Role Of Genetic Variation Research Articles

The role of genetic factors in microtia: A systematic review

Background: Microtia is a congenital malformation of the outer ears caused by improper embryonic development. The origin of microtia and causes of its variations remain unknown. Because of the lack of clarity regarding the role of genetic variables in microtia, we conducted a systematic review to qualitatively identify the genes most important in the development of microtia to provide an up-to-date review. Methods: Using six search engines, we searched all published studies related to the genetic factors of isolated microtia and syndromic microtia. The identified publications were screened and selected based on inclusion and exclusion criteria by the authors and assessed for methodological quality using the Joanna Briggs Institute (JBI) critical appraisal tools. We found 40 studies, including 22 studies on syndromic microtia and 18 studies on isolated microtia. Data extraction of each study was arranged in tabulation for syndromic and isolated microtia. The extracted data were: first author’s surname, year of publication, country of origin, study design, sample characteristic and gene assessed. Results: After the data were extracted, analyzed, and reviewed, the most common gene suspected to be involved in isolated microtia was Homeobox A2 (HOXA2, 12.1%). Conversely, in syndromic microtia, the two most common genes supposed to play a role were Fibroblast Growth Factor 3 (FGF3, 47.2%) and Treacher–Collins–Franceschetti syndrome 1 (TCOF1, 30.2%). From the studies, the three most prevalent genes associated with microtia were HOXA2 (10%), FGF3 (8.4%), and TCOF1 (5.4%). In syndromic microtia, the most common mutation types were deletion in TCOF1 (46.9%) and missense and deletion in FGF3 (both 38%), and in isolated microtia, the most common mutation type was silent in HOXA2 (54.2%). Conclusions: In summary, genetic factors are involved in microtia; thus, molecular analysis is strongly advised. PROSPERO registration: CRD42021287294 (25/10/21).

Epigenetic induction may speed up or slow down speciation with gene flow.

Speciation is less likely to occur when there is gene flow between nascent species. Natural selection can oppose gene flow and promote speciation if there is variation in ecological conditions among the nascent species' locations. Previous theory on ecological speciation with gene flow has focused primarily on the role of genetic variation in ecological traits, largely neglecting the role of nongenetic inheritance or transgenerational plasticity. Here, we build and analyze models incorporating both genetic and epigenetic inheritance, the latter representing a form of nongenetic inheritance. We investigate the rate of speciation for a population that inhabits two patches connected by migration, and find that adaptively biased epigenetic induction can speed up or slow down speciation, depending on the form of the map from genotype and epigenotype to phenotype. While adaptively relevant epigenetic variation can speed up speciation by reducing the fitness of migrants and hybrids, it can also slow down speciation. This latter effect occurs when the epialleles are able to achieve adaptation faster than the genetic alleles, thereby weakening selection on the latter.

Generation of isofemale lines from hypoxia tolerant Drosophila melanogaster population

Hypoxia is a common pathological element in many human diseases. Understanding the mechanisms that underlie hypoxia tolerance or susceptibility is essential for developing novel strategies for treatment or prevention. Through experimental evolution, we obtained a Drosophila melanogaster population that can live perpetually in severe, normally lethal, hypoxic environments. We generated a Panel of Low Oxygen Tolerant (PLOT) isofemale lines (total 79 lines) from this hypoxia tolerant population to study or identify the specific genetic mechanisms that are responsible for the hypoxia tolerant trait. These isofemale lines showed significantly higher hypoxia tolerance as compared to their wildtype parental isofemale lines and the wildtype DGRP (Drosophila melanogaster Genetic Reference Panel) isofemale lines. For example, 95% of the PLOT lines showed hypoxia tolerance with eclosion rate >50% at 5% O2 level. In contrast, none of the parental lines and only 15% of the DGRP lines had similar eclosion rates under the same hypoxic condition. Furthermore, under the lethal condition with 4% O2, our PLOT lines exhibited a wide range of eclosion rate from 1% to 80% with a clear pattern of Gaussian‐Distribution, demonstrating that these PLOT flies may provide us a unique opportunity to study the molecular basis of stress‐directed evolution, such as the role of genetic variations in the protein coding regions and functional DNA elements in hypoxia adaptation. These PLOT lines can also be used to study phenotypic plasticity as well as genetic‐epigenetic interactions in hypoxic, or other stressful, environments.

IDF21-0406 Genetic variants in the Carnosine-Carnosinase system and their impact on diabetic nephropathy

Background: The role of carnosine-carnosinase system in diabetic nephropathy has been established through various studies in animal models. It has been proven that low carnosinase secretion promotes high circulating carnosine levels which acts as a protective factor against adverse effects of hyperglycemia on renal cells. While genetic variants in the carnosinase gene (CNDP1) could influence carnosinase concentration, variants in the carnosine synthase gene (CARNS1) which synthesizes carnosine and variants in the SLC15A4 and SLC15A2 genes which are involved in the renal transport of carnosine could influence carnosine concentration thereby causing nephropathy. Aim: To study the association of genetic variants in the carnosine-carnosinase system (CARNS1, CNDP1, SLC15A4 and SLC15A2) with nephropathy and their influence on carnosinase levels in south Indian population. Method: Study Participants: 580 type 2 diabetes individuals without nephropathy (DM) and 597 type 2 diabetes individuals with nephropathy (DN) from Dr. Mohan’s Diabetes Specialities Centre, Chennai, India. Methodology: Genomic DNA was extracted from blood samples using phenol chloroform method. A total of 27 SNPs from the four genes were genotyped using MassARRAY. The levels of carnosinase in serum was measured in 116 DM and 93 DN participants using commercially available ELISA kit. Results: The D18S880 repeat polymorphism (5-8 repeats of Leucine) in CNDP1 gene and rs1626067 SNP of CARNS1 gene showed significant association with DN. The odds ratio for DN after adjusting for potential confounders such as age, sex, BMI, HbA1c, duration of diabetes and systolic blood pressure for the 6L/XL genotype of D18S880 and the GA genotype of rs1626067 as compared to their respective homozygous normal genotypes was 0.67 (95%CI: 0.48-0.94, p=0.022) and 0.68 (95% CI:0.49-0.93, p=0.016) respectively. The levels of carnosinase (mean±SE in picogram/mL) was significantly higher in DN (3.07±0.19) compared to DM group (2.48±0.13, p=0.038). Discussion: This study gains significance as the role of genetic variants in the carnosine-carnosinase system in DN remains largely unexplored. Most of the studies so far have focussed only on the CNDP1 gene. The association of D18S880 Leucine repeat with DN is significant as it is present in the signal peptide region of CNDP1 gene and may play a role in the secretion of carnosinase. The association of rs1626067 SNP in CARNS1 with DN has not been reported so far. This SNP is positioned in the 3́UTR region of CARNS1 and hence could alter the binding of transcription factors and have a regulatory effect. The significant difference in serum carnosinase levels between DM and DN groups was an interesting finding. When the groups were further stratified based on the genotypes, the sample size was less than 50 in each group and was not sufficiently powered to study the correlation of enzyme levels and genotypes. Measuring the levels and activity of carnosinase in larger number of samples will help identify whether the genetic variations influence the enzyme levels. If found, targeted dietary intervention studies giving carnosine supplements to those carrying the susceptible alleles can be undertaken to alleviate the burden of nephropathy.

Investigating the role of abscisic acid and its catabolites on senescence processes in green asparagus under controlled atmosphere (CA) storage regimes

Asparagus (Asparagus officinalis) is a highly perishable crop with a short postharvest life. Although some research has been done on the application of controlled atmosphere (CA), it has not been sufficiently explored and the underlying mechanisms controlling asparagus senescence processes are not well understood, restricting its potential for commercial application. The aim of this study was to investigate for the first time the link between abscisic acid (ABA) and ABA catabolites and senescence in asparagus stored under a range of different CA conditions. Two different set-ups were run in parallel; a traditional CA delivered by an International Controlled Atmosphere (ICA) system with continuous gas supply and LabPods™ fitted with sensors for real time monitoring of respiration rate (RR) and respiratory quotient (RQ) and able to retain established CA conditions with minimum gas supply requirements. The role of genetic variability was also studied by including two UK grown asparagus cultivars ‘Gijnlim’ and ‘Jaleo’ adapted for different climatic conditions. The results indicated that ABA and its catabolites were present in significantly higher concentrations in the air stored spears (control) compared to CA throughout storage, irrespective of cultivar, and were associated with accelerated senescence processes observed in control samples, such as textural changes indicative of spear toughening, discolouration, sugar depletion and asparagine accumulation. Furthermore, partial least squares regression (pls-r) applied for both cultivars, successfully differentiated samples based on O2 and CO2 concentrations and storage duration, both in cold storage and during shelf-life with the separation being driven primarily by ABA and its catabolites. Physiological and biochemical results indicated that all three CA conditions tested ([CA1] 2.5% O2, 3% CO2, [CA2] 2.5% O2, 6% CO2 and [CA3] 2.5% O2, 10% CO2) successfully retained quality parameters including texture, colour, moisture content and visual appearance longer compared to air (control); however, they did not completely suppress the development of ‘tip-breakdown’ (a physiological disorder also known as tip rot) towards the end of storage, which coincided with rising concentrations of phaseic acid indicating an activation of the abscisic biosynthetic and catabolic pathway. It can be concluded that CA conditions can delay senescence for at least 3-weeks (2 weeks cold storage and 1 week shelf-life), by lowering metabolic rate and respiratory quotient (RQ) within the spears compared to control, and through successfully regulating ABA biosynthetic and catabolic pathways.

Role of genetic variants and host polymorphisms on COVID-19: From viral entrance mechanisms to immunological reactions.

Coronavirus disease 2019 (COVID‐19), caused by a highly pathogenic emerging virus, is called severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). Knowledge regarding the pathogenesis of this virus is in infancy; however, investigation on the pathogenic mechanisms of the SARS‐CoV‐2 is underway. In COVID‐19, one of the most remarkable characteristics is the wide range of disease manifestation and severity seen across individuals of different ethnic backgrounds and geographical locations. To effectively manage COVID‐19 in the populations, beyond SARS‐CoV‐2 detection, serological response assessment, and analytic techniques, it is critical to obtain knowledge about at‐risk individuals and comprehend the identified variations in the disease's severity in general and also in the populations' levels. Several factors can contribute to variation in disease presentation, including population density, gender and age differences, and comorbid circumstances including diabetes mellitus, hypertension, and obesity. Genetic factors presumably influence SARS‐CoV‐2 infection susceptibility. Besides this, COVID‐19 has also been linked with a higher risk of mortality in men and certain ethnic groups, revealing that host genetic characteristics may affect the individual risk of death. Also, genetic variants involved in pathologic processes, including virus entrance into cells, antiviral immunity, and inflammatory response, are not entirely understood. Regarding SARS‐CoV‐2 infection characteristics, the present review suggests that various genetic polymorphisms influence virus pathogenicity and host immunity, which might have significant implications for understanding and interpreting the matter of genetics in SARS‐CoV‐2 pathogenicity and customized integrative medical care based on population investigation.

The role of genetic variants involved with ferroptosis regulator genes in predicting outcomes in patients (pts) with RAS-mutant metastatic colorectal cancer (mCRC): Data from MAVERICC and TRIBE trials.

197 Background: Ferroptosis, an iron-dependent programmed cell death, is one of the anti-tumor mechanisms of anti-angiogenesis drugs. RAS mutation can confer ferroptosis in colorectal cancer (CRC). Previous studies suggested that polymorphisms of ferroptosis regulator genes are associated with the increased risk of CRC. Therefore, we hypothesized that genetic variants in the ferroptosis regulator genes may predict first-line treatment outcome in RAS-mutant mCRC pts treated with bevacizumab (bev)-based chemotherapy. Methods: Genomic DNA from blood samples of mCRC pts enrolled in two independent randomized trials, MAVERICC (FOLFIRI+bev arm: discovery cohort, RAS-mutant, n = 56; control-1: RAS-wildtype, n = 87) and TRIBE (FOLFOXIRI+bev arm: validation cohort, RAS-mutant, n = 57; control-2: RAS-wildtype, n = 34), was genotyped through the OncoArray, a customized array manufactured by Illumina including approximately 530K SNP markers. The impact on outcome of 13 selected SNPs in 5 main ferroptosis regulator genes (ACSL4, LPCAT3, SLC3A2, SLC7A11, ALOX15) was analyzed. Results: In the MAVERICC bev cohort, pts with RAS-mutant tumors carrying ALOX15 rs7217186 any C allele (n = 35) showed significant longer overall survival (OS) than carrier of T/T allele (n = 5) in both univariate (24.97 vs. 12.22 months, hazard ratio [HR] = 0.23; 95% confidence interval [CI]: 0.06-0.9; p = 0.02) and multivariate (HR = 0.06; 95%CI 0.007-0.5; p = 0.009) analysis. In the TRIBE bev cohort, RAS-mutant carriers of any C allele (n = 30) showed numerically longer progression-free survival (PFS), compared to carriers of T/T allele (n = 13) in both univariate (11.91 vs. 9.47 months, HR = 0.45; 95%CI 0.2-1.02; p = 0.05) and multivariate (HR = 0.42; 95%CI 0.16-1.1; p = 0.09) analysis. Conversely, RAS-wildtype carriers of any C allele (n = 17) showed significant shorter PFS than T/T carriers in the TRIBE bev cohort (8.91 vs. 15.59 months, univariate HR = 3.39, 95%CI: 1.03-11.18, p = 0.04). Conclusions: Our study demonstrated for the first time that ALOX15 polymorphisms may have different predictive values for the bev-based treatment in mCRC patients based on RAS mutational status. These findings may provide novel insights for the combination of ferroptosis inducers and anti-VEGF treatment.

Molecular Characterization of Two Known SRD5A2 Gene Variants in Mexican Patients With Disorder of Sexual Development.

Background: The 5α-reductase type 2 deficiency (5α-RD2) is a specific form of disorder of sexual development (DSD). Pathogenic variants in the SRD5A2 gene, which encodes this enzyme, are responsible for 46,XY DSD. Objective: The objective of the study was to investigate the genetic etiology of 46,XY DSD in two Mexican families with affected children. Materials and methods: The SRD5A2 gene of the parents and affected children was screened in both families via polymerase chain reaction amplification and DNA direct sequencing. The role of genetic variants in enzymatic activity was tested by site-directed mutagenesis. Results: Subject 1 presented two variants: p.Glu197Asp and p.Pro212Arg. Subject 2 was homozygous for the variant p.Glu197Asp. The two variants were reported in early studies. The directed mutagenesis study showed that the p.Glu197Asp and p.Pro212Arg variants lead to a total loss of enzymatic activity and, consequently, abnormal genitalia development in the patients. Conclusion: These results suggest that p.Glu197Asp and p.Pro212Arg are pathogenic variants that lead to the phenotypic expression of DSD. 5α-RD2 is of extreme importance not only because of its frequency (it is rare) but also because of its significance in understanding the mechanism of androgen action, the process of sexual differentiation, and the factors that influence normal sexual behavior.

Low Back Pain With Persistent Radiculopathy; the Clinical Role of Genetic Variants in the Genes SOX5, CCDC26/GSDMC and DCC.

In a recently published genome-wide association study (GWAS) chronic back pain was associated with three loci; SOX5, CCDC26/GSDMC and DCC. This GWAS was based on a heterogeneous sample of back pain disorders, and it is unknown whether these loci are of clinical relevance for low back pain (LBP) with persistent radiculopathy. Thus, we examine if LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy is associated with the selected single nucleotide polymorphisms (SNPs); SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. In this prospective cohort study, subjects admitted to a secondary health care institution due to an acute episode of LBP with radiculopathy, reported back pain, leg pain, and Oswestry Disability Index (ODI), were genotyped and followed up at 12 months (n = 338). Kruskal-Wallis H test showed no association between the SNPs and back pain, leg pain or ODI. In conclusion, LBP with radiculopathy 12 months after an acute episode of LBP with radiculopathy, is not associated with the selected SNPs; SOX5 rs34616559, CCDC26/GSDMC rs7833174 and DCC rs4384683. This absent or weak association suggests that the SNPs previously associated with chronic back pain are not useful as prognostic biomarkers for LBP with persistent radiculopathy.

Role of Genetic Variations in CDK2, CCNE1 and p27KIP1 in Prostate Cancer.

Our aim was to investigate possible influences of genetic variants in genes involved in the G1/S transition [cyclin-dependent kinase-2 (CDK2), cyclin E1 (CCNE1) and cyclin-dependent kinase inhibitor 1B (p27KIP1)] on the expression/activity of their corresponding proteins and to assess the functional impact of these variants on the risk of prostate cancer. We genotyped 530 cases and 562 healthy controls for two relevant single nucleotide polymorphisms (CDK2 rs2069408 and CCNE1 rs997669) by TaqMan genotyping assay. p27KIP1 rs2066827 polymorphisms were studied by polymerase chain reaction-restriction fragment length polymorphism assay. In addition, the expression of CDK2, CCNE1 and p27KIP1 was evaluated by quantitative real-time-polymerase chain reaction and western blotting in 44 prostate cancer tissues and 31 benign prostatic hyperplasia tissues. No association was found between CDK2 rs2069408, CCNE1 rs997669 or p27KIP1 rs2066827 polymorphisms and an increased risk of prostate cancer development. Higher CDK2 expression was more prevalent in those with rs2069408 GG genotype than in AA carriers (p>0.05). We also noted reduced p27KIP1 protein expression in those with the p27KIP1 G109 allele. No difference was observed for CCNE1 expression in relation to the risky genotype (CC). A significant association was detected between CCNE1 mRNA overexpression and development of higher-grade carcinomas (Gleason score >7, p<0.05). Polymorphisms CDK2 rs2069408, CCNE1 rs997669 and p27KIP1 rs2066827 have no significant impact on prostate cancer risk nor on the gene and protein expression of CDK2, CCNE1 and p27KIP1, although high CCNE1 expression was significantly associated with a higher tumour grade in patients with prostate cancer.

The Role of Gene Variants in the Iron Metabolism of Anemic Adolescent Girls.

Background and objectivesIron deficiency anemia (IDA) and the role of genetic variants in determining the iron status in adolescent girls are not yet well-understood. This study aims to investigate the association of the rs602662, rs1049296, rs1805051, rs855791, rs224589, and rs11568350 genes with IDA and iron bio-status parameters.MethodsThis study consisted of 132 patients (IDA group) and 110 healthy controls. The genotype was analyzed through polymerase chain reaction-restriction fragment length polymorphism.ResultsNo differences were noted in the distribution of genotype and allele frequency single nucleotide polymorphism between the IDA and control group. In the IDA group, the GA carriers of rs602662 had a higher hemoglobin concentration (P=0.02) and packed cell volume (P=0.007), whereas transferrin saturation was increased in AA (P=0.02). The genetic variants rs1049296, rs1805051, rs224589, and rs855791 had a non-statistical significance on hematological parameters. Both the GT and TT carriers of the rs11568350 gene showed a low hemoglobin concentration (P=0.02 and <0.001) and mean corpuscular hemoglobin in GT carrier (P=0.01), whereas the TT risk of this gene showed a decreased packed cell volume (P=0.01). In the control patients, no association was observed with serum iron and hematological parameters.ConclusionOf these genetic variants, the GG and GA genotype frequency in rs602662 and the GG, GT, and TT in rs11568350 were associated with low iron status in anemic patients compared to the control patients.

Abstract 12296: Clinical and Functional Genetic Characterization of the Role of Cardiac Calcium Channel Variants in the Early Repolarization Syndrome

Introduction: Early repolarization syndrome (ERS) is an inherited sudden cardiac death syndrome. Hypothesis: In this study we test the role of genetic variants in cardiac calcium channel genes in the pathogenesis of ERS and probes the underlying mechanisms. Methods: PCR-based next-generation sequencing was carried out using a targeted gene approach. Unrelated ERS probands carrying calcium channel variants were evaluated clinically and compared with matched healthy controls. Wild type (WT) and mutant CACNA1C genes were co-expressed with CACNB2b and CACNA2D1 in HEK293 cells and studied using whole-cell patch-clamp and confocal fluorescence microscope . Results: Among 104 ERS probands, 16 carried pathogenic variants in calcium channel genes (32.2±14.6 years old, 87.5% male). The symptoms at diagnosis included syncope (56.3%), ventricular tachycardia/fibrillation (VT/VF, 62.5%), sudden cardiac death (SCD, 56.3%). Three cases (18.8%) had a family history of SCD or syncope. Eight patients (50.0%) had a single calcium gene rare variant. The other half carried rare variants in other ERS susceptible genes. Compared with controls, the heart rate was slower (72.7±8.9 vs. 65.6±16.1 bpm), QTc interval was shorter (408.2±21.4 vs. 386.8±16.9 ms) and Tp-e/QT was longer (0.22±0.05 vs.0.28±0.04) in calcium mutation carriers. Electrophysiological analysis of one mutation, CACNA1C -P817S revealed that the density of I Ca was reduced by approximately 84.6% compared to WT (-3.1±2.5 vs. -20.5±3.6 pA/pF, n=11 and 15, respectively). Heterozygous expression of mutant channels was associated with a 51.3% reduction of I Ca . Steady-state inactivation was shifted to more negative potentials and significantly accelerated. Confocal microscopy revealed trafficking impairment of CACNA1C -P817S (peripheral/central intensity: 0.94±0.1 in WT vs. 0.33±0.1 in P817S, n=10 and 9, respectively). Conclusions: ERS associated with loss of function (LOF) genetic defects in genes encoding the cardiac calcium channel represents a unique clinical entity characterized by decreased heart rate and QTc, as well as increased transmural dispersion of repolarization. In the case of CACNA1C -P817S impaired trafficking of the channel to the membrane contributes to the LOF.

The role of genetic diversity and arbuscular mycorrhizal fungal diversity in population recovery of the semi-natural grassland plant species Succisa pratensis

BackgroundEcosystem restoration is as a critical tool to counteract the decline of biodiversity and recover vital ecosystem services. Restoration efforts, however, often fall short of meeting their goals. Although functionally important levels of biodiversity can significantly contribute to the outcome of ecosystem restoration, they are often overlooked. One such important facet of biodiversity is within-species genetic diversity, which is fundamental to population fitness and adaptation to environmental change. Also the diversity of arbuscular mycorrhizal fungi (AMF), obligate root symbionts that regulate nutrient and carbon cycles, potentially plays a vital role in mediating ecosystem restoration outcome. In this study, we investigated the relative contribution of intraspecific population genetic diversity, AMF diversity, and their interaction, to population recovery of Succisa pratensis, a key species of nutrient poor semi natural grasslands. We genotyped 180 individuals from 12 populations of S. pratensis and characterized AMF composition in their roots, using microsatellite markers and next generation amplicon sequencing, respectively. We also investigated whether the genetic makeup of the host plant species can structure the composition of root-inhabiting AMF communities.ResultsOur analysis revealed that population allelic richness was strongly positively correlated to relative population growth, whereas AMF richness and its interaction with population genetic diversity did not significantly contribute. The variation partitioning analysis showed that, after accounting for soil and spatial variables, the plant genetic makeup explained a small but significant part of the unique variation in AMF communities.ConclusionsOur results confirm that population genetic diversity can contribute to population recovery, highlighting the importance of within-species genetic diversity for the success of restoration. We could not find evidence, however, that population recovery benefits from the presence of more diverse AMF communities. Our analysis also showed that the genetic makeup of the host plant structured root-inhabiting AMF communities, suggesting that the plant genetic makeup may be linked to genes that control symbiosis development.

What the New Definition of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Left Behind: Genetically Acquired Fatty Liver Disease (GAFLD).

What the New Definition of Metabolic Dysfunction-Associated Fatty Liver Disease (MAFLD) Left Behind: Genetically Acquired Fatty Liver Disease (GAFLD).

APOC3 genetic variation, serum triglycerides, and risk of coronary artery disease in Asian Indians, Europeans, and other ethnic groups

BackgroundHypertriglyceridemia has emerged as a critical coronary artery disease (CAD) risk factor. Rare loss-of-function (LoF) variants in apolipoprotein C-III have been reported to reduce triglycerides (TG) and are cardioprotective in American Indians and Europeans. However, there is a lack of data in other Europeans and non-Europeans. Also, whether genetically increased plasma TG due to ApoC-III is causally associated with increased CAD risk is still unclear and inconsistent. The objectives of this study were to verify the cardioprotective role of earlier reported six LoF variants of APOC3 in South Asians and other multi-ethnic cohorts and to evaluate the causal association of TG raising common variants for increasing CAD risk.MethodsWe performed gene-centric and Mendelian randomization analyses and evaluated the role of genetic variation encompassing APOC3 for affecting circulating TG and the risk for developing CAD.ResultsOne rare LoF variant (rs138326449) with a 37% reduction in TG was associated with lowered risk for CAD in Europeans (p = 0.007), but we could not confirm this association in Asian Indians (p = 0.641). Our data could not validate the cardioprotective role of other five LoF variants analysed. A common variant rs5128 in the APOC3 was strongly associated with elevated TG levels showing a p-value 2.8 × 10− 424. Measures of plasma ApoC-III in a small subset of Sikhs revealed a 37% increase in ApoC-III concentrations among homozygous mutant carriers than the wild-type carriers of rs5128. A genetically instrumented per 1SD increment of plasma TG level of 15 mg/dL would cause a mild increase (3%) in the risk for CAD (p = 0.042).ConclusionsOur results highlight the challenges of inclusion of rare variant information in clinical risk assessment and the generalizability of implementation of ApoC-III inhibition for treating atherosclerotic disease. More studies would be needed to confirm whether genetically raised TG and ApoC-III concentrations would increase CAD risk.

Genetic diversity and relatedness in aquaculture and marina populations of the invasive tunicate Didemnum vexillum in the British Isles

Introductions of invasive, non-native species in the marine environment are increasing as human activity within coastal areas rises. Genetic datasets are useful tools to identify source populations, track routes of invasions, and illuminate the role of genetic variation in the establishment and subsequent spread of novel introductions. Here, a microsatellite dataset is used to estimate the genetic diversity and population structure of 7 introduced Didemnum vexillum populations in Britain and Ireland, 4 of which are associated with aquaculture and 3 with marinas. Genetic differentiation observed between these populations indicates human-mediated transport as the main mechanism underlying the population structure of D. vexillum in Britain and Ireland. In addition to elucidating patterns of population structure we found that aquaculture sites showed significantly higher genetic diversity (measured as allelic richness) in comparison to the marina sites. We discuss these findings in relation to the history of each invasion, the complex life history of D. vexillum, and available evidence of the relative invasiveness of these populations. Our results show numerous interesting patterns which highlight further research avenues to elucidate the complex factors underlying the global spread of this successful invader.

Correlation Between the Gut Microbiome and Immunotherapy Response in Inflammatory Bowel Disease: A Systematic Review of the Literature.

Inflammatory bowel disease (IBD) is an autoimmune disease associated with dysbiosis within the gastrointestinal tract. Characteristic taxonomic shifts of microbial populations are observed in disease progression and remission; however, despite similarities, there are many differences among individuals presenting with IBD including IBD subset, clinical course, and response to therapy. Much is still unknown about how these taxonomic shifts interact with immunotherapy and how genetic variants contribute. In this systematic review, we aimed to compile information on the interactions of the gut microbiome with immunotherapy in the course of disease and treatment of IBD patients. This systematic review was conducted as per the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines and the PubMed database was methodically screened for literature search including keywords and Medical Subject Headings (MeSH) terms for relevant articles.The quality appraisal was completed using the Cochrane Tool, Newcastle-Ottawa checklist, and the Scale for the Assessment of Narrative Review Articles (SANRA) checklist, as appropriate, and 11 relevant articles were included in this systematic review. Our review concludes that although there are characteristic taxonomic shifts between diseased and healthy patients, genetic variants are an important consideration in the predictive quality of disease and treatment decisions. The comparison between interactions of microbial populations and treatment in addition to the role of genetic variants may provide insight into treatment non-responders. Due to our limitations in current knowledge including the complexity of the microcosm, ethnic genetic variations among human populations, and our focus on relevant articles published in English over the past six years, we may have missed relevant studies. Future studies should focus on the comparison between Western and other cultural populations as well as further implementation of Genome-Wide Association Studies (GWAS) in clinical predictability.

GA Genotype of the Arg280His Polymorphism on The XRCC1 Gene: Genetic Susceptibility Genotype in Differentiated Thyroid Carcinomas?

Differentiated thyroid carcinomas (DTC) are the most common form of endocrine malignancies. The role of genetic variations in the development of papillary thyroid carcinoma (PTC) is approximately 60.0-70.0%. The X-ray repair cross-complementing group 1 (XRCC1) protein has an important role in DNA repair mechanisms and genomic polymorphisms of XRCC1 gene affect the function of the protein. In the present case-control study, we aimed to compare the genotype frequency distributions of XRCC1 single nucleotide polymorphisms (SNPs) in terms of the presence of other risk factors (Hashimoto’s thyroiditis, smoking, obesity, radiation exposure) in patients with thyroid nodules who had fine-needle aspiration biopsy (FNAB) and/or thyroid surgery due to thyroid cancer. The genotype frequency distributions of three common XRCC1 SNPs (Arg194Trp, Arg399Gln, Arg280His) were compared to those with DTC (n = 228), benign thyroid nodules (BTN, n = 100) and healthy controls (n = 93) in terms of certain pre defined risk factors such as the presence of Hashimoto’s thyroiditis, smoking, obesity, a family history of thyroid cancer and radiation exposure. The frequency of the GA genotype of Arg280His in DTC cases was found to be higher than in those with BTN and the healthy control group (p <0.001). The DTC group had the lowest frequency of AA genotype of Arg280His (35.5%, p <0.001). Among those with a family history of thyroid cancer, 78.9% had a GA genotype and 21.1% had the AA genotype of Arg280His (p = 0.004). The Arg280His GA genotype was more common in DTC than in cancer-free controls. The GA genotype frequency was also high in DTC cases with a family history of thyroid cancer.

Characterization of Genetic Variants in the SLC5A5 Gene and Associations With Breast Milk Iodine Concentration in Lactating Women of African Descent: The NUPED Study.

Background: The sodium iodide symporter is responsible for the transfer of iodine into breast milk and is encoded for by the SLC5A5 gene. The role of genetic variants in the SLC5A5 gene locus in relation to the transfer of iodine from plasma into breast milk in healthy lactating individuals has, to our knowledge, not been explored.Objective: To identify and characterize possible genetic variants of the SLC5A5 gene in women of African descent living in urban South Africa, and to study associations with breast milk iodine concentrations (BMIC) in lactating women.Methods: This study is affiliated to the Nutrition during Pregnancy and Early Development (NuPED) cohort study (n = 250 enrolled pregnant women). In a randomly selected sub-sample of 32 women, the SLC5A5 gene was sequenced to identify known and novel variants. Of the identified variants, genotyping of selected variants was performed in all pregnant women who gave consent for genetic analyses (n = 246), to determine the frequency of the variants in the study sample. Urinary iodine concentration (UIC) in spot urine samples and BMIC were measured to determine iodine status. Associations of SLC5A5 genetic variants with BMIC were studied in lactating women (n = 55).Results: We identified 27 variants from sequencing of gene exomes and 10 variants were selected for further study. There was a significant difference in BMIC between the genotypes of the rs775249401 variant (P = 0.042), with the homozygous GG group having lower BMIC [86.8 (54.9–167.9) μg/L] compared to the (A) allele carriers rs775249401(AG+AA) [143.9 (122.4–169.3) μg/L] (P = 0.042). Of the rs775249401(GG), 49% had UIC <100 μg/L and 61% had BMIC <100 μg/L. On the other hand, 60% of the rs775249401(AG+AA) carriers had UIC <100 μg/L, and none had a BMIC <100 μg/L.Conclusion: Our results suggest that A-allele carriers of rs775249401(AG+AA) are likely to have higher iodine transfer into breast milk compared to the homozygous GG counterparts. Thus, genetic variations in the SLC5A5 gene may play an important role in the transfer of iodine from plasma into breast milk and may partially explain inter-individual variability in BMIC.

Single Nucleotide Polymorphisms in Genes Encoding Toll-Like Receptors 7 and 8 and Their Association with Proviral Load of SRLVs in Goats of Polish Carpathian Breed.

Simple SummaryThe purpose of the study was to identify SNPs in genes encoding TLR7 and TLR8 in goats of Carpathian breed and analyze their association with the SRLVs provirus concentration. A total of 14 SNPs were detected, 6 SNPs in the TLR7 gene locus and 8 SNPs in the TLR8 gene. These SNPs were located in intron, 3′UTR and 5′UTR regions and within the coding sequences leading to the synonymous mutations. Our results revealed that 9 out 14 identified polymorphisms were associated with the SRLVs proviral concentration. This finding supports a role for genetic variations of TLR7 and TLR8 in SRLVs infection.Toll-like receptors (TLRs) 7 and 8 are important in single-stranded viral RNA recognition, so genetic variation of these genes may play a role in SRLVs infection and disease progression. Present study aimed to identify SNPs in genes encoding TLR7 and TLR8 in goats of Carpathian breed and analyze their association with the SRLVs provirus concentration as index of disease progression. A total of 14 SNPs were detected, 6 SNPs in the TLR7 gene locus and 8 SNPs in the TLR8 gene. Nine of the 14 identified polymorphisms, 4 in the TLR7 gene and 5 in TLR8 gene, were significantly associated with the SRLVs proviral concentration. These SNPs were located in 3′UTR, 5′UTR and intron sequences as well as in the coding sequences, but they led to silent changes. Homozygous genotypes of three TLR7 SNPs (synonymous variant 1:50703293, 3′UTR variant 1:50701297 and 5′UTR variant 1:50718645) were observed in goats with lower provirus copy number as well as in seronegative animals. The results obtained in this study suggest that SNPs of TLR7/TLR8 genes may induce differential innate immune response towards SRLVs affecting proviral concentration and thereby disease pathogenesis and progression. These findings support a role for genetic variations of TLR7 and TLR8 in SRLVs infection and warrants further studies on the effect of TLR7/TLR8 polymorphisms on SRLVs infection in different populations.