European Populations Research Articles

First Records of Feather Mites and Haemosporidian Parasites in the Isabelline Wheatear (Oenanthe isabellina) from the Westernmost Part of the Species Breeding Range

Host range expansions are an important factor for shaping the community of associated symbiotic organisms. Birds, as a highly mobile group of animals, are of particular interest to study with respect to the diversity and the distribution of the organisms using them as hosts during such large-scale movements. The Isabelline wheatear (Oenanthe isabellina) is a species with a main breeding area in Asia, which has expanded west, towards the Balkans, since the middle of the last century. We collected feather mites and blood samples for haemosporidian parasites screening from adult and juvenile Isabelline wheatears from the westernmost edge of the species breeding area in western Bulgaria. The feather mite species Alaudicola rosickyi (Černy, 1963), previously found on other wheatear species, was found for the first time on Isabelline wheatears. One species of avian malaria parasites—Plasmodium relictum (Grassi and Feletti, 1891) (lineage SGS1)—represented the first record of a malaria parasite in this host species in Europe. Increasing the sampling in the South European populations of the species will shed light on blood parasite species diversity and will reveal if other feather mite species have followed their host during its breeding range expansion.

Evidence-based data support strategies for the prevention of Hymenoptera venom anaphylaxis.

This review aims to identify phenotypes at-risk of Hymenoptera venom-induced anaphylaxis (HVA), focusing on different perspectives (epidemiological, clinical, and therapeutic) in order to adapt future preventive strategies. HVA remains one of the leading causes of anaphylaxis, with a broad pattern of symptoms. Although most cases occur outside healthcare settings, data indicate a high emergency admission rate due to insect stings. Mortality is often underestimated because of the lack of witnesses and difficulties in recognizing the signs and the culprit. Targeting risk factors could be a clue to improve these statistics and the prognosis of the disease.Potential risk factors for severe HVA in the European population are basal serum tryptase (BST) above 8 μg, mast cell disorders, the absence of skin symptoms, and cardiovascular conditions requiring the use of beta blockers and ACE inhibitors. Identifying these criteria, mainly based on clinical patterns, helps to develop personalized strategies for management and prevention. With a personalized medicine approach, phenotypes must be characterized to adapt to the management of patients suffering from Hymenoptera venom anaphylaxis (HVA), including venom immunotherapy (VIT). In this systematic review, all articles mentioned systemic reactions with heterogeneous severity degrees. Half of those reported grade III-IV systemic reactions (Ring and Messmer). HVA clinical patterns could be worsened by one Hymenoptera sting, a patient's history with mast cell disorders, or cardiovascular diseases. VIT failure was attributed to bee venom extract and monotherapy in two-thirds of publications. Findings stress the difficulty of having uniform epidemiological data on HVA and the lack of financial support in some world regions to support appropriate management of these conditions. Although observing a heterogeneity of data, we were able to identify potential risk factors, in particular for the severe cases. We believe our work will support allergists and health professionals to implement improved personalized management of patients suffering from severe HVA.

European and African-specific plasma protein-QTL and metabolite-QTL analyses identify ancestry-specific T2D effector proteins and metabolites.

Initially focused on the European population, multiple genome-wide association studies (GWAS) of complex diseases, such as type-2 diabetes (T2D), have now extended to other populations. However, to date, few ancestry-matched omics datasets have been generated or further integrated with the disease GWAS to nominate the key genes and/or molecular traits underlying the disease risk loci. In this study, we generated and integrated plasma proteomics and metabolomics with array-based genotype datasets of European (EUR) and African (AFR) ancestries to identify ancestry-specific muti-omics quantitative trait loci (QTLs). We further applied these QTLs to ancestry-stratified T2D risk to pinpoint key proteins and metabolites underlying the disease-associated genetic loci. We nominated five proteins and four metabolites in the European group and one protein and one metabolite in the African group to be part of the molecular pathways of T2D risk in an ancestry-stratified manner. Our study demonstrates the integration of genetic and omic studies of different ancestries can be used to identify distinct effector molecular traits underlying the same disease across diverse populations. Specifically, in the AFR proteomic findings on T2D, we prioritized the protein QSOX2; while in the AFR metabolomic findings, we pinpointed the metabolite GlcNAc sulfate conjugate of C21H34O2 steroid. Neither of these findings overlapped with the corresponding EUR results.

Acceleration of skeletal maturation in Central Europe over the last two decades: insights from two cohorts of healthy children

BackgroundDeviations between the determination of bone age (BA) according to Greulich and Pyle (G&P) and chronological age (CA) are common in Caucasians. Assessing these discrepancies in a population over time requires analysis of large samples and low intra-observer variability in BA estimation, both can be achieved with artificial intelligence-based software. The latest software-based reference curve contrasting the BA determined by G&P to the CA of Central European children dates back over two decades.ObjectiveTo examine whether the reference curve from a historical cohort from the Netherlands (Rotterdam cohort) between BA determined by G&P and CA still applies to a current Central European cohort and derive a current reference curve.Materials and methodsThis retrospective single-center study included 1,653 children and adolescents (aged 3–17 years) who had received a radiograph of the hand following trauma. The G&P BA estimated using artificial intelligence-based software was contrasted with the CA, and the deviations were compared with the Rotterdam cohort.ResultsAmong the participants, the mean absolute error between BA and CA was 0.92 years for girls and 0.97 years for boys. For the ages of 8 years (boys) and 11 years (girls) and upward, the mean deviation was significantly greater in the current cohort than in the Rotterdam cohort. The reference curves of both cohorts also differed significantly from each other (P < 0.001 for both boys and girls).ConclusionThe BA of the current Central European population and that of the curve from the Rotterdam cohort from over two decades ago differ. Whether this effect can be attributed to accelerated bone maturation needs further evaluation.

Teleworking: does it make workers healthier and productive? A cross-sectional study on a Southern European population

BackgroundTeleworking (TW) has recently shifted from a marginal into a common practice. Yet, concerns have been raised regarding potential work-health negative effects, related to the reduced socialization, and extended working hours with computers at home, possibly offset by reduced commuting time or better individual work-life balance. This paper aims at describing the influence of TW on health, well-being, and productivity perceptions, and how this is shaped by TW conditions.MethodsWe collected data from workers of 25 companies that exert their activity in Portugal. Data were completed with a representative sample of workers who regularly participate in surveys (total N = 1,069). We applied an on-line questionnaire from September the 1st 2022 to December the 1st 2022. We performed a simple descriptive analysis of each variable. Then, we analyzed the relationship between TW conditions and self-reported health, and between TW conditions at home and productivity, using logistic regression models.ResultsWe observed a high prevalence of self-perceived health worsening (15.9%), mostly among those with poor TW conditions. Most teleworkers enjoyed favorable TW conditions, despite limited company support. Relevant changes were observed in lifestyle factors, towards more smoking (5.5%), alcohol drinking (4.5%), and worse diet (10.1%). Two thirds reported enhanced productivity. A statistically significant relationship was observed between inadequate TW conditions, health deterioration, and lower productivity. A 6.0% point (pp) increased risk of productivity worsening was observed when employees faced at least one inadequate condition at home (no private working place at home, inadequate heating, artificial light, or absence of well-being at home). The risk of health deterioration increased by 12.9 pp when facing at least one of these inadequate conditions, and by 6.3 under hybrid TW, compared to one or two days of TW.ConclusionsMost teleworkers highlighted a positive perspective about teleworking. Yet, TW conditions are not favorable for all workers, with consequences on health, well-being, and productivity, suggesting that further support is needed for teleworkers to protect their health at home, and reach its maximum benefit.

Evaluating the effect of green tea intake on cardiovascular diseases: A Mendelian randomization study in European and East Asian populations.

Previous research shows that more than 70% of cardiovascular diseases (CVDs) are attributed to modifiable risk factors. Here, we investigated relationship between consumption of green tea in European and East Asian populations and risk of CVDs using Mendelian randomization (MR). Instrumental variables for green tea intake were obtained from genome-wide association studies (GWASs) of 64,949 Europeans and 152,653 East Asians. GWASs for CVDs were derived from UK BioBank and BioBank Japan projects. The main method selected for MR analysis was either the inverse variance weighted (IVW) or Wald ratio, depending on the quantity of single nucleotide polymorphisms. Furthermore, we performed sensitivity analyses to confirm the reliability of the findings. Based on the results of IVW, there is no causal relationship between consumption of green tea and risk of 4 CVDs among Europeans (atrial fibrillation: OR = 1.000, 95% CI: 0.995-1.005, P = .910; heart failure: OR = 1.003, 95% CI: 0.994-1.012, P = .542; ischemic stroke: OR = 1.002, 95% CI: 0.993-1.011, P = .690; coronary artery disease: OR = 1.001, 95% CI: 0.996-1.007, P = .677). Sensitivity analyses and supplementary MR analyses also verify the robustness of the findings. Likewise, there was no correlation between the consumption of green tea and the occurrence of CVDs in East Asians. The consumption of green tea is not associated with a reduced risk of CVDs in populations from Europe and East Asia. This means that those who are trying to reduce their risk of CVDs by drinking more green tea may not benefit from doing so.

Genetic testing in early-onset atrial fibrillation.

Atrial fibrillation (AF) is a globally prevalent cardiac arrhythmia with significant genetic underpinnings, as highlighted by recent large-scale genetic studies. A prominent clinical and genetic overlap exists between AF, heritable ventricular cardiomyopathies, and arrhythmia syndromes, underlining the potential of AF as an early indicator of severe ventricular disease in younger individuals. Indeed, several recent studies have demonstrated meaningful yields of rare pathogenic variants among early-onset AF patients (∼4%-11%), most notably for cardiomyopathy genes in which rare variants are considered clinically actionable. Genetic testing thus presents a promising opportunity to identify monogenetic defects linked to AF and inherited cardiac conditions, such as cardiomyopathy, and may contribute to prognosis and management in early-onset AF patients. A first step towards recognizing this monogenic contribution was taken with the Class IIb recommendation for genetic testing in AF patients aged 45 years or younger by the 2023 American College of Cardiology/American Heart Association guidelines for AF. By identifying pathogenic genetic variants known to underlie inherited cardiomyopathies and arrhythmia syndromes, a personalized care pathway can be developed, encompassing more tailored screening, cascade testing, and potentially genotype-informed prognosis and preventive measures. However, this can only be ensured by frameworks that are developed and supported by all stakeholders. Ambiguity in test results such as variants of uncertain significance remain a major challenge and as many as ∼60% of people with early-onset AF might carry such variants. Patient education (including pretest counselling), training of genetic teams, selection of high-confidence genes, and careful reporting are strategies to mitigate this. Further challenges to implementation include financial barriers, insurability issues, workforce limitations, and the need for standardized definitions in a fast-moving field. Moreover, the prevailing genetic evidence largely rests on European descent populations, underscoring the need for diverse research cohorts and international collaboration. Embracing these challenges and the potential of genetic testing may improve AF care. However, further research-mechanistic, translational, and clinical-is urgently needed.

Metabolic activity of CYP2C19 and CYP2D6 on antidepressant response from 13 clinical studies using genotype imputation: a meta-analysis

Cytochrome P450 enzymes including CYP2C19 and CYP2D6 are important for antidepressant metabolism and polymorphisms of these genes have been determined to predict metabolite levels. Nonetheless, more evidence is needed to understand the impact of genetic variations on antidepressant response. In this study, individual clinical and genetic data from 13 studies of European and East Asian ancestry populations were collected. The antidepressant response was clinically assessed as remission and percentage improvement. Imputed genotype was used to translate genetic polymorphisms to metabolic phenotypes (poor, intermediate, normal, and rapid+ultrarapid) of CYP2C19 and CYP2D6. CYP2D6 structural variants cannot be imputed from genotype data, limiting the determination of metabolic phenotypes, and precluding testing for association with response. The association of CYP2C19 metabolic phenotypes with treatment response was examined using normal metabolizers as the reference. Among 5843 depression patients, a higher remission rate was found in CYP2C19 poor metabolizers compared to normal metabolizers at nominal significance but did not survive after multiple testing correction (OR = 1.46, 95% CI [1.03, 2.06], p = 0.033, heterogeneity I2 = 0%, subgroup difference p = 0.72). No metabolic phenotype was associated with percentage improvement from baseline. After stratifying by antidepressants primarily metabolized by CYP2C19, no association was found between metabolic phenotypes and antidepressant response. Metabolic phenotypes showed differences in frequency, but not effect, between European- and East Asian-ancestry studies. In conclusion, metabolic phenotypes imputed from genetic variants using genotype were not associated with antidepressant response. CYP2C19 poor metabolizers could potentially contribute to antidepressant efficacy with more evidence needed. Sequencing and targeted pharmacogenetic testing, alongside information on side effects, antidepressant dosage, depression measures, and diverse ancestry studies, would more fully capture the influence of metabolic phenotypes.

Genome-wide meta-analysis identifies ancestry-specific loci for Alzheimer's disease.

Alzheimer's disease (AD) is a devastating neurological disease with complex genetic etiology. Yet most known loci have only identified from the late-onset type AD in populations of European ancestry. We performed a two-stage genome-wide association study (GWAS) of AD totaling 6878 Chinese and 63,926 European individuals. In addition to the apolipoprotein E (APOE) locus, our GWAS of two independent Chinese samples uncovered three novel AD susceptibility loci (KIAA2013, SLC52A3, and TCN2) and a novel ancestry-specific variant within EGFR (rs1815157). More replicated variants were observed in the Chinese (31%) than in the European samples (15%). In combining genome-wide associations and functional annotations, EGFR and TCN2 were prioritized as two of the most biologically significant genes. Phenome-wide Mendelian randomization suggests that high mean corpuscular hemoglobin concentration might protect against AD. The current study reveals novel AD susceptibility loci, emphasizes the importance of diverse populations in AD genetic research, and advances our understanding of disease etiology. Loci KIAA2013, SLC52A3, and TCN2 were associated with Alzheimer's disease (AD) in Chinese populations. rs1815157 within the EGFR locus was associated with AD in Chinese populations. The genetic architecture of AD varied between Chinese and European populations. EGFR and TCN2 were prioritized as two of the most biologically significant genes. High mean corpuscular hemoglobin concentrations might have protective effects against AD.

Causal relationship between type 2 diabetes and glioblastoma: bidirectional Mendelian randomization analysis

As the prevalence of Type 2 Diabetes Mellitus (T2DM) and Glioblastoma (GBM) rises globally, the relationship between T2DM and GBM remains controversial. This study aims to investigate whether genetically predicted T2DM is causally associated with GBM. We performed bidirectional Mendelian randomization (MR) analysis using data from genome-wide studies on T2DM (N = 62,892) and GBM (N = 218,792) in European populations. The results of the inverse-variance weighted (IVW) approach served as the primary outcomes. We applied Cochran’s Q test and MR-Egger regression for heterogeneity assessment. Leave-one-out analysis was used to evaluate whether any single SNP significantly influenced the observed effect. Our findings reveal a significant causal association between T2DM and an increased risk of GBM (OR [95% CI] 1.70 [1.09, 2.65], P = 0.019). Conversely, the reverse association between T2DM and GBM was insignificant (OR [95% CI] 1.00 [0.99, 1.01], P = 0.408) (P > 0.40). Furthermore, the results from Cochran’s Q-test and funnel plots in the MR-Egger method indicated no evidence of pleiotropy between the SNPs and GBM. Additionally, we mapped causal SNPs to genes and identified 10 genes, including MACF1, C1orf185, PTGFRN, NOTCH2, ABCB10, GCKR, THADA, RBMS1, SPHKAP, and PPARG, located on chromosomes 1, 2, and 3. These genes are involved in key biological processes such as the BMP signaling pathway and various metabolic pathways relevant to both conditions. This study provides robust evidence of a significant causal relationship between T2DM and an increased risk of GBM. The identified SNP-mapped genes highlight potential biological mechanisms underlying this association.

Clinical and molecular characterization of limb-girdle muscular dystrophy 2G/R7 in a large cohort of Brazilian patients.

Limb-girdle muscular dystrophy type 2G/R7 (LGMD2G/R7) is an ultra-rare condition initially identified within the Brazilian population. We aimed to expand clinical and genetic information about this disease, including its worldwide distribution. A multicenter historical cohort study was performed at 13 centers in Brazil in which data from index cases and their affected relatives from consecutive families with LGMD2G/R7 were reviewed from July 2017 to August 2023. Additionally, a systematic literature review was conducted to identify case reports and series of the disease worldwide. Forty-one LGMD2G/R7 cases were described in the Brazilian cohort, being all subjects homozygous for the c.157C>T/(p.Gln53*) variant in TCAP. Survival curves showed that the median disease duration before individuals required walking aids was 21 years. Notably, women exhibited a slower disease progression, requiring walking aids 13 years later than men. LGMD2G/R7 was frequently reported not only in Brazil but also in China and Bulgaria, with 119 cases identified globally, with possible founder effects in the Brazilian, Eastern European, and Asian populations. These findings are pivotal in raising awareness of LGMD2G/R7, understanding its progression, and identifying potential modifiers. This can significantly contribute to the development of future natural history studies and clinical trials for this disease.

Systematic Review and Meta-Analysis of Lifestyle and Reproductive Factors Associated with Risk of Breast Cancer in Asian Women.

Assessing breast cancer risks from lifestyle and reproductive factors is critical for developing population-specific risk prediction tools. However, limited studies have evaluated these risks in recent Asian birth cohorts. We systematically reviewed articles published from January 2010 to December 2023, examining breast cancer risk factors in Asian women. Data were described narratively, estimates pooled, and prevalence and attributable proportions compared across Asian populations. Of the 128 studies reviewed, 103 reported adjusted effect sizes for meta-analysis. Lifestyle and reproductive factors were predictive of breast cancer risk in Asian women, with varying impacts on premenopausal and postmenopausal women. Relative risks were similar within Asian populations and in comparison to European populations, except for menarche, menopause, and hormone receptor therapy. However, risk factor distributions differed across populations. While alcohol intake (21%) and oral contraceptive use (20%) emerged as the most attributable modifiable risk factors in Europeans, passive smoking (24%) and higher BMI (17%, ≥24 kg/m2 among postmenopausal women) were predominant in Asians. Our study shows that while the effects of lifestyle and reproductive breast cancer risk factors are largely similar across different populations, their distributions vary. Our analysis underscores the importance of considering population-specific risk factor distributions when developing risk prediction tools for Asian populations.

Worldwide distribution of genetic factors related to severity of COVID-19 infection

Background Genome-wide association studies of COVID-19 severity have been carried out mostly on European or East Asian populations with small representation of other world regions. Here we explore the worldwide distribution and linkage disequilibrium (LD) patterns of genetic variants previously associated with COVID-19 severity. Methods We followed up the results of a large Spanish genome-wide meta-analysis on 26 populations from the 1000 Genomes Project by calculating allele frequencies and LD scores of the nine most significant SNPs. We also used the entire set of summary statistics to compute polygenic risk scores (PRSs) and carried out comparisons at the population and continental level. Results We observed the strongest differences among continental regions for the five top SNPs in chromosome 3. European, American, and South Asian populations showed similar LD patterns. Average PRSs in South Asian and American populations were consistently higher than those observed in Europeans. While PRS distributions were similar among South Asians, the American populations showed striking differences among them. Conclusions Considering the caveats of PRS transferability across ethnicities, our analysis showed that American populations present the highest genetic risk score, hence potentially higher propensity, for COVID-19 severity. Independent validation is warranted with additional summary statistics and phenotype data.

Genome-wide meta-analyses of cross substance use disorders in European, African, and Latino ancestry populations.

Genetic risks for substance use disorders (SUDs) are due to both SUD-specific and SUD-shared genes. We performed the largest multivariate analyses to date to search for SUD-shared genes using samples of European (EA), African (AA), and Latino (LA) ancestries. By focusing on variants having cross-SUD and cross-ancestry concordant effects, we identified 45 loci. Through gene-based analyses, gene mapping, and gene prioritization, we identified 250 SUD-shared genes. These genes are highly expressed in amygdala, cortex, hippocampus, hypothalamus, and thalamus, primarily in neuronal cells. Cross-SUD concordant variants explained ~ 50% of the heritability of each SUD in EA. The top 5% individuals having the highest polygenic scores were approximately twice as likely to have SUDs as others in EA and LA. Polygenic scores had higher predictability in females than in males in EA. Using real-world data, we identified five drugs targeting identified SUD-shared genes that may be repurposed to treat SUDs.

Genetic link between KIF1A mutations and amyotrophic lateral sclerosis: evidence from whole-exome sequencing.

Genetics have been shown to have a substantial impact on amyotrophic lateral sclerosis (ALS). The ALS process involves defects in axonal transport and cytoskeletal dynamics. It has been identified that KIF1A, responsible for encoding a kinesin-3 motor protein that carries synaptic vesicles, is considered a genetic predisposing factor for ALS. The analysis of whole-exome sequencing data from 1,068 patients was conducted to examine the genetic link between ALS and KIF1A. For patients with KIF1A gene mutations and a family history, we extended the analysis to their families and reanalyzed them using Sanger sequencing for cosegregation analysis. In our cohort, the KIF1A mutation frequency was 1.31% (14/1,068). Thirteen nonsynonymous variants were detected in 14 ALS patients. Consistent with the connection between KIF1A and ALS, the missense mutation p.A1083T (c.3247G>A) was shown to cosegregate with disease. The mutations related to ALS in our study were primarily located in the cargo-binding region at the C-terminal, as opposed to the mutations of motor domain at the N-terminal of KIF1A which were linked to hereditary peripheral neuropathy and spastic paraplegia. We observed high clinical heterogeneity in ALS patients with missense mutations in the KIF1A gene. KIF5A is a more frequent determinant of ALS in the European population, while KIF1A accounts for a similar proportion of ALS in both the European and Chinese populations. Our investigation revealed that mutations in the C-terminus of KIF1A could increase the risk of ALS, support the pathogenic role of KIF1A in ALS and expand the phenotypic and genetic spectrum of KIF1A-related ALS.

Seasonal and Daily Movement Patterns by Wels Catfish (Silurus glanis) at the Northern Fringe of Its Distribution Range

Fish behavior often varies across a species’ distribution range. Documenting how behaviors vary at fringes in comparison to core habitats is key to understanding the impact of environmental variation and the evolution of local adaptations. Here, we studied the behavior of Wels catfish (Silurus glanis) in Lake Möckeln, Sweden, which represent a European northern fringe population. Adult individuals (101–195 cm, N = 55) were caught and externally marked with data storage tags (DSTs). Fifteen DSTs were recovered a year after tagging, of which 11 tags contained long-term high-resolution behavioral data on the use of vertical (depth) and thermal habitats. This showed that the catfish already became active in late winter (&lt;5 °C) and displayed nocturnal activity primarily during summer and late autumn. The latter included a transition from the bottom to the surface layer at dusk, continuous and high activity close to the surface during the night, and then descent back to deeper water at dawn. During the daytime, the catfish were mainly inactive in the bottom layer. These behaviors contrast with what is documented in conspecifics from the core distribution area, perhaps reflecting adaptive strategies to cope with lower temperatures and shorter summers.

Genetic variability of Roma population in Serbia: The perspective from autosomal STR markers.

Genetic variability of Roma population was shaped by the strong influence of genetic drift and gene flow during the migrations from their ancestral homeland in Indian subcontinent towards Europe. In addition, social stigmatization in many European countries, as a consequence of different cultural heritage and social practices, induced further genetic differentiation and sub structuring within the population. Although many populations genetic studies on European Roma were carried out, the genetic structure of the Serbian Roma has not been described yet, since only the modest number of individuals from this territory was analyzed. The main aim of this study was the characterization of genetic variability of the Roma and the assessment of intrapopulation genetic differentiation based on the analysis of 21 autosomal STR loci of 259 self-identified unrelated individuals from Serbia. Intrapopulation analysis revealed divergence of Roma groups illustrating the effect of the historical events after their arrival on Balkan Peninsula and emphasizing significance of the religious affiliation on admixture with autochthonous population. Genetic distance analysis showed the greatest similarity of the studied population with the Middle Eastern populations, while South Asian and European population were more distant. Our results demonstrate that Roma groups in this region of Balkan Peninsula do not represent completely isolated, but rather admixed populations with different proportion of gene flow with other Roma and non-Roma groups.

NK Cytotoxicity Mediated by NK-92 Cell Lines Expressing Combinations of Two Allelic Variants for FCGR3.

Natural killer (NK) cells play an important role in the surveillance of viral infections and cancer. NK cell antibody-dependent cellular cytotoxicity (ADCC) and direct cytotoxicity are mediated by the recognition of antibody-coated target cells through the Fc gamma receptor IIIA (FcγRIIIa/CD16) and by ligands of activating/inhibitory NK receptors, respectively. Allelic variants of the FCGR3A gene include the high-affinity single-nucleotide polymorphism (SNP) rs396991 (V176F), which is associated with the efficacy of monoclonal antibody (mAb) therapies, and the SNP rs10127939 (L66H/R). The contribution of FCGR3A SNPs to NK cell effector functions remains controversial; therefore, we generated a panel of eight NK-92 cell lines expressing specific combinations of these SNPs and tested their cytotoxicities. NK-92 cells were stably transfected with plasmids containing different combinations of FCGR3A SNPs. Messenger RNA and FcγRIIIa/CD16 cell surface expressions were detected using new generation sequencing (NGS) and flow cytometry, respectively. All FcγRIIIa/CD16-transfected NK-92 cell lines exhibited robust ADCC against three different target cell lines with minor differences. In addition, enhanced direct NK cytotoxicity against K562 target cells was observed, suggesting a mechanistic role of FcγRIIIa/CD16 in direct NK cytotoxicity. In conclusion, we generated eight FcγRIIIa/CD16-transfected NK-92 cell lines carrying different combinations of two of the most studied FCGR3A SNPs, representing the major genotypes described in the European population. The functional characterization of these cell lines revealed differences in ADCC and direct NK cytotoxicity that may have implications for the design of adoptive cancer immunotherapies using NK cells and tumor antigen-directed mAbs.

Causal Effects and Immune Cell Mediators of Prescription Analgesic Use and Risk of Liver Cancer and Precancerosis in European Population: A Mendelian Randomization Study.

Diverse clinical observations and basic studies have been conducted to explore the implications of analgesic medications in liver diseases. However, the direct causal relationship between prescription analgesic use (PAU) and the risk of liver cancer and precancerosis remains unclear. Thus, we aimed to reveal the conceivable causal effect of PAU on liver cancer and precancerosis, with immune cells as mediating factors. Two-sample Mendelian randomization (MR) analyses were performed to ascertain the causality of PAU on liver cancer and precancerosis. Sensitivity analysis approaches were employed to assess the heterogeneity and pleiotropy of results. Our findings revealed a causal correlation between different PAUs and the risk of liver cancer and alcoholic liver disease (ALD). Specifically, salicylic acid derivatives (SADs) and anilide medications were found to have a protective effect on liver cancer. And non-steroidal anti-inflammatory drugs (NSAIDs) and anilide medications showed a causal impact on ALD. Finally, mediation analyses found that anilide medications influence liver cancer through different immune cell phenotypes. Our research provides new genetic evidence for the causal impact of PAU on liver cancer and precancerosis, with the mediating role of immune cells demonstrated, offering a valuable foundation for researching analgesic medications in liver cancer and precancerosis treatment.

Evaluation of the associations of interlukin-7 genetic variants with toxicity and efficacy of immune checkpoint inhibitors: A replication study of a Japanese population, based on the findings of a European genome-wide association study.

Recent genome-wide association studies of European populations have identified rs16906115, a single-nucleotide polymorphism in the interleukin-7 gene, as a predictor of immune-related adverse events (irAEs) and the therapeutic efficacy of immune checkpoint inhibitors. We evaluated this single-nucleotide polymorphism in a Japanese population. From January 2021, we stored host DNA from individuals who received various types of immune checkpoint inhibitors. From this population, we categorized 510 participants into cases (grade ≥2 irAEs) and controls (received ≥3 immune checkpoint inhibitor doses, follow-up ≥12weeks, no irAEs), and divided 339 hepatocellular carcinoma patients treated with atezolizumab/bevacizumab into responders and non-responders, evaluated using the modified response evaluation criteria in solid tumors. We compared the minor allele frequencies of rs16906115 between cases and controls, and responders and non-responders. In the irAE prediction analysis of 234 cases and 276 controls, the minor allele frequency was 0.244 in the case group and 0.265 in the control group. This difference is not significant. In the analysis predicting the therapeutic efficacy for hepatocellular carcinoma patients, the responders had a significantly lower minor allele frequency of 0.220, compared with 0.300 for the non-responders (p=0.022). Univariate and multivariate analyses identified the minor allele homozygosity as a significant predictor of treatment response, with odds ratios of 0.292 (p=0.015) in the univariate analysis and 0.315 (p=0.023) in the multivariate analysis. In our Japanese cohort, no association was found between the rs16906115 minor allele and irAEs or treatment efficacy. The minor allele homozygosity may be associated with a negative therapeutic outcome. UMIN Clinical Trials Registry with the number UMIN000043798.