Population-specific Variation Research Articles

A thermo-physiologically consistent approach for studying the heat-health nexus with hierarchical generalized additive modelling: Application in Athens urban area (Greece)

The significance of the thermo-physiological determinants of heat-related deaths has been recognized since antiquity. Still, the impact of heat on human health in the modern era is repeatedly assessed in the epidemiological literature based solely on the environmental drivers of heat stress, primarily using aggregated daily metrics of air temperature. Going beyond this simplified approach, here we showcase a prototype heat-health modelling method that incorporates thermo-physiological principles and accounts for variability across different regions and populations, using the advanced human-biometeorological mPET (modified Physiologically Equivalent Temperature) index. This novel approach is based on a hierarchical general additive modelling framework. By applying the framework in the vulnerable to heat stress Athens urban area in Greece, we demonstrate, for the first time in epidemiological terms, that fatal heat-related risk is strongly associated with daylong (> 6 h) strong heat stress exposure. We also show that atmospherically and thermo-physiologically driven location- and population-specific variations in exposure, as well as short-term acclimatization, contribute to heat-effect occurrence and modification. These novel outcomes assist in establishing links between environmental epidemiological and thermo-physiological research. This is of great importance for supporting robust and effective public health interventions, especially in cities, which are particularly heat stress susceptible.

A simple calculation formula for the insertion depth of catheter of the central venous access port in Chinese patients

BackgroundThe catheter tip placed between the T6 and T7 vertebrae is recognized as an optimal position for the totally implantable venous access ports (TIVAPs). This study aimed to propose a simple formula for calculating the optimal insertion depth of the right internal jugular central venous catheter (CVC) of TIVAP in Chinese patients. MethodsThis was a prospective observational study. The medical records of 151 patients with TIVAPs placement were retrospectively analyzed. Patient's height and actual insertion depth of CVC were used to build a simple linear regression model. The Peres’ formula was revised to better calculate the optimal insertion depth of the right internal jugular CVC of TIVAPs, accounting for population-specific anatomical variations observed in Chinese patients. A total of 158 patients scheduled for TIVAPs placement were prospectively recruited. The insertion depth of catheter was preoperatively determined according to the established formula, and postoperative chest X-ray was performed to determine the position of catheter tip. The rate of proper position of catheter (the catheter tip within T6 or T7 vertebrae) was calculated to assess the clinical feasibility and effectiveness of the new formula. ResultsThe proper position rate was 64.24% (97/151) in the retrospective group. According to patients’ height and insertion depth of CVC of these 97 cases with proper position, Peres’ formula was revised to ‘insertion depth = 0.1*height – 4 (cm)’. Based on insertion depth predicted by the new formula, the proper position rate in the prospective group reached 86.08% (136/158). ConclusionThe simple formula for calculating the insertion depth of right internal jugular CVC of TIVAPs is clinically feasible for Chinese patients.

Genetic Basis of Hearing Loss in Mongolian Patients: A Next-Generation Sequencing Study.

The genetic landscape of sensorineural hearing impairment (SNHI) varies across populations. In Mongolia, previous studies have shown a lower prevalence of GJB2 mutations and a higher frequency of variants in other deafness-related genes. This study aimed to investigate the genetic variants associated with idiopathic SNHI in Mongolian patients. We utilized the next-generation sequencing for investigating the causative mutations in 99 Mongolian patients with SNHI. We identified pathogenic variants in 53 of the 99 SNHI patients (54%), with SLC26A4 being the most frequently mutated gene. The c.919-2A>G variant in SLC26A4 was the most prevalent, accounting for 46.2% of the mutant alleles. In addition, we identified 19 other known and 21 novel mutations in a total of 21 SNHI genes in autosomal recessive or dominant inheritance patterns. Our findings expand the understanding of the genetic landscape of SNHI in Mongolia and highlight the importance of considering population-specific variations in genetic testing and counseling for SNHI.

FGFR3 alterations in bladder cancer: Sensitivity and resistance to targeted therapies.

In this review, we revisit the pivotal role of fibroblast growth factor receptor 3 (FGFR3) in bladder cancer (BLCA), underscoring its prevalence in both non-muscle-invasive and muscle-invasive forms of the disease. FGFR3 mutations in up to half of BLCAs play a well-established role in tumorigenesis, shaping distinct tumor initiation patterns and impacting the tumor microenvironment (TME). Emphasizing the importance of considering epithelial-mesenchymal transition profile and TME status, we revisit their relevance in predicting responses to immune checkpoint inhibitors in FGFR3-mutated BLCAs. This writing highlights the initially promising yet transient efficacy of the FGFR inhibitor Erdafitinib on FGFR3-mutated BLCA, stressing the pressing need to unravel resistance mechanisms and identify co-targets for future combinatorial studies. A thorough analysis of recent preclinical and clinical evidence reveals resistance mechanisms, including secondary mutations, epigenetic alterations in pathway effectors, phenotypic heterogeneity, and population-specific variations within FGFR3 mutational status. Lastly, we discuss the potential of combinatorial treatments and concepts like synthetic lethality for discovering more effective targeted therapies against FGFR3-mutated BLCA.

Population genomics unravels a lag phase during the global fall armyworm invasion

The time that elapsed between the initial introduction and the proliferation of an invasive species is referred to as the lag phase. The identification of the lag phase is critical for generating plans for pest management and for the prevention of biosecurity failure. However, lag phases have been identified mostly through retrospective searches of historical records. The agricultural pest fall armyworm (FAW; Spodoptera frugiperda) is native to the New World. FAW invasion was first reported from West Africa in 2016, then it spread quickly through Africa, Asia, and Oceania. Here, using population genomics approaches, we demonstrate that the FAW invasion involved an undocumented lag phase. Invasive FAW populations have negative signs of genomic Tajima’s D, and invasive population-specific genetic variations have particularly decreased Tajima’s D, supporting a substantial amount of time for the generation of new mutations in introduced FAW populations. Model-based diffusion approximations support the existence of a period with a cessation of gene flow between native and invasive FAW populations. Taken together, these results provide strong support for the presence of a lag phase during the FAW invasion. These results show the usefulness of using population genomics analyses to identify lag phases in biological invasions.

Molecular Mechanisms of Temperature Tolerance Plasticity in an Arthropod.

How species thrive in a wide range of environments is a major focus of evolutionary biology. For many species, limited genetic diversity or gene flow among habitats means that phenotypic plasticity must play an important role in their capacity to tolerate environmental heterogeneity and to colonize new habitats. However, we have a limited understanding of the molecular components that govern plasticity in ecologically relevant phenotypes. We examined this hypothesis in a spider species (Stegodyphus dumicola) with extremely low species-wide genetic diversity that nevertheless occupies a broad range of thermal environments. We determined phenotypic responses to temperature stress in individuals from four climatic zones using common garden acclimation experiments to disentangle phenotypic plasticity from genetic adaptations. Simultaneously, we created data sets on multiple molecular modalities: the genome, the transcriptome, the methylome, the metabolome, and the bacterial microbiome to determine associations with phenotypic responses. Analyses of phenotypic and molecular associations reveal that acclimation responses in the transcriptome and metabolome correlate with patterns of phenotypic plasticity in temperature tolerance. Surprisingly, genes whose expression seemed to be involved in plasticity in temperature tolerance were generally highly methylated contradicting the idea that DNA methylation stabilizes gene expression. This suggests that the function of DNA methylation in invertebrates varies not only among species but also among genes. The bacterial microbiome was stable across the acclimation period; combined with our previous demonstrations that the microbiome is temporally stable in wild populations, this is convincing evidence that the microbiome does not facilitate plasticity in temperature tolerance. Our results suggest that population-specific variation in temperature tolerance among acclimation temperatures appears to result from the evolution of plasticity in mainly gene expression.

An amplicon panel for high-throughput and low-cost genotyping of Pacific oyster.

Maintaining genetic diversity in cultured shellfish can be challenging due to high variance in individual reproductive success, founder effects, and rapid genetic drift, but is important to retain adaptive potential and avoid inbreeding depression. To support broodstock management and selective breeding in cultured Pacific oysters (Crassostrea (Magallana) gigas), we developed an amplicon panel targeting 592 genomic regions and SNP variants with an average of 50 amplicons per chromosome. Target SNPs were selected based on elevated observed heterozygosity or differentiation in Pacific oyster populations in British Columbia, Canada. The use of the panel for parentage applications was evaluated using multiple generations of oysters from a breeding program on Vancouver Island, Canada (n = 181) and families selected for Ostreid herpesvirus-1 resistance from the Molluscan Broodstock Program in Oregon, USA (n = 136). Population characterization was evaluated using wild, naturalized, farmed, or hatchery oysters sampled throughout the Northern Hemisphere (n = 190). Technical replicates showed high genotype concordance (97.5%; n = 68 replicates). Parentage analysis found suspected pedigree and sample handling errors, demonstrating the panel's value for quality control in breeding programs. Suspected null alleles were identified and found to be largely population dependent, suggesting population-specific variation impacting target amplification. Null alleles were identified using existing data without the need for pedigree information, and once they were removed, assignment rates increased to 93.0% and 86.0% of possible assignments in the two breeding program datasets. A pipeline for analyzing the amplicon sequence data from sequencer output, amplitools, is also provided.

Genetic analysis of different subtypes of aseptic pustulosis in the Chinese population.

Aseptic pustulosis involves inflammatory skin conditions with nonbacterial pustules on erythema, accompanied by neutrophil and eosinophil infiltration in the epidermis. Dysregulation of the interleukin (IL)-36 pathway leads to neutrophil aggregation and pustule formation. Variants in IL36RN, CARD14, AP1S3, MPO, SERPINA3 and BTN3A3 have been identified in generalized pustular psoriasis (GPP) in the past. Some patients with acrodermatitis continua of Hallopeau (ACH), palmoplantar pustulosis and acute generalized exanthematous pustulosis (AGEP) also exhibit mutations in IL36RN, CARD14 and AP1S3, albeit with regional and population-specific variations. This study aims to explore a shared genetic foundation among those with aseptic pustulosis. We performed Sanger sequencing on six genes in 126 patients with aseptic pustulosis. Genetic analysis identified IL36RN variants strongly associated with ACH, AGEP and subcorneal pustular dermatosis (SPD). Immunohistochemistry revealed elevated inflammatory cytokines in all subtypes. This study establishes a significant association between IL36RN variants and ACH, AGEP and SPD, emphasizing the IL-1/IL-36-chemokine-neutrophil axis as a common pathogenic mechanism. Targeting this axis holds promise for therapeutic interventions for aseptic pustulosis.

Validating Thai translations of perceptual soundscape attributes: A non-Procrustean approach with a Procrustes projection

Measurement of a psychological construct across populations without a common linguistic medium often necessitates the development of multiple translations of the psychometric tool across multiple languages, dialects, or other population-specific variations. In this follow-up (Stage 2) study, a listening test using a shared set of 27 stimuli from the Soundscape Attribute Translation Project (SATP) was conducted with Thai-speaking participants using the set of Thai translations of the eight perceptual affective quality (PAQ) descriptors selected in earlier (Stage 1) work through a structured evaluation questionnaire. Principal component analysis was performed on the listening test data to obtain a rank-two reduction of the responses with maximal explained variance. In order to align the principal component space to the two-dimensional circumplex space, this work presents a simple and numerically stable method based on the orthogonal Procrustes projection, to find the optimal two-dimensional orthogonal transform that aligns the first two principal components with the axes corresponding to Pleasantness and Eventfulness as defined in ISO/TS 12913-3:2019. Analysis of the listening test responses indicated good to excellent interrater reliability, reflecting the general comprehensibility of the translations to laypersons. Subsequent analyses yielded a two-dimensional projection with ▪ explained variance and near-perfect alignment of the composite Pleasantness and Eventfulness axes. Angular locations of the individual translated PAQs are located within ▪ of their theoretically ideal locations and preserve angular ordering, albeit with imperfect equiangularity. Cross-analysis against the results from Stage 1 showed that the structured evaluation may be partially useful in anticipating potential imperfections of the PAQ translations and their angular locations in Stage 2.

Abstract LB336: The African Cancer Atlas: Leveraging African data to diversify precision oncology

Abstract Africa has some of the highest age adjusted cancer mortality rates globally and cancer incidence in Africa is expected to double by 2040. Despite this disproportionate burden of disease, African cancer patients are woefully understudied along the cancer continuum. People of African descent are significantly underrepresented in cancer research, accounting for less than 3% of globally available genomic data and are often the least well served by advances in precision medicine.To address this gap, we have initiated the African Cancer Atlas project. This is an Africa-centred approach to overcoming cancer inequities - providing much needed biological and clinical data, but also seeking to identify and address the social determinants of inequities both within the continent and between high and low-middle income countries (LMIC). We have established an oncology partner network across 9 geographically dispersed African countries (Senegal, Côte d’Ivoire, Ghana, Nigeria, Kenya, Uganda, Zimbabwe, South Africa, and Tunisia). We have developed LMIC-specific standardised protocols and best practices for sample collection and processing across multiple sites and continue to build a well-annotated bank of tissue, plasma, bone marrow and PBMC from individuals with breast, prostate, gastrointestinal cancers, liver, urinogenital and pediatric cancers that will be unrivalled in its diversity. So far, 1800 cancer samples have been collected and banked. We have also built a unique cloud-based clinical data management platform to facilitate the collection of longitudinal clinical metadata into a unified clinico-demographic database. We have initiated extensive genomic and molecular profiling of African-specific cancers using whole exome/genome sequencing (WES/WGS) of paired germline and tumour samples as well as RNA- sequencing of tumors. We have so far completed the first 200 WES, representing the first cancer samples sequenced entirely on the African continent. Ongoing work is investigating how population-specific genetic variation contributes to cancer risk, identifying driver mutations, somatic copy number alterations (SCNAs) and mutational signatures that can point to disease-relevant environmental exposures or impaired core biological pathways. Comparative analysis with existing cancer genomics cohorts will determine the prevalence of known hotspot mutations, cancer drivers and or common SCNAs in African cancer genomes. By comparing with available data for African Americans and other diasporan Africans, we will provide better understanding of cancer aetiology related to African ancestry applicable to the broader African diasporic communities in other regions of the world. We are also collecting data to assess socio-economic and health system factors affecting access to cancer care and survival across all study sites. Socio-demographic data collection is integrated with tissue/biodata collection creating digital longitudinal hospital-based cohorts. We will develop systems that integrate genomics, molecular demographics and clinical data with machine learning and a publicly accessible portal for data access and analytics will be available for the broader scientific community. Ultimately, this project will contribute towards better understanding of cancer among people of African descent and make precision oncology more effective for diverse populations. Citation Format: Yaw Bediako, Joyce Ngoi, Ruth Kiome, Seth Agyemang, Stephen Darkoh, Audrey Lemacon, Aida Manu, Frank Onyambu, Kanny Diallo, Lily Paemka, David Hutchful, Emmanuella Amoako, Abdoulaye Diallo. The African Cancer Atlas: Leveraging African data to diversify precision oncology [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(7_Suppl):Abstract nr LB336.

Population-specific variations in KCNH2 predispose patients to delayed ventricular repolarization upon dihydroartemisinin-piperaquine therapy.

Dihydroartemisinin-piperaquine is efficacious for the treatment of uncomplicated malaria and its use is increasing globally. Despite the positive results in fighting malaria, inhibition of the Kv11.1 channel (hERG; encoded by the KCNH2 gene) by piperaquine has raised concerns about cardiac safety. Whether genetic factors could modulate the risk of piperaquine-mediated QT prolongations remained unclear. Here, we first profiled the genetic landscape of KCNH2 variability using data from 141,614 individuals. Overall, we found 1,007 exonic variants distributed over the entire gene body, 555 of which were missense. By optimizing the gene-specific parametrization of 16 partly orthogonal computational algorithms, we developed a KCNH2-specific ensemble classifier that identified a total of 116 putatively deleterious missense variations. To evaluate the clinical relevance of KCNH2 variability, we then sequenced 293 Malian patients with uncomplicated malaria and identified 13 variations within the voltage sensing and pore domains of Kv11.1 that directly interact with channel blockers. Cross-referencing of genetic and electrocardiographic data before and after piperaquine exposure revealed that carriers of two common variants, rs1805121 and rs41314375, experienced significantly higher QT prolongations (ΔQTc of 41.8 ms and 61 ms, respectively, vs 14.4 ms in controls) with more than 50% of carriers having increases in QTc >30 ms. Furthermore, we identified three carriers of rare population-specific variations who experienced clinically relevant delayed ventricular repolarization. Combined, our results map population-scale genetic variability of KCNH2 and identify genetic biomarkers for piperaquine-induced QT prolongation that could help to flag at-risk patients and optimize efficacy and adherence to antimalarial therapy.

Abstract 1017: Characterizing immune cell infiltration in colorectal cancer tumor microenvironment among Native Hawaiians

Abstract Background Colorectal cancer (CRC) is recognized as a heterogeneous disease, ranking third in new cancer diagnoses and second in cancer-related deaths globally and nationally. CRC incidence is higher in the state of Hawaii compared to the U.S. overall. This study focuses on profiling immune cell infiltration in Native Hawaiian(NH)-specific CRC tumor microenvironments. Identifying the race-specific tumor infiltrating microenvironment may uncover potential mechanisms for CRC development in the NH population. Methods Deidentified, archival formalin-fixed paraffin-embedded tumor samples from Native Hawaiian patients diagnosed with primary CRC between 1990 and 2006 were obtained from the Hawaii Tumor Registry. RNA was extracted from tumor and adjacent normal tissues. RNA-seq data from Caucasian American (CA) CRC samples were obtained from The Cancer Genome Atlas (TCGA) and the Gene Expression Omnibus (GEO). Differentially expressed genes for each cohort were identified via DESeq2 with Benjamini-Hochberg multiple testing q-value<0.05 and a cutoff of 2-fold change. From the gene expression profiles, we applied the ESTIMATE algorithm to calculate the overall immune cell infiltration score for each sample. Based on a deconvolution algorithm, known as CIBERSORT to estimate the abundance of 22 immune cell types, we profiled the tumor-infiltrating immune cells present in each cohort’s paired samples, respectively. To improve the accuracy, p-value and root mean squared error were counted for each sample. Data with p<0.05 were filtered and selected for the next analysis. The fraction of immune cell subpopulations was evaluated and compared between paired tumor and adjacent normal tissues in NH and CA cohorts. Results In the NH cohort, we found the overall immune cell infiltration score was significantly lower in cancer tissues than the adjacent normal tissues (p<0.05), and there were significantly higher fractions of activated dendritic cells, resting natural killer (NK), and follicular helper T cells in tumor tissues compared to adjacent non-tumor tissues (p<0.05). Furthermore, the fractions of activated NK cells and plasma cells were significantly lower in tumor tissues than in adjacent non-tumor tissues in NH (p<0.05). Resting NK cells are upregulated in both the NH and the CA cohorts, while plasma cells are the only immune cell type downregulated in either cohort. In the NH cohort, activated dendritic cells and follicular helper T cells are exclusively upregulated, while activated NK cells are downregulated relative to the CA cohort. Conclusion This study demonstrates that the NH cohort displays distinctive immunological variances between tumor and adjacent non-tumor tissues which distinguishes them from the CA cohort. This emphasizes the significance of acknowledging population-specific genetic variations which may help understand race specific difference in CRC. Citation Format: Yuanyuan Fu, Gino Quintal, Masaki Nasu, Mayumi Jijiwa, Sudhir K. Rai, Isam Mohd-Ibrahim, Yu Chen, Hua Yang, Zhanwei Wang, Christina Wai, Owen Chan, Brenda Y. Hernandez, Youping Deng. Characterizing immune cell infiltration in colorectal cancer tumor microenvironment among Native Hawaiians [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1017.

Abstract P347: Variability in Predictive Error of Waist Circumference Models: A Stratified Analysis Based on Body Mass Index, Waist Circumference, and Their Ratio

Introduction: Waist circumference (WC) independently predicts cardiovascular risks, yet clinical measurements are sporadic. Some models have been developed for WC prediction, with body mass index (BMI) as a key predictor. While these models are generally efficient, variability in error across distinct subpopulations is possible. This study aimed to assess the prediction error (PE) variability of WC models across different strata of BMI, WC, and their ratio, and to evaluate the role of BMI for WC prediction. Hypothesis: 1) PE varies across BMI, WC, and their interrelated strata. 2) BMI is a key feature for WC prediction. Methods: Data from 30,298 individuals from the National Health and Nutrition Examination Survey (2007-2018) were analyzed. After outlier removal and kNN-imputation for missing values, machine learning predictive models for WC were developed. The base model included age, gender, ethnicity, height, weight, and BMI. A non-BMI model was also formulated, incorporating demographics and clinical variables selected via a feature-selection process. Root Mean Square Error (RMSE) across BMI, WC, and ratio of BMI-decile to WC-decile categories were assessed. Results: The base model's RMSE for the entire cohort was 5.70. Stratification by BMI revealed higher error rates for obesity classes II (5.88) and III (12.28), contrasting with lower RMSEs in participants with normal BMI (3.95), overweight (4.63), and obesity class I (5.41). Individuals with high WC had an increased RMSE (6.28) compared to those with low WC (5.04). Those with a BMI-decile/WC-decile below one had elevated error (6.98) compared to those with ratios equal to (4.60) or above one (5.52). Across all categories, the base model outperformed the non-BMI model (Figure 1). Conclusion: WC model PE demonstrated variability across BMI, WC, and their respective ratios, underscoring the predictive significance of BMI for WC. Considering population-specific variations in predictive WC modeling is important within clinical and research sets.

Causal associations of immune cell phenotypes with migraine: A mendelian randomization study.

The interaction between the immune system and the brain, crucial for blood-brain barrier integrity, is a potential factor in migraine development. Although there's evidence of a connection between immune dysregulation and migraine, a clear causal link has been lacking. To bridge this knowledge gap, we performed a two-sample Mendelian randomization (MR) analysis of 731 immune cell phenotypes to determine their causality with migraine, of which parameters included fluorescence, cell abundance, count, and morphology. Sensitivity and pleiotropy checks validated our findings. After applying a false discovery rate correction, our MR study identified 35 of 731 immune phenotypes with a significant causal link to migraine (p < 0.05). Of these, 24 showed a protective effect (inverse variance weighting : p< 0.05, odds ratio <1), and 11 were risk factors (inverse variance weighting : p< 0.05, odds ratio >1). Although limited by population sample size and potential population-specific genetic variations, our study uncovers a significant genetic link between certain immune cell markers and migraine, providing new insights into the disorder's pathophysiology. These discoveries are crucial for developing targeted biomarkers and personalized treatments. The research enhances our understanding of immune cells' role in migraine and may substantially improve patient outcomes and lessen its socio-economic impact.

Morphometric Assessment of Sellar Turcica: Tertiary Neurocenter study from Nepal.

Introduction: The sella turcica (ST) is a vital structure located in the median position within the middle cranial fossa and is frequently utilized in cephalometric for assessing craniofacial features. However, there is limited literature available regarding cephalometry of the ST in Nepal. Consequently, this study aimed to establish the normal dimensions of the ST in the Nepalese population and explore the potential difference in radio-morphometric measurement among sexes. Materials &amp; Methods: This study encompassed a descriptive, cross-sectional chart review conducted at the Upendra Devkota Memorial National Institute of Neurological and Allied Sciences over a three-month period. Morphometric assessment of the ST was performed using computed tomography scans. A single radiologist employed an EV Insite DICOM viewer to measure and record the length, depth, and antero-posterior diameter of the ST. Independent-Samples t-test was employed to compare the means between sexes, and a significance level of p &lt; 0.05 was considered statistically significant. Results: Among the 385 cases analyzed, 199 were male (51.8%) and 185 were female (48.2%), resulting in a male-to-female ratio of 1.07:1. The age range of the patients was 20 to 87 years, with a mean age of 44.5 ± 18.5 years. The mean dimensions of the sella turcica were determined as 9.32 mm for length, 7.07 mm for depth, and 10.29 mm for the antero-posterior diameter. Conclusions: The findings of this study indicate that the ST dimensions in the Nepalese population are relatively smaller compared to those reported in various other countries. Additionally, no statistically significant differences were observed in ST dimensions between males and females within the Nepalese population. These results emphasize the importance of considering populationspecific variations when utilizing cephalometric measurements and provide valuable reference standards for future studies and accurate assessment of craniofacial morphology in the Nepalese population.

Whole genome sequencing reveals population diversity and variation in HIV-1 specific host genes.

HIV infection continues to be a major global public health issue. The population heterogeneity in susceptibility or resistance to HIV-1 and progression upon infection is attributable to, among other factors, host genetic variation. Therefore, identifying population-specific variation and genetic modifiers of HIV infectivity can catapult the invention of effective strategies against HIV-1 in African populations. Here, we investigated whole genome sequences of 390 unrelated HIV-positive and -negative individuals from Botswana. We report 27.7 million single nucleotide variations (SNVs) in the complete genomes of Botswana nationals, of which 2.8 million were missing in public databases. Our population structure analysis revealed a largely homogenous structure in the Botswana population. Admixture analysis showed elevated components shared between the Botswana population and the Niger-Congo (65.9%), Khoe-San (32.9%), and Europeans (1.1%) ancestries in the population of Botswana. Statistical significance of the mutational burden of deleterious and loss-of-function variants per gene against a null model was estimated. The most deleterious variants were enriched in five genes: ACTRT2 (the Actin Related Protein T2), HOXD12 (homeobox D12), ABCB5 (ATP binding cassette subfamily B member 5), ATP8B4 (ATPase phospholipid transporting 8B4) and ABCC12 (ATP Binding Cassette Subfamily C Member 12). These genes are enriched in the glycolysis and gluconeogenesis (p < 2.84e-6) pathways and therefore, may contribute to the emerging field of immunometabolism in which therapy against HIV-1 infection is being evaluated. Published transcriptomic evidence supports the role of the glycolysis/gluconeogenesis pathways in the regulation of susceptibility to HIV, and that cumulative effects of genetic modifiers in glycolysis/gluconeogenesis pathways may potentially have effects on the expression and clinical variability of HIV-1. Identified genes and pathways provide novel avenues for other interventions, with the potential for informing the design of new therapeutics.

Despite genetic isolation in sympatry, post-copulatory reproductive barriers have not evolved between bat- and human-associated common bedbugs (Cimex lectularius L.)

BackgroundThe common bedbug Cimex lectularius is a widespread ectoparasite on humans and bats. Two genetically isolated lineages, parasitizing either human (HL) or bat (BL) hosts, have been suggested to differentiate because of their distinct ecology. The distribution range of BL is within that of HL and bedbugs live mostly on synanthropic bat hosts. This sympatric co-occurrence predicts strong reproductive isolation at the post-copulatory level.ResultsWe tested the post-copulatory barrier in three BL and three HL populations in reciprocal crosses, using a common-garden blood diet that was novel to both lineages. We excluded pre-copulation isolation mechanisms and studied egg-laying rates after a single mating until the depletion of sperm, and the fitness of the resulting offspring. We found a higher sperm storage capability in BL, likely reflecting the different seasonal availability of HL and BL hosts. We also observed a notable variation in sperm function at the population level within lineages and significant differences in fecundity and offspring fitness between lineages. However, no difference in egg numbers or offspring fitness was observed between within- and between-lineage crosses.ConclusionsDifferences in sperm storage or egg-laying rates between HL and BL that we found did not affect reproductive isolation. Neither did the population-specific variation in sperm function. Overall, our results show no post-copulatory reproductive isolation between the lineages. How genetic differentiation in sympatry is maintained in the absence of a post-copulatory barrier between BL and HL remains to be investigated.

A comparison of the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in patients with hypertension.

Objective: This study aims to compare the effects of hydrochlorothiazide and captopril on glucose and lipid metabolism in hypertensive patients. Study Design: Prospective Observational. Setting: Hayatabad Medical Complex Peshawar. Period: December 2022 to May 2023. Material &amp; Methods: Approach was employed to investigate the metabolic impact of these antihypertensive medications. Involving a cohort of 660 hypertensive individuals. Data collection spanned over 12-week duration, with fasting glucose and lipid profiles assessed at baseline and 4, 8, and 12 weeks. Participants were categorized into hydrochlorothiazide and captopril groups, receiving standardized dosages of 25 mg/day and 50 mg/day, respectively. Fasting blood samples were analyzed for glucose and lipid parameters. Statistical analyses included paired t-tests and subgroup comparisons. Results: Both groups exhibited reductions in fasting glucose and lipid levels; however, these changes were not statistically significant within the 12-week timeframe. Comparison with national and international studies underscores population-specific variations in antihypertensive effects on metabolism. Conclusion: This study provides insights into the metabolic effects of hydrochlorothiazide and captopril among hypertensive patients. While immediate changes were not significant, the study contributes to the body of knowledge and calls for further research with extended follow-up and broader participant cohorts.

Genomic ancestry in kidney cancer: Correlations with clinical and molecular features.

Genetic ancestry (GA) refers to population hereditary patterns that contribute to phenotypic differences seen among race/ethnicity groups, and differences among GA groups may highlight unique biological determinants that add to our understanding of health care disparities. A retrospective review of patients with renal cell carcinoma (RCC) was performed and correlated GA with clinicopathologic, somatic, and germline molecular data. All patients underwent next-generation sequencing of normal and tumor DNA using Memorial Sloan Kettering-Integrated Mutation Profiling of Actionable Cancer Targets, and contribution of African (AFR), East Asian (EAS), European (EUR), Native American, and South Asian (SAS) ancestry was inferred through supervised ADMIXTURE. Molecular data was compared across GA groups by Fisher exact test and Kruskal-Wallis test. In 953 patients with RCC, the GA distribution was: EUR (78%), AFR (4.9%), EAS (2.5%), SAS (2%), Native American (0.2%), and Admixed (12.2%). GA distribution varied by tumor histology and international metastatic RCC database consortium disease risk status (intermediate-poor: EUR 58%, AFR 88%, EAS 74%, and SAS 73%). Pathogenic/likely pathogenic germline variants in cancer-predisposition genes varied (16% EUR, 23% AFR, 8% EAS, and 0% SAS), and most occurred in CHEK2 in EUR (3.1%) and FH in AFR (15.4%). In patients with clear cell RCC, somatic alteration incidence varied with significant enrichment in BAP1 alterations (EUR 17%, AFR 50%, SAS 29%; p=.01). Comparing AFR and EUR groups within The Cancer Genome Atlas, significant differences were identified in angiogenesis and inflammatory pathways. Differences in clinical and molecular data by GA highlight population-specific variations in patients with RCC. Exploration of both genetic and nongenetic variables remains critical to optimize efforts to overcome health-related disparities.

Global comparative transcriptomes uncover novel and population-specific gene expression in esophageal squamous cell carcinoma

BackgroundEsophageal squamous cell carcinoma (ESCC) has a poor prognosis and is one of the deadliest gastrointestinal malignancies. Despite numerous transcriptomics studies to understand its molecular basis, the impact of population-specific differences on this disease remains unexplored.AimsThis study aimed to investigate the population-specific differences in gene expression patterns among ESCC samples obtained from six distinct global populations, identify differentially expressed genes (DEGs) and their associated pathways, and identify potential biomarkers for ESCC diagnosis and prognosis. In addition, this study deciphers population specific microbial and chemical risk factors in ESCC.MethodsWe compared the gene expression patterns of ESCC samples from six different global populations by analyzing microarray datasets. To identify DEGs, we conducted stringent quality control and employed linear modeling. We cross-compared the resulting DEG lists of each populations along with ESCC ATLAS to identify known and novel DEGs. We performed a survival analysis using The Cancer Genome Atlas Program (TCGA) data to identify potential biomarkers for ESCC diagnosis and prognosis among the novel DEGs. Finally, we performed comparative functional enrichment and toxicogenomic analysis.ResultsHere we report 19 genes with distinct expression patterns among populations, indicating population-specific variations in ESCC. Additionally, we discovered 166 novel DEGs, such as ENDOU, SLCO1B3, KCNS3, IFI35, among others. The survival analysis identified three novel genes (CHRM3, CREG2, H2AC6) critical for ESCC survival. Notably, our findings showed that ECM-related gene ontology terms and pathways were significantly enriched among the DEGs in ESCC. We also found population-specific variations in immune response and microbial infection-related pathways which included genes enriched for HPV, Ameobiosis, Leishmaniosis, and Human Cytomegaloviruses. Our toxicogenomic analysis identified tobacco smoking as the primary risk factor and cisplatin as the main drug chemical interacting with the maximum number of DEGs across populations.ConclusionThis study provides new insights into population-specific differences in gene expression patterns and their associated pathways in ESCC. Our findings suggest that changes in extracellular matrix (ECM) organization may be crucial to the development and progression of this cancer, and that environmental and genetic factors play important roles in the disease. The novel DEGs identified may serve as potential biomarkers for diagnosis, prognosis and treatment.