Dominant Genetic Factors Research Articles

Hotspots and trends of risk factors in gastric cancer: A visualization and bibliometric analysis.

The lack of specific symptoms of gastric cancer (GC) causes great challenges in its early diagnosis. Thus it is essential to identify the risk factors for early diagnosis and treatment of GC and to improve the survival rates. To assist physicians in identifying changes in the output of publications and research hotspots related to risk factors for GC, constructing a list of key risk factors, and providing a reference for early identification of patients at high risk for GC. Research articles on risk factors for GC were searched in the Web of Science core collection, and relevant information was extracted after screening. The literature was analyzed using Microsoft Excel 2019, CiteSpace V, and VOSviewer 1.6.18. A total of 2514 papers from 72 countries and 2507 research institutions were retrieved. China (n = 1061), National Cancer Center (n = 138), and Shoichiro Tsugane (n = 36) were the most productive country, institution, or author, respectively. The research hotspots in the study of risk factors for GC are summarized in four areas, namely: Helicobacter pylori (H. pylori) infection, single nucleotide polymorphism, bio-diagnostic markers, and GC risk prediction models. In this study, we found that H. pylori infection is the most significant risk factor for GC; single-nucleotide polymorphism (SNP) is the most dominant genetic factor for GC; bio-diagnostic markers are the most promising diagnostic modality for GC. GC risk prediction models are the latest current research hotspot. We conclude that the most important risk factors for the development of GC are H. pylori infection, SNP, smoking, diet, and alcohol.

Abstract 16300: Genetic Influences on Cardiovascular Deaths During Various Follow-Up Lengths in the 45-Year Longitudinal Twin Study

Background: Genetic factors are known to affect cardiovascular and coronary heart death. The more deaths occur during the longer follow-up period in a longitudinal study. However, it is unclear whether follow-up lengths affect genetic influences on the mortality from total cardiovascular (CVD) and coronary heart diseases (CHD). Objective: To determine genetic influences on the mortality from CVD and CHD over various years of follow-up in the 45-year longitudinal National Heart, Lung, and Blood Institute (NHLBI) Twin Study. Method: A total of 1024 middle-aged, white male, veteran twins (512 pairs), including 253 monozygotic and 261 dizygotic twin pairs, were initially enrolled during 1969-1973 and then followed up on vital status and causes of death through December 31, 2015. Tetrachoric correlation coefficients were estimated for CHD and CVD death at 20, 30, and 45 years of follow-up, respectively. Genetic and environmental influences on the death were quantified using the best-fitting structural equation model selected with the smallest Akaike's Information Criterion value and the parsimony rule. Results: The age at death ranged from 43.9 to 97.3 years over a 45-year follow-up. Tetrachoric correlation coefficients in dizygotic twins were less than half of that in monozygotic twins over 20, 30, and 45 years of follow-up for CVD but over 20 and 30 years for CHD, respectively. Dominant genetic factors explained 40% (95% CI 5% ~ 68%), 39 % (16% ~ 59%), and 24% (4% ~ 43%) of variation in CVD death over 20, 30, and 45 years of follow-up, respectively, while the remaining variation in CVD death was explained by unique environmental factors during each follow-up period. For CHD death, unique environmental factors explained all variation over 20 and 45 years of follow-up. By contrast, dominant genetic factors explained 26% (95% CI -6% ~ 53%) variation in CHD death over 30 years of follow-up while the remaining variation was explained by unique environmental factors. Conclusion: Dominant genetic factors consistently influence cardiovascular mortality over 20 to 45 years of follow-up, implying a twin study of cardiovascular death can control for genetic confounding during this period.

Fine mapping and identifying candidate gene of Y underlying yellow peel in Cucurbita pepo.

As a conspicuous trait, peel color is one of the most important characteristics that affects commodity quality and consumer preferences. The locus Y underlying yellow peel in Cucurbita pepo (zucchini) was first reported in 1922; however, its molecular mechanism is still unknown. In this study, a genetic analysis revealed that yellow peel is controlled by a single dominant genetic factor. Furthermore, Y was mapped in a ~170 kb region on chromosome 10 by bulked segregated analysis (BSA) and fine mapping in F2 and BC1 segregating populations. The candidate region harbors fifteen annotated genes, among which Cp4.1LG10g11560 (CpCHLH) is regarded as a promising candidate gene. CpCHLH encodes a magnesium chelatase H subunit involved in chlorophyll biosynthesis, and its mutation can result in a reduction in chlorophyll content and yellow phenotype. Interestingly, a large fragment (~15 kb) duplication containing incomplete CpCHLH was inserted in the candidate interval, resulting in two reformed CpCHLH proteins in the yellow parental line. It is most likely that the reformed CpCHLH proteins act as a malfunctional competitor of the normal CpCHLH protein to interrupt the formation of chlorophyll. Overall, the isolation of Y will shed light on the molecular mechanism of the peel color regulation of zucchini and lay a foundation for breeding.

Does polyploidy inhibit sex chromosome evolution in angiosperms?

Dioecy is rare in flowering plants (5–6% of species), but is often controlled genetically by sex-linked regions (SLRs). It has so far been unclear whether, polyploidy affects sex chromosome evolution, as it does in animals, though polyploidy is quite common in angiosperms, including in dioecious species. Plants could be different, as, unlike many animal systems, degenerated sex chromosomes, are uncommon in plants. Here we consider sex determination in plants and plant-specific factors, and propose that constraints created at the origin of polyploids limit successful polyploidization of species with SLRs. We consider the most likely case of a polyploid of a dioecious diploid with an established SLR, and discuss the outcome in autopolyploids and allopolyploids. The most stable system possibly has an SLR on just one chromosome, with a strongly dominant genetic factor in the heterogametic sex (e.g., xxxY male in a tetraploid). If recombination occurs with its homolog, this will prevent Y chromosome degeneration. Polyploidy may also allow for reversibility of multiplied Z or X chromosomes into autosomes. Otherwise, low dosage of Y-linked SLRs compared to their multiple homologous x copies may cause loss of reliable sex-determination at higher ploidy levels. We discuss some questions that can be studied using genome sequencing, chromosome level-assemblies, gene expression studies and analysis of loci under selection.

VKORC1 gene polymorphism (-1639G>A) in warfarin therapy patients of Pakistani population.

To observe vitamin K epoxide reductase complex subunit 1-1639 G>A polymorphism in patients resistant to warfarin therapy, and to calculate the allele frequency of the polymorphism in local patients. The cross-sectional case-control study was conducted at the Punjab Institute of Cardiology, Lahore, from 2013 to 2014 and comprised patients with heart valve replacement. Thy were divided into warfarin-resistant group 1 taking 10mg/day, 70mg/week and control group 2 taking a standard dose of 5mg/day, 35mg/week. The vitamin K epoxide reductase complex subunit 1-1639 G>A polymorphism analysis was done by polymerase chain reaction, followed by restriction fragment length polymorphism technique. Data was analysed using SPSS 20. Of the 146 patients, there were 73(50%) in each of the two groups. In group 1, there were 37(50.68%) males and 36(49.32%) were females with an overall mean age of 33±12 years, while group 2 had 36(49.32%) males and 37(50.68%) females with an overall mean age of 37±13 years. There were no significant differences in mean values of age, serum cholesterol, triglycerides and albumin levels between the groups (p>0.05). The G allele was the most frequently found in both groups, with 140(96%) in group-1 and 137(94%) in group-2. Overall, the homozygous GG genotype was significantly higher in the sample 132(90.4%) (p<0.05). There was evidence found that vitamin K epoxide reductase complex subunit 1-1639 G>A polymorphism alone may not be the dominant genetic factor associated with warfarin response variability.

Pulmonary fibrosis distal airway epithelia are dynamically and structurally dysfunctional

The airway epithelium serves as the interface between the host and external environment. In many chronic lung diseases, the airway is the site of substantial remodeling after injury. While, idiopathic pulmonary fibrosis (IPF) has traditionally been considered a disease of the alveolus and lung matrix, the dominant environmental (cigarette smoking) and genetic (gain of function MUC5B promoter variant) risk factor primarily affect the distal airway epithelium. Moreover, airway-specific pathogenic features of IPF include bronchiolization of the distal airspace with abnormal airway cell-types and honeycomb cystic terminal airway-like structures with concurrent loss of terminal bronchioles in regions of minimal fibrosis. However, the pathogenic role of the airway epithelium in IPF is unknown. Combining biophysical, genetic, and signaling analyses of primary airway epithelial cells, we demonstrate that healthy and IPF airway epithelia are biophysically distinct, identifying pathologic activation of the ERBB-YAP axis as a specific and modifiable driver of prolongation of the unjammed-to-jammed transition in IPF epithelia. Furthermore, we demonstrate that this biophysical state and signaling axis correlates with epithelial-driven activation of the underlying mesenchyme. Our data illustrate the active mechanisms regulating airway epithelial-driven fibrosis and identify targets to modulate disease progression.

Genes, other than Muc5b, play a role in bleomycin-induced lung fibrosis.

Idiopathic pulmonary fibrosis (IPF) is an incurable genetic disease that affects 5 million people worldwide. The gain-of-function MUC5B promoter variant rs35705950 is the dominant genetic risk factor for IPF, yet has a low penetrance. This raises the possibility that other genes and transcripts affect the penetrance of MUC5B. Previously, we have shown that the concentration of Muc5b in bronchoalveolar epithelia is directly associated with the extent and persistence of bleomycin-induced lung fibrosis in mice. In this study, we investigated whether bleomycin-induced lung injury is Muc5b dependent in genetically divergent strains of mice. Specifically, mice from the eight Diversity Outbred (DO) founders were phenotyped for Muc5b expression and lung fibrosis 3 wk after intratracheal bleomycin administration. Although we identified strains with low Muc5b expression and minimal lung fibrosis (CAST/EiJ and PWK/PhJ) and strains with high Muc5b expression and extensive lung fibrosis (NZO/H1LtJ and WSB/EiJ), there also were strains that did not demonstrate a clear relationship between Muc5b expression and lung fibrosis (129S1/SvlmJ, NOD/ShiLtJ, and C57BL/6J, A/J). Hierarchical clustering suggests that other factors may work in concert with or potentially independent of Muc5b to promote bleomycin-induced lung injury and fibrosis. This study suggests that these strains and their recombinant inbred crosses may prove helpful in identifying the genes and transcripts that interact with Muc5b and cause lung fibrosis.

Haplotype structure analysis of a locus associated with fruit skin type on chromosome 8 in Japanese pear

Fruit skin type is one of the most important components of fruit appearance. Pears have three types of fruit skin—russet, intermediate, and smooth—depending on the extent of the cork layer on the epicarp. Russet type is controlled by a dominant genetic factor, R, and a quantitative trait locus (QTL) associated with fruit skin type has been identified on chromosome 8. Although some markers have been developed, the relationship between their alleles and fruit skin type has not been established across multiple cultivars; thus, the effectiveness of these markers in marker-assisted selection (MAS) has not been demonstrated. In this study, haplotypes of 93 accessions estimated by Beagle 4.0 were classified into the major haplotypes HAP1–HAP8 using new simple sequence repeat (SSR) markers Psc07, Psc34, and Psc03. Out of the eight haplotypes, HAP1–HAP7 were found in Japanese pear, whereas HAP8 was specific to Chinese pear. By comparing the haplotypes and phenotypes of accessions and F1 populations, we found that HAP1–HAP3 and HAP7 had dominant effects and promoted cork layer formation, whereas HAP4–HAP6 and HAP8 were recessive and did not contribute to russeting. All eight haplotypes can be distinguished completely by Psc07 and Psc03, which would be useful for MAS. This information on haplotype structure of accessions and molecular markers associated with fruit skin type will be useful for future pear breeding programs.

Sick leave due to back pain, common mental disorders and disability pension: Common genetic liability.

Back pain and common mental disorders are often comorbid and known risk factors for future disability pension. However, the reason for the covariation is not known. The aim was to investigate the common genetic and environmental influences on the covariation between sick leave due to back pain, sick leave due to common mental disorders and disability pension. Register data from the Swedish Social Insurance Agency on sick leave due to back pain, common mental disorders and disability pension between 2005 and 2018, in a population-based sample of 56,686 working age twins was used to construct biometric twin models to calculate if the covariation between the traits were due to Additive (A) or Dominant (D) genetic factors, Common environmental factors (C) or unique Environmental factors (E), for women and men. The phenotypic correlations ranged between 0.17 and 0.25. A common factor common pathway AE model fitted best for both women and men. The latent underlying common factor, that explained the covariation was mostly explained by genetic factors (87% for women and 90% for men). Each trait was also influenced by its own unique genetic and unique environment factors. A higher heritability was found for disability pension than for sick leave. The covariation between sick leave due to back pain and common mental disorders, and disability pension were mostly explained by common genetic factors, while the unique variation in each trait was influenced by both genetic and environmental factors not shared within the twin pairs. A common genetic liability seems to be of importance in the comorbidity of sick leave due to back pain and common mental disorders and the transition to disability pension, both among women and men. However, the proportion in each trait that was explained by genetic factors was somewhat higher for men than for women in all traits. This may be of importance to consider in intervention or prevention efforts.

APOE4 is Associated with Differential Regional Vulnerability to Bioenergetic Deficits in Aged APOE Mice

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason for the association between APOE4 and AD remains unclear. While much of the research has focused on the ability of the apoE4 protein to increase the aggregation and decrease the clearance of Aβ, there is also an abundance of data showing that APOE4 negatively impacts many additional processes in the brain, including bioenergetics. In order to gain a more comprehensive understanding of APOE4′s role in AD pathogenesis, we performed a transcriptomics analysis of APOE4 vs. APOE3 expression in the entorhinal cortex (EC) and primary visual cortex (PVC) of aged APOE mice. This study revealed EC-specific upregulation of genes related to oxidative phosphorylation (OxPhos). Follow-up analysis utilizing the Seahorse platform showed decreased mitochondrial respiration with age in the hippocampus and cortex of APOE4 vs. APOE3 mice, but not in the EC of these mice. Additional studies, as well as the original transcriptomics data, suggest that multiple bioenergetic pathways are differentially regulated by APOE4 expression in the EC of aged APOE mice in order to increase the mitochondrial coupling efficiency in this region. Given the importance of the EC as one of the first regions to be affected by AD pathology in humans, the observation that the EC is susceptible to differential bioenergetic regulation in response to a metabolic stressor such as APOE4 may point to a causative factor in the pathogenesis of AD.

A High-Density Linkage Map of the Forage Grass Eragrostis curvula and Localization of the Diplospory Locus.

Eragrostis curvula (Schrad.) Nees (weeping lovegrass) is an apomictic species native to Southern Africa that is used as forage grass in semiarid regions of Argentina. Apomixis is a mechanism for clonal propagation through seeds that involves the avoidance of meiosis to generate an unreduced embryo sac (apomeiosis), parthenogenesis, and viable endosperm formation in a fertilization-dependent or -independent manner. Here, we constructed the first saturated linkage map of tetraploid E. curvula using both traditional (AFLP and SSR) and high-throughput molecular markers (GBS-SNP) and identified the locus controlling diplospory. We also identified putative regulatory regions affecting the expressivity of this trait and syntenic relationships with genomes of other grass species. We obtained a tetraploid mapping population from a cross between a full sexual genotype (OTA-S) with a facultative apomictic individual of cv. Don Walter. Phenotypic characterization of F1 hybrids by cytoembryological analysis yielded a 1:1 ratio of apomictic vs. sexual plants (34:27, X2 = 0.37), which agrees with the model of inheritance of a single dominant genetic factor. The final number of markers was 1,114 for OTA-S and 2,019 for Don Walter. These markers were distributed into 40 linkage groups per parental genotype, which is consistent with the number of E. curvula chromosomes (containing 2 to 123 markers per linkage group). The total length of the OTA-S map was 1,335 cM, with an average marker density of 1.22 cM per marker. The Don Walter map was 1,976.2 cM, with an average marker density of 0.98 cM/marker. The locus responsible for diplospory was mapped on Don Walter linkage group 3, with other 65 markers. QTL analyses of the expressivity of diplospory in the F1 hybrids revealed the presence of two main QTLs, located 3.27 and 15 cM from the diplospory locus. Both QTLs explained 28.6% of phenotypic variation. Syntenic analysis allowed us to establish the groups of homologs/homeologs for each linkage map. The genetic linkage map reported in this study, the first such map for E. curvula, is the most saturated map for the genus Eragrostis and one of the most saturated maps for a polyploid forage grass species.

Neuronal hyperactivity due to loss of inhibitory tone in APOE4 mice lacking Alzheimer\u2019s disease-like pathology

The ε4 allele of apolipoprotein E (APOE) is the dominant genetic risk factor for late-onset Alzheimer’s disease (AD). However, the reason APOE4 is associated with increased AD risk remains a source of debate. Neuronal hyperactivity is an early phenotype in both AD mouse models and in human AD, which may play a direct role in the pathogenesis of the disease. Here, we have identified an APOE4-associated hyperactivity phenotype in the brains of aged APOE mice using four complimentary techniques—fMRI, in vitro electrophysiology, in vivo electrophysiology, and metabolomics—with the most prominent hyperactivity occurring in the entorhinal cortex. Further analysis revealed that this neuronal hyperactivity is driven by decreased background inhibition caused by reduced responsiveness of excitatory neurons to GABAergic inhibitory inputs. Given the observations of neuronal hyperactivity in prodromal AD, we propose that this APOE4-driven hyperactivity may be a causative factor driving increased risk of AD among APOE4 carriers.

Comparison of HLA DQA1 and DQB1 Genes by Multiplex Ligation-Dependent Probe Amplification and Next Generation Sequencing Technologies for Celiac Disease Risk Determination

Introduction: Celiac disease is a systemic autoimmune disease with chronic gastrointestinal disorder caused by intolerance to gluten proteins. The most dominant genetic risk factors are the specific genotypes encoding the Human Leukocyte Antigen (HLA) class II molecule genes, DQA1 and DQB1. The DQ2.5 variant (DQA1*05/DQB1*02 alleles) is present in 90-95% of patients with celiac disease. The DQ8 variant (DQA1*03/DQB1*0302) and DQ2.2 variant (DQA1*02/DQB1*02) are found in most of the remaining patients. A positive test is indicative of genetic susceptibility but does not necessarily mean disease development. A negative test has a more significant value because gluten intolerance rarely occurs in the absence of specific HLA predisposing alleles. In the current study we compared Multiplex Ligation-dependent Probe Amplification (MLPA) and Next Generation Sequencing (NGS) technologies for identifying Celiac disease risk HLA alleles. Methods: DNA was extracted from either saliva or whole-blood archival samples obtained from commercial vendors using Qiagen DNA mini extraction kits. MLPA assay probe mix designed to detect the HLA alleles implicated in Celiac disease consists of 29 specific fluorescent labeled amplification products. The PCR products are separated by capillary gel electrophoresis on the ABI 3500 Genetic Analyzer yielding a specific electropherogram. Based on the presence and relative height of individual probe, as compared to the relative probe peak height in various reference samples, the HLA allele in the patient sample was determined. For Next Generation sequencing assay, long range PCR products of HLA DQA1 and DQB1 genes were pooled to prepare bar coded NGS libraries. Equimolar pools of the barcoded libraries were sequenced on the Illumina MiSeq platform by paired end 151 bp sequencing. Demultiplexed FASTQ files were aligned to HLA variant database and genotypes were identified. Results: A total of 26 samples with different HLA variants were analyzed by both MLPA and NGS assay panel. The samples included DQ2.5, DQ8, DQ2.2, both heterozygous and homozygous variants, negatives and positive control cell line DNA samples. Data is summarized in Table 1. There was 100% concordance between the two technologies in determining the Celiac disease risk alleles. DNA dilution studies showed that both technologies were optimal with a minimum of 40 ng of DNA input. The workflow for MLPA was simple with sample to data generation completed within 24 hours. NGS assay was laborious with highly technical library preparation, sequencing and data analysis with sample to data in 48 hours. However, NGS technology results in a high resolution genotyping whereas MLPA assay is limited to 5 alleles of DQA1 and DQB1 genes.Table: Table. HLA DQA1 and DQB1 genotyping data summary- MLPA and NGS dataConclusion: Both methods are reliable and efficient to provide necessary information for celiac disease risk evaluation. In the future if high resolution HLA genotyping is needed, NGS may be more applicable.

A New Look at Genetic and Environmental Architecture on Lipids Using Non-Normal Structural Equation Modeling in Male Twins: The NHLBI Twin Study.

This study examined genetic and environmental influences on the lipid concentrations of 1028 male twins using the novel univariate non-normal structural equation modeling (nnSEM) ADCE and ACE models. In the best fitting nnSEM ADCE model that was also better than the nnSEM ACE model, additive genetic factors (A) explained 4%, dominant genetic factors (D) explained 17%, and common (C) and unique (E) environmental factors explained 47% and 33% of the total variance of high-density lipoprotein cholesterol (HDL-C). The percentage of variation explained for other lipids was 0% (A), 30% (D), 34% (C) and 37% (E) for low-density lipoprotein cholesterol (LDL-C); 30, 0, 31 and 39% for total cholesterol; and 0, 31, 12 and 57% for triglycerides. It was concluded that additive and dominant genetic factors simultaneously affected HDL-C concentrations but not other lipids. Common and unique environmental factors influenced concentrations of all lipids.

Osteosarcoma inheritance in two families of Scottish deerhounds

BackgroundOsteosarcoma is the most common neoplastic disease in Scottish Deerhounds. For Deerhounds, a 2007 population-based study concluded that a single dominant genetic factor largely governed disease risk. For Greyhounds, Rottweilers, and Irish Wolfhounds, a 2013 genome-wide association study found multiple genetic markers in each breed, with each marker only weakly associated with the disease.We obtained from two breeders the pedigrees, age (if alive) or age at death, and osteosarcoma status for two families of Scottish Deerhounds, designated Cohorts K and T. A dog was considered unaffected only if it was osteosarcoma-free and at least 8.5 years old. We analyzed the data in two ways, by assuming either a single recessive genetic factor or a single dominant genetic factor with high penetrance.ResultsCohort K contained 54 evaluable dogs representing 12 litters. Cohort T contained 56 evaluable dogs representing eight litters. Osteosarcoma seemed clearly heritable in both cohorts; however, having a parent with osteosarcoma raised a pup’s risk of developing osteosarcoma to 38% for Cohort K but 78% for Cohort T, suggesting the possibility of different genetic risk factors in each cohort. In Cohort K, osteosarcoma inheritance fit well with a single, recessive, autosomal risk factor, although we could not rule out the possibility of a single dominant risk factor with incomplete penetrance. In Cohort T, inheritance could be explained well by a single, dominant, autosomal risk factor but was inconsistent with recessive expression.ConclusionsInheritance of osteosarcoma in two Scottish Deerhound families could be explained well by a single genetic risk factor residing on an autosome, consistent with a 2007 report. In one family, inheritance was consistent with dominant expression, as previously reported. In the other family, inheritance fit better with recessive expression, although the possibility of a dominant genetic factor influenced by one or more other genetic factors could not be ruled out. In either case, the results suggest that there may be at least two different genetic risk factors for osteosarcoma in Deerhounds.

Evidence of reactive gene-environment correlation in preschoolers' prosocial play with unfamiliar peers.

The development of prosocial behaviors during the preschool years is essential for children's positive interactions with peers in school and other social situations. Although there is some evidence of genetic influences on prosocial behaviors, very little is known about how genes and environment, independently and in concert, affect prosocial behaviors in young children. This study of 126 twin and sibling pairs examined 5-year-old preschool children's positive behaviors (prosocial and easy-going) while playing freely with an unfamiliar, same-age, same-sex peer. Children were randomly paired, allowing us to rule out passive (parent-influenced environment) and active (child-driven peer choices) gene-environment correlations as potential influences on the results. We found evidence of reactive gene-environment correlation, demonstrating that children who are genetically more likely to act prosocially and to be temperamentally outgoing appear to evoke more prosocial and easy-going behaviors from an unfamiliar peer. We also found that both dominant genetic and nonshared environmental factors were significant influences on preschoolers' prosocial play behaviors, but that neither genetic nor shared environmental factors were significant for easy-going play behaviors. These findings shed important light on influences of prosocial behaviors in preschoolers. Via inherited tendencies, preschool children's positive behaviors evoke similar positive behaviors from their play peers. Given that prosocial behaviors are preludes to a large range of important socially appropriate behaviors, prosocial children should be encouraged to interact with their peers to potentially create a more positive atmosphere within social contexts.

Heritability assessment of cartilage metabolism. A twin study on circulating procollagen IIA N-terminal propeptide (PIIANP)

The aim of this investigation was to estimate the heritability of circulating collagen IIA N-terminal propeptide (PIIANP) by studying mono- and dizygotic healthy twin pairs at different age and both genders. 598 monozygotic (MZ) and dizygotic (DZ) twin individuals aged 18-59 years were recruited from the Danish Twin Registry. PIIANP was measured by competitive ELISA. The similarity of circulating PIIANP among MZ and DZ twins was assessed by intraclass correlations according to traits. The heritability was estimated by variance component analysis accounting for additive and dominant genetic factors as well as shared and non-shared environment but ignoring epistasis (genetic inter-locus interaction) and gene-environment interaction. The intraclass correlation of PIIANP in MZ and DZ twins was 0.69 (0.60-0.76) and 0.46 (0.34-0.58) respectively indicating a significant genetic impact on PIIANP in serum. Additive genetic effects explained 45% (21-70%), shared environment 24% (7-53%) and non-shared environment 31% (24-39%) of the total variance. The heritability estimate did not differ across ages and between genders. The study shows that approximately 45% of the collagen IIA synthesis as assessed by the collagen IIA N-terminal propeptide in serum is attributable to genetic effectors while individual and shared environment account for 24% and 31% respectively. The heritability does not differ between genders or according to age.

Variability of warfarin dose response associated with CYP2C9 and VKORC1 gene polymorphisms in Chinese patients

To investigate the prevalence and implication of cytochrome P450, family 2, subfamily C, polypeptide 9 (CYP2C9) variants and vitamin K epoxide reductase complex, subunit 1 (VKORC1)-1639 G > A polymorphisms in Chinese patients receiving warfarin therapy. Chinese Han patients requiring oral warfarin therapy were consecutively enrolled. Correlations between CYP2C9*1, *2, *3, *4, *5 variants and VKORC1-1639 G > A polymorphisms, fourth-day international normalized ratios (INRs) and warfarin maintenance dose were investigated. Out of 101 patients, there were no significant differences in fourth-day INR or warfarin daily maintenance doses between patients with CYP2C9*1*1 and CYP2C9*1*3 genotypes. Patients with the VKORC1-1639 AA genotype had a higher fourth-day INR (1.87 ± 0.14) than those with the VKORC1-1639 AG genotype (1.32 ± 0.15). Warfarin maintenance dose for patients with the VKORC1-1639 AA genotype (2.40 ± 0.70 mg/day) was significantly lower than for patients with the VKORC1-1639 AG genotype (4.83 ± 0.70 mg/day). Unlike Caucasian populations, VKORC1-1639 G > A polymorphisms in the Chinese population may be the dominant genetic factors associated with warfarin response variability.

Variation in the TLR10/TLR1/TLR6 locus is the major genetic determinant of interindividual difference in TLR1/2-mediated responses

Toll-like receptor (TLR)-mediated innate immune responses are important in early host defense. Using a candidate gene approach, we previously identified genetic variation within TLR1 that is associated with hyper-responsiveness to a TLR1/2 agonist in vitro and with death and organ dysfunction in patients with sepsis. Here we report a genome-wide association study designed to identify genetic loci controlling whole blood cytokine responses to the TLR1/2 lipopeptide agonist, Pam3CSK4 ex vivo. We identified a very strong association (p<1×10−27) between genetic variation within the TLR10/1/6 locus on chromosome 4, and Pam3CSK4-induced cytokine responses. This was the predominant association explaining over 35% of the population variance for this phenotype. Notably, strong associations were observed within TLR10 suggesting genetic variation in TLR10 may influence bacterial lipoprotein-induced responses. These findings establish the TLR10/1/6 locus as the dominant common genetic factor controlling inter-individual variability in Pam3CSK4-induced whole blood responses in the healthy population.

High prevalence of congenital hypothyroidism in Isfahan: Do familial components have a role?

Background:Despite elimination of iodine deficiency, the rates of both permanent and transient congenital hypothyroidism (CH) in our study were higher than the comparable worldwide rates, which emphasize the major role of genetic factors in the pathogenesis of CH and many studies in this regard confirm this possibility.Materials and Methods:In this review, we report all studies that established during CH screening program regarding familial and genetic component of the disease.Results:Although we could not entirely ignore the possible role of environmental and autoimmune factors in the development and function of thyroid gland, our findings strongly suggest the role of genetic factors as dominant etiologic factor in CH.Conclusion:The studies support the existence of a familial component of CH involving dominant genetic predisposition factors with a low penetrance. Considering the polygenic/multifactorial basis of CH, they suggest the possible involvement of other unknown genes in the pathogenesis of the disease, which may also follow non-Mendelian pattern of inheritance.