The genetic study of ischemia induced arrhythmia and potassium channels

Objectives Ischemia induced arrhythmia(ventricular tachycardia/ventricular fibrillation) is one of the major causes of death.Potassium channels change are likely to be responsible for the ischemia-related arrhythmias.Cardiac potassium current is the major outward current involved in cardiac repolarization.The properties of potassium channels have been intensively studied.Here,we investigated the association between ischemia induced arrhythmia and potassium channels genetic variations.Methods 23 patients with ventricular tachycardia/ventricular fibrillation induced by ischemia were selected as objects.5ML peripheral blood were taken from each person,from which DNA was extracted us- ing a standard enzymatic phenol-chloroform method.Candidate genes(HERG、KCNJ2、KCNQ1、Mink、Mirp1、Kir2.1、KV4.3、Kir3.1、KV1.5、Kir6.1、Kir6.2、Kir2.1) Were screened for potassium channels gene mutations with direct sequencing methods.Results Here 4 potassium channels gene mutations have been discovered.In the gene coding for the ATP-sensitive K^+ channels subunit Kir6.2,there is a change from valine to isoleucine at the position of 326(V326I).At the position 448,arginine substitutes proline(P448R) in the KC-NQ1 gene.In the gene KCNJ2 two mutations have been found(P156L,Q193H).Conclusions This study implicated that there is a high relationship between ischemia induced arrhythmia and the mutation of potassium channels.In order to identify the precisely relationship there is need functional analysis.

Genetic study and molecular breeding for high phosphorus use efficiency in maize

Phosphorus is the second most important macronutrient after nitrogen and it has many vital functions in the life of plants.Most soils have a low available P content,which has become a key limiting factor for increasing crop production.Also,low P use efficiency(PUE)of crops in conjunction with excessive application of P fertilizers has resulted in serious environmental problems.Thus,dissecting the genetic architecture of crop PUE,mining related quantitative trait loci(QTL)and using molecular breeding methods to improve high PUE germplasm are of great significance and serve as an efficient approach for the development of sustainable agriculture.In this review,molecular and phenotypic characteristics of maize inbred lines with high PUE,related QTL and genes as well as low-P responses are summarized.Based on this,a breeding strategy applying genomic selection as the core,and integrating the existing genetic information and molecular breeding techniques is proposed for breeding high PUE maize inbred lines and hybrids.

Peters-Plus Syndrome: What Outcome in the Absence of Genetic Confirmation? A Case Report

Anterior segment dysgenesis is a group of non-acquired ocular anomalies whose cause is multifactorial;many genes are involved. It is characterized by developmental anomalies of the tissues of the anterior segment, of which Peters-Plus syndrome is included. Our aim is to describe the different ophthalmological and systemic aspects of Peters-Plus syndrome in order to improve the quality of diagnosis of this syndrome even in the absence of genetic confirmation, especially in low-income countries or when genetic studies are not available. In this observation, we report the case of a newborn with Peters-Plus syndrome admitted to the neonatology unit. The diagnosis was made on the basis of clinical-radiological criteria, and treatment consisted of caring for the baby and the parents, given the particular psychological context often associated with the birth of a baby with polymalformative syndrome. From this study, Peters-Plus syndrome should be borne in mind in a fetus with typical ocular anomalies, unusual facial appearance and long tubular bone insufficiency, especially in the presence of a positive family history. In such cases, prenatal diagnosis could be an option for the couples. A genetic study should be undertaken to confirm the clinical diagnosis and provide appropriate genetic counseling and prenatal diagnostic options.

A Genetic Susceptibility Study of Lung Cancer Risk Potentially Associated with Polycyclic Aromatic Hydrocarbon Inhalation Exposure

For lifetime non-smokers, lung cancer risk is mainly associated with inhalation exposure to air pollution. For the Chinese population, indoor air pollution due to solid fuel combustion has been the primary source of inhalation exposure for decades. Polycyclic aromatic hydrocarbons （PAHs） are the by-products of incomplete combustion.

Differences in clinical and genetic characteristics between early-and late-onset narcolepsy in a Han Chinese cohort

Early-and late-onset narcolepsy constitutes two distinct diagnostic subgroups.However,it is not clear whether symptomology and genetic risk factors differ between early-and late-onset narcoleptics.This study compared clinical data and single-nucleotide polymorphisms(SNPs)between early-and late-onset patients in a large cohort of 899 Han Chinese narcolepsy patients.Blood,cerebrospinal fluid,and clinical data were prospectively collected from patients,and patients were genotyped for 40 previously reported narcolepsy risk-conferring SNPs.Genetic risk scores(GRSs),associations of five different sets of SNPs(GRS1–GRS5)with early-and late-onset narcolepsy,were evaluated using logistic regression and receiver operating characteristic curves.Mean sleep latency was significantly shorter in early-onset cases than in late-onset cases.Symptom severity was greater among late-onset patients,with higher rates of sleep paralysis,hypnagogic hallucinations,health-related quality of life impairment,and concurrent presentation with four or more symptoms.Hypocretin levels did not differ significantly between early-and late-onset cases.Only rs3181077(CCR1/CCR3)and rs9274477(HLA-DQB1)were more prevalent among early-onset cases.Only GRS1(26 SNPs;OR=1.513,95%CI:0.893–2.585;P<0.05)and GRS5(6 SNPs;OR=1.893,95%CI:1.204–2.993;P<0.05)were associated with early-onset narcolepsy,with areas under the receiver operating characteristic curves of 0.731 and 0.732,respectively.Neither GRS1 nor GRS5 included SNPs in HLA regions.Our results indicate that symptomology and genetic risk factors differ between early-and late-onset narcolepsy.This protocol was approved by the Institutional Review Board(IRB)Panels on Medical Human Subjects at Peking University People’s Hospital,China(approval No.Yuanlunshenlinyi 86)in October 2011.

Genetic epidemiology of diabetic retinopathy

The disease burden of diabetic retinopathy(DR)is tremendous around the world.While DR is correlated with hemoglobin A1c(HbA1c)and duration of diabetes,genetic differences likely account for variation in susceptibility to DR.DR is a polygenic disorder with demonstrated heritability.However,linkage and admixture analyses,candidate gene association studies,and genome-wide association studies(GWAS)have not identified many loci for DR that can be consistently replicated.Larger,collaborative,multi-ethnic GWAS are needed to identify common variants with small effects.Rigorous defining of controls groups as patients with a long duration of diabetes without DR,and case groups as patients with severe DR will also aid in finding genes associated with DR.Replication in independent cohorts will be key to establishing associated loci for DR.Investigations of mitochondrial DNA and epigenetics in DR are ongoing.Whole exome sequencing presents new opportunities to identify rare variants that might be implicated in DR development.Continued research in the genetic epidemiology of DR is needed,with the potential to elucidate pathogenesis and treatment of an important disease.

Non-alcoholic fatty liver disease: the problems we are facing

OBJECTIVE: To review the current state of research in non-alcoholic fatty liver disease (NAFLD). DATA RESOURCES: Searching Medline (1994-2002) and Chinese Medical Journals Index (1998- 2002) for articles on NAFLD. RESULTS: NAFLD is a new and challenging field with increasing recognition although its pathogenesis is poorly understood. 'Two hits' hypothesis is still the leading theory guiding current research. CONCLUSIONS: Genetic study is a promising way that might lead to breakthrough in NAFLD research. NAFLD study in China is at an initial stage and there is a long way to go.

KIT and platelet-derived growth factor receptor α wild-type gastrointestinal stromal tumor associated with neurofibromatosis type 1: Two case reports

BACKGROUND Gastrointestinal stromal tumors(GISTs) associated with neurofibromatosis are uncommon compared to their gastrointestinal counterparts. Patients with neurofibromatosis type 1(NF-1) have an increased risk of developing gastrointestinal tumors, including rare types such as GIST.CASE SUMMARY A 60-year-old male Chinese patient was diagnosed with NF-1 10 years ago and presented with upper abdominal discomfort and black stools. Endoscopic ultrasonography and an enhanced abdominal computed tomography scan revealed a mass located 4 cm from the muscular layer of the descending duodenum. A 59-year-old Chinese woman who was diagnosed with NF-1 25 years ago presented with sudden unconsciousness and black stools. Multiple masses in the duodenum were noted by echogastroscopy and an enhanced abdominal computed tomography scan. Both patients presented with cutaneous neurofibromas. The histologic examination of tumors from both patients revealed spindle cells and low mitotic activity. Immunohistochemically, the tumor cells showed strong positivity for KIT(CD117), DOG-1, CD34, and Dehydrogenase Complex Subunit B, and negativity for SMA, desmin, S-100, and β-catenin. None of the six tumors from two patients had KIT exon 9, 11, 13, or 17 or platelet-derived growth factor receptor α exon 12 or 18 mutation, which is a typical finding for sporadic GISTs. None of the six tumors from the two patients had a BRAFV600 E mutation. The patients were alive and well during the follow-up period(range:0.6-5 yr).CONCLUSION There have been only a few previous reports of GISTs associated with NF-1.Although GISTs associated with NF-1 have morphologic and immunohistochemical similarities with GISTs, the pathogenesis, incidence,genetic background, and prognosis are not completely known. A medical history of NF-1 in a patient who has gastrointestinal bleeding or anemia and an intraabdominal mass with nonspecific computed tomography features may help in diagnosing GIST by virtue of the well-known association of these two entities.Molecular genetic studies of cases indicated that GISTs in NF-1 patients have a different pathogenesis than sporadic GISTs.

Quantitative trait loci for the number of vertebrae on Sus scrofa chromosomes 1 and 7 independently influence the numbers of thoracic and lumbar vertebrae in pigs

Although quantitative trait loci（QTLs） for number of thoracic-lumbar vertebrae have been identified on Sus scrofa chromosomes（SSCs） 1 and 7, the influence of these QTLs on the thoracic and lumbar vertebrae is not clear. The aim of this study was to identify single nucleotide polymorphisms（SNPs） associated with total number of thoracic-lumbar vertebrae and for each trait（number of thoracic and lumbar vertebrae） separately. A total of 581 individuals from an F2 Large White×Minzhu population were genotyped using an SNP60 K chip. Performing a genome-wide association study（GWAS） for total number of thoracic-lumbar vertebrae, 38 significant SNPs were identified in two QTL regions located on SSC1 and SSC7. Performing a GWAS for number of thoracic vertebrae only, 72 significant SNPs were located on SSC7. While performing a GWAS for number of lumbar vertebrae only, 17 significant SNPs were identified on SSC1. Gene mining suggested that the gene encoding orphan nuclear receptor, germ cell nuclear factor（NR6A1） on SSC1 was a strong candidate affecting the number of lumbar vertebrae in pigs. Additionally, genes encoding vertnin（VRTN）, prospero homeobox 2（PROX2）, Finkel-Biskis-Jinkins murine osteosarcoma viral oncogene homolog（FOS）, and transforming growth factor beta 3（TGFB3） may be important candidates affecting the number of thoracic vertebrae in pigs. QTLs on SSC1 and SSC7 independently influenced the numbers of thoracic and lumbar vertebrae. These results shed light on the complex genetic background of vertebrae development in pigs.

Malocclusion May Be Attributed to Variation among 10 Genes

Introduction: The goal of this study was to utilize physical characteristics instead of placing subjects in arbitrary diagnostic categories to test for associations with genetic variants. Methods: Forty-four single nucleotide polymorphisms were tested for association with specific cephalometric measurements in thirty-nine University of Pittsburgh Dental Registry and DNA Repository orthodontic subjects. Cephalometric measurements included an evaluation of FMA, a Wits appraisal, and a Steiner’s ANB analysis. Genetic markers were genotyped using polymerase chain reaction and Taqman chemistry. Chi-square and Fischer’s exact tests (α = 0.05) were used in investigation of overrepresentation of marker alleles. Samples were divided into groups based upon having an FMA, Wits, or ANB measurement above or below the mean of the cohort studied. Secondary analysis was done for sex and ethnicity to determine their effect on FMA, Wits, or ANB. Results: An association between FMA measurements was discovered in the following genes: ACTN3, CASP4, ESR1, FGF13, KRT7, and PITX2. An association between Wits measurements was discovered in the following genes: ACTN2, BTBD11, CASP4, FGF3, and FGF10. No associations were found with ANB. Conclusions: Genetic markers in several genes at different loci may contribute to craniofacial deformities in humans. This approach of using physical measurements may be an advantage to placing patients in arbitrary diagnostic categories.

DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children

Developmental dyslexia is a complex reading and writing disorder with strong genetic components. In previous genetic studies about dyslexia, a number of candidate genes have been identified. These include DCDC2, which has repeatedly been associated with developmental dyslexia in various European and American populations. However, data regarding this relationship are varied according to population. The Uyghur people of China represent a Eurasian population with an interesting genetic profile. Thus, this group may provide useful information about the association between DCDC2 gene polymorphisms and dyslexia. In the current study, we examined genetic data from 392 Uyghur children aged 8–12 years old from the Xinjiang Uyghur Autonomous Region of China. Participants included 196 children with dyslexia and 196 grade-, age-, and gender-matched controls. DNA was isolated from oral mucosal cell samples and fourteen single nucleotide polymorphisms（rs6456593, rs1419228, rs34647318, rs9467075, rs793862, rs9295619, rs807701, rs807724, rs2274305, rs7765678, rs4599626, rs6922023, rs3765502, and rs1087266） in DCDC2 were screened via the SNPscan method. We compared SNP frequencies in five models（Codominant, Dominant, Recessive, Heterozygote advantage, and Allele） between the two groups by means of the chi-squared test. A single-locus analysis indicated that, with regard to the allele frequency of these polymorphisms, three SNPs（rs807724, rs2274305, and rs4599626） were associated with dyslexia. rs9467075 and rs2274305 displayed significant associations with developmental dyslexia under the dominant model. rs6456593 and rs6922023 were significantly associated with developmental dyslexia under the dominant model and in the heterozygous genotype. Additionally, we discovered that the T-G-C-T of the four-marker haplotype（rs9295619-rs807701-rs807724-rs2274305） and the T-A of the two-marker haplotype（rs3765502-1087266） were significantly different between cases and controls. Thus, we conclude that DCDC2 gene polymorphisms are associated with developmental dyslexia in Chinese Uyghur children.

Finding susceptible and protective interaction patterns in large-scale genetic association study

Interaction detection in large-scale genetic asso- ciation studies has attracted intensive research interest, since many diseases have complex traits. Various approaches have been developed for finding significant genetic interactions. In this article, we propose a novel framework SRMiner to detect interacting susceptible and protective genotype patterns. SR- Miner can discover not only probable combination of single nucleotide polymorphisms （SNPs） causing diseases but also the corresponding SNPs suppressing their pathogenic func- tions, which provides a better prospective to uncover the un- derlying relevance between genetic variants and complex dis- eases. We have performed extensive experiments on several real WeUcome Trust Case Control Consortium （WTCCC） datasets. We use the pathway-based and the protein-protein interaction （PPI） network-based evaluation methods to verify the discovered patterns. The results show that SRMiner successfully identifies many disease-related genes verified by the existing work. Furthermore, SRMiner can also infer some uncomfirmed but highly possible disease-related genes.

Studying gene duplication and genetic variation of budding yeast:a systems and interdisciplinary approach

Budding yeast (Saccharomyces cerevisiae) is a single cell model organism that is amenable to genome wide experimental interrogation using high-throughput genomics, proteomics

An Adaptive Weighted Sum Test for Family-Based Multi-Marker Association Studies

Backgrounds: Although many disease-associated common variants have been discovered through genome-wide association studies, much of the genetic effects of complex diseases have not been explained. Population-based association studies are vulnerable to population stratification. A possible solution is to use family-based tests. However, if tests only estimate the genetic effect from the within-family variation to avoid population stratification, they may ignore the useful genetic information from between-family variation and lose power. Methods: We have developed an adaptive weighted sum test for family-based association studies. The new test uses data driven weights to combine two test statistics, and the weights measure the strength of population stratification. When population stratification is strong, the proposed test will automatically put more weight on one statistic derived from within-family variation to maintain robustness against spurious positives. On the other hand, when the effect of population stratification is relatively weak, the proposed test will automatically put more weight on the other statistic derived from both within-family and between-family variation to make use of both sources of genetic variation;and at the same time, the degrees of freedom of the test will be reduced and power of the test will be increased. Results: In our study, the proposed method achieves a higher power in most scenarios of linkage disequilibrium structure as well as Hap Map data from different genes under different population structures while still keeping its robustness against population stratification.

Implicit Hypotheses Are Hidden Power Droppers in Family-Based Association Studies of Secondary Outcomes

Family-based tests of association between a genetic marker and a disease constitute a common design to dissect the genetic architecture of complex traits. The FBAT software is one of the most popular tools to perform such studies. However, researchers are also often interested in the genetic contribution to a more specific manifestation of the phenotype (e.g. severe vs. non-severe form) known as a secondary outcome. Here, what we demonstrate is the limited power of the classical formulation of the FBAT statistic to detect the effect of genetic variants that influence a secondary outcome, in particular when these variants also impact on the onset of the disease, the primary outcome. We prove that this loss of power is driven by an implicit hypothesis, and we propose a derivation of the original FBAT statistic, free from this implicit hypothesis. Finally, we demonstrate analytically that our new statistic is robust and more powerful than FBAT for the detection of association between a genetic variant and a secondary outcome.

The genetics of Behcet’s disease in a Chinese population

Behcet’s disease is defined as a multisystemic inflammatory disease.Although the precise pathogenesis and etiology is still a mystery,accumulating evidence shows that genetic variants of immune-related genes have a profound influence on the development of Behcet’s disease.To explore the genetic factors for Behcet’s disease,our group investigated the association of Behcet’s disease with multiple immune response genes and has identified multiple Behcet’s disease-related immunoregulatory pathways in the Chinese Han population.A large number of gene polymorphisms were studied including STAT4,IL23R,CD40,CCR1/CCR3,STAT3,OPN,IL17,JAK2,MCP-1,CTLA4,PD-1,PD-L1,PD-L2,TGRBR3,CCR6,PTPN22,FCRL3,IRF5,SUMO4 and UBAC2.Significant associations were found between Behcet’s disease and STAT4,IL23R,CD40,CCR1/CCR3,STAT3,MCP-1,TGFBR3,FCRL3,SUMO4,UBAC2.These genetic predisposition studies support an important role for both lymphocyte differentiation as well as ubiquitination pathways.These findings are helpful in elucidating the pathogenesis of Behcet’s disease and hopefully will allow the development of novel treatment regimes.

Genetic studies of schizophrenia:an update

Schizophrenia（SCZ） is a complex and heterogeneous mental disorder that affects about 1% of global population. In recent years,considerable progress has been made in genetic studies of SCZ. A number of common variants with small effects and rare variants with relatively larger effects have been identifi ed. These variants include risk loci identifi ed by genome-wide association studies,rare copy-number variants identifi ed by comparative genomic analyses,and de novo mutations identified by high-throughput DNA sequencing. Collectively,they contribute to the heterogeneity of the disease. In this review,we update recent discoveries in the fi eld of SCZ genetics,and outline the perspectives of future directions.

The Biological Significance of Multi-copy Regions and Their Impact on Variant Discovery

Identification of genetic variants via high-throughput sequencing(HTS)technologies has been essential for both fundamental and clinical studies.However,to what extent the genome sequence composition affects variant calling remains unclear.In this study,we identified 63,897 multi-copy sequences(MCSs)with a minimum length of 300 bp,each of which occurs at least twice in the human genome.The 151,749 genomic loci(multi-copy regions,or MCRs)harboring these MCSs account for 1.98% of the genome and are distributed unevenly across chromosomes.MCRs containing the same MCS tend to be located on the same chromosome.Gene Ontology(GO)analyses revealed that 3800 genes whose UTRs or exons overlap with MCRs are enriched for Golgirelated cellular component terms and various enzymatic activities in the GO biological function category.MCRs are also enriched for loci that are sensitive to neocarzinostatin-induced double-strand breaks.Moreover,genetic variants discovered by genome-wide association studies and recorded in dbSNP are significantly underrepresented in MCRs.Using simulated HTS datasets,we show that false variant discovery rates are significantly higher in MCRs than in other genomic regions.These results suggest that extra caution must be taken when identifying genetic variants in the MCRs via HTS technologies.

Association of polymorphisms in the DCDC2 gene with developmental dyslexia in the Han Chinese

Background Genetic association studies on populations of European origin have identified the DCDC2 gene as a susceptibility locus for developmental dyslexia.Here,we sought to investigate the association of DCDC2 polymorphisms with developmental dyslexia in children of Han Chinese origin.Methods We undertook a case-control genetic association study on 76 dyslexic children and 79 non-dyslexic matched controls.We isolated DNA from oral mucosal cell samples and genotyped two DCDC2 coding-sequence single nucleotide polymorphisms,rs2274305 and rs6456593,in each sample using SNaPshot single nucleotide extension.We compared the allele and genotype frequencies between the groups using the X2 test and analyzed the relationship between dyslexia and the polymorphism at both loci using unconditional logistic regression.We also predicted haplotypes and compared their frequencies between the two groups.Results The differences in the genotype distribution and the allelic genes of the two single nucleotide luci of the DCDC2 gene,rs2274305 and rs6456593,between the two dyslexic and non-dyslexic groups were statistically meaningless （P 〉0.05）.The differences in the haplotype distributions of the DCDC2 gene between the dyslexic and normal group were statistically meaningless （P 〉0.05）.Conclusion The DCDC2 gene may not be a susceptibility factor for developmental dyslexia among the Han Chinese.However,methodological issues may have prevented the detection of oositive associations.