Association of Hck genetic polymorphisms with gene expression and COPD

Polymorphonuclear leukocytes (PMNs) are major effector cells in the chronic airway inflammation in chronic obstructive pulmonary disease (COPD). PMN degranulation is associated with degradation of extracellular matrix and tissue damage. Hck is an essential molecule in the signaling pathway regulating PMN degranulation. We hypothesized that polymorphisms affect the expression level of Hck, which, in turn, modulates PMN mediator release and tissue damage and influences the development of COPD. Here we systematically investigated genetic tag polymorphisms of the Hck gene, Hck mRNA and protein expression pattern in PMNs, and PMN mediator release (myeloperoxidase) in 60 healthy white subjects, and assessed their association with the use of several genetic models. The association of genetic polymorphisms with COPD-related phenotypes was determined in the lung healthy study cohort (LHS). We identified a novel 15 bp insertion/deletion polymorphism (8,656 L/S) in intron 1 of the Hck gene, which was associated with differential expression of Hck protein and PMN myeloperoxidase release. In the LHS cohort, there was significant interaction between the 8,656 L/S polymorphism and smoking on baseline lung function and 8,656 L/S was associated with bronchodilator response. These data suggest that the insertion/deletion polymorphism could be a functional polymorphism of the Hck gene, may contribute to COPD pathogenesis and modify COPD-related phenotypes.     

Genetic analysis of human lymphocyte proteins by two-dimensional gel electrophoresis: 4. Genetic polymorphism of cytosol 100k polypeptide

Summary We describe a genetic polymorphism of a human cellular polypeptide with mol. wt. 100,000, detected in peripheral blood lymphocytes by high resolution two-dimensional electrophoresis. Three different electrophoretic types (1-1, 2-1, and 2-2) of the polypeptide have been identified. Family and population studies indicate that the three phenotypes of the polypeptide are determined by two common alleles at a single autosomal locus. The polypeptide occurs in the cytosol and is one of the abundant polypeptides of B-lymphoblastoid cells, T-lymphoblastoid cells, fibroblasts, and HeLa cells. The data indicate that the cytosol polypeptide with mol.wt. 100,000 shows a genetic polymorphism determined by aew autosomal locus. It is proposed that the polypeptide and its locus be temporarily designated cytosol 100k polypeptide (C100k polypeptide) and C100P, respectively. In a Japanese population, the gene frequencies of C100P ¹ and C100P ² were 0.907 and 0.093, respectively.     

The SLC19A1 80G>A polymorphism is not associated with male infertility

Previous studies have revealed that genetic factors may be involved in regulating folate turnover, e.g. methylenetetrahydrofolate reductase polymorphism in the development of male infertility. Folate transporter, encoded by the SLC19A1 gene, commonly referred to as reduced folate carrier (RFC) is a transmembrane protein, which transfers hydrophilic folates across the cell membrane. It was hypothesized that common polymorphism within the SLC19A1 gene (rs1051266:G>A, 80G>A) may alter RFC function. The aim of this study was to investigate a potential association between the SLC19A1 80G>A polymorphism and male infertility in a case–control study. The SLC19A1 80G>A polymorphism was determined by means of a polymerase chain reaction (PCR)-restriction fragment length polymorphism (RFLP) assay in 213 infertile Caucasian men and 226 ethnically matched controls. The distribution of SLC19A1 genotypes in the infertile men was as follows: GG 26.8%, GA 51.2%, AA 22.1% and in fertile men: GG 24.8%, GA 50.4%, AA 24.8%, and was comparable in the both the evaluated groups. Odds ratios (95% confidence interval, CI): 0.90 (0.59–1.38) and 0.88 (0.56–1.36) for dominant and recessive models remained non-significant, also after adjustment for age: 0.89 (0.57–1.37) and 0.80 (0.51–1.25), respectively. Our study demonstrated that polymorphism 80G>A of the SLC19A1 gene is not associated with male infertility.     

Rejecting strictly allopatric speciation on a continental island: prolonged postdivergence gene flow between Taiwan (Leucodioptron taewanus,Passeriformes Timaliidae) and Chinese (L. canorum canorum) hwameis

Allopatry is conventionally considered the geographical mode of speciation for continental island organisms. However, strictly allopatric speciation models that assume the lack of postdivergence gene flow seem oversimplified given the recurrence of land bridges during glacial periods since the late Pliocene. Here, to evaluate whether a continental island endemic, the Taiwan hwamei (Leucodioptron taewanus, Passeriformes Timaliidae) speciated in strict allopatry, we used weighted‐regression‐based approximate Bayesian computation (ABC) to analyse the genetic polymorphism of 18 neutral nuclear loci (total length: 8500 bp) in Taiwan hwamei and its continental sister species, the Chinese hwamei (L. canorum canorum). The nonallopatry model was found to fit better with observed genetic polymorphism of the two hwamei species (posterior possibility = 0.82). We also recovered unambiguous signals of nontrivial bidirectional postdivergence gene flow (N_em » 1) between Chinese hwamei and Taiwan hwamei until 0.5 Ma. Divergence time was estimated to be 3.5 to 2 million years earlier than that estimated from mitochondrial cytochrome b sequences. Finally, using the inferred nonallopatry model to simulate genetic variation at 24 nuclear genes examined showed that the adiponectin receptor 1 gene may be under divergent adaptation. Our findings imply that the role of geographical barrier may be less prominent for the speciation of continental island endemics, and suggest a shift in speciation studies from simply correlating geographical barrier and genetic divergence to examining factors that facilitate and maintain divergence, e.g. differential selection and sexual selection, especially in the face of interpopulation gene flow.     

TAP1 I333V gene polymorphism and type 1 diabetes mellitus: a meta‐analysis of 2248 cases

Transporter associated with antigen processing 1 (TAP1) I333V gene polymorphism has been suggested to be associated with type 1 diabetes mellitus (T1DM) susceptibility. However, the results from individual studies are inconsistent. To explore the association of TAP1 I333V gene polymorphisms with T1DM, a meta‐analysis involving 2246 cases from 13 individual studies was conducted. The pooled odd ratios (ORs) and their corresponding 95% confidence intervals (95% CIs) were evaluated by a fixed‐effect model. A significant relationship was observed between TAP1 I333V gene polymorphism and T1DM in allelic (OR: 1.35, 95% CI: 1.08–1.68, P = 0.007), dominant (OR: 1.462, 95% CI: 1.094–1.955, P = 0.010), homozygous (OR: 1.725, 95% CI: 1.082–2.752, P = 0.022), heterozygous (OR: 1.430, 95% CI: 1.048–1.951, P = 0.024) and additive (OR: 1.348, 95% CI: 1.084–1.676, P = 0.007) genetic models. No significant association between TAP1 I333V gene polymorphism and T1DM was detected in a recessive genetic model (OR: 1.384, 95% CI: 0.743–2.579, P = 0.306) in the entire population, especially among Caucasians. No significant association between them was found in an Asian or African population. TAP1 I333V gene polymorphism was significantly associated with increased T1DM risk. V allele carriers might be predisposed to T1DM susceptibility.     

Biochemical and genetic studies on rabbit hemoglobin. II. Electrophoretic polymorphism of theα-chain

A genetic polymorphism of rabbit (Oryctolagus cuniculus) hemoglobin chain is demonstrated by means of acid starch gel electrophoresis. The polymorphism is not detected by isoelectric focusing and may be based upon neutral for neutral amino acid substitutions in accordance with previous findings by means of amino acid sequencing. Segregation analysis was performed on 15 matings with 49 offspring and confirmed the initial genetic hypothesis of three common codominant alleles at an autosomal locus. The calculated gene frequencies in a random sample of 86 unrelated individuals areHBA*1=0.73,HBA*2=0.22, andHBA*3=0.05.     

CDKN2B-AS1 gene rs4977574 A/G polymorphism and coronary heart disease: A meta-analysis of 40,979 subjects

It has been implied that there is a possible relationship between cyclin-dependent protein kinase inhibitors antisense RNA 1 (CDKN2B-AS1) gene rs4977574 A/G polymorphism and coronary heart disease (CHD) susceptibility. However, as the research results are discrepant, no distinct consensus on this issue has been reached so far. In order to further elaborate the latent association of the CDKN2B-AS1 gene rs4977574 A/G polymorphism and CHD, this present meta-analysis was conducted. There were 40,979 subjects of 17 individual studies in the present meta-analysis. The pooled odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were estimated to determine the association strength. Considering the significant heterogeneity among the individual studies, the random-effect models were used. In the current meta-analysis, a significant association between CDKN2B-AS1 gene rs4977574 A/G polymorphism and CHD was found under allelic (OR: 1.18, 95% CI: 1.08–1.29, p = 4.83×10⁻⁴), recessive (OR: 1.36, 95% CI: 1.11–1.67, p = 0.003), dominant (OR: 0.71, 95% CI: 0.58–0.86, p = 6.26×10⁻⁴), heterozygous (OR:1.210, 95% CI: 1.076–1.360, p = 0.001), homozygous (OR: 1.394, 95% CI: 1.163–1.671, p = 3.31×10⁻⁴) and additive (OR: 1.180, 95% CI: 1.075–1.295, p = 4.83×10⁻⁴) genetic models. A more significant association between them was found in the Asian population than that in the whole population under these genetic models (p < 0.05). However, no significant association between them was found in the Caucasian population (p > 0.05). CDKN2B-AS1 gene rs4977574 A/G polymorphism was associated with CHD susceptibility, especially in the Asian population. G allele of CDKN2B-AS1 gene rs4977574 A/G polymorphism is the risk allele for CHD.     

Genetic variation in vitamin D receptor gene (Fok1:rs2228570) is associated with risk of coronary artery disease

Objective: The Fok1 polymorphism (rs2228570) in vitamin D receptor gene appears to be the only polymorphism influencing size of translated protein. Investigations into its association with coronary artery disease (CAD) are sparse.

Methods: Male patients (n?=?98) with verified CAD were recruited alongside age- and sex-matched controls (n?=?55). Genotyping was performed by PCR-RFLP and plasma 25-Hydroxyvitamin D levels were assessed by HPLC-UV.

Results: The C-variant (mutant) was predominantly expressed in patients compared to controls (68.9% versus 55.5%; p?=?0.025). The observed genotypes were not associated with 25-Hydroxyvitamin D levels.

Conclusion: This study presents Fok1 polymorphism as a potential genetic marker for CAD.     

KCNQ1 rs2237892 C→T gene polymorphism and type 2 diabetes mellitus in the Asian population: a meta‐analysis of 15,736 patients

The KCNQ1 rs2237892 C→T gene polymorphism is reportedly associated with T2DM susceptibility, but various studies show conflicting results. To explore this association in the Asian population, a meta‐analysis of 15,736 patients from 10 individual studies was performed. The pooled odds ratios (ORs) and their 95% confidence intervals (CIs) were evaluated using random‐effect or fixed‐effect models. A significant relationship between the KCNQ1 rs2237892 C→T gene polymorphism and T2DM was observed in the Asian population under the allelic (OR, 1.350; 95% CI, 1.240–1.480; P < 0.00001), recessive (OR: 0.650; 95% CI: 0.570–0.730; P < 0.00001), dominant (OR: 1.450; 95% CI: 1.286–1.634; P < 0.00001), and additive (OR: 1.346; 95% CI: 1.275–1.422; P < 0.00001) genetic models. In the subgroup analysis by race, a significant association was found in Chinese, Korean and Malaysia population, but not in Indian population. KCNQ1 rs2237892 C→T gene polymorphism was found to be significantly associated with increased T2DM risk in the Asian population, except Indian population. The C allele of the KCNQ1 rs2237892 C→T gene polymorphism may confer susceptibility to T2DM.     

Genetic variation in the apolipoprotein H (β2-glycoprotein I) gene affects plasma apolipoprotein H concentrations

Apolipoprotein H (apoH, protein; APOH, gene) is a single chain glycoprotein that exists in plasma both in a free form and in combination with lipoprotein particles. ApoH has been implicated in several physiologic pathways, including lipid metabolism, coagulation, and the production of antiphospholipid antibodies. The wide range of interindividual variation in plasma apoH levels is thought to be under genetic control, but its molecular basis is unknown. APOH displays a common structural polymorphism with the occurrence of three common alleles (APOH*1, APOH*2, and APOH*3), the APOH*2 allele being the most frequent in all populations. The relationship between the APOH polymorphism and plasma apoH levels is unknown. In this study, we have determined the impact of this APOH polymorphism on apoH levels in 455 normoglycemic non-Hispanic Whites (220 men and 235 women) from the San Luis Valley, Colorado. Mean plasma apoH levels, determined by capture enzyme-linked immunosorbent assay, were 20.0±0.2 mg/dl (range: 3.4–31.2 mg/dl) with no significant difference between men and women. In women, but not in men, age had a significant effect on plasma apoH levels explaining 3.4% of its phenotypic variance. ApoH levels also correlated positively with cholesterol (P=0.015), HDL-cholesterol (P=0.044), and triglyceride (P=0.037) in women, but not in men. An analysis of variance (ANOVA) of adjusted plasma apoH levels showed significant association with the APOH polymorphism in both men and women (P<0.0001), and the APOH polymorphism accounted for 11.4% and 13.6% of the variation in apoH levels in men and women, respectively. Compared with the APOH*1 and APOH*2 alleles, the APOH*3 allele was associated with significantly lower plasma apoH levels. At the molecular level, APOH*3 can be further subdivided into two distinct forms, called APOH*3 ^W and APOH*3 ^B . The APOH*3 ^W form is more common in US Whites and is the result of a missense mutation at codon 316. An ANOVA for the codon 316 polymorphism revealed that this polymorphism is a major determinant of plasma apoH variation (P<0.0001). This study indicates that common genetic variation in the APOH gene is a significant determinant of plasma apoH levels in non-Hispanics Whites and should be useful in evaluating the role of the APOH genetic variation in various metabolic pathways in which apoH has been implicated. Electronic Publication     

Spatiotemporal environmental heterogeneity and the maintenance of the tailspot polymorphism in the variable platyfish (Xiphophorus variatus)

Genetic variation is critical for adaptive evolution. Despite its importance, there is still limited evidence in support of some prominent theoretical models explaining the maintenance of genetic polymorphism within populations. We examined 84 populations of Xiphophorus variatus, a livebearing fish with a genetic polymorphism associated with physiological performance, to test: (1) whether niche differentiation explains broad‐scale maintenance of polymorphism, (2) whether polymorphism is maintained among populations by local adaptation and migration, or (3) whether heterogeneity in explicit environmental variables could be linked to levels of polymorphism within populations. We found no evidence of climatic niche differentiation that could generate or maintain broad geographic variation in polymorphism. Subsequently, hierarchical partitioning of genetic richness and partial mantel tests revealed that 76% of the observed genetic richness was partitioned within populations with no effect of geographic distance on polymorphism. These results strongly suggest a lack of migration‐selection balance in the maintenance of polymorphism, and model selection confirmed a significant relationship between environmental heterogeneity and genetic richness within populations. Few studies have demonstrated such effects at this scale, and additional studies in other taxa should examine the generality of gene‐by‐environment interactions across populations to better understand the dynamics and scale of balancing selection.     

Genetic analysis of human lymphocyte proteins by two-dimensional gel electrophoresis: 2. Genetic polymorphism of lymphocyte cytosol 64K polypeptide

Summary We describe a genetic polymorphism of human lymphocyte cytosol major polypeptide with mol. wt. 64,000, detected in peripheral blood lymphocytes by high resolution two-dimensional electrophoresis. Three different electrophoretic types (1-1, 2-1, 2-2) of the polypeptide have been identified. Family and population studies indicate that the three phenotypes of the polypeptide are determined by two common alleles at a single autosomal locus. The polypeptide occurs in the cytosol and is predominent in peripheral blood lymphocytes, B-lymphoblastoid cells, T-lymphoblastoid cells, lymph node, and spleen. The polypeptide has not been detected in HeLa cells, fibroblasts, erythrocytes, serum, and cerebrum. Traces of the polypeptide exist in liver, kidney, and skeletal muscle. It is proposed that the polypeptide and its locus be temporarily designated lymphocyte cytosol 64K polypeptide (LC64K polypeptide) andLC64P, respectively. In a Japanese population, the gene frequencies ofLC64P ¹ andLC64P ² were 0.936 and 0.064, respectively. The data suggest thatLC64P is a new locus, product of which shows genetic polymorphism and is associated with the function and/or the structure of lymphocytes.     

Beta-naphthoflavone inhibits the induction of hepatic oestrogen-dependent proteins by 17alpha-ethynylestradiol in mosquitofish (Gambusia holbrooki)

Quantification of metallothioneins (MTs) is classically associated with a cellular response to heavy metal contamination and is used in the monitoring of disturbed ecosystems. Despite the characterization of several MT genes in marine bivalves, only a few genetic studies have used MT genes as potential biomarkers of pollution. The aim of this study was to assess whether MT gene polymorphism could be used to monitor exposure of the Pacific oyster Crassostrea gigas to heavy metals and to develop specific genetic markers for population genetic studies in relation to environmental stress. The polymorphism of two exons of the C. gigas MT gene CgMT1 were studied using polymerase chain reaction single-strand conformation polymorphism (PCR-SSCP) in both field populations exposed to various metals concentrations and in experimentally exposed populations. High frequencies of two SSCP types in exons 2 and 3 of the CgMT1 gene have found to be significantly associated with tolerance to metals in experimental and field oyster populations. The use of MT1 gene polymorphism in C. gigas as in the present study should therefore be of high ecological relevance. In conclusion, the analysis of the types in these two CgMT1 gene exons, which can confer a greater tolerance to heavy metals, can constitute a good biomarker of effect of the presence of heavy metals in ecosystems.     

Neuronal nitric oxide synthase (NOS1) and its adaptor,NOS1AP,as a genetic risk factors for psychiatric disorders

Nitric oxide (NO) is a gaseous transmitter produced by nitric oxide synthases (NOSs). The neuronal isoform (NOS‐I, encoded by NOS1) is the main source of NO in the central nervous system (CNS). Animal studies suggest that nitrinergic dysregulation may lead to behavioral abnormalities. Unfortunately, the large number of animal studies is not adequately reflected by publications concerning humans. These include post‐mortem studies, determination of biomarkers, and genetic association studies. Here, we review the evidence for the role of NO in psychiatric disorders by focusing on the human NOS1 gene as well as biomarker studies. Owing to the complex regulation of NOS1 and the varying function of NOS‐I in different brain regions, no simple, unidirectional association is expected. Rather, the ‘where, when and how much’ of NO formation is decisive. Present data, although still preliminary and partially conflicting, suggest that genetically driven reduced NO signaling in the prefrontal cortex is associated with schizophrenia and cognition. Both NOS1 and its interaction partner NOS1AP have a role therein. Also, reduced NOS1 expression in the striatum determined by a length polymorphism in a NOS1 promoter (NOS1 ex1f‐VNTR) goes along with a variety of impulsive behaviors. An association of NOS1 with mood disorders, suggested by animal models, is less clear on the genetic level; however, NO metabolites in blood may serve as biomarkers for major depression and bipolar disorder. As the nitrinergic system comprises a relevant target for pharmacological interventions, further studies are warranted not only to elucidate the pathophysiology of mental disorders, but also to evaluate NO function as a biomarker.     

β3 Adrenergic Receptor Polymorphism and Obesity‐Related Phenotypes in Hypertensive Patients

Objectives: Obesity is a complex trait that is affected by both environmental and genetic risk factors. The β₃ adrenergic receptor (ADRB3) is expressed in adipose tissue and plays a role in energy metabolism. A missense mutation on codon 64 of this gene (W64R) is associated with receptor malfunction. Previous studies examining the relation between this polymorphism and obesity produced inconsistent findings. The current study assessed the association between the W64R genotype and obesity‐related phenotypes, including body weight, BMI, and serum triglycerides, cholesterol, and glucose. Research Methods and Procedures: We determined the ADRB3 W64R genotypes and fasting serum lipid and glucose concentrations for 695 hypertensive adults (336 men, 359 women) from a rural county in Anhui Province, China. Multivariate linear regression models were fit to detect associations between the genetic polymorphism and obesity‐related phenotypes. Results: The ADRB3 W64R polymorphism was significantly associated with body weight and BMI in men but not in women. After controlling for potential confounding variables, men who were homozygous for the R64 allele were 11.8 kg heavier (p < 0.001) and had a BMI that was 3.7 kg/m² greater (p = 0.001) than men who were homozygous for the W64 allele. Serum concentrations of lipids and glucose were found not associated with the genetic polymorphism. Discussion: The ADRB3 R64 allele was associated with increased body weight and BMI in men but not in women. The genetic association was not modified by triglyceride, cholesterol, blood glucose, or blood pressure levels of the subjects.     

A serum protein polymorphism determinant on chromosome 9 of Mus musculus

Summary Genetic polymorphism for a previously undescribed serum protein has been found among inbred strains of Mus musculus. The new serum protein locus, gene symbol Sep-1, has been located on Chromosome 9, gene order Lap-1-Sep-1-Mpi-1-d-Mod-1, by utilizing information obtained from 52 recombinant inbred strains together with standard genetic backcrosses. The strain distribution pattern for this locus, supernatant malic enzyme, and transferrin, also on Chromosome 9, are given for 67 inbred strains. Because the genotype of SEP-1 can be determined for individual mice without killing them, Sep-1 is a very useful gene in linkage studies and experimental biology.     

Genetic polymorphism of the iron-regulatory protein-1 and -2 genes in age-related macular degeneration

Iron can be involved in the pathogenesis of AMD through the oxidative stress because it may catalyze the Haber–Weiss and Fenton reactions converting hydrogen peroxide to free radicals, which can induce cellular damage. We hypothesized that genetic polymorphism in genes related to iron metabolism may predispose individuals to the development of AMD and therefore we checked for an association between the g.32373708 G>A polymorphism (rs867469) of the IRP1 gene and the g.49520870 G>A (rs17483548) polymorphism of the IRP2 gene and AMD risk as well as the modulation of this association by some environmental and life-style factors. Genotypes were determined in DNA from blood of 269 AMD patients and 116 controls by the allele-specific oligonucleotide-restriction fragment length polymorphism and the polymerase chain reaction-restriction fragment length polymorphism. An association between AMD, dry and wet forms of AMD and the G/G genotype of the g.32373708 G>A-IRP1 polymorphism was found (OR 3.40, 4.15, and 2.75). On the other hand, the G/A genotype reduced the risk of AMD as well as its dry or wet form (OR 0.23, 0.21, 0.26). Moreover, the G allele of the g.49520870 G>A-IRP2 polymorphism increased the risk of the dry form of the disease (OR 1.51) and the A/A genotype and the A allele decreased such risk (OR 0.43 and 0.66). Our data suggest that the g.32373708 G>A-IRP1 and g.49520870 G>A-IRP2 polymorphisms may be associated with increased risk for AMD.     

基于SSR分子标记的延胡索遗传多样性研究

采用SSR分子标记分析延胡索的遗传多样性,筛选出多态性高、稳定性好的12对引物,对19个居群360份延胡索样品进行了群体遗传分析。结果表明:(1)12对SSR引物共扩增出多态性位点227个,检测到4~9个等位基因,平均等位基因数目为5.25个,表现出丰富的多态性;延胡索居群具有较高的遗传多样性(Na=5.25,I=1.192 6,H=0.387 9),物种间遗传分化程度高(Fst=0.388 3),基因流较弱(Nm=0.393 8)。(2)UPGMA聚类分析和贝叶斯距离分析结果表明,19个居群明显聚为4大支;Mantle Test结果(r=0.326,P=0.01)表明,地理位置相近的种群亲缘关系更近。研究认为,延胡索的遗传结构是该物种自交为主的繁育系统、克隆生长、地理隔离以及居群间有限的基因流共同作用的结果,故对该物种的保护应以就地保护为主。