NAPG mutation in family members with hereditary hemorrhagic telangiectasia in China.

BACKGROUND: Hereditary hemorrhagic telangiectasia (HHT) is a disease characterized by arteriovenous malformations in the skin and mucous membranes. We enrolled a large pedigree comprising 32 living members, and screened for mutations responsible for HHT. METHODS: We performed whole-exome sequencing to identify novel mutations in the pedigree after excluding three previously reported HHT-related genes using Sanger sequencing. We then performed in silico functional analysis of candidate mutations that were obtained using a variant filtering strategy to identify mutations responsible for HHT. RESULTS: After screening the HHT-related genes, activin A receptor-like type 1 (ACVRL1), endoglin (ENG), and SMAD family member 4 (SMAD4), we did not detect any co-segregated mutations in this pedigree. Whole-exome sequencing analysis of 7 members and Sanger sequencing analysis of 16 additional members identified a mutation (c.784A > G) in the NSF attachment protein gamma (NAPG) gene that co-segregated with the disease. Functional prediction showed that the mutation was deleterious and might change the conformational stability of the NAPG protein. CONCLUSIONS: NAPG c.784A > G may potentially lead to HHT. These results expand the current understanding of the genetic contributions to HHT pathogenesis.

Single-cell sequencing and its application in breast cancer.

Breast cancer originates from ducts and epithelial cells, and gradually develops from hyperplasia to atypical hyperplasia, in situ (adeno) carcinoma, to early and advanced invasive carcinoma. Traditional high-throughput sequencing mainly aims to identify candidate 'driver genes' attributable to development and progression of breast cancer, which has deficiencies in characterizing genomic structure alteration and subclone evolution, and thus ignores intratumoral, intertumoral or interpatient heterogeneity. The single-cell sequencing technology analyzes transcriptome (e.g., gene copy number and gene expression), explores cellular composition, differentiation and fate, fine-maps the tumor microenvironment, and provides supporting evidence for accurate stratification as well as personalized, precise therapy. At the same time, a complex relationship between breast cancer cells and T cells, macrophages and other immune cells can be revealed, thus facilitating discovery of new therapeutic targets and immune checkpoints. Here, we review state-of-the-art single-cell sequencing technologies and its application in breast cancer, in order to decipher multi-faceted alterations in the crosstalk/interactions between tumors and its microenvironments at the single-cell level, and provide a basis for better understanding of complicated pathogenesis and new avenues for immunotherapy.

Discovery of susceptibility loci associated with tuberculosis in Han Chinese.

Genome-wide association studies (GWASs) have revealed the worldwide heterogeneity of genetic factors in tuberculosis (TB) susceptibility. Despite having the third highest global TB burden, no TB-related GWAS has been performed in China. Here, we performed the first three-stage GWAS on TB in the Han Chinese population. In the stage 1 (discovery stage), after quality control, 691 388 SNPs present in 972 TB patients and 1537 controls were retained. After replication on an additional 3460 TB patients and 4862 controls (stages 2 and 3), we identified three significant loci associated with TB, the most significant of which was rs4240897 (logistic regression P = 1.41 × 10-11, odds ratio = 0.79). The aforementioned three SNPs were harbored by MFN2, RGS12 and human leukocyte antigen class II beta chain paralogue encoding genes, all of which are candidate immune genes associated with TB. Our findings provide new insight into the genetic background of TB in the Han Chinese population.

[Involvement of sympathetic nervous system in the pathogenesis of hypertension].

Sustained activation of sympathetic nervous system in response to stimulation of a wide variety of stress factors is an independent risk factor for the development of essential hypertension. Adrenal hormone biosynthesis pathway as an important part of the sympathetic nervous system consists of hormones, neurotransmitters, receptors, and a variety of synthases and invertases. In this article, we have systematically reviewed research progresses made in elucidating the interactions between genes of the adrenal hormone biosynthesis pathway and stress factors in the pathogenesis of essential hypertension.

New insight into the genes susceptible to asthma.

There is considerable worldwide interest in identifying genes related to susceptibility to asthma. Progress has been slow in part because of the complexity and heterogeneity of the disease. Although at least 170 genes located on 10 chromosomes have been associated with or in linkage with asthma and asthma-related phenotypes, the majority of the reports have either been preliminary or the results have been controversial. In order to overcome the problems with the inherent complexity of asthma and methodological issues, the authors propose a strategy for identification of asthma susceptibility genes based on theories of systems biology and bioinformatics and candidate gene approach.

[Comparison on mitochondrial ATP6, ATP8 and Cyt b genes between Chinese Tibetans in three different zones: detecting the signature of natural selection on mitochondrial genome].

Mitochondrial DNA (mtDNA) differs from nuclear genome in many aspects such as lack of recombination, thus the investigation of mtDNA plays an essential role in human evolutionary history. We compared different sequences (approximately 2 kb) of ATP6, ATP8 and Cyt b genes in mtDNA among Tibetans in three different zones and found that the whole mtDNA sequences of the three genes, ATP6 and ATP 8 genes deviate gradually from neutral model with the increase of altitudes, yet no differences were observed. Also we found that the effect of purifying selection on Cyt b gene was elevated with the decrease of altitudes. Meanwhile, there was a possibility for the adaptive selection in ATP6 gene, which had an enhanced trend with the increase of altitudes. Thus, the geographic environment is the main determinant for selection, namely, different geographic environment has direct effect on selection.

[Comparative analysis of the complete mitochondrial genome between Tibetan and Han population].

OBJECTIVE: To construct the haplogroup and perform an analysis of mitochondrial whole-genome sequence in Tibetan and Han Chinese. Variations of nucleotide of mitochondrial DNA (mtDNA) were identified and compared between the Tibetan and Han population. METHODS: The mtDNA whole sequences of 40 Tibetan and 50 Han individuals were sequenced by an Applied Biosystems 3730 DNA automatic sequencer. The sequences were assembled using software phredPhrap16.0, and all assembled sequences were manually verified according to the criterion of rCRS (revised Cambridge Reference Sequence). The haplogroups of mtDNA were constructed using phylogenetic analysis according to the criteria of MITOMAP by Network method. The data were elucidated by integrated methods. RESULTS: Authors' results showed that all the pooled 90 subjects belonged to the Macrohaplogroup M and N, and were classified into 13 haplogroups. No differences were observed among the haplogroups of the two populations except for M9 haplogroup. A total of 21 variants were detected by comparing the mtDNA whole sequences between Tibetan and Han population; of those, 5 variants have not been reported before. In addition, we constructed the haplotypes of 5 variants harboring the D-loop region, and founded prominent difference in both supertype 1 and supertype 2 between Tibetan and Han population. CONCLUSION: The phylogenetic analysis indicates that the Tibetan and Han ethnic groups shared close maternal relationship in origin. The biological implication of the significant variants is worth elucidating; whether they are the results of adaptive selection or neutral selection or pathological variations need to be further studied.

Targeted capture sequencing identifies novel genetic variations in Chinese patients with idiopathic inflammatory myopathies.

OBJECTIVES: Previous association studies have identified genetic variants in the human leukocyte antigen (HLA) complex as substantial risk factors for idiopathic inflammatory myopathies (IIMs). However, a great number of genes are located in the HLA region, and thus fine mapping is quite necessary. METHODS: Targeted capture sequencing were performed on the whole HLA region in 42 IIM patients and 24 healthy controls. A microarray analysis was applied to analyze gene expression profiles in additional 20 newly diagnosed IIM and five healthy controls. RESULTS: The HLA region was confirmed to be associated with IIMs in Chinese patients. By gene expression profiling and pathway analysis, several genes were identified as candidates for IIM risk factors, including HLA-A, HLA-B, HLA-DRB5, HLA-DRB1, HLA-DQA1, HLA-DQB1 and HLA-DQB2. Interestingly, p.Y107V of the HLA-DRB1 was predicted to be a potential causal non-synonymous variation for IIMs that may affect the antigen-binding groove of the HLA-II molecule. CONCLUSIONS: Our data have revealed novel genetic variations in the HLA region of IIM patients and provide new insight into the pathogenesis and diagnosis of IIMs.

[Construction of haplotype and haplotype block based on tag single nucleotide polymorphisms and their applications in association studies].

Human genome has structures of haplotype and haplotype block which provide valuable information on human evolutionary history and may lead to the development of more efficient strategies to identify genetic variants that increase susceptibility to complex diseases. Haplotype block can be divided into discrete blocks of limited haplotype diversity. In each block, a small fraction of ptag SNPsq can be used to distinguish a large fraction of the haplotypes. These tag SNPs can be potentially useful for construction of haplotype and haplotype block, and association studies in complex diseases. There are two general classes of methods to construct haplotype and haplotype blocks based on genotypes on large pedigrees and statistical algorithms respectively. The author evaluate several construction methods to assess the power of different association tests with a variety of disease models and block-partitioning criteria. The advantages, limitations and applications of each method and the application in the association studies are discussed equitably. With the completion of the HapMap and development of statistical algorithms for addressing haplotype reconstruction, ideas of construction of haplotype based on combination of mathematics, physics, and computer science etc will have profound impacts on population genetics, location and cloning for susceptible genes in complex diseases, and related domain with life science etc.

Interaction and relationship between angiotensin converting enzyme gene and environmental factors predisposing to essential hypertension in Mongolian population of China.

OBJECTIVE: To investigate the association of specific functional gene ACE (I/D) variants of the renin-angiotensin system with essential hypertension (EH) and interaction between ACE (I/D) gene and risk factors for EH in a genetically homogenous Mongolia rural population of China. METHODS: Individuals (n=1099) were recruited from general population of Kezuohouqi Banner in Inner Mongolian Autonomous Region. RESULTS: The association was found between ACE genotype DD plus ID and EH, with an interaction between ACE genotype DD plus ID and cigarette smoking in an additive model. Cigarette smoking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 7.10 to 1.16. Interaction between ACE genotype DD plus ID and alcohol drinking on EH appeared an additive model. Alcohol drinking index and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 1.66 to 1.09. BMI and ACE gene showed a low exposure-gene (LEG) effect on EH, with interaction indices from 6.15 to 2.49. Interactions between ACE genotype and WHR on EH showed a multiplicative model. In a short,there was an interaction between ACE gene and cigarette smoking, alcohol drinking and BMI on EH, especially in a low dose-exposure effect CONCLUSION: It is important for individuals who carry ACE D allele gene to prevent EH, and furthermore, to prevent and control coronary heart disease, in a view of population-based prevention.

Mapping and localization of susceptible genes in asthma.

OBJECTIVE: To elucidate the development of mapping and localization of susceptible genes on chromosomes to asthma related phenotypes. DATA SOURCES: Published articles about susceptibility genes for asthma related phenotypes were selected using PubMed. STUDY SELECTION: Using methods of candidate gene positional clone and genome-wide scan with linkage and association analysis to determine the location in the genome of susceptibility genes to asthma and asthma related phenotypes. RESULTS: There are multiple regions in the genome harboring susceptibility genes to asthma and asthma related phenotypes, including chromosomes 5, 11, 12, 6, 2, 3, 13, 7, 14, 9, 19 and 17. Many of these regions contain candidate genes involved in asthma development and progression. Some susceptible genes may affect the phenotype expression or response to therapy. In addition, the interaction of multiple genes with the environment may contribute to the susceptibility to asthma. CONCLUSIONS: As an essential step toward cloning the susceptible genes to asthma, fine mapping and localization on chromosomes are definitely needed. Novel powerful tools for gene discovery and the integration of genetics, biology and bioinformatics should be pursued.