearing impairment (ARHI) is a major disability among the elder population. Chronic inflammation is an important factor in the development of ARHI. Interleukin-1 (IL-1) plays a key role in inflammation and may be associated with ARHI. The aim of this study is to analyze the associations of single nucleotide polymorphisms (SNPs) of IL-1 receptor genes with ARHI in an elderly population in Taiwan. METHOD: Participants ≥65 years of age were recruited for audiometric tests and genetic analyses. The bilateral pure-tone average (PTA) of high-tone hearing levels was calculated for ARHI evaluation. The associations of SNPs of the IL-1 receptor type 1 gene (IL1R1) (rs3917225 and rs2234650) and type 2 gene (IL1R2) (rs4141134 and rs2071008) with ARHI were analyzed in 182 ARHI-susceptible (case) and 176 ARHI-resistant (control) participants. RESULTS: The G allele of IL1R1 rs3917225 showed a decreased risk of ARHI after adjustments for sex, age, and noise exposure. The GG genotype of IL1R1 rs3917225 in all hereditary models and the TT genotype of IL1R2 rs2071008 in the recessive model also showed decreased risks of ARHI after adjustments. CONCLUSION: These findings suggest that IL1R1 and IL1R2 polymorphisms may contribute to the decreased risk of ARHI in the elderly population.

Prevalence of Persistent Tinnitus and Dizziness in an Elderly Population in Southern Taiwan.

OBJECTIVES: Tinnitus and dizziness are common among the elderly. The conditions may increase depression, and patients may become susceptible to falls, thereby affecting the quality of life of the geriatric population. Investigating the prevalence of persistent tinnitus and chronic/recurrent dizziness in an elderly population and analyzing the association of certain comorbidities with tinnitus and dizziness in southern Taiwan were the main purposes of this study. MATERIALS AND METHODS: This was a cross-sectional study performed in a metropolitan hospital. Hearing tests were conducted in a total of 597 volunteers aged ≥65 years involving 322 (53.9%) men and 275 (46.1%) women recruited in the study. The pure tone average (PTA) and hearing handicap (HH) score were calculated. Patients completed questionnaires regarding the history of hypertension and diabetes and symptoms of tinnitus and dizziness. The association of gender, age, PTA/HH, body mass index (BMI), hypertension, diabetes, and metabolic syndrome (MetS) with tinnitus and dizziness were analyzed. RESULTS: The prevalence of persistent tinnitus and chronic/recurrent dizziness was 32.0% and 24.1%, respectively. Tinnitus or dizziness were not associated with age, BMI, hypertension, diabetes, and MetS but was associated with hearing impairment. Women and those with fasting glucose levels <100 mg/dL were more likely to experience dizziness. CONCLUSION: Persistent tinnitus and dizziness were common in an elderly population in southern Taiwan. These findings may help develop strategies to promote the quality of life in the elderly population.

The Association of GRM7 Single Nucleotide Polymorphisms with Age-Related Hearing Impairment in a Taiwanese Population.

OBJECTIVES: Age-related hearing impairment (ARHI) is a major disability among the elderly. This study aimed to analyze the association of single nucleotide polymorphisms (SNPs) of metabotropic glutamate receptor 7 (GRM7) gene with ARHI in an elderly population in Taiwan. MATERIALS AND METHODS: This was a community-based study performed in a metropolitan hospital. Participants ≥65 years of age were recruited. Participants with a pure tone average (PTA) of speech frequencies in the better ear of >35 decibel hearing level (dBHL) were classified into the case group, whereas those with PTA ≤25 dBHL were classified into the control group. The association of SNPs rs11928865, rs1353828, rs9814809, and rs9880404 with ARHI was analyzed. RESULTS: In 106 cases and 190 controls, alleles of all SNPs were found not to be associated with ARHI. The genotype of rs9880404 was found to be associated with ARHI in a dominant pattern, but the genotypes of rs11928865, rs1353828, and rs9814809 were found not to be associated with ARHI. CONCLUSION: GRM7 SNPs are associated with susceptibility to ARHI, but the significance of this finding in a Taiwanese population differed from that observed in European studies. Further studies may help to determine Taiwanese (Asian)-specific SNPs associated with ARHI.

Cytokeratin-18 and uric acid predicts disease severity in Taiwanese nonalcoholic steatohepatitis patients.

BACKGROUND & AIMS: Identification of disease severity remains a challenge in the management of non-alcoholic steatohepatitis (NASH). Cytokeratin-18 (CK18), is a recently developed non-invasive biomarker for NASH. We aimed to assess the performance of CK18 in disease severity prediction among Taiwanese NASH patients. METHODS: A total of 76 biopsy-proven NASH patients (54 males, age = 41.0 ± 13.5 years) were consecutively recruited. The optimal cutoff values of CK18 for each stage of fibrosis were correlated with their histopathological manifestations. RESULTS: There were 23 (30.3%) patients of Metavir fibrosis stage 0 (F0), 32 (42.1%) patients of F1, 14 (18.4%) patients of F2, and 7 (9.2%) patients of F3-4, respectively. The CK18 levels among those patients of F0, F1, F2, F3-4 were 86.7 ± 75.6 U/L, 122.4 ± 123.8 U/L, 160.7 ± 120.4 U/L, and 507.3 ± 343 U/L, respectively (trend for P<0.001). The adjusted optimal cutoff value for F2 prediction was 312.5 U/L, yielding the sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV), and the accuracy of 96.4%, 28.6%, 77.9%, 75%, and 77.6%, respectively (P = 0.009). For the prediction of advanced fibrosis (F3-4), the adjusted optimal cutoff value was 374.5 U/L, yielding the sensitivity, specificity, PPV, NPV, and the accuracy of 97.1%, 54.1%, 95.7%, 66.7%, and 77.6%, respectively (P = 0.003). Among those patients without hyperuricemia, the PPV, NPV, and accuracy of CK18 reached 100%, 95.8%, and 96%, respectively (P<0.001). CONCLUSIONS: CK18 combined with uric acid measurement is a promising non-invasive biomarker for prediction of disease severity in NASH patients. TRIAL REGISTRATION: ClinicalTrials.gov NCT01068444.

25-Hydroxy vitamin D suppresses hepatitis C virus replication and contributes to rapid virological response of treatment efficacy.

AIM: 25-Hydroxy vitamin D (Vit D) plays a role in treatment outcomes in chronic hepatitis C virus (HCV) infection. We aimed to clarify whether HCV replication is inhibited by Vit D in HCV replicon cells. Clinical implication was assessed for rapid virological response (RVR) and sustained virological response (SVR) among those patients receiving antiviral therapy. METHODS: Cell survival and viral loads were observed in Con1 (genotype 1b) and J6/JFH (genotype 2a) cells treated with different doses of Vit D. Three groups of patients with different treatment responses were recruited to assess their Vit D levels: group A, RVR-/SVR-; group B, RVR+/SVR-; and group C, RVR+/SVR+. RESULTS: The viral load of Con1 cells decreased by 69%, 80%, and 86% following treatment with 1 µM, 5 µM, and 10 µM Vit D, respectively (P < 0.0001). In J6/JFH cells, it decreased by 12%, 55%, and 80.5% following treatment with 1 µM, 5 µM, and 10 µM Vit D, respectively (P < 0.0001). There was a significant increase of Vit D between chronic hepatitis C groups, ranging from 4.4 ± 5.6 ng/mL in group A (n = 44), to 17.2 ± 11.6 ng/mL in group B (n = 44), and 32.5 ± 37.5 ng/mL of group C (n = 44) (P < 0.001). Advanced fibrosis (odds ratio = 0.13, 95% confidence interval = 0.04-0.41, P < 0.001) and Vit D deficiency (<10 ng/mL) (odds ratio = 0.11, 95% confidence interval = 0.03-0.43, P = 0.001) were predictive of SVR in the multivariate regression analysis. CONCLUSION: Vitamin D decreases HCV replication and also contributes to early treatment viral kinetics.

PNPLA3 genetic variants determine hepatic steatosis in non-obese chronic hepatitis C patients.

The influence of patatin-like phospholipase domain-containing 3 (PNPLA3) genetic variants in the development of liver steatosis in Asian chronic hepatitis C patients remains elusive. A total of 1018 biopsy-proven chronic hepatitis C patients were enrolled for evaluation. The proportions of PNPLA3 rs738409 GG genotype carriage were 7.8% (44/563), 15.8% (58/367) and 19.3% (17/88) in patients with no (liver fat content < 5%), mild (5-33%) and moderate/severe (> 66%) hepatic steatosis, respectively (trend P < 0.001). Stepwise logistic regression analysis revealed that the strongest factor independently associated with steatosis was the carriage of the PNPLA3 rs738409 GG genotype (odds ratio [OR]/95% confidence intervals [CI]:2.34/1.557-3.515, P < 0.001). Among the patients with BMI < 24 kg/m(2), carriage of the rs738409 GG genotype was the only factor associated with hepatic steatosis (OR/CI:3.44/1.824-6.500, P < 0.001). PNPLA3 genetic variants had minimal effects on hepatic steatosis among overweight or obese patients. Compared to patients with BMI < 24 kg/m(2)/non-GG genotype, those with BMI >24 kg/m(2)/GG genotype were more likely to have hepatic steatosis (OR/CI:3.87/2.292-6.524, P < 0.001). In conclusions, both PNPLA3 genetic variants and BMI played important roles in hepatic steatosis among Asian chronic hepatitis C patients. However, the genetic effect was mainly restricted to non-obese patients.

Association of diabetes and PNPLA3 genetic variants with disease severity of patients with chronic hepatitis C virus infection.

BACKGROUND & AIMS: Genetic variants of patatin-like phospholipase domain-containing 3 (PNPLA3) and diabetes are associated with liver disease severity, in patients with chronic hepatitis C (CHC) infection. We aimed at exploring their interaction in determining hepatitis C virus (HCV)-related liver fibrosis. METHODS: The PNPLA3 genetic polymorphism at rs738409 was verified in 1077 biopsy-proven CHC patients. Other clinical variables, including diabetes status, were analysed for factors associated with bridging fibrosis. RESULTS: Patients with advanced liver fibrosis had higher proportions of the GG genotype (14.5% vs. 10.4%, p=0.06 in recessive model) and GG/GC genotype carriage (64.0% vs. 56.8%, p=0.03 in dominant model). Stepwise logistic regression analysis revealed that factors predictive of advanced liver fibrosis included age (odds ratio [OR]: 1.02, 95% confidence intervals [CI]: 1.008-1.037, p=0.002), diabetes (OR: 1.81, CI: 1.236-2.653, p=0.002), α-fetoprotein (OR: 1.006, CI: 1.001-1.01, p=0.01), platelet counts (OR: 1.009, CI: 1.006-1.012, p<0.001), and PNPLA3 rs738409 CG/GG genotype (OR: 1.34, CI: 1.006-1.785, p=0.046). When patients were grouped according to their diabetes status, the PNPLA3 genetic variants were associated with advanced liver fibrosis in diabetic patients only, but not in non-diabetic patients. The PNPLA3 gene was the most important predictive factor of bridging fibrosis in diabetic patients, using the recessive model (OR: 4.53, CI: 1.356-15.106, p=0.014) or the dominant model (OR: 2.20, CI: 1.026-4.734, p=0.04). Compared to non-diabetic patients, patients with the diabetes/GG genotype were more likely to have advanced liver fibrosis (OR: 8.79, CI: 2.889-26.719, p<0.001), followed by those with diabetes/non-GG genotype (OR: 1.55, CI: 1.048-2.286, p=0.03). CONCLUSIONS: The effect of PNPLA3 genetic variants in HCV-related advanced liver fibrosis was enhanced in diabetic patients. The strong genetic-environmental interaction contributed to the high risk of advanced liver disease in CHC patients.

Abbott RealTime HBV assay is more sensitive in detection of low viral load and little impacted by drug resistant mutation in chronic hepatitis B patients under nucleot(s)ide analogues therapy.

BACKGROUND: Selection of drug-resistant strains may lead to failure of HBV antiviral therapy. There is little information whether there is detection difference in drug resistant mutations between different viral load assays of HBV. OBJECTIVES: This study is aimed to investigate whether there is drug-resistant strains related detection difference between Abbott RealTime HBV (RealTime) and CobasAmpliPrep/CobasTaqMan HBV assays 2.0 (TaqMan). STUDY DESIGN: One hundred and thirty-four CHB patients who received HBV anti-viral therapy were enrolled. HBV virological markers were tested 3 months apart regularly. Serum HBV DNA levels were determined using the TaqMan and RealTime. YMDD (rt180M and rt204V) mutation was checked in patients who experienced virologic breakthrough (VBT). RESULTS: The correlation of HBV DNA observed between the RealTime and TaqMan was good for all 571 samples (R2 = 0.797; P<0.001). However, the correlation in the 434 samples with HBV DNA level <3 log10 IU/ml was not as good as in all samples (R2 = 0.457). Overall, 21.5% of samples had a detection difference of ≥ 1 log10 IU/ml with 91.9% of these having HBV DNA level <3 log10 IU/ml. Twenty-four patients experienced VBT. Three of these patients had acquired the YMDD mutation and exhibited discordant viral load results between the two methods tested. In each case, persistent HBV DNA was detected by RealTime and undetectable with TaqMan. Of the patients who experienced a VBT and had acquired YMDD mutation, 4.7% had undetectable HBV DNA by TaqMan while all were detectable with RealTime. CONCLUSIONS: RealTime assay is more sensitive and is little impacted by the development of drug resistant mutation.

Baseline gamma-glutamyl transferase levels strongly correlate with hepatocellular carcinoma development in non-cirrhotic patients with successful hepatitis C virus eradication.

BACKGROUND & AIMS: Hepatitis C virus (HCV)-infected patients with cirrhosis remain at risk of hepatocellular carcinoma (HCC) even after achieving sustained virological response (SVR). The aim of the study was to explore the incidence and risk for HCC among non-cirrhotic patients with an SVR. METHODS: A total of 642 patients with an SVR after peginterferon/ribavirin therapy were enrolled with a median follow-up period of 53.0 months (range: 6-133 months). RESULTS: Thirty-three of the 642 (5.1%) patients developed HCC over 2324.8 person-years of follow-up. Cox regression analysis revealed that the strongest predictive factor of HCC occurrence was liver cirrhosis (HR 4.98, 95% CI 2.32-10.71, p<0.001), followed by age (HR 1.06, 95% CI 1.02-1.11, p=0.005) and γGT levels (HR 1.008, 95% CI 1.004-1.013, p<0.001). The incidence of HCC did not differ between patients with high and low baseline γGT levels among patients with cirrhosis (p=0.53), but the incidence of HCC was significantly higher in non-cirrhotic patients with high γGT levels compared with those with low γGT levels (p=0.001). Cox regression analysis revealed that the strongest factors associated with HCC development in non-cirrhotic sustained responders were baseline γGT levels (HR 6.44, 95% CI 2.20-18.89, p=0.001) and age (HR 3.68, 95% CI 1.33-10.17, p=0.012). The incidence of HCC was not different between older non-cirrhotic patients with high γGT levels and cirrhotic patients (p=0.34). CONCLUSIONS: HCC remains a threat in non-cirrhotic patients with an SVR. Serum γGT levels helped to identify potential patients at high risk.