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To identify genetic contributions to type 2 diabetes (T2D) and related glycemic traits (fasting glucose, fasting insulin, and HbA1c), we conducted genome-wide association analyses (GWAS) in up to 7,178 Chinese subjects from nine provinces in the China Health and Nutrition Survey (CHNS). We examined patterns of population structure within CHNS and found that allele frequencies differed across provinces, consistent with genetic drift and population substructure. We further validated 32 previously described T2D- and glycemic trait-loci, including G6PC2 and SIX3-SIX2 associated with fasting glucose. At G6PC2, we replicated a known fasting glucose-associated variant (rs34177044) and identified a second signal (rs2232326), a low-frequency (4%), probably damaging missense variant (S324P). A variant within the lead fasting glucose-associated signal at SIX3-SIX2 co-localized with pancreatic islet expression quantitative trait loci (eQTL) for SIX3, SIX2, and three noncoding transcripts. To identify variants functionally responsible for the fasting glucose association at SIX3-SIX2, we tested five candidate variants for allelic differences in regulatory function. The rs12712928-C allele, associated with higher fasting glucose and lower transcript expression level, showed lower transcriptional activity in reporter assays and increased binding to GABP compared to the rs12712928-G, suggesting that rs12712928-C contributes to elevated fasting glucose levels by disrupting an islet enhancer, resulting in reduced gene expression. Taken together, these analyses identified multiple loci associated with glycemic traits across China, and suggest a regulatory mechanism at the SIX3-SIX2 fasting glucose GWAS locus. [ABSTRACT FROM AUTHOR]

Fusarium oxysporumf. sp.cubense, particularly the tropical race 4 (TR4), is the most destructive fungal pathogen of banana and can cause significant economic losses. However, the molecular mechanisms underlying the pathogenicity and virulence of the fungus are poorly understood. In this study, we characterized the mutant W2987, which was derived through T-DNA insertional mutagenesis of a wild-type TR4 isolate. W2987 showed slower growth, produced fewer conidia and was less virulent than the wild-type strain. Thermal asymmetric interlaced-PCR (TAIL-PCR) analysis showed that the T-DNA was inserted in the 3′ untranslated region (UTR) of an open reading frame (ORF) in W2987. BLAST search results indicated that the ORF encodes a hypothetical protein with unknown function. Phylogenetic analysis of the gene sequences from variousFusariumisolates showed that theF. oxysporumf. sp.cubenseTR4 isolates were distinct from otherF. oxysporumisolates. One pair of primers based on the 3′ UTR sequence of the putative virulence gene amplified a specific PCR product from theF. oxysporumf. sp.cubenseTR4 isolates but not from other races andFusariumspecies. This result indicates that this genetic locus possibly associated with virulence is unique and reliable for diagnosis and detection ofF. oxysporumf. sp.cubenseTR4. [ABSTRACT FROM PUBLISHER]

Abstract: Hepatitis B virus (HBV) with a C/D recombinant genotype is dominant in Tibet. A rapid, simple and specific genotyping system, consisting of three real-time PCR assays, was developed for the determination of genotypes C and D as well as two forms of recombinant C/D. Overall, 95% of the 22 samples were genotyped accurately. This system is considered to be a useful method for large-scale genotype surveys in Tibet. [Copyright &y& Elsevier]

Background: Hypospadias is a common congenital malformation of male external genitalia, which mainly manifests as an abnormal urethral opening on the ventral side of the penis. The etiology and clinical phenotype of hypospadias is highly heterogeneous, and its clinical diagnosis is challenging. Currently, over 70% of patients have an unknown etiology. Here, we performed a targeted analysis of gene mutations in 130 patients with hypospadias of unknown etiology to find the precise genetic cause. Methods: We developed a targeted next‐generation sequencing (NGS) panel, encompassing the exon coding regions of 105 genes involved in external genitalia and urogenital tract development and performed sequencing analysis on 130 children with hypospadias of unknown etiology. Results: In total, 25 patients with hypospadias (19.2%) were found to have 20 mutations among the nine genes involved in external genitalia and urogenital tract development, including 16 reported and four novel mutation sites. Twenty‐two patients (16.9%) had diagnostic variants. Multiple genetic mutations were identified in three of the 25 patients. Hypospadias combined with micropenis was the most common phenotype (68%) in 25 patients. Conclusions: Higher frequency mutations were identified in SRD5A2 (52%) and AR (24%) in our patient cohort. Middle or posterior hypospadias with micropenis may be significant indicators of genetic variations. Polygenic inheritance may be a rare genetic cause of hypospadias. [ABSTRACT FROM AUTHOR]

Psoriasis-2 (PSORS2) is caused by the heterozygous mutation of the caspase recruitment domain 14 (CARD14) gene on chromosome 17q25. To evaluate the contribution of CARD14 variants in psoriasis of the Chinese Han population, we performed deep sequencing of the CARD14 gene in 372 Chinese Han patients with psoriasis. The exonic nucleotide variants were confirmed by Sanger sequencing in the affected individuals and 1114 controls. In 27 patients with psoriasis, we identified 15 variations, including three novel variants: c.381C>G (p.Cys127Trp), c.712A>G (p.Met238Val) and c.2260_2261delinsGG (p.Gln754Gly). These findings could enrich and update the Human Gene Mutation Database of CARD14 variants for psoriasis. [ABSTRACT FROM AUTHOR]

Background: Dwarfism is a common severe growth disorder, but the etiology is unclear in the majority of cases. Recombinant human growth hormone may be a treatment option, but it has limited efficacy. The currently known laboratory assays do not meet the precision requirements for clinical diagnosis. Here, we have constructed a targeted next-generation sequencing (NGS) panel of selected genes that are suspected to be associated with dwarfism for genetic screening. Methods: Genetic screening of 91 children with short stature of unknown etiology was performed with the help of the NGS panel. All the coding regions and exon-intron boundaries of 166 genes were included in the panel. To clarify the pathogenicity of these mutations, their clinical data were reviewed and analyzed. Results: The assay identified p.A72G, p.I282V, and p.P491S variants of the PTPN11 gene and a p.I437T variant of the SOS1 gene in 4 cases with Noonan syndrome. A frameshift mutation (p.D2407fs) of the ACAN gene was identified in a case of idiopathic short stature with moderately advanced bone age. A p.R904C variant of the COL2A1 gene was found in a patient, who was accordingly diagnosed with Stickler syndrome. Severe short stature without limb deformity was associated with a p.G11A variant of HOXD13. In addition, we evaluated evidence that a p.D401N variant of the COMP gene may cause multiple epiphyseal dysplasia. Conclusions: Our findings suggest that syndromes, particularly Noonan syndrome, may be overlooked due to atypical clinical features. This gene panel has been verified to be effective for the rapid screening of genetic etiologies associated with short stature and for guiding precision medicine-based clinical management. [ABSTRACT FROM AUTHOR]

Apolipoprotein A5 ( APOA5 ) gene plays a key role in plasma triglyceride (TG) metabolism, and shows the involvement in coronary artery disease (CAD). A set of single nucleotide polymorphisms around the APOA5 gene was identified to be associated with plasma TG levels. It is of biological and clinical importance to discern the genuine genetic determinants. A polymorphism in 3′ untranslated region of the APOA5 gene, rs2266788, is deserving of investigation for suggestive clues from the association in multiple independent studies. In this study, rs2266788 was genotyped in 3222 unrelated subjects consisting of 2062 CAD cases and 1160 controls. The statistical analyses indicated that the minor C allele of rs2266788 was significantly associated with elevated plasma TG levels and higher CAD risk. In normal human liver tissues, comparison of global APOA5 mRNA levels among genotypes and allelic expression imbalance analysis showed the decreased gene expression for the C allele. Luciferase assays confirmed a concordant result that transcriptional activity was lowered for the C allele compared with the T allele in four cell lines. Multiple lines of evidence in our study supported that rs2266788 was causally associated with plasma TG levels conferring CAD risk in Han Chinese population owing to a cis -acting effect to the APOA5 gene expression. [ABSTRACT FROM AUTHOR]

[Display omitted] • A sandwich-type electrochemical biosensor for ctDNA detection was designed through facile steps. • The synthesized MWCNTs-PDA-Au-Pt shows excellent catalytic capacity and was used as SPs' label for signal amplification. • The electrochemical biosensor exhibits satisfactory sensitivity for ctDNA detection. • The proposed sandwich-type scheme is a promising method in clinical ctDNA diagnosis. It is of great importance to accurately analyze circulating tumor DNA (ctDNA), for the reason that it serves as one of the particularly informative cancer biomarkers for disease diagnosis, therapy, and prognosis. However, sensitive detection of ctDNA remains a challenging task and the design of feasible sensing method plays a significant role in ctDNA analysis. In this work, a novel sandwich-type electrochemical biosensor was developed through a facile way for sensitive detection of ctDNA using nanocomposites (MWCNTs-PDA-Au-Pt) as signal probes' (SPs) label (SPs-label) for signal amplification. The current response of the nanocomposites towards H 2 O 2 reduction was used to quantitatively detect target DNA and distinguish base-mismatched DNA sequences. Characterizations reveal that Au-Pt alloy nanoparticles are uniformly dispersed on MWCNTs-PDA and the resultant MWCNTs-PDA-Au-Pt shows excellent response toward the reduction of H 2 O 2 , which could largely amplify the current response. Electrochemical analysis of electrode modification process confirms that the sandwich-type structure was successfully formed through step-wise reactions, including fixation of capture probes (CPs) on the surface of the screen-printed gold electrode, recognition between CPs and target DNA (T-DNA), hybridization between T-DNA and SPs. Under optimal experimental conditions, the proposed ctDNA biosensor exhibits a wide linear range from 1 × 10−15 to 1 × 10−8 mol/L with a detection limit as low as 5 × 10−16 mol/L (S/N = 3), unprecedented selectivity towards T-DNA and other base-mismatched DNAs (even for only single base-mismatched sequences), and superb long-term stability. This work demonstrates the sandwich-type scheme is a promising method for practical applications in clinical ctDNA diagnosis. [ABSTRACT FROM AUTHOR]

Summary We comprehensively analyzed clinical, genomic, and transcriptomic data of a cohort of 465 primary triple-negative breast cancer (TNBC). PIK3CA mutations and copy-number gains of chromosome 22q11 were more frequent in our Chinese cohort than in The Cancer Genome Atlas. We classified TNBCs into four transcriptome-based subtypes: (1) luminal androgen receptor (LAR), (2) immunomodulatory, (3) basal-like immune-suppressed, and (4) mesenchymal-like. Putative therapeutic targets or biomarkers were identified among each subtype. Importantly, the LAR subtype showed more ERBB2 somatic mutations, infrequent mutational signature 3 and frequent CDKN2A loss. The comprehensive profile of TNBCs provided here will serve as a reference to further advance the understanding and precision treatment of TNBC. Graphical Abstract Highlights • We build the genomic and transcriptomic landscape of 465 primary TNBCs • Chinese TNBC cases demonstrate more PIK3CA mutations and LAR subtype • Transcriptomic data classify TNBCs into four subtypes • Multi-omics profiling identifies potential targets within specific TNBC subtypes Jiang et al. characterize primary Chinese triple-negative breast cancer (TNBC) and classify it into four subtypes. They find that these TNBCs have more frequent PIK3CA mutations and chromosome 22q11 copy-number gains than non-Asian TNBCs and that the LAR subtype has more ERBB2 somatic mutations and CDKN2A loss. [ABSTRACT FROM AUTHOR]