Genotype Combinations Research Articles

The absence of seroconversion after exposition to hepatitis C virus is not related to KIR-HLA genotype combinations (GEHEP-012 study)

Background & aimsIt has been reported that specific killer-cell immunoglobulin-like receptors (KIRs) and HLA genotype combinations, such as KIR2DS4/HLA-C1 with presence of KIRDL2 or KIRDL3, homozygous KIRDL3/HLA-C1 and KIR3DL1/≥2HLA-Bw4, are strongly associated with the lack of active infection and seroconversion after exposition to hepatitis C virus (HCV). ObjectiveTo determine whether these KIR-HLA combinations are relevant factors involved in that phenotype. Patients and methodsIn this retrospective case-control study, genotype data from a genome-wide association study previously performed on low susceptibility to HCV-infection carried out on 27 high-risk HCV-seronegative (HRSN) individuals and 743 chronically infected (CI) subjects were used. HLA alleles were imputed using R package HIBAG v1.2223 and KIR genotypes were imputed using the online resource KIR*IMP v1.2.0. ResultsIt was possible to successfully impute at least one KIR-HLA genotype combination previously associated with the lack of infection and seroconversion after exposition to HCV in a total of 23 (85.2%) HRSN individuals and in 650 (87.5%) CI subjects. No KIR-HLA genotype combination analyzed was related to the HRSN condition. ConclusionsOur results suggest that those KIR-HLA genotype combinations are not relevant factors involved in the lack of infection and seroconversion after exposition to HCV. More studies will be needed to completely understand this phenotype.

Genomic basis of melanin-associated phenotypes suggests colour-specific environmental adaptations in tawny owls.

Feathers comprise a series of evolutionary innovations but also harbour colour, a key biological trait known to co-vary with life history or complex traits. Those relationships are particularly true in melanin-based pigmentation species due to known pleiotropic effects of the melanocortin pathway - originating from melanin-associated phenotypes. Here, we explore the molecular basis of melanin colouration and expected co-variation at the molecular level in the melanin-based, colour polymorphic system of the tawny owl (Strix aluco). An extensive body of literature has revealed that grey and brown tawny owl colour morphs differ in a series of life history and behavioural traits. Thus, it is plausible to expect co-variation also at molecular level between colour morphs. To investigate this possibility, we assembled the first draft genome of the species against which we mapped ddRADseq reads from 220 grey and 150 brown morphs - representing 10 years of pedigree data from a population in Southern Finland - and explored genome-wide associations with colour phenotype. Our results revealed putative molecular signatures of cold adaptation strongly associated with the grey phenotype, namely, a non-synonymous substitution in MCHR1, plus 2 substitutions in non-coding regions of FTCD and FAM135A whose genotype combinations obtained a predictive power of up to 100% (predicting grey colour). These suggest a molecular basis of cold environment adaptations predicted to be grey-morph specific. Our results potentially reveal part of the molecular machinery of melanin-associated phenotypes and provide novel insights towards understanding the functional genomics of colour polymorphism in melanin-based pigmented species.

Excitatory to inhibitory synaptic ratios are unchanged at presymptomatic stages in multiple models of ALS.

Hyperexcitability of motor neurons and spinal cord motor circuitry has been widely reported in the early stages of Amyotrophic Lateral Sclerosis (ALS). Changes in the relative amount of excitatory to inhibitory inputs onto a neuron (E:I synaptic ratio), possibly through a developmental shift in synapse formation in favour of excitatory transmission, could underlie pathological hyperexcitability. Given that astrocytes play a major role in early synaptogenesis and are implicated in ALS pathogenesis, their potential contribution to disease mechanisms involving synaptic imbalances and subsequent hyperexcitability is also of great interest. In order to assess E:I ratios in ALS, we utilised a novel primary spinal neuron / astrocyte co-culture system, derived from neonatal mice, in which synapses are formed in vitro. Using multiple ALS mouse models we found that no combination of astrocyte or neuron genotype produced alterations in E:I synaptic ratios assessed using pre- and post-synaptic anatomical markers. Similarly, we observed that ephrin-B1, a major contact-dependent astrocytic synaptogenic protein, was not differentially expressed by ALS primary astrocytes. Further to this, analysis of E:I ratios across the entire grey matter of the lumbar spinal cord in young (post-natal day 16-19) ALS mice revealed no differences versus controls. Finally, analysis in co-cultures of human iPSC-derived motor neurons and astrocytes harbouring the pathogenic C9orf72 hexanucleotide repeat expansion showed no evidence of a bias toward excitatory versus inhibitory synapse formation. We therefore conclude, utilising multiple ALS models, that we do not observe significant changes in the relative abundance of excitatory versus inhibitory synapses as would be expected if imbalances in synaptic inputs contribute to early hyperexcitability.

Potentially functional variants of INPP5D and EXOSC3 in immunity B cell-related genes are associated with non-small cell lung cancer survival.

B cells are adaptive immune cells in the tumor microenvironment and play an important role in tumor development and metastasis. However, the roles of genetic variants of the immunity B cell-related genes in the survival of patients with non-small cell lung cancer (NSCLC) remain unknown. In the present study, we first evaluated associations between 10,776 single nucleotide polymorphisms (SNPs) in 220 immunity B cell-related genes and survival of NSCLC in a discovery dataset of 1,185 patients from the Prostate, Lung, Colorectal and Ovarian (PLCO) Cancer Screening Trial. We found that 369 SNPs were significantly associated with overall survival (OS) of NSCLC in multivariable Cox proportional hazards regression analysis (P ≤ 0.05, Bayesian false discovery probability ≤ 0.80), of which 18 SNPs were validated in another independent genotyping dataset of 984 patients from the Harvard Lung Cancer Susceptibility (HLCS) Study. We then performed linkage disequilibrium (LD) analysis, followed by stepwise analysis with a multivariable Cox regression model. Finally, two independent SNPs, inositol polyphosphate-5-phosphatase D (INPP5D) rs13385922 C>T and exosome component 3 (EXOSC3) rs3208406 A>G, remained significantly associated withNSCLC OS with a combined hazards ratio (HR) of 1.14 (95% confidence interval = 1.06-1.23, P = 2.41×10-4) and 1.20 (95% confidence interval = 1.14-1.28, P = 3.41×10-9), respectively. Furthermore, NSCLC patients with the combination of unfavorable genotypes for these two SNPs were associated with a poor OS (P trend = 0.0002) and disease-specific survival (DSS, P trend < 0.0001) in the PLCO dataset. Expression quantitative trait loci (eQTL) analysis suggested that the INPP5D rs6782875 T allele was significantly correlated with elevated INPP5D mRNA expression levels in normal lung tissues and whole blood samples, while the EXOSC3 rs3208406 G allele was significantly correlated with increased EXOSC3 mRNA expression levels in normal lung tissues. Our data indicated that genetic variants in these immunity B cell-related genes may predict NSCLC survival possibly by influencing the gene expression.

A preliminary study on the association of single nucleotide polymorphisms and methylation of dopamine system-related genes with psychotic symptoms in patients with methamphetamine use disorder.

Methamphetamine use disorder (MAUD) can substantially jeopardize public security due to its high-risk social psychology and behaviour. Given that the dopamine reward system is intimately correlated with MAUD, we investigated the association of single nucleotide polymorphisms (SNPs), as well as methylation status of dopamine receptor type 4 (DRD4), catechol-O-methyltransferase (COMT) genes, and paranoid and motor-impulsive symptoms in MAUD patients. A total of 189 MAUD patients participated in our study. Peripheral blood samples were used to detect 3 SNPs and 35 CpG units of methylation in the DRD4 gene promoter region and 5 SNPs and 39 CpG units in the COMT gene. MAUD patients with the DRD4 rs1800955 C allele have a lower percentage of paranoid symptoms than those with the rs1800955 TT allele. Individuals with paranoid symptoms exhibited a reduced methylation degree at a particular DRD4 CpG2.3 unit. The interaction of the DRD4 rs1800955 C allele and the reduced DRD4CpG2.3 methylation degree were associated with a lower occurrence of paranoid symptoms. Meanwhile, those with the COMT rs4818 CC allele had lower motor-impulsivity scores in MAUD patients but greater COMT methylation levels in the promoter region and methylation degree at the COMT CpG 51.52 unit. Therefore, based only on the COMT rs4818 CC polymorphism, there was a negative correlation between COMT methylation and motor-impulsive scores. Our preliminary results provide a clue that the combination of SNP genotype and methylation status of the DRD4 and COMT genes serve as biological indicators for the prevalence of relatively high-risk psychotic symptoms in MAUD patients.

Barley Yellow Dwarf Virus Influences Its Vector's Endosymbionts but Not Its Thermotolerance.

The barley yellow dwarf virus (BYDV) of cereals is thought to substantially increase the high-temperature tolerance of its aphid vector, Rhopalosiphum padi, which may enhance its transmission efficiency. This is based on experiments with North American strains of BYDV and R. padi. Here, we independently test these by measuring the temperature tolerance, via Critical Thermal Maximum (CTmax) and knockdown time, of Australian R. padi infected with a local BYDV isolate. We further consider the interaction between BYDV transmission, the primary endosymbiont of R. padi (Buchnera aphidicola), and a transinfected secondary endosymbiont (Rickettsiella viridis) which reduces the thermotolerance of other aphid species. We failed to find an increase in tolerance to high temperatures in BYDV-infected aphids or an impact of Rickettsiella on thermotolerance. However, BYDV interacted with R. padi endosymbionts in unexpected ways, suppressing the density of Buchnera and Rickettsiella. BYDV density was also fourfold higher in Rickettsiella-infected aphids. Our findings indicate that BYDV does not necessarily increase the temperature tolerance of the aphid transmission vector to increase its transmission potential, at least for the genotype combinations tested here. The interactions between BYDV and Rickettsiella suggest new ways in which aphid endosymbionts may influence how BYDV spreads, which needs further testing in a field context.

Relationships between the mutations of the goat GATA binding protein 4 gene and growth traits

Osteogenesis is a complex multilevel process regulated by multiple genes. The GATA binding protein 4 (GATA4) gene has been extensively studied for its pivotal role in bone genesis and bone differentiation. However, its relationship with the growth traits of Shaanbei white cashmere (SBWC) and Guizhou black (GB) goats remains unclear. This work aims to investigate the potential influence of genetic mutations in the GATA4 gene on the growth traits goats. Thus, two Insertion/deletion (InDel) polymorphisms (8-bp-InDel and 9-bp-InDel) were screened and detected in a total of 1161 goats (including 980 SBWC goats and 181 GB goats) using PCR and agarose gel electrophoresis. The analyses revealed that there were two genotypes (ID and DD) for these two loci. In SBWC goats, 8-bp-InDel and 9-bp-InDel loci were significantly associated with heart girth (HG) and hip width (HW). Notably, individuals with DD genotype of 8-bp-InDel locus were superior while those with DD genotype of 9-bp-InDel locus were inferior. Correlation analyses of the four combined genotypes revealed significant associations with cannon circumference (CC), body height (BH), HG and HW. This work provides a foundation for the application of molecular marker-assisted selection (MAS) in goat breeding programs. Furthermore, the findings highlight the potential of the GATA4 gene and its genetic variations as valuable indicators for selecting goats with desirable growth traits.

Machine learning analyses reveal circadian clock features predictive of anxiety among UK biobank participants

Mood disorders, including depression and anxiety, affect almost one-fifth of the world’s adult population and are becoming increasingly prevalent. Mutations in circadian clock genes have previously been associated with mood disorders both directly and indirectly through alterations in circadian phase, suggesting that the circadian clock influences multiple molecular pathways involved in mood. By targeting previously identified single nucleotide polymorphisms (SNPs) that have been implicated in anxiety and depressive disorders, we use a combination of statistical and machine learning techniques to investigate associations with the generalized anxiety disorder assessment (GAD-7) scores in a UK Biobank sample of 90,882 individuals. As in previous studies, we observed that females exhibited higher GAD-7 scores than males regardless of genotype. Interestingly, we found no significant effects on anxiety from individual circadian gene variants; only circadian genotypes with multiple SNP variants showed significant associations with anxiety. For both sexes, severe anxiety is associated with a 120-fold increase in odds for individuals with CRY2_AG(rs1083852)/ZBTB20_TT(rs1394593) genotypes and is associated with a near 40-fold reduction in odds for individuals with PER3-A_CG(rs228697)/ZBTB20_TT(rs1394593) genotypes. We also report several sex-specific associations with anxiety. In females, the CRY2/ZBTB20 genotype combination showed a > 200-fold increase in odds of anxiety and PER3/ZBTB20 and CRY1 /PER3-A genotype combinations also appeared as female risk factors. In males, CRY1/PER3-A and PER3-B/ZBTB20 genotype combinations were associated with anxiety risk. Mediation analysis revealed direct associations of CRY2/ZBTB20 variant genotypes with moderate anxiety in females and CRY1/PER3-A variant genotypes with severe anxiety in males. The association of CRY1/PER3-A variant genotypes with severe anxiety in females was partially mediated by extreme evening chronotype. Our results reinforce existing findings that females exhibit stronger anxiety outcomes than males, and provide evidence for circadian gene associations with anxiety, particularly in females. Our analyses only identified significant associations using two-gene combinations, underscoring the importance of combined gene effects on anxiety risk. We describe novel, robust associations between gene combinations involving the ZBTB20 SNP (rs1394593) and risk of anxiety symptoms in a large population sample. Our findings also support previous findings that the ZBTB20 SNP is an important factor in mood disorders, including seasonal affective disorder. Our results suggest that reduced expression of this gene significantly modulates the risk of anxiety symptoms through direct influences on mood-related pathways. Together, these observations provide novel links between the circadian clockwork and anxiety symptoms and identify potential molecular pathways through which clock genes may influence anxiety risk.

Risk for Seasonal Affective Disorder (SAD) Linked to Circadian Clock Gene Variants.

Molecular pathways affecting mood are associated with circadian clock gene variants and are influenced, in part, by the circadian clock, but the molecular mechanisms underlying this link are poorly understood. We use machine learning and statistical analyses to determine the circadian gene variants and clinical features most highly associated with symptoms of seasonality and seasonal affective disorder (SAD) in a deeply phenotyped population sample. We report sex-specific clock gene effects on seasonality and SAD symptoms; genotypic combinations of CLOCK3111/ZBTB20 and PER2/PER3B were significant genetic risk factors for males, and CRY2/PER3C and CRY2/PER3-VNTR were significant risk factors for females. Anxiety, eveningness, and increasing age were significant clinical risk factors for seasonality and SAD for females. Protective factors for SAD symptoms (in females only) included single gene variants: CRY1-GG and PER3-VNTR-4,5. Clock gene effects were partially or fully mediated by diurnal preference or chronotype, suggesting multiple indirect effects of clock genes on seasonality symptoms. Interestingly, protective effects of CRY1-GG, PER3-VNTR-4,5, and ZBTB20 genotypes on seasonality and depression were not mediated by chronotype, suggesting some clock variants have direct effects on depressive symptoms related to SAD. Our results support previous links between CRY2, PER2, and ZBTB20 genes and identify novel links for CLOCK and PER3 with symptoms of seasonality and SAD. Our findings reinforce the sex-specific nature of circadian clock influences on seasonality and SAD and underscore the multiple pathways by which clock variants affect downstream mood pathways via direct and indirect mechanisms.

Genetic variants in myostatin and its receptors promote elite athlete status

BackgroundWhile product of the myostatin gene (MSTN) is an important factor influencing muscle growth, which is well confirmed in nonhuman species, it has not been clearly confirmed whether MSTN expression influences interindividual differences in skeletal muscle mass, affects posttraining changes, or plays a role in the age-related loss of muscle mass and function in humans. Although the inconclusive results are usually explained by ethnic differences and the low frequency of some alleles, it is possible that the role of receptors (ACVR2A and ACVR2B) that affect the biological activity of myostatin is crucial. Therefore, we investigated the sequences of the MSTN, ACVR2A, and ACVR2B genes and determined the interaction between allelic variants and athletic performance and competition level in the Caucasian population. One hundred-two athletes were recruited for the sequencing study, and whole-genome sequencing (WGS) was performed. Second, 330 athletes and 365 controls were included, and real-time PCR was performed.ResultsThe sequence analysis revealed two polymorphisms relatively common in the athlete cohort, and the alternate allele showed overrepresentation in athletes: MSTN rs11333758 and ACVR2A rs3764955. Regarding the polymorphic site MSTN rs11333758, there was a significant overrepresentation of the –/– genotype in all high-elite and mixed-sport high-elite athletes. Carriers of the ACVR2A rs3764955 CC and GG genotypes were more likely to be elite and high-elite athletes. In addition, carriers of the CC genotype were more likely to be in the mixed-sport subelite group. The gene‒gene interaction analysis revealed that mixed-sport high elite athletes showed significant underrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 AA genotype combination. In the same group, we observed a significant overrepresentation of the ACVR2A rs3764955 GC - MSTN rs11333758 –/– and the ACVR2A rs3764955 CC - MSTN rs11333758 –/– genotype combinations.ConclusionsWe showed that the specific genotypes of the MSTN rs11333758 and ACVR2A rs3764955, either individually or in gene‒gene combination, are significantly associated with athletes’ competition level in the Polish population, especially in the mixed-sports athlete group. Thus, although further research is required, these polymorphisms, alone or in combination with other polymorphisms, are among the numerous candidates that could explain individual variations in muscle phenotypes.

Diversity and distribution of Aphanomyces astaci in a European hotspot of ornamental crayfish introductions

Ornamental trade has become an important introduction pathway of non-native aquatic species worldwide. Correspondingly, there has been an alarming increase in the number of established crayfish of aquarium origin in Europe over the previous decade. The oomycete Aphanomyces astaci, the pathogen causing crayfish plague responsible for serious declines of European crayfish populations, is dispersed with introduced North American crayfish. The role of ornamental taxa in introducing and spreading different genotypes of this pathogen in open waters remains unclear. We investigated the distribution, prevalence, and diversity of A. astaci in Budapest, Hungary, which became a hotspot of aquarium crayfish introductions. Their establishment in this area was facilitated by locally abundant thermal waters. We screened for A. astaci in six host taxa from 18 sites sampled between 2018 and 2021: five cambarids (Cambarellus patzcuarensis, Faxonius limosus, Procambarus alleni, P. clarkii, P. virginalis) and one native astacid (Pontastacus leptodactylus). The pathogen was confirmed at five sampled sites in four host taxa: P. virginalis, P. clarkii, F. limosus, and for the first time in European open waters also in P. alleni. Genotyping was successful only in individuals from two different brooks where multiple host species coexisted but revealed unexpected patterns. Mitochondrial B-haplogroup of A. astaci, previously usually reported from Pacifastacus leniusculus or infected European species, was detected in P. virginalis at both sites, and in both F. limosus and P. virginalis sampled from a thermally stable tributary of Barát brook in 2018. In contrast, A-haplogroup of A. astaci was detected in coexisting F. limosus, P. virginalis and P. clarkii sampled in the same watercourse just a few hundred meters downstream in 2020. Additional genotyping methods indicated that a previously unknown A. astaci strain was associated with the latter haplogroup. One P. virginalis individual from 2020 was apparently co-infected by strains representing both mitochondrial haplogroups. The results indicated multiple sources of A. astaci in Budapest, likely directly associated with the introduction of ornamental species, interspecific transmission of this pathogen among ornamental hosts, and potential for a quick spatial or temporal turnover of dominant A. astaci strains at a certain locality. This highlights that in regions with high richness of potential A. astaci hosts, host taxon/pathogen genotype combinations become unpredictable, which might prevent reliable genotyping of pathogen sources in local crayfish mass mortalities.

Polymorphisms of PLIN1 and MOGAT1 genes and their association with feed efficiency in Hu sheep

Feed cost accounts for a high proportion of sheep production, and improving sheep's utilization of feed will reduce production costs and improve economic benefits. The purpose of this study was to investigate the expression characteristics of PLIN1 and MOGAT1 genes and the relationship between their polymorphisms and feed efficiency traits in Hu sheep, and to find molecular Genetic marker that can be used in breeding. The expression levels of PLIN1 and MOGAT1 genes in various tissues were determined using quantitative real-time PCR (qRT-PCR). The results showed that PLIN1 and MOGAT1 genes were widely expressed in heart, liver, spleen, lungs, kidneys, rumen, duodenum, muscle, lymph, and tail fat. The PLIN1 gene had the highest expression level in in the tail fat compared to the other nine tissues. The expression levels of MOGAT1 gene in liver, tail fat, lung and heart was significantly higher than in kidney, muscle and lymph. The expression level of MOGAT1 was lowest in muscle compared to the other tissues (heart, liver, spleen, lung, rumen and tail fat). We recorded the body weight (BW80 and BW180) and feed intake (FI) information of 985 male Hu sheep at 80 and 180 days of age, and calculated the daily average feed intake (ADFI), average daily gain (ADG), and feed conversion rate (FCR) from 80 to 180 days of age. Two intronic mutations, g.18517910 A > G and g.224856118 G > C, were identified in PLIN1 and MOGAT1 genes by PCR amplification and Sanger sequencing. MassARRAY ® SNP detection technology was used to genotype the DNA of 985 Hu sheep and analyze its association with feed efficiency traits. The results showed that the SNP g.18517910 A > G was significantly associated with BW80, BW180, FI, ADFI and FCR (P < 0.05), while SNP g.2248561118 G > C was significantly associated with FCR (P < 0.05). Meanwhile, significant differences were also observed in different combinations of genotypes (P < 0.05). Therefore, these two polymorphic loci can serve as candidate molecular markers for improving feed utilization efficiency in Hu sheep.

Molecular characterization of SPATA6 and association of its SNPs with testicular size in sheep

The testis is an important organ for maintaining fertility in males, and testis size is positively correlated with ejaculate volume, sperm motility, thus fertility. Spermatogenesis-associated 6 (SPATA6) is an evolutionarily conserved testis-specific gene reported in many species. However, the effect of SPATA6 expression levels on testicular development and the effect of single nucleotide polymorphisms (SNPs) on testis and epididymis phenotype in sheep have not been studied. The purpose of the research was to investigate the expression profile of SPATA6 and its effect on testicular development and to confirm the effect of SNPs on the testis and epididymis phenotype. In this study, we detected a 1245bp coding sequence (CDS) of SPATA6 and encoded 414 amino acids. The expression levels of SPATA6 were significantly higher in the testis than in other tissues and gradually increased with testis development. Moreover, the expression level in the large testis was significantly higher than that in the small testis at six months. A total of 11 SNPs were detected in the coding region of SPATA6 by cDNA-pooling sequencing and improved multiplex ligation detection reaction (iMLDR) methods. Correlation analysis showed that SNP2 (c. 3631C > G) significantly affected left epididymis weight (LEW) and right epididymis weight (REW), and SNP10 (c. 937 A > G) significantly affected REW. And the combined genotype of SNP1 (c. 4245 G > A) and SNP2 significantly affected REW. The current study concluded that SPATA6 plays an important role in testicular development and the SNPs significantly associated with the epididymis phenotype can provide molecular markers for the early selection of high-fertility Hu sheep.

Molecular Screening of the Thrombophilic Variants Performed at G-141 Laboratory among Saudi Infertile Women

Infertility is a major issue at present and is a common disease that exists in both male and female reproductive systems, described as failure to attain pregnancy. The most important physiological phenomenon for establishing clinical pharmacy is defined as female infertility (FI). Obesity enhances the risks for many chronic disorders, especially causing a high risk for women’s reproductive health. The relationship between infertile women and thrombophilia is characterized by abnormal blood coagulation. Among the thrombophilic variants, Factor V Leiden (FVL), prothrombin (PT) and methyl tetrahydrofolate reductase (MTHFR) in genes such as G1691A (rs6020), G20210A (rs1799963) and C677T (rs1801133) are commonly studied in the majority of human diseases. In this case–control study, we investigated the role of thrombophilic variants such as G1691A, G20210A and C677T in the FVL, PII and MTHFR genes in Saudi infertile women. Based on sample size calculation, 100 female infertile and 100 control (fertile) women were selected based on inclusion and exclusion criteria. Genotyping was performed with polymerase chain reaction and followed with precise restriction enzymes, which can accurately detect the nucleotide amendment variants in G1691A, G20210A and C677T. The required statistics were applied between the case (infertile) and control (fertile) women to document the role of the G1691A, G20210A and C677T variants in Saudi infertile women. In this study, age, weight and BMI were found to be high in the control women in comparison to the infertile women. None of the genotypes, genetic models or allele frequencies were associated with G1691A, G20210A or C677T SNPs (p &gt; 0.05). Furthermore, the regression model and ANOVA analysis also showed negative statistical associations. The combination of genotypes and allele frequencies among G1691A, G20210A and C677T SNPs showed positive associations in the recessive model (p = 0.0006). Finally, the GMDR model showed moderate associations with the gene–gene interaction, dendrogram and depletion models. Finally, this study confirmed that thrombophilic SNPs have no role and may not be involved in Saudi infertile women.

New insights into the role of VKORC1 polymorphisms for optimal warfarin dose selection in Caribbean Hispanic patients through an external validation of a population PK/PD model

Warfarin, an oral anticoagulant, has been used for decades to prevent thromboembolic events. The complex interplay between CYP2C9 and VKORC1 genotypes on warfarin PK and PD properties is not fully understood in special sub-groups of patients. This study aimed to externally validate a population pharmacokinetic/pharmacodynamic (PK/PD) model for the effect of warfarin on international normalized ratio (INR) and to evaluate optimal dosing strategies based on the selected covariates in Caribbean Hispanic patients. INR, and CYP2C9 and VKORC1 genotypes from 138 patients were used to develop a population PK/PD model in NONMEM. The structural definition of a previously published PD model for INR was implemented. A numerical evaluation of the parameter-covariate relationship was performed. Simulations were conducted to determine optimal dosing strategies for each genotype combinations, focusing on achieving therapeutic INR levels. Findings revealed elevated IC50 for G/G, G/A, and A/A VKORC1 haplotypes (11.76, 10.49, and 9.22 mg/L, respectively), in this population compared to previous reports. The model-guided dosing analysis recommended daily warfarin doses of 3–5 mg for most genotypes to maintain desired INR levels, although subjects with combination of CYP2C9 and VKORC1 genotypes * 2/* 2-, * 2/* 3- and * 2/* 5-A/A would require only 1 mg daily. This research underscores the potential of population PK/PD modeling to inform personalized warfarin dosing in populations typically underrepresented in clinical studies, potentially leading to improved treatment outcomes and patient safety. By integrating genetic factors and clinical data, this approach could pave the way for more effective and tailored anticoagulation therapy in diverse patient groups.

The Relationship Between Odontogenic Cyst and P53 Codon 72 And P53 Codon 175 Variants in Turkish Patients

Objective: Odontogenic cysts that cause bone destruction can exhibit various types of metaplasia. Inherited genetic variants in codons 72 and 175, the hotspot codons of p53, known as the guardian of the genome, can cause a wide variety of cancers. We aimed to investigate the effects of the p53 codon 72 and p53 codon 175 variants on odontogenic cyst formation. Methods: This research encompassed 71 individuals with odontogenic cysts and 90 without any conditions as a control group. After DNA was extracting, the p53 codon 72 was detected using PCR techniques, while p53 codon 175 was identified through allele-specific amplification-PCR. Results: The presence of the p53 codon 72 GG genotype and its G allele was less frequent in the group with odontogenic cysts compared to the healthy participants. Conversely, the C allele was found more often in the cyst-afflicted group. For the p53 codon 175, the AA genotype and A allele were more common in the affected group, while the G allele was more predominant in the control group. Conclusion: The p53 codon 175 AA genotype and A allele, p53 codon 72 C allele, and p53 codon 72/codon 175 CCAA combined genotype may be associated with odontagenic cyst formation. Individuals with this allele and genotype can be considered at risk for odontagenic cyst formation.

The Effect of Genotype Combinations of Wolbachia and Its Drosophila melanogaster Host on Fertility, Developmental Rate and Heat Stress Resistance of Flies.

The best-known effect of the intracellular bacterium Wolbachia is its mostly negative influence on the reproduction of the host. However, there is evidence of a positive influence of Wolbachia on the host's resistance to stress, pathogens, and viruses. Here, we analyzed the effects of two Wolbachia strains belonging to wMel and wMelCS genotypes on D. melanogaster traits, such as fertility, survival under acute heat stress, and developmental rate. We found that D. melanogaster lines under study differ significantly in the above-mentioned characteristics, both when the natural infection was preserved, and when it was eliminated. One of Wolbachia strains, wMel, did not affect any of the studied traits. Another strain, wMelPlus, had a significant effect on the development time. Moreover, this effect is observed not only in the line in which it was discovered but also in the one it was transferred to. When transferred to a new line, wMelPlus also caused changes in survival under heat stress. Thus, it could be concluded that Wolbachia-Drosophila interaction depends on the genotypes of both the host and the symbiont, but some Wolbachia effects could depend not on the genotypes, but on the fact of recent transfer of the symbiont.

Non‑synonymous polymorphisms in the HRC and ADRB1 genes may be associated with all‑cause death in patients with non‑ischemic heart failure.

Sudden cardiac death (SCD) is an unpredictable and common mode of death in patients with heart failure (HF). Alterations in calcium handling may lead to malignant arrhythmias, resulting in SCD, and variants in calcium signaling-related genes have a significant association with SCD. Therefore, the aim of the present retrospective cohort study was to investigate the association of Ser96Ala [histidine-rich calcium-binding protein (HRC)], Ser49Gly [β1-adrenergic receptor (ADRB1)], Arg389Gly (ADRB1) and Gly1886Ser [ryanodine receptor 2 (RYR2)] polymorphisms with serious arrhythmic events and overall mortality in patients with HF with reduced left ventricular ejection fraction of non-ischemic etiology. In total, 136 patients with HF underwent physical examination, routine laboratory tests, non-invasive assessment of cardiac function and an invasive electrophysiological study. The primary outcome was the occurrence of serious arrhythmic events, set as either SCD or appropriate implantable cardioverter-defibrillator (ICD) therapy, and the secondary outcome was all-cause death. During a median follow-up of 37 months, arrhythmic events occurred in 26 patients (19%) and 41 patients (30%) died. Patients carrying the Ser allele of the Ser96Ala polymorphism in HRC had worse survival than those with the Ala/Ala genotype (log-rank P=0.043). Despite the difference in survival time, the Ala/Ala genotype was not associated with all-cause death in the regression analysis [unadjusted hazard ratio (HR)=0.17; 95% CI, 0.02-1.21]. Regarding the Ser49Gly and Arg389Gly polymorphisms in ADRB1, homozygosity for the major alleles at both sites (Ser49Ser and Arg389Arg) was associated with a two-fold increased risk of all-cause death compared with the other genotype combinations (unadjusted HR=1.98; 95% CI, 1.02-3.82). However, this association was lost after controlling for clinical covariates. No association was observed for the Gly1886Ser polymorphism in RYR2. Overall, the present findings are concurrent with the hypothesis that the Ser96Ala (HRC), Ser49Gly (ADRB1) and Arg389Gly (ADRB1) polymorphisms may be associated with HF prognosis. In particular, the Ser96Ala polymorphism might aid in risk stratification and patient selection for ICD implantation.

Combinations of blood biomarkers in a real‐life memory clinic in Thailand

AbstractBackgroundDifferent Alzheimer’s disease (AD) blood‐based biomarkers (BBM) exhibit unique patterns and trajectories throughout the natural history of AD, and thus, their combination may result in a higher diagnostic accuracy. While the usefulness of BBM combinations had been demonstrated in research cohorts, their performance in real‐life memory clinics is unclear. Additionally, previous BBM studies have been largely confined to high‐income countries and have often excluded non‐white populations. We aimed to evaluate the performance of BBM combinations in a real‐world clinical setting, specifically in a memory clinic in ThailandMethodThe study enrolled 64 memory clinic patients who had undergone amyloid‐positron emission tomography (PET) or cerebrospinal fluid (CSF) assessment for AD biomarkers. Plasma amyloid‐β42 (Aβ42), Aβ40, p‐tau181 were quantified for each participant using single molecule array as well as APOE genotype determined. The accuracy of individual biomarkers in discriminating amyloid status (as confirmed by PET or CSF) were assessed using receiver operating characteristic (ROC) analysis. Logistic regression models were then created for different BBM combinations, and their performance was determined using ROC analysis. To ensure robustness and generalizability of the results, two‐fold cross‐validation was repeated 10 times on the best‐performing modelResultThe study consisted of 47 (73.4%) female participants with a median age of 70.0 years (interquartile range: 63.75‐75.25). Amyloid status was positive in 43 (67.2%) of the participants. Plasma Aβ42/Aβ40 ratio, Aβ42/p‐tau181 ratio and p‐tau181 had areas under the curve (AUC) of 0.68 (95% confidence interval (CI) 0.52‐0.84), 0.88 (95%CI 0.79‐0.98) and 0.87 (95%CI 0.79‐0.96) for detecting amyloid status, respectively. Logistic regression models that included APOE genotype, Aβ, and p‐tau181 had the highest AUC of 0.90‐0.91. Two‐fold cross‐validation performed on the model that included APOE genotype and the Aβ42/p‐tau181 ratio revealed an average AUC of 0.90 (standard deviation: 0.029) over 10 repeatsConclusionThe combination of APOE genotype, plasma Aβ, and p‐tau181 displayed an exceptionally high diagnostic accuracy in discriminating amyloid status in a memory clinic setting. However, further studies are needed to evaluate the cost‐effectiveness of various ways to implement BBMs into real‐world clinical practice, particularly in low‐ and middle‐income countries

Combinatorial analysis of ACE and ACE2 polymorphisms reveals protection against COVID-19 worsening: A genetic association study in Brazilian patients.

Since angiotensin-converting enzyme 2, ACE2, was identified as the receptor for SARS-CoV-2 and considering the intense physiological interplay between the two angitensinases isoforms, ACE and ACE2, as counter-regulatory axis of the renin-angiotensin system, we proposed the evaluation of polymorphisms in these two key regulators in relation to COVID-19 severity. A genetic association study involving 621 COVID-19 hospitalized patients from Brazil was performed. All subjects had a confirmed diagnosis of COVID-19 via RT-PCR. Patients were categorized into two groups: the "mild" group (N = 296), composed of individuals hospitalized in ward beds who progressed to cure, and the "severe" group (N = 325), composed of individuals who required hospitalization in an intensive care unit (ICU), or who died. Blood samples were genotyped for ACE I/D polymorphism and ACE2 G8790A polymorphism by real-time PCR via TaqMan assay. The analysis of combined polymorphisms revealed a protective role for genotypic profile II/A_ (ORA = 0,26; p = 0,037) against the worsening of COVID-19 in women. The results indicate a protection profile to COVID-19 progression, in which the II/A_ carriers have almost four times less chance of a severe outcome. It is proposed that a decreased activity of ACE (deleterious effects) in conjunction with an increased ACE2 activity (protective effects), should be the underlying mechanism. The findings are unprecedented once other studies have not explored the genotypic combination analysis for ACE and ACE2 polymorphisms and bring perspectives and expectations for dealing with the COVID-19 pandemic based on definitions of genetically-based risk groups within the context of personalized medicine.