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.

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.

Genetic Variations and Nonalcoholic Fatty Liver Disease:Field Synopsis,Systematic Meta-Analysis,and Epidemiological Evidence

Objective To systematically summarize the published literature on the genetic variants associated with nonalcoholic fatty liver disease(NAFLD).Methods Literature from Web of Science,PubMed,and Embase between January 1980 and September 2022 was systematically searched.Meta-analyses of the genetic variants were conducted using at least five data sources.The epidemiologic credibility of the significant associations was graded using the Venice criteria.Results Based on literature screening,399 eligible studies were included,comprising 381 candidate gene association,16 genome-wide association,and 2 whole-exome sequencing studies.We identified 465 genetic variants in 173 genes in candidate gene association studies,and 25 genetic variants in 17 genes were included in the meta-analysis.The meta-analysis identified 11 variants in 10 genes that were significantly associated with NAFLD,with cumulative epidemiological evidence of an association graded as strong for two variants in two genes(HFE,TNF),moderate for four variants in three genes(TM6SF2,GCKR,and ADIPOQ),and weak for five variants in five genes(MBOAT7,PEMT,PNPLA3,LEPR,and MTHFR).Conclusion This study identified six variants in five genes that had moderate to strong evidence of an association with NAFLD,which may help understand the genetic architecture of NAFLD risk.

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.

SHEsis,a powerful software platform for analyses of linkage disequilibrium,haplotype construction,and genetic association at polymorphism loci

In multiloci-based genetic association studies of complex diseases, a powerful and high efficient tool for analyses oflinkage disequilibrium (LD) between markers, haplotype distributions and many chi-square/p values with a large numberof samples has been sought for long. In order to achieve the goal of obtaining meaningful results directly from raw data,we developed a robust and user-friendly software platform with a series of tools for analysis in association study withhigh efficiency. The platform has been well evaluated by several sets of real data.

No association between cyclooxygenase-2 and uridine diphosphate glucuronosyltransferase 1A6 genetic polymorphisms and colon cancer risk

AIM：To investigate the association of variations in the cyclooxygenase-2 （COX2） and uridine diphosphate glucuronosyltransferase 1A6 （UGTIA6） genes and non-steroidal anti-inflammatory drugs （NSAIDs） use with risk of colon cancer.METHODS： NSAIDs, which are known to reduce the risk of colon cancer, act directly on COX2 and reduce its activity. Epidemiological studies have associated variations in the COX2 gene with colon cancer risk, but others were unable to replicate this finding. Similarly,enzymes in the UGT1A6 gene have been demonstrated to modify the therapeutic effect of NSAIDs on colon adenomas. Polymorphisms in the UGTIA6 gene have been statistically shown to interact with NSAID intake to influence risk of developing colon adenomas, but not colon cancer. Here we examined the association of tagging single nucleotide polymorphisms （SNPs） in the COX2 and UGTIA6 genes, and their interaction with NSAID consumption, on risk of colon cancer in a population of 422 colon cancer cases and 481 population controls.RESULTS： No SNP in either gene was individually statistically significantly associated with colon cancer, nor did they statistically significantly change the protective effect of NSAID consumption in our sample. Like others, we were unable to replicate the association of variants in the COX2 gene with colon cancer risk （P 〉 0.05）,and we did not observe that these variants modify the protective effect of NSAIDs （P 〉 0.05）. We were able to confirm the lack of association of variants in UGT1A6 with colon cancer risk, although further studies will have to be conducted to confirm the association of these variants with colon adenomas.CONCLUSION： Our study does not support a role of COX2 and UGTIA6 genetic variations in the development of colon cancer.

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.

What is new in the pathogenesis and treatment of IgA glomerulonephritis

Recently,new findings have been clarified concerning both pathogenesis and treatment of IgA nephritis.The four hits theory has been confirmed but several genetic wide association studies have allowed finding several genes connected with the pathogenesis of the disease.All these new genes apply to each of the four hits.Additionally,new discoveries concerning the microbiota and its connection with immune system and IgA generation have allowed finding out the role of the mucosa in IgA nephropathy pathogenesis.The IgA treatment is also changed included the future possibilities.The treatment of the chronic kidney disease,associated with the nephropathy,is mandatory,since the beginning of the disease.The classical immunosuppressive agents have poor effect.The corticosteroids remain an important cornerstone in any phase of the disease.More effect is related to the treatment of B cells and plasma cells.In particular,in very recent studies have been documented the efficacy of anti B cell-activating factor and anti A proliferation-inducing ligand agents.Most of these studies are to date in phase II/III.Finally,new agents targeting complement are arising.These agents also are still in randomized trials and act principally in hit 4 where the immunocomplexes in the mesangium activate the different pathways of the complement cascade.

Nitric Oxide:from a mysterious labile factor to the molecule of the Nobel Prize Recent progress in nitric oxide research

NO is now known to be an important messenger molecule in biology.It regulates a variety of functions within cells and tissues including vasodilation, neurotransmission and immunological process. This review will focus on the nitric oxide synthase gene family and recent progress on molecular genetic analysis of NOS1, NOS2 and N0S3 genes.

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.

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.