Graves' disease is the leading cause of hyperthyroidism affecting 1.0–1.6% of the population. Antithyroid drugs are the treatment cornerstone, but may cause life-threatening agranulocytosis. Here we conduct a two-stage association study on two separate subject sets (in total 42 agranulocytosis cases and 1,208 Graves' disease controls), using direct human leukocyte antigen genotyping and SNP-based genome-wide association study. We demonstrate HLA-B*38:02 (Armitage trend Pcombined=6.75 × 10−32) and HLA-DRB1*08:03 (Pcombined=1.83 × 10−9) as independent susceptibility loci. The genome-wide association study identifies the same signals. Estimated odds ratios for these two loci comparing effective allele carriers to non-carriers are 21.48 (95% confidence interval=11.13–41.48) and 6.13 (95% confidence interval=3.28–11.46), respectively. Carrying both HLA-B*38:02 and HLA-DRB1*08:03 increases odds ratio to 48.41 (Pcombined=3.32 × 10−21, 95% confidence interval=21.66–108.22). Our results could be useful for antithyroid-induced agranulocytosis and potentially for agranulocytosis caused by other chemicals.

Background Recent genetic progress has allowed for the molecular diagnosis of Parkinson's disease. However, genetic causes of PD vary widely in different ethnicities. Mutational frequencies and clinical phenotypes of genes associated with PD in Asian populations are largely unknown. The objective of this study was to identify the mutational frequencies and clinical spectrums of multiple PD‐causative genes in a Taiwanese PD cohort. Methods A total of 571 participants including 324 patients with early‐onset parkinsonism (onset age, <50 years) and 247 parkinsonism pedigrees were recruited at a tertiary referral center in Taiwan from 2002 to 2017. Genetic causes were identified by an integrated approach including gene dosage analysis, a targeted next‐generation sequencing panel containing 40 known PD‐causative genes, repeat‐primed polymerase chain reaction, and whole‐exome sequencing analysis. Results Thirty of the 324 patients with early‐onset parkinsonism (9.3%) were found to carry mutations in Parkin , PINK1 , or PLA2G6 or had increased trinucleotide repeats in SCA8 . Twenty‐nine of 109 probands with autosomal‐recessive inheritance of parkinsonism (26.6%) were found to carry mutations in Parkin , PINK1 , GBA , or HTRA2 . The genetic causes for the 138 probands with an autosomal‐dominant inheritance pattern of parkinsonism were more heterogeneous. Seventeen probands (12.3%) carried pathogenic mutations in LRRK2 , VPS35 , MAPT , GBA , DNAJC13 , C9orf72 , SCA3, or SCA17 . A novel missense mutation in the UQCRC1 gene was found in a family with autosomal‐dominant inheritance parkinsonism via whole‐exome sequencing analysis. Conclusions Our findings provide a better understanding of the genetic architecture of PD in eastern Asia and broaden the clinical spectrum of PD‐causing mutations. © 2019 The Authors. Movement Disorders published by Wiley Periodicals, Inc. on behalf of International Parkinson and Movement Disorder Society.

Cochlear implantation is currently the treatment of choice for children with severe to profound hearing impairment. However, the outcomes with cochlear implants (CIs) vary significantly among recipients. The purpose of the present study is to identify the genetic determinants of poor CI outcomes. Twelve children with poor CI outcomes (the “cases”) and 30 “matched controls” with good CI outcomes were subjected to comprehensive genetic analyses using massively parallel sequencing, which targeted 129 known deafness genes. Audiological features, imaging findings, and auditory/speech performance with CIs were then correlated to the genetic diagnoses. We identified genetic variants which are associated with poor CI outcomes in 7 (58%) of the 12 cases; 4 cases had bi-allelic PCDH15 pathogenic mutations and 3 cases were homozygous for the DFNB59 p.G292R variant. Mutations in the WFS1, GJB3, ESRRB, LRTOMT, MYO3A, and POU3F4 genes were detected in 7 (23%) of the 30 matched controls. The allele frequencies of PCDH15 and DFNB59 variants were significantly higher in the cases than in the matched controls (both P < 0.001). In the 7 CI recipients with PCDH15 or DFNB59 variants, otoacoustic emissions were absent in both ears, and imaging findings were normal in all 7 implanted ears. PCDH15 or DFNB59 variants are associated with poor CI performance, yet children with PCDH15 or DFNB59 variants might show clinical features indistinguishable from those of other typical pediatric CI recipients. Accordingly, genetic examination is indicated in all CI candidates before operation.

Purpose: Here, we aim to investigate the molecular mechanism of regorafenib and verify the potential druggable target for the treatment of hepatocellular carcinoma (HCC).Experimental Design: HCC cell lines (PLC5, HepG2, Hep3B, SK-Hep1, and HA59T) were used to investigate the in vitro effect of regorafenib. Phosphatase activity was analyzed in HCC cells and purified SHP-1 proteins. PLC5-bearing mice were used to test the therapeutic efficiency of 20 and 40 mg/kg/d treatment with regorafenib (n ! 8 mice). The clinical relevance of STAT3 signaling was investigated with 142 tumor samples from different patients with HCC. Descriptive statistical analysis was used to compare the baseline characteristics of patients and the expression of p-STAT3.Results: Regorafenib inhibited STAT3-related signaling in a dose-dependent manner and was a more potent inhibitor of STAT3 than sorafenib. Regorafenib increased SHP-1 phosphatase activity in purified SHP-1 protein directly. N-SH2 domain deletion and D61A mutants mimicking open-form SHP-1 partially abolished regorafenib-induced STAT3 inhibition and apoptosis. Importantly, a higher level of expression of STAT3 was found in patients with advanced clinical stages (P ¼ 0.009) and poorly differentiated tumors (P ¼ 0.035).Conclusions: Regorafenib induced significant tumor inhibition by relieving the autoinhibited N-SH2 domain of SHP-1 directly and inhibiting p-STAT3 signals. STAT3 may be suitable as a prognostic marker of HCC development, and may be a druggable target for HCC-targeted therapy using regorafenib. Clin Cancer Res; 20(22); 5768-76. Ó2014 AACR.

BackgroundGraves' disease (GD) is the leading cause of hyperthyroidism and thyroid eye disease inherited as a complex trait. Although geoepidemiology studies showed relatively higher prevalence of GD in Asians than in Caucasians, previous genetic studies were contradictory concerning whether and/or which human leukocyte antigen (HLA) alleles are associated with GD in Asians.Methodology/Principal FindingsWe conducted a case-control association study (499 unrelated GD cases and 504 controls) and a replication in an independent family sample (419 GD individuals and their 282 relatives in 165 families). To minimize genetic and phenotypic heterogeneity, we included only ethnic Chinese Han population in Taiwan and excluded subjects with hypothyroidism. We performed direct and comprehensive genotyping of six classical HLA loci (HLA-A, -B, -C, -DPB1, -DQB1 and -DRB1) to 4-digit resolution. Combining the data of two sample populations, we found that B*46:01 (odds ratio under dominant model [OR]  = 1.33, Bonferroni corrected combined P [PBc]  = 1.17×10−2), DPB1*05:01 (OR  = 2.34, PBc = 2.58×10−10), DQB1*03:02 (OR  = 0.62, PBc  = 1.97×10−2), DRB1*15:01 (OR  = 1.68, PBc = 1.22×10−2) and DRB1*16:02 (OR  = 2.63, PBc  = 1.46×10−5) were associated with GD. HLA-DPB1*05:01 is the major gene of GD in our population and singly accounts for 48.4% of population-attributable risk.Conclusions/SignificanceThese GD-associated alleles we identified in ethnic Chinese Hans, and those identified in other Asian studies, are totally distinct from the known associated alleles in Caucasians. Identification of population-specific association alleles is the critical first step for individualized medicine. Furthermore, comparison between different susceptibility/protective alleles across populations could facilitate generation of novel hypothesis about GD pathophysiology and indicate a new direction for future investigation.

Background: Phospholipase A2 group VI (PLA2G6) mutations associated with neurodegeneration (PLAN) manifest as heterogeneous neurodegenerative disorders with variable ages of onset. The genotype-phenotype correlation is not well-established. We aim to describe three adult patients with PLAN and combined these data with results from previous studies to elucidate adult-onset PLA2G6 phenotype-genotype correlations. Case presentations: The first index patient presented with dystonia-parkinsonism starting at age 31 years, accompanied by major depression and cognitive decline. Genetic analysis using targeted next generation sequencing (NGS) panel, Sanger sequencing, and segregation analyses revealed a compound heterozygous mutation, c.991G > T (p.D331Y)/c.1077G > A (M358IfsX), in PLA2G6. The other two patients had levodopa-responsive, early-onset parkinsonism, starting in their late twenties. Both patients had homozygous c.991G > T (p.D331Y) mutations in PLA2G6. Patient characteristics of our reported 3 cases were compared to those of 32 previously described (2008 to 2019) patients with adult-onset PLAN. Among the combined cohort of 35 patients with adult-onset PLAN, 14 had dystonia-parkinsonism, 17 had early-onset Parkinson's disease, 3 had hereditary spastic paraparesis, and one had ataxia. The c.991G > T (p. D331Y) mutation was almost exclusively found in Chinese patients, suggesting a common founder effect. All patients with homozygous p.D331Y mutations had levodopa-responsive, early-onset PD (100%); while other mutations mostly led to dystonia-parkinsonism, ataxia, spasticity, and combine psychiatric comorbidities. Conclusions: We showed that adult-onset PLAN could present as purely parkinsonism features, without brain iron accumulation, particularly patients with homozygous p.D331Y mutations. Compound heterozygous mutations, including heterozygous p.D331Y, produced heterogeneous phenotypes, without obvious levodopa responsiveness.

in a cohort from a population with the world's third highest incidence of KD, we demonstrated that the C-allele of ITPKC SNP rs28493229 is associated with KD susceptibility and BCG scar reactivation during the acute phase, although its frequency is lower than that in the Japanese cohort (22.6%), suggesting this SNP contributes to KD susceptibility through induced hyperimmune function reflected in the BCG reactivation.

This study demonstrated a full coverage of ABO by capture-based panel, phasing analysis with NGS in ABO genotyping resolved heterogeneity with novel allele and microchimerism findings. This approach provided a more precise method for subtyping and thereby leading to safer transfusion.