Differences In Allele Frequencies Research Articles

Pharmacogenomic profiling of the South Korean population: Insights and implications for personalized medicine

Adverse drug reactions (ADRs) pose substantial public health issues, necessitating population-specific characterization due to variations in pharmacogenes. This study delineates the pharmacogenomic (PGx) landscape of the South Korean (SKR) population, focusing on 21 core pharmacogenes. Whole genome sequencing (WGS) was conducted on 396 individuals, including 99 healthy volunteers, 95 patients with chronic diseases, 81 with colon cancer, 81 with breast cancer, and 40 with gastric cancer, to identify genotype-specific drug dosing recommendations. Our detailed analysis, utilizing high-throughput genotyping (HTG) of CYP2D6 and comparative data from the 1,000 Genomes Project (1 KG) and the US National Marrow Donor Program (NMDP), revealed significant pharmacogenetic diversity in core pharmacogenes such as CYP2B6, CYP2C19, CYP4F2, NUDT15, and CYP2D6. Notably, intermediate metabolizer frequencies for CYP2B6 in SKR (3.28%) were comparable to Europeans (5.77%) and East Asians (5.36%) but significantly differed from other global populations (p < 0.01). For CYP2C19, 48.74% of SKR individuals were classified as intermediate metabolizers, with the *35 allele (2.02%) being unique to SKR, the allele not observed in other East Asian populations. Additionally, the high-risk *3 allele in CYP4F2 was significantly more frequent in SKR (34.72%) than in other East Asian populations (p < 0.01). NUDT15 poor metabolizers were found in 0.76% of SKR, aligning closely with other East Asians (1.59%), while TPMT poor metabolizers were predominantly observed in Europeans and Africans, with one case in SKR. We identified significant allele frequency differences in CYP2D6 variants rs1065852 and rs1135840. Among the 72 drugs analyzed, 93.43% (n = 370) of patients required dosage adjustments for at least one drug, with an average of 4.5 drugs per patient. Moreover, 31.31% (n = 124) required adjustments for more than five drugs. These findings reveal the substantial pharmacogenetic diversity of the SKR population within the global population, emphasizing the urgency of integrating population-specific PGx data into clinical practice to ensure safe and effective drug therapies. This comprehensive PGx profiling in SKR not only advances personalized medicine but also holds the potential to significantly improve healthcare outcomes on a broader scale.

Mapping the relative accuracy of cross-ancestry prediction

The overwhelming majority of participants in genome-wide association studies (GWAS) have European (EUR) ancestry, and polygenic scores (PGS) derived from EURs often perform poorly in non-EURs. Previous studies suggest that between-ancestry differences in allele frequencies and linkage disequilibrium are significant contributors to the poor portability of PGS in cross-ancestry prediction. We hypothesize that the portability of (local) PGS varies significantly over the genome. Therefore, we develop a method, MC-ANOVA, to estimate the loss of accuracy in cross-ancestry prediction attributable to allele frequency and linkage disequilibrium differences between ancestries. Using data from the UK Biobank we develop PGS relative accuracy (RA) maps quantifying the local portability of EUR-derived PGS in non-EUR ancestries. We report substantial variability in RA along the genome, suggesting that even in ancestries with low overall RA of EUR-derived effects (e.g., African), there are regions with high RA. We substantiate our findings using six complex traits, which show that EUR-derived effects from regions where MC-ANOVA predicts high RA also have high empirical RA in real PGS. We provide software implementing MC-ANOVA and RA maps for several non-EUR ancestries. These maps can be used to interpret similarities and differences in GWAS results between groups and to improve cross-ancestry prediction.

Mapping an avirulence gene in the sunflower parasitic weed Orobanche cumana and characterization of host selection based on virulence alleles

BackgroundSunflower broomrape (Orobanche cumana Wallr.) is a holoparasitic plant that jeopardizes sunflower production in most areas of Europe and Asia. Recently, populations with increased virulence, classified as race GGV, have been identified in Southern Spain’s Guadalquivir Valley gene pool. These populations overcome resistance genes in hybrids resistant to the predominant race FGV. This study aimed to (i) determine the inheritance and map the avirulence trait segregating in a cross between O. cumana individuals from populations EK23 (FGV) and IN201 (GGV), and (ii) characterize the host effect on the IN201 parental population allelic diversity.ResultsA segregating population consisting of 144 F2:3 families was evaluated for virulence using a differential sunflower genotype (Hybrid 1, resistant to race FGV and susceptible to race GGV) and genotyped with SNP markers. The ratio of avirulent to virulent F2:3 families was not significantly different to 1:3 (χ2 = 0.93; P = 0.34), indicating monogenic control of the avirulence/virulence trait. The AvrG−GV locus was mapped on the upper end of O. cumana chromosome 2, 9.2 cM distal from the SNP markers OS04791 and OS02805. Secretome analysis in the AvrG−GV region revealed a cysteine-rich CAP superfamily- and a glucan 1,3-beta-glucosidase family 3-encoding genes as possible candidates for AvrG−GV. SNP allelic analysis on the IN201 population parasitizing a highly susceptible genotype or the differential genotype Hybrid 1 showed that (i) IN201 structure was shaped towards virulent alleles at SNP loci linked to AvrG−GV (ii) there were significant allelic frequency differences associated with the host genotype at AvrG−GV–linked loci.ConclusionsThis study mapped for the first time an avirulence gene in parasitic plants using a classical genetic approach, confirmed a gene-for-gene model in the O.cumana –sunflower system, and showed the implication of this single avirulence gene in determining the structure of broomrape populations subjected to selection pressure posed by a resistant genotype. The results will contribute to a better understanding of the interaction between crops and weedy parasitic plants, and to effectively manage evolution of virulence by sustainable control strategies based on host genetic resistance.

Frequencies of an IFNL4 Variant in an Admixed Population from Amazonia and Its Influence on Hepatitis C Infection

The rs12979860 polymorphism, related to the IFNL4 gene, is suggested as a factor that impacts fibrosis progression in hepatitis C virus (HCV) infection and exhibits a wide distribution pattern across global populations. In this retrospective cross-sectional study, we aimed to investigate the frequency of this variant in an Amazonian population from Brazil, as well as its association with liver fibrosis development and its staging in HCV carriers. Our results show a significant association of the TT genotype in the sample of patients with HCV (OR = 2.291; 95% CI = 1.088–4.826; p = 0.033) and the greater frequency of the T allele (62.1%), which is similar to the those of African populational groups. Populational genetics analysis showed significant differences in allele frequencies on global levels. The frequency of the C allele in the study population (37.8%) was like that of the African population (39.7%), and differed from all other populations, which ranged from 62.5% to 92.9%. These findings suggest that rs12979860 plays a role in susceptibility to hepatitis C. Additionally, they allow us to propose that the response to hepatitis C infection in this group may resemble that of the African population.

Clinical, biochemical, and genetic study of TACE/TNF-α/ACE signaling pathway in pediatric COVID-19 infection.

: Pediatric patients infected with coronavirus disease 2019 (COVID-19) have unique clinical characteri-stics. Tumor necrosis factor (TNF) is a proinflammatory cytokine that greatly contributes to tumor pathogenesis. : To describe the presenting characteristics of COVID-19 infection among pediatric patients, and investi-gate the possible role of the TNF-α signaling pathway. : This prospective case-control study included 50 Egyptian pediatric patients with COVID-19 and 50 healthy controls. Clinical, laboratory, and radiological as-sessments were performed. Serum TNF-alpha (TNF-α), TNF-α-converting enzyme (TACE), and angiotensin-con-verting enzyme 2 (ACE2) were measured using enzyme-linked immunosorbent assay. ACE (I/D) (rs4646994), ACE2 rs2285666, and TNF-α-308G/A single nucleotide poly-morphisms (SNPs) were performed using conventional polymerase chain reaction techniques with or without restriction fragment length polymorphism. : The median age was 1 year (interquartile range [IQR], 0.31-2.50 years) in the case group and 1.45 years (IQR, 1.00-3.00) in the control group. The main presenting symptoms were fever (92%), dry cough (74%), and dyspnea (72%). The lymphocytic count was normal in 14 patients (28%), decreased in 16 patients (32%), and in creased in 20 patients (40%) of the case group. Positive chest com-puted tomography finding of COVID-19 infection were demonstrated among 40% of patients using COVID-19 Re-porting and Data System categories (ground-glass op-acity with or without consolidations in the lungs). There were significant increased serum TACE and TNF-α with decreased ACE2 levels among cases versus controls (P< 0.001). The GG genotype and G allele of the TNF-α-308G/A SNP were significantly higher in patients than in controls (P<0.05 for both), with insignificant differences in genotype and allelic frequencies in the ACE (I/D) (rs4646994) and ACE2 rs2285666 SNPs. : The TNF signaling pathway was significantly activated in pediatric COVID-19 infection. Only the TNF-α-308G/A SNP was significantly associated with pediatric COVID-19 infection.

Forensic STR Loci and Schizophrenia: An Exploration of Implications for Forensic Applications and Genetic Privacy

Background/Objectives: Short tandem repeat (STR) loci are widely used in forensic genetics for identification and kinship analysis. Traditionally, these loci were selected to avoid medical associations, but recent studies suggest that loci such as TH01 and D16S539 may be linked to psychiatric conditions like schizophrenia. This study explores these potential associations and considers the privacy implications related to disease susceptibility. Methods: We analyzed 19 STR loci, including CODIS core loci and additional loci like Penta D and Penta E. Statistical analyses were conducted on a dataset of schizophrenia patients and matched control individuals to assess the relationship between STR polymorphisms and schizophrenia risk. Results: No significant associations were found between the 19 analyzed loci and schizophrenia in this dataset. While initial analyses revealed minor allele frequency differences at the D3S1358, D13S317, and TPOX loci between the schizophrenia and control groups, these differences did not retain statistical significance following Bonferroni correction (corrected p &lt; 0.0026 for all loci). Conclusions: Although no significant associations were found between STR loci and schizophrenia, this study highlights the importance of considering the potential for forensic DNA data to reveal health-related information. As forensic DNA databases continue to expand, there is a growing need to reassess ethical and legal guidelines to ensure the protection of individual privacy. Future research should continue exploring these genetic associations with larger, more diverse samples to further understand their implications.

Stochastic Epigenetic Modification and Evolution of Sex Determination in Vertebrates.

In this report, we propose a novel mathematical model of the origin and evolution of sex determination in vertebrates that is based on the stochastic epigenetic modification (SEM) mechanism. We have previously shown that SEM, with rates consistent with experimental observation, can both increase the rate of gene fixation and decrease pseudogenization, thus dramatically improving the efficacy of evolution. Here, we present a conjectural model of the origin and evolution of sex determination wherein the SEM mechanism alone is sufficient to parsimoniously trigger and guide the evolution of heteromorphic sex chromosomes from the initial homomorphic chromosome configuration, without presupposing any allele frequency differences. Under this theoretical model, the SEM mechanism (i) predated vertebrate sex determination origins and evolution, (ii) has been conveniently and parsimoniously co-opted by the vertebrate sex determination systems during the evolutionary transitioning to the extant vertebrate sex determination, likely acting "on top" of these systems, and (iii) continues existing, alongside all known vertebrate sex determination systems, as a universal pan-vertebrate sex determination modulation mechanism.

Association of BRAF V600E allele frequency with clinicopathologic outcomes in papillary thyroid cancer.

BRAF V600E mutation is the most common genetic driver of papillary thyroid cancer (PTC), where it is found with various allele frequency (AF), reflecting the proportion of cells carrying the mutant and wild-type gene alleles. To determine whether BRAF V600E AF can improve prognostication and inform initial surgical management of PTC. Retrospective cohort study (2016-2019). UCLA health. Consecutive patients with Bethesda V/VI nodules and isolated BRAF V600E mutation who underwent surgery with histopathology showing PTC. Blinded ThyroSeq v3 molecular analysis after completion of initial management and follow-up. Aggressive histopathology and cancer persistence/recurrence. Of 73 patients, the median BRAF V600E AF was 25.5% (IQR, 16.7-34.3%). Higher median AF was seen in patients classified as American Thyroid Association (ATA) high-risk (37%) vs. intermediate-risk (25.3%, p<0.01) and low-risk (24.7%, p<0.01), largely attributed to higher AF in patients with gross extrathyroidal extension (ETE) (40.1% vs. 25.2% without gross ETE, p=0.02). No differences in AF were observed on the basis of lymph node positivity or presence of aggressive variants of PTC. A higher BRAF V600E AF was also found in patients with tumors ≥2cm vs. <2cm (median 32.0% vs. 24.4%, p<0.01). Over 4.1 years of follow-up, disease persistence/recurrence was found in 7 patients (9.4%) and was associated with higher median AF than those without recurrence (35.3% vs. 25.2%, p=0.02). Higher AF was associated with poorer recurrence-free survival (AF≥35%, HR 7.40, CI 1.4-38.1). Higher AF was associated with gross ETE and increased recurrence risk. This may inform initial management in patients with PTC harboring an isolated BRAF V600E mutation.

ABC Family Gene Polymorphisms and Cognitive Functions Interact to Influence Antidepressant Efficacy.

The importance of identifying relevant indicators of antidepressant efficacy is highlighted by the low response rates to antidepressant treatment for depression. The ABC gene family, encoding ATP-dependent transport proteins facilitating the transport of psychotropic drugs, has drawn attention. This study delved into the relationship between antidepressant efficacy and seven single nucleotide polymorphisms of ABCB1 and ABCB6 genes. A total of 549 depressed patients participated in the study, and all completed a 6-week course of antidepressant treatment. Cognitive function was assessed at baseline and post-treatment. Patients were categorized based on post-treatment HAMD-17 scores (with HAMD≤7 indicating remission), and comparisons were made between different groups in terms of allelic gene frequencies and genotypes. Logistic regression was used to explore the interaction between cognitive function and genotype on efficacy. Dual-luciferase reporter assays were performed to compare the regulatory effects of rs1109866 allele variants on the ABCB6 promoter. There were no notable differences in allelic gene frequencies and genotypes between the remission and non-remission groups. Nonetheless, a significant interaction was identified between the rs1109866 genotype and language fluency-related indicators concerning efficacy (p=0.029) before correction. The dual-luciferase reporter assays demonstrated markedly higher fluorescence intensity of rs1109866-C compared to that of rs1109866-T (p<0.001). Relying solely on genetic polymorphisms of ABC family genes as predictors of antidepressant treatment response may not be sufficient. However, the interaction between the rs1109866 and cognition plays a pivotal role. The potentially enhanced transcriptional activity of rs1109866-C might offer insight into its impact on antidepressant efficacy.

EPID-16. GENOMIC ANCESTRY-RELATED RISK RATIOS FOR GLIOBLASTOMA INCIDENCE AMONG GLOBAL POPULATIONS AND RACIAL/ETHNIC GROUPS WITHIN THE UNITED STATES

Abstract Glioblastoma (GBM) incidence varies globally, elevated rates in Europe and lower rates in Asia, Latin America, and Africa. While partially attributable to national differences in cancer diagnosis and reporting practices, analogous patterns exist within diverse Western nations. Ancestry-associated differences in GBM risk allele frequencies (RAFs) could contribute, a hypothesis supported by our prior multiethnic genome-wide association studies (GWAS). Leveraging variant effect estimates from large GBM GWAS datasets and ancestry-stratified allele frequency data from diverse reference populations (ALFA, GNOMAD, 1000 Genomes Project), we estimate the extent of GBM incidence differences across populations that can be attributed to underlying variation in RAF at the seventeen known GBM risk loci. Aggregate differences in RAF between global populations (Europe, West-Africa, East Asia) were associated with a &amp;gt;20% reduction in the normalized GBM risk-ratio (RR) in Africans compared to Europeans (RR=0.78) and a &amp;gt;50% reduction in East Asians compared to Europeans (RR=0.47). The frequency of GBM risk alleles was generally highest in Europeans, but four alleles found most commonly in Africans are at loci regulating telomere maintenance (TERC, TERT, OBFC1/STN1, RTEL1). We repeated analyses using RAF data from U.S. populations (African-Americans, Latinos, and non-Hispanic Whites). Compared to non-Hispanic Whites, aggregate differences in RAF were associated with a 15% reduction in GBM risk among African-Americans (RR=0.85) and a 28% reduction among Latinos (RR=0.72). We conclude that a sizable proportion of the reduced GBM incidence in Latinos and Asians, relative to non-Hispanic Whites, can be accounted for by population-level differences in RAF at known loci. However, registry-based analyses consistently report a two-fold lower incidence of GBM in African Americans relative to non-Hispanic Whites which is poorly explained by RAF differences at known loci. Further work is needed to identify structural, environmental, and biological factors contributing to unresolved differences in GBM incidence.

Allele frequency impacts the cross-ancestry portability of gene expression prediction in lymphoblastoid cell lines

Population-level genetic studies are overwhelmingly biased toward European ancestries. Transferring genetic predictions from European ancestries to other ancestries results in a substantial loss of accuracy. Yet, it remains unclear how much various genetic factors, such as causal effect differences, linkage disequilibrium (LD) differences, or allele frequency differences, contribute to the loss of prediction accuracy across ancestries. In this study, we used gene expression levels in lymphoblastoid cell lines to understand how much each genetic factor contributes to lowered portability of gene expression prediction from European to African ancestries. We found that cis-genetic effects on gene expression are highly similar between European and African individuals. However, we found that allele frequency differences of causal variants have a striking impact on prediction portability. For example, portability is reduced by more than 32% when the causal cis-variant is common (minor allele frequency, MAF >5%) in European samples (training population) but is rarer (MAF <5%) in African samples (prediction population). While large allele frequency differences can decrease portability through increasing LD differences, we also determined that causal allele frequency can significantly impact portability when the impact from LD is substantially controlled. This observation suggests that improving statistical fine-mapping alone does not overcome the loss of portability resulting from differences in causal allele frequency. We conclude that causal cis-eQTL effects are highly similar in European and African individuals, and allele frequency differences have a large impact on the accuracy of gene expression prediction.

ERAP1 Gene Variants and Haplotypes Associated With Psoriasis Vulgaris of Han Chinese in Inner Mongolia.

This study aimed to investigate the association between genetic variants of ERAP1 (OMIM: 606832) and psoriasis vulgaris (PsV) susceptibility in Inner Mongolia Han nationality. For primary screening, the subjects included 142 PsV cases and 100 healthy controls without psoriasis. The 27 exons of ERAP1 gene were sequenced to screen significant genetic variants. For the validation study, the subjects included 1030 PsV cases and 965 healthy controls. A total of 18 mutations were detected for genetic variants of significance in primary screening and previously reported genetic variants. In primary screening stage, 13 genetic variants of ERAP1 showed an association with psoriasis. A total of 18 genetic variants were typed for the validation, and 12 genetic variants were associated with PsV in Inner Mongolia Han population. Stratified analysis showed significant differences in the allele frequencies of 8 ERAP1 genetic variants in cases with positive family history, and significant differences in allele frequencies among 9 ERAP1 genetic variants in patients with negative family history. A risk haplotype (TCCCTCCAGACC) was significantly associated with PsV, and the most risk haplotype was E730/K528/R127/E56. ERAP1 gene mutation may be associated with PsV and HLA-C*06:02 in Han nationality in Inner Mongolia. A risk haplotype of four-nonsynonymous mutation (E730/K528/R127/E56) is associated with PsV.

Afro-Latin American Pharmacogenetics of CYP2D6, CYP2C9, and CYP2C19 in Dominicans: A Study from the RIBEF-CEIBA Consortium.

Background/Objectives: Research on pharmacogenetic variability in response to prescribed drugs and across ethnic groups is essential for personalized medicine, particularly in admixed and unstudied populations. For the first time, this study examines CYP2D6, CYP2C9, and CYP2C19 alleles and genotypes in 197 healthy volunteers from the Dominican Republic, as part of the RIBEF-CEIBA collaborative network. Methods: The analysis focuses on the participants' tri-hybrid genomic ancestry, with CYP alleles determined by real-time PCR and molecular ancestry inferred using 90 AIMs. Linear regression was used to associate ancestry components with CYP frequencies. Results: The average ancestry was 23.8% European, 42.6% Native American, and 33.6% African, the latter being higher than in most Latin American populations. Native American ancestry was also higher than expected. Predicted phenotype frequencies based on genotypes were 4.2% poor metabolizers (gPMs) and 3.6% ultrarapid metabolizers (gUMs) for CYP2D6, as well as 3% gPMs, 22.8% rapid metabolizers (gRMs), and 1.5% gUMs for CYP2C19. No gPM individuals were observed for CYP2C9. Certain alleles associated with decreased CYP2D6 activity (*17 and *29) and increased CYP2C19 activity (*17 and gUMs) were positively linked with African ancestry and negatively with Native American ancestry. Rare CYP2C9 alleles (*5 and *6) with clinical relevance were additionally found. Conclusions: These findings build on previous results from the RIBEF-CEIBA collaborative network, demonstrating differences in allele frequencies of CYP2D6, CYP2C9, and CYP2C19 in relation to genomic ancestry. In summary, ethnicity must be considered in the development of pharmacogenetic guidelines for clinical application, research, and regulation to avoid widening the biotechnology gap and to allow Personalized Medicine to reach the entire world population.

Identification of genetic variants by using a whole exome sequencing approach in Taiwanese patients with Brugada Syndrome

Abstract Background Brugada Syndrome (BrS) is a life-threatening arrhythmia disease primarily affecting young men. Many genetic studies have been conducted mainly in Caucasian BrS patients to identify potential genetic drivers. SCN5A mutations are less common in Asian BrS patients (around 10%) compared to Caucasian patients (20-30%). This means the pathogenic process of more than 70% of BrS patients remains unclear. With the advancement in NGS technologies, we can conduct genome-wide screening of DNA variants in BrS patients efficiently. Purpose Since less than 30% of the BrS patients have known genetic drivers for the disease, we aimed to identify more DNA variants in BrS patients by using the whole exome sequencing (WES) approach. Furthermore, we evaluated the landscape of DNA variants in the two groups of BrS patients according to whether they have SCN5A mutations or not. Methods A total of 201 BrS patients were recruited for the WES experiments. After obtaining the raw sequencing data, we performed the quality check procedures using the multiQC and Trimmomatic softwares (Figure 1). For reads passing the quality check, the BWA algorithm was used for the alignment. Next, the samtools, bamtools, and Picard methods were used to remove duplicates and perform the sorting. Subsequently, those sorted sequencing files were used to call the DNA variants by using the GATK approach and annotate them using the ANNOVAR method. The 201 BrS patients were classified into two different groups based on their mutation status of SCN5A, presentation of sudden cardiac death (SCD), and SCD along with syncope. The gene-based algorithm, SKAT, was used to analyze the summarized effects of DNA variants located in a single gene. For each DNA variant, Fisher's exact test was used to compare the allele frequency in the BrS patients under their groupings. Results The WES approach in the 201 BrS patients revealed a total of 205,454 variants, which were further categorized into two groups, common variants (51,867) and rare variants (153,587), based on their allele frequencies (5%). The SKAT algorithm was performed in the 30 genes that have been previously reported to be associated with BrS. No significant differences were observed in any gene in BrS patients for the common variants. Intriguingly, KCNJ8, SCN1B, ZFPM2, MAPRE2, and KCNE5 showed significant differences in allele frequencies between the SCN5A+ and SCN5A- patients (Figure 2). Fisher's exact test further revealed that three DNA variants (chr19:35524980, chr12:21926440, chr6:126210346) were significantly enriched in SCN5A+ patients. The 5 DNA variants located in ZFPM2 showed a linkage disequilibrium block and were enriched in SCN5A+ patients. Conclusions The WES approach in BrS patients revealed DNA variants that were reported in previous studies. Several DNA variants were significantly enriched in SCN5A+ patients, suggesting that the genome-wide mutation landscape was different in SCN5A+ and SCN5A- BrS patients.Figure 1Figure 2

Association of polymorphism of apolipoprotein e gene with acute myocardial infarction and its short term clinical outcome

Abstract Background/Introduction Myocardial infarction (MI) is a multifactorial disease influenced by environmental and genetic factors. Apolipoprotein E (ApoE) is a protein incorporated into serum lipoproteins directing their catabolism via binding to receptors. It is a structural component of both chylomicrons and very low density lipoprotein (VLDL) remnants. ApoE is thought to play a central role in atherosclerosis by participating in overall plasma cholesterol homeostasis. In addition to other classical risk factors, positive family history of cardiovascular disease (CVD) has been found to be significantly and independently associated with MI in epidemiological studies (1). Besides traditional cardiovascular risk factors it is likely that additional genetic factors like ApoE gene polymorphism may interact with environmental factors to determine overall cardiovascular risk of an individual to develop MI. Purpose The purpose of our study was to determine the risk of association of variants of ApoE gene with Acute Myocardial Infarction. Moreover, we also wanted to study the impact of ApoE gene polymorphism in short term major adverse cardiac events (MACE) in patients with MI not willing for coronary intervention. Methods In this case control study a total of 200 consecutively admitted AMI patients admitted to the coronary care unit of our hospital were enrolled to the study along with 200 age and gender matched controls admitted during the same time period . ApoE gene polymorphism was detected by DNA extraction, DNA amplification by PCR in a DNA thermal cycler followed by restriction enzyme digestion(2). Chi square test was used to investigate the difference in genotype and allele frequencies in casend controls and also between observed and expected frequencies in the realm of Hardy-Weinberg equilibrium. Odds Ratio (OR) with 95 % confidence interval and p values were calculated while analysing the association of different genotypes of ApoE genetic polymorphism with the disease and MACE. Logistic regression analysis was carried out amongst the groups under consideration to find the unadjusted OR and adjusted OR of the genotypes in relation to the disease.p&amp;lt;0.05 was considered as significant Analysis was done in SPSS software. Results Besides the traditional risk factors Apo E4 allele (OR 2.298, CI 1.305-4.044 ) and Apo E3/E4 genotype (OR 2.116, CI 1.008-4.443, p=0.048) showed strong of association with the disease. There was a higher population of Apo E3/E4 genotypes and Apo E2/E3 genotypes with MACE events (25.6% and 28.6%), while the common ApoE3/E3 genotypes had a MACE event of 10.5 %. However, the difference was not significant (p=0.071, Χ 2 =8.63 df =4). Similarly, ApoE4 allele showed a non significantly higher MACE events (p=0.22, Χ 2 =3.01 df =4) Conclusion ApoE4 allele and ApoE3/E4 genotype are strongly and independently associated with AMI.RISK FACTORS AND RISK OF MIGenotype and MACE

An atlas of genetic effects on the monocyte methylome across European and African populations.

Elucidating the genetic architecture of DNA methylation is crucial for decoding complex disease etiology. However, current epigenomic studies are often limited by incomplete methylation coverage and heterogeneous tissue samples. Here, we present the first comprehensive, multi-ancestry human methylome atlas of purified human monocytes, generated through integrated whole-genome bisulfite sequencing and whole-genome sequencing from 298 European Americans (EA) and 160 African Americans (AA). By analyzing over 25 million methylation sites, we identified 1,383,250 and 1,721,167 methylation quantitative trait loci (meQTLs) in cis- regions for EA and AA populations, respectively, revealing both shared (880,108 sites) and population-specific regulatory patterns. Furthermore, we developed population-specific DNAm imputation models, enabling methylome-wide association studies (MWAS) for 1,976,046 and 2,657,581 methylation sites in EA and AA, respectively. These models were validated through multi-ancestry analysis of 41 complex traits from the Million Veteran Program. The identified meQTLs, MWAS models, and data resources are freely available at www.gcbhub.org and https://osf.io/gct57/ .

That's Not a Hybrid: How to Distinguish Patterns ofAdmixture and Isolation By Distance.

Describing naturally occurring genetic variation is a fundamental goal of molecular phylogeography and population genetics. Popular methods for this task include STRUCTURE, a model-based algorithm that assigns individuals to genetic clusters, and principal component analysis (PCA), a parameter-free method. The ability of STRUCTURE to infer mixed ancestry makes it popular for documenting natural hybridisation, which is of considerable interest to evolutionary biologists, given that such systems provide a window into the speciation process. Yet, STRUCTURE can produce misleading results when its underlying assumptions are violated, like when genetic variation is distributed continuously across geographic space. To test the ability of STRUCTURE and PCA to accurately distinguish admixture from continuous variation, we use forward-time simulations to generate population genetic data under three demographic scenarios: two involving admixture and one with isolation by distance (IBD). STRUCTURE and PCA alone cannot distinguish admixture from IBD, but complementing these analyses with triangle plots, which visualise hybrid index against interclass heterozygosity, provides more accurate inference of demographic history, especially in cases of recent admixture. We demonstrate that triangle plots are robust to missing data, while STRUCTURE and PCA are not, and show that setting a low allele frequency difference threshold for ancestry-informative marker (AIM) identification can accurately characterise the relationship between hybrid index and interclass heterozygosity across demographic histories of admixture and range expansion. While STRUCTURE and PCA provide useful summaries of genetic variation, results should be paired with triangle plots before admixture is inferred.

Investigating Leptin Gene Variants and Methylation Status in Relation to Breastfeeding and Preventing Obesity.

Objective: We investigated whether the results of leptin gene (LEP) 2548G/A (rs7799039) and leptin receptor gene (LEPR) 668 A/G (rs1137101) variants, as well as the methylation analysis of CpG regions at nucleotides -31 and -51 of the LEP gene, showed any differences between breastfed and non-breastfed children in this study. Materials and Methods: The cross-sectional study included 100 children aged 2-5 years who were attending nursery and kindergarten and had been accepted to the Department of General Paediatrics. Infants who were exclusively breastfed for the first six months after birth constituted the study group, and those who were not only breastfeed constituted the control group. Methylation percentages at CpG islands of the LEP gene were compared between exclusively breastfed and non-exclusively breastfed infants, and the statistical significance was analyzed by looking for changes in LEP -31 and -51 nt methylation and LEP 2548G/A ve LEPR 668 A/G variants. Results: Both groups were compared by feeding, and the association of LEPR and LEP gene polymorphisms and -51 nt and -31 nt methylations were analyzed. There were no significant differences between the groups regarding genotype and allele frequency for the LEPR 668 A/G, LEP 2548 G/A gene variant, -31 nt methylation, and -51 nt methylation status. Similarly, there was no significant difference in genotype and allele frequency for the LEPR 668 A/G gene variant in terms of duration of exclusive breastfeeding, total breastfeeding, body mass index, family obesity, and satiety status. However, maternal support from family elders and physical activity increased the 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. Conclusions: Maternal support from family elders and physical activity were associated with increased 51 nt methylation, but this methylation was not significantly affected by BMI, age, or satiety status. However, there are not enough studies in this area to reach a definitive conclusion, and further research is needed.

Insights into trait-association of selection signatures and adaptive eQTL in indigenous African cattle

BackgroundAfrican cattle represent a unique resource of genetic diversity in response to adaptation to numerous environmental challenges. Characterising the genetic landscape of indigenous African cattle and identifying genomic regions and genes of functional importance can contribute to targeted breeding and tackle the loss of genetic diversity. However, pinpointing the adaptive variant and determining underlying functional mechanisms of adaptation remains challenging.ResultsIn this study, we use selection signatures from whole-genome sequence data of eight indigenous African cattle breeds in combination with gene expression and quantitative trait loci (QTL) databases to characterise genomic targets of artificial selection and environmental adaptation and to identify the underlying functional candidate genes. In general, the trait-association analyses of selection signatures suggest the innate and adaptive immune system and production traits as important selection targets. For example, a large genomic region, with selection signatures identified for all breeds except N’Dama, was located on BTA27, including multiple defensin DEFB coding-genes. Out of 22 analysed tissues, genes under putative selection were significantly enriched for those overexpressed in adipose tissue, blood, lung, testis and uterus. Our results further suggest that cis-eQTL are themselves selection targets; for most tissues, we found a positive correlation between allele frequency differences and cis-eQTL effect size, suggesting that positive selection acts directly on regulatory variants.ConclusionsBy combining selection signatures with information on gene expression and QTL, we were able to reveal compelling candidate selection targets that did not stand out from selection signature results alone (e.g. GIMAP8 for tick resistance and NDUFS3 for heat adaptation). Insights from this study will help to inform breeding and maintain diversity of locally adapted, and hence important, breeds.

Genomic association of SNPs rs4077582 of CYP11A1 and rs700519 of CYP19A1 genes with polycystic ovarian syndrome.

Polycystic Ovarian Syndrome (PCOS) is a complex endocrine disorder that affects women of reproductive age. Several candidate genes have been shown to be associated with PCOS. Previous studies have shown that variations in CYP11A1 and CYP19A1 genes are associated with hormonal dysregulation associated with PCOS in different ethnic populations. This study aims to investigate the genomic association between SNPs rs4077582 of CYP11A1 and rs700519 of CYP19A1 and the development of PCOS in Pakistani population. A total of 280 subjects were recruited for the study, including 142 PCOS cases diagnosed based on Rotterdam criteria and 138 age-matched controls. The anthropometric, hormonal and biochemical parameters of all subjects were analyzed. Genomic DNA was extracted and genotyping of the selected SNPs was performed using Sanger sequencing. Further, we also examined the genotypic-phenotypic correlation analysis for various clinical and biochemical parameters for SNP rs4077582 of CYP11A1. We found significant differences in allele frequency (OR = 0.42, 95% CI = 0.30-0.60, χ2 = 16.3693, p = 0.000052) and genotypic frequency (χ2 = 26.4376, p = 0.00001) between PCOS women and controls for SNP rs4077582 of CYP11A1. Genotype-phenotype correlation analysis showed a significant difference in FAI (p = 0.005), testosterone (p = 0.001), androstenedione (p = 0.005) and urea (p = 0.049) levels between the three genotypes. No association between SNP rs700519 of CYP19A1 and PCOS was observed. Our results suggest the role of SNP rs4077582 of CYP11A1 gene in the clinical manifestation of PCOS in Pakistani women.