Host genetic ancestry plays an important role in shaping somatic mutation landscapes and may influence therapeutic outcomes as well as the risk of developing treatment-related adverse events. As genetic ancestry has been associated with differential susceptibility to melanoma subtypes, distinct somatic mutation frequencies and variable responses to immune checkpoint inhibitors warrant further investigation. This study investigated the genetic ancestry of a North American melanoma population using banked biospecimens from 744 patients enrolled in the ECOG-ACRIN E1609 phase III clinical trial (stages IIIB, IIIC, M1a, or M1b). Peripheral blood samples were genotyped using the Illumina Infinium Global Screening Array v3.0 + Multi-Disease BeadChip, followed by quality control, integration with reference dataset, and linkage disequilibrium pruning (198 064 single nucleotide polymorphisms). Dimensionality reduction was performed with Uniform Manifold Approximation and Projection analysis, and genetic ancestry was inferred using unsupervised ADMIXTURE models. Most patients (728 of 744; 97.8%) had predominant European (EUR) ancestry, followed by minor representation from admixed American (12 of 744; 1.6%) and East Asian (4 of 744; 0.5%) populations. Moreover, based on ADMIXTURE model ( K = 5), 96.9% of participants had an estimated EUR ancestry proportion exceeding 80%. Self-reported race and ethnicity demonstrated strong concordance with genetically inferred ancestry, although a small subset of participants exhibited discordant ancestry components. Participants who self-identified as Hispanic exhibited mixed EUR-Admixed American ancestry components. Most patients represented predominant EUR ancestry, with limited representation of non-EUR populations. Integrating ancestry-informed genomic analyses will enhance understanding of melanoma susceptibility, improve prediction of immune-related adverse events, and support the development of tailored immunotherapy strategies.

Hypertension is an important target for primordial prevention of complex, noncommunicable diseases, and its prevalence remains high across populations. The urban population in India is at a high risk of hypertension, but the genetic basis of hypertension in this population remains poorly understood. We conducted a pooled whole-blood genome-wide association study of 28 pools representing 1402 participants of the Diabetes In Sindhi Families In Nagpur (DISFIN) study, which enrolled families of probands with type 2 diabetes (T2D). Genotyping was done using Illumina's Global Screening Array. From a total of 608,550 single-nucleotide variants, 191 were found to be significantly associated with hypertension even after adjusting for metabolic comorbidities, batch effects, pooling error, kinship status, and pooling variation. These variants mapped to 180 well-characterized genes comprising 55 (31%) genes, and encode long noncoding RNAs (lncRNAs). Many of the genes significantly associated with hypertension (including 35% of the lncRNAs) have also been reported by other studies. However, we identified novel genes (SBF2, ARHGAP12, EPAS1, CLEC16A, and LRPPRC) to be associated with hypertension. The most significantly associated lncRNA gene was FLYWCH-AS1. Bioinformatic analyses indicated that these novel genes are likely to have functional importance in hypertension. Our study thus points to the potential candidate genes associated with hypertension in endogamous Sindhi families with T2D patients. The replicable and functional role of these candidate genes should be investigated in future studies.

Muscle strength decline is a hallmark of aging and contributes to frailty and bone deterioration, yet the genomic and epigenomic mechanisms predicting functional strength remain unclear. We applied a multiomics approach to identify genetic and epigenetic signatures of muscle strength variability in postmenopausal women. A total of 141 women aged 50-70 yr underwent functional tests, biochemical analysis, anthropometry, blood pressure assessment, and dual-energy X-ray absorptiometry. Participants were classified into higher- and lower-strength groups based on validated upper and lower limb tests. Genome-wide genotyping was performed with the Illumina Global Screening Array, and DNA methylation was measured using the Illumina EPIC 850 K array. A polygenic risk score (PRS) was generated in a training cohort (n = 100) and validated in an independent group (n = 41). Epigenetic scores (EpiScores) were calculated using MethylDetectR, and four fitness-related epigenetic clocks (DNAmGrip, DNAmGait, DNAmVO2max, and DNAmFitAge) were derived with the methylclock package. Twelve single-nucleotide polymorphisms (SNPs) were associated with strength phenotypes, and the PRS predicted group classification with 51.2% accuracy. Epigenetic analysis revealed 12 differentially methylated regions, including higher bone morphogenetic protein 1 (BMP1) EpiScore levels in women with greater strength. Functional enrichment indicated pathways related to bone remodeling and vascular regulation. In the lower strength group, BMP1 EpiScore correlated inversely with femoral neck T-score (r = -0.66, P = 0.037). A meta-analysis of public muscle transcriptomes showed that resistance training increases BMP1 expression. These findings highlight molecular mechanisms linking genetic and epigenetic variation to musculoskeletal aging and functional decline in postmenopausal women.NEW & NOTEWORTHY This study integrates genome-wide genotyping, DNA methylation, and transcriptomic validation to reveal genetic and epigenetic determinants of muscle strength in postmenopausal women. We identify novel SNPs, a predictive polygenic risk score, and higher BMP1 epigenetic scores linked to greater muscle strength and bone remodeling pathways. These multiomics insights provide potential biomarkers for musculoskeletal aging and targets for strategies to preserve strength and skeletal health in older women.

Childhood obesity is a major global public-health challenge. Insulin resistance (IR) is a critical driver of later cardiometabolic alterations. A comprehensive understanding of the molecular mechanisms underlying the initial development of childhood IR is essential for timely prevention and intervention. In this study, we aimed to assess the association between IR and blood DNA methylation in a longitudinal study from childhood into adolescence. The PUBMEP study included a longitudinal core of 90 children with paired blood samples collected at both pre-pubertal and pubertal stages. For cross-sectional analyses, this sample was expanded to 99 pre-pubertal and 129 pubertal participants. IR status was defined according to clinically relevant sex- and pubertal stage specific HOMA-IR cut-offs, as recommended by pediatric expert clinicians. Genotype data was obtained with the Infinium Global Screening Array, and blood DNA methylation sites with the Infinium MethylationEPIC BeadChip. Epigenome-wide associations with IR status and trajectories were tested using linear models in the longitudinal and cross-sectional sets. FDR-adjusted significant CpG sites were assessed with sex- and age-standardised cardiometabolic z-scores (adiposity, lipids, blood pressure, glycaemia and IR) at each stage. mQTL analyses were performed to identify genetic variants that drive IR-associated methylation signals. We identified 120 CpG sites related to obesity-associated IR in the context of pubertal transition that remained significant after global FDR correction (FDR < 0.05). These CpG sites showed distinct methylation profiles that tracked IR trajectories from prepuberty to puberty, with consistent differences across children whose IR improved, worsened or remained stable, with several of them also related to cardiometabolic traits at pubertal stage, including adiposity measures, blood pressure and glycaemic indices. Among the FDR-significant CpG sites with biological relevance for IR, methylation at CpG sites annotated to SLC2A9, PEPD, TSC2, EGLN3, EHD2 and VASN showed consistent associations with pubertal HOMA-IR z-score and, for several loci, with adiposity and blood pressure measures, with methylation changes paralleling IR worsening, improvement or stability across puberty. An mQTL look-up in GoDMC identified 25 cis SNP CpG associations corresponding to 20 of the 120 CpG sites, including CpG sites in SLC2A9 and TSC2, indicating that only a fraction of these IR-associated CpG sites is likely to be partly influenced by nearby genetic variants. This longitudinal EWAS in children with obesity shows that specific blood DNA methylation signatures mirror IR status and track its evolution across the pubertal transition, with opposing methylation trajectories distinguishing improving from persistent IR. The identification of CpG sites at VASN, SLC2A9, PEPD, EGLN3, EHD2 and TSC2 links IR trajectories to pathways involved in vascular signalling, urate transport, extracellular matrix remodelling, and hypoxia sensing and nutrient signalling. Complementary mQTL analyses suggest that while some of this epigenetic variation is influenced by local genetic factors, a substantial component is likely acquired in response to metabolic and external exposures. If replicated and functionally characterised, these findings may help refine our understanding of the early molecular architecture of obesity-related IR and inform future strategies for cardiometabolic risk assessment and timing of preventive interventions.

Development and validation of a capture sequencing panel containing 9000 SNPs for inferring distant relatives in East Asian populations.

Abstract Background Crohn’s Disease (CD) is characterized by a chronic, relapsing inflammation of the intestine of unknown cause. The current hypothesis is that microbial or environmental factors induce gut inflammation in genetically susceptible individuals, leading to chronic intestinal inflammation. The association between CD genetic risk and the gut microbiome as it relates to risk of CD development remains unclear. Aims To investigate whether CD polygenic risk score (PRS) can predict CD onset and whether host genetic susceptibility to CD is associated with alterations in gut microbiome in first-degree relatives (FDRs). Methods Stool samples and clinical metadata were collected from 2753 healthy FDRs of CD patients in the GEM cohort. Host genotype was measured using Immunochip, Exomechip and the Illumina Global Screening Array chip and imputed using the TOPMed Imputation Server. A CD-polygenic risk score (PRS) was derived based on previous IBD GWAS summary statistics. Subjects were stratified into quartiles (Q1-Q4) based on their PRS, with Q4 representing the highest PRS. 16S rRNA gene amplicon sequencing was performed to determine the relative abundance of genus-level taxa using the DADA2 pipeline. Fecal calprotectin (FCP) was measured by ELISA. Results Among 2753 healthy FDRs, 78 developed CD during a median of 3.4 years from recruitment. Subjects in Q4 of the CD-PRS were more likely to develop CD than those in Q1: HR = 3.76 (95% CI: 1.73-8.17, p = 0.001). After adjusting for FCP, the increased risk remained significant for Q4 vs Q1 (HR = 2.23, 95% CI: 1.01-4.95, p = 0.048). No significant difference in Shannon alpha diversity was observed across PRS quartiles (p = 0.155). PERMANOVA indicated that PRS explained only 0.13% of beta diversity variation. CD PRS was associated with lower prevalence of Izemoplasmatales, and Oscillospiraceae pseudoflavonifractor, Peptococcaceae uncultured, Lachnospiraceae roseburia, Ruminococcaceae, Oscillospiraceae UCG-005, and Oscillospiraceae UCG-003 and higher prevalence of Carnobacteriaceae granulicatella (q &amp;lt; 0.05). None of the taxa significantly modified or mediated the relationship between PRS and CD risk. Conclusions CD-PRS is significantly associated with increased risk of CD among FDRs, but not with gut microbial alpha or beta diversity. While certain individual taxa are associated with higher PRS, there was no evidence of interaction or mediating effect of the gut microbiome with PRS on CD risk. Funding Agencies CCC, CIHRHelmsley Charitable Trust

ABSTRACTBackgroundHypomorphic variants of sucrase‐isomaltase (SI) have been associated with irritable bowel syndrome (IBS) in adults, but how their presence influences therapeutic outcomes is uncertain.AimsTo investigate the frequency of sucrase‐isomaltase hypomorphic variants in patients with IBS and their association with short‐ and long‐term outcomes after initiation of a FODMAP diet.MethodsClinical outcomes in patients with IBS were retrospectively examined at mean 7.1 (range 2.5–13.4) years after being educated on a FODMAP diet by a gastrointestinal dietitian and their current food intake (Comprehensive Nutrition Assessment Questionnaire) and gastrointestinal symptoms were documented at interview. DNA extracted from whole blood samples was analysed with the Illumina Global Screening Array for sucrase‐isomaltase hypomorphic variants.ResultsOf 72 participants (62% female, median age 59 years), 54% had at least one hypomorphic variant of which 85% were single‐carriers. On adjusted binary logistic regression analysis, no differences were noted across SI hypomorphic genotypic groups for retrospective analysis of initial response to a FODMAP diet or long‐term symptom control. Current dietary intakes of sucrose or starch were not different between non‐carriers and carriers, were directly related to FODMAP intake and did not differ in carriers according to adequacy of symptom control. Findings in those with diarrhoea‐predominant IBS (n = 29) were similar to the those in the whole group. Too few double‐carriers (n = 6) precluded the definition of associations.ConclusionsThe presence of single sucrase‐isomaltase hypomorphic variants is common but was not associated with short‐ or long‐term outcomes or dietary intake for patients with IBS who were taught a FODMAP diet.

Hair cortisol concentration (HCC) reflects long-term hypothalamic–pituitary–adrenal (HPA) axis activity and is a biomarker of chronic stress. Although HCC has been linked to mental health, less is known about how genetic susceptibility and early adversity jointly influence cortisol regulation, particularly in low- and middle-income countries (LMICs). This study examined whether harsh parenting predicts adolescent HCC and whether this association is moderated by genetic variation. Data were drawn from 1,823 participants in the 2004 Pelotas (Brazil) Birth Cohort, followed at ages 6, 11, and 15. Genetic data were obtained using the Illumina Global Screening Array v2, and HCC was measured at age 15 using ELISA. Harsh parenting was assessed using the Conflict Tactics Scales: Parent–Child Version, and cumulative exposure was analyzed using linear regression models. Gene-by-environment interaction analyses tested whether rs11621961 moderated the association between harsh parenting and HCC. Greater cumulative exposure to harsh parenting, particularly overall harsh parenting and corporal punishment, was associated with higher HCC at age 15. Evidence of G × E interaction indicated stronger associations among individuals carrying more copies of the T allele, suggesting a gene-dosage effect. These findings highlight how genetic susceptibility may amplify the physiological consequences of early-life stress in LMIC settings.

BackgroundAt present, there is no consensus on which genotyping platform should serve as the standard for clinical polygenic risk score (PRS) implementation. Previous studies have compared the overall performance and concordance of different genotyping and sequencing technologies; however, these analyses have generally averaged the results over the whole genome. We evaluated differences in a 313-variant breast cancer PRS (PRS313) across genomic platforms and their impact on risk stratification.MethodsWe compare PRS313 derived from genotyping arrays (Global Screening Array [GSA], OncoArray-500K [OncoArray], Global Diversity Array [GDA], custom Axiom_PrecipV1 array [ThermoFisher]) and low-coverage genome sequencing (lc-WGS) in 2 cell lines and 92 individuals. Probes are designed for all variants on ThermoFisher (success rate: 259/313). Sanger sequencing profiles indels. Concordance of high-risk classification (PRS313scoresum > 0.6) across platforms is assessed using Kappa statistics.ResultsIn saliva samples, indel concordance with Sanger sequencing varies widely (Kappa: 0.007-1.000). PRS313-ThermoFisher is predictable from other platforms using linear models, despite systematic differences. Greater agreement is observed between arrays with high imputation overlap (e.g., GDA ~ GSA slope=0.986). Agreement in high-risk classification before mean correction is moderate (Fleiss’s Kappa=0.552) and improves after mean correction (Kappa=0.650). Arrays with similar designs show higher agreement before mean correction (Kappa=0.745). Mean correction narrows high-risk proportions from 4-45% to 15-21%. Overall, 26 of 92 samples are classified as high risk on at least one platform, but only 7 are high risk across all. When restricting to identical variants across all platforms for PRS313 calculation, the corresponding number of high-risk individuals are 24 and 11.ConclusionOur findings demonstrate that platform-specific variability can influence PRS313 estimates to potentially reclassify individuals around clinically relevant thresholds.

Pharmacogenomics enables treatments to be tailored to individual genetic profiles, optimizing efficacy while reducing adverse effects. The Clinical Pharmacogenetics Implementation Consortium (CPIC) classifies gene-drug pairs by their level of evidence. Level A and B pairs are considered actionable, indicating that prescribers should (A) or could (B) modify therapy. This cross-sectional study aimed to assess the prevalence of actionable CPIC variants in the Montreal Heart Institute (MHI) Hospital Cohort. Genotyping was performed at the MHI Beaulieu-Saucier Pharmacogenomics Center using Agena's MassARRAY and Illumina's Global Screening Array. Genes ABCG2, CYP2B6, CYP2C9, CYP2C19, CYP2D6, CYP3A5, CYP4F2, DPYD, HLA-A, HLA-B, SLCO1B1, TPMT, UGT1A1, and VKORC1 were analyzed in 10,082 participants. Participants had an average of 3.9 genes with actionable variants, and among the full cohort, 99.7% carried at least one actionable variant. Of the 65 CPIC level A or B gene-drug pairs evaluated, 57 involved medications used by at least one participant. Nearly 40% of participants had at least one actionable gene-drug pair - that is, they were taking a medication for which they carried an actionable variant. This study confirms the high prevalence of actionable genetic variants in individuals with or at high risk of cardiovascular diseases.

BackgroundThe APOE ε4 polymorphism is the most well‐established genetic risk factor for sporadic Alzheimer's disease (AD). Although the underlying mechanisms remain unclear, AD has well‐documented environmental and genetic risk factors, suggesting an interplay that may involve epigenetic processes such as DNA methylation. We propose that DNA methylation occurs in an APOE allele‐specific manner, serving as a pathway through which genotype drives downstream physiological changes and disease development.MethodsThis research utilized pre‐existing data from over 2,300 extensively characterized pre‐frontal cortex post‐mortem brain samples, collected from various cohorts (as described in PMID: 34112773). APOE genotype for each sample was either directly assessed or imputed from genotyping data generated using the Infinium Global Screening Array. DNA methylation profiles were obtained using Illumina 450K or EPIC arrays, with consistent, stringent quality control and data normalization procedures implemented to ensure consistency and reliability. An epigenome‐wide association study was conducted to examine the influence of APOE genotype on genome‐wide DNA methylation patterns, accounting for AD pathology and other confounders including age, sex, post‐mortem interval and cell proportions.ResultsOur findings reveal distinct DNA methylation differences among APOE allele groups, suggesting a possible epigenetic mechanism through which APOE ε4 influences gene regulation.ConclusionThis extensive analysis underscores the role of DNA methylation as a potential mediator of genetic vulnerability to AD in the context of APOE, supporting further exploration into its contribution to disease progression.

BackgroundThe DAWN Alzheimer's Research Study is a multi‐site international project to recruit African‐American, Hispanic/Latino, and African participants for genomic studies of Alzheimer's Disease (AD). In addition to clinical evaluations, cognitive assessments and biomarker data collection, array‐based representative genotyping is being performed for all participants. To increase the value of these genotypic data a vastly richer dataset can be created using imputation, a process that requires a whole genome sequenced reference dataset. High quality imputation depends on having large reference datasets representative of the ancestries of the target dataset. Using inadequate reference datasets results in low imputation quality, fewer usable imputed variants and hinders downstream analysis. Given the inclusion of African‐ancestry participants (whose reference datasets are small) in the DAWN study, we examined the impact of using different strategies on the accuracy of genotype imputation.MethodUsing DAWN study data generated by the Illumina Global Screening Array, we performed genotype imputation using the TopMED R3 dataset and compared these results to a meta‐imputation workflow using TopMED R3 supplemented by the Africa 6K dataset. This comparison explicitly tests the impact of increasing African ancestry in the imputation reference panel. Imputation results were assessed for chromosomes 1, 10, and 20 for total count of imputed variants, and by comparing variant counts across a range of imputation quality (R2) and variant rarity (MAF) filter criteria to identify apparent trends.ResultAn additional 190,784 (0.3%) variants are captured from the meta‐imputed (64,370,296) vs the single‐imputed (64,179,512) dataset. Variant quality also improves, with an increase of ∼80,000 (5%) filter‐passing variants (R2 > 0.8) in the meta‐imputation compared to the TopMED‐only imputation results (Figure 1).ConclusionThe use of meta‐imputation to better match the genetic background of the DAWN dataset through the use of multiple imputation references significantly increases the density and quality of the resulting genotypic dataset, enabling more powerful studies of AD genetics. This demonstrates the utility of meta‐imputation for better matching the genetic background of samples when performing imputation.

Neuropathic pain is a complex chronic condition with a multifactorial etiology that includes genetic susceptibility. However, the genetic basis of neuropathic pain remains poorly understood. We aimed to investigate genetic variants associated with the presence and intensity of neuropathic pain using genome-wide association analyses in the GeNeuP cohort, comprised of 1146 deeply phenotyped individuals with peripheral neuropathy from Norway. Genotyping was performed using the Illumina Global Screening Array, and analyses were conducted to test associations with the presence and intensity of neuropathic pain. No significant associations were detected at the genome-wide significance level ( P < 5 × 10 -8 ) for either the presence or intensity of neuropathic pain. However, at the subthreshold level ( P < 10 -6 ), 3 single nucleotide polymorphisms (annotated to the CHRDL1 and MCF2L gene and a long non-coding RNA) were associated with intensity of neuropathic pain. A targeted candidate gene analysis of 163 genes previously implicated in neuropathic pain and neuropathy did not yield significant associations. These results highlight the complexity of the genetic architecture underlying neuropathic pain and the challenges in identifying common variants with detectable effects. The identification of subthreshold associations of genes involved in synaptic plasticity is intriguing and merits further investigation. Larger studies with refined phenotyping will be essential to validate these signals and to advance understanding of the genetic contributors to neuropathic pain.

BackgroundMaternal self-reported ethnicity (SRE) is associated with pre-eclampsia (PE) risk and is included in prediction models.ObjectivesThe objectives of the study were to examine whether genetic ancestry estimates are associated with PE and improve the FMF (Fetal Medicine Foundation) PE risk model performance.MethodsPE cases and matched controls from the Harris-Birthright Cohort were genotyped using the Illumina Global Screening Array. Genetic ancestries were estimated using a multiethnic reference panel. African genetic ancestries were incorporated into logistic regression models alongside established clinical risk factors. Area under receiver operating characteristic curves of FMF models with and without genetic ancestries was compared.ResultsThis case-control study included 5,207 women: 3,513 White (1,382 PE cases, 2,131 controls) and 1,694 Black SRE (745 PE cases, 949 controls). Ethnicity-ancestry discrepancy was present in 11.3% of self-reporting Black and 5.3% of self-reporting White individuals. Higher West African genetic ancestry was independently associated with increased PE odds. Among self-reporting White women, those with 50% to 100% West African (AFR) ancestry had higher risk vs those with <5% (adjusted OR: 6.46; 95% CI: 3.37 to 12.98; P < 0.001). In self-reporting Black women, lower West AFR ancestry (50% to 84.9%) reduced risk vs those with 85% to 100% (adjusted OR: 0.60; 95% CI: 0.45-0.80; P < 0.001). Incorporating genetic ancestry did not improve FMF model performance.ConclusionsSRE imperfectly represents genetic ancestry in multiethnic populations. West AFR ancestry independently associates with the PE risk, supporting biological relevance of ancestry-based stratification. However, genetic ancestry did not improve the gold-standard clinical prediction model performance. Large genomic studies in multiethnic cohorts are needed to delineate the genetic architecture of PE.

PROK1 locus variant identified as a genetic determinant of anthracycline-related cardiomyopathy in long-term childhood acute leukemia survivors

Abstract Description Anti-nuclear autoantibodies (ANA) appear years before SLE classification, however, most healthy ANA+ individuals will never develop clinical illness. We sought to identify molecular profiles driving transitions during preclinical autoimmunity development. Proteomic and transcriptomic profiles for 67 subjects (ANA-, ANA+, ILE; SLE) were assessed, respectively; using Olink Explore HT and CITE-Seq. Signatures specific for disease progression were identified using logistic regression and machine learning models, adjusting for age and genetic ancestry. Subjects were genotyped using the Infinium Global Screening Array. Mitochondrial and intracellular sensing proteins such as MAVS, TAX1BP1, RIGI, ITCH, TRAF3 highly correlated (r2 &amp;gt;0.8) with innate cytokine IL1B in early stages of disease progression, and are associated with Memory T, Th2 (p = 0.02), and Activated B cells (p = 0.005). Moreover, Th2 frequencies are increased in ANA+ and ILE (q = 0.02). In ANA+ individuals, inference of gene regulatory networks revealed increased interactions between pattern recognition proteins driven by MAVS. Additionally, we found alleles in ubiquitin pathway members correlated with altered expression of UBXN2B and TRIM25 in ANA+ and ILE individuals. Those findings are potentially associated with dysregulation of mitophagy in cell type and state specific manner. Identified signatures specific to ANA+ individuals suggest alterations in immune response regulation during early stages of disease development. Funding Sources ADAPTS U01AI176244, MONA LISA U01AI176135, UMAI144292, ORDRCC AR073750, OSCTR GM104938 Topic Categories Computational and Systems Immunology (COMP)

Abstract Disclosure: E.M. Bomberg: Novo Nordisk. L.G. Spector: None. A. Raduski: None. Z. Lu: None. C. Im: None. T.M. Jenkins: None. T.H. Inge: Standard Bariatrics, Teleflex, Medtronic, Mediflix, Independent Medical Expert Consulting Services, Wolters Kluwer (UpToDate). J.R. Ryder: Boehringer Ingelheim, Eli Lilly &amp; Company, Recordati, Calorify. Background: Body mass index (BMI) reductions following metabolic/bariatric surgery (MBS) are highly variable. We sought to evaluate if genetic risk for obesity, as determined by a BMI genetic risk score (GRS), is associated with 6- and 12-month weight loss response after MBS (vertical sleeve gastrectomy, roux-en-Y gastric bypass) among adolescents with obesity enrolled in Teen Longitudinal Assessment of Bariatric Surgery (Teen LABS; NCT00474318). We secondarily sought to determine if a BMI GRS might help differentiate 10-year non-responders with responders. Methods: We included adolescents who underwent MBS and had 6-month outcomes available (e.g., BMI), and limited analyses to those of European ancestry given a lack of available multi-ancestry BMI GRS. Genotyping was performed using an InfiniumTM Global Screening Array. A BMI GRS was constructed for each participant based on ∼2.1 million genetic variants (Khera et al., Cell, 2019). We used linear regression to analyze associations between a BMI GRS and 6- and 12-month BMI and weight change, and logistic regression to compare 10-year responders to non-responders (higher versus lower %BMI change) as determined by latent class analyses (LCA). We performed sensitivity analyses with participants categorized into BMI GRS quartiles (lowest to highest). Models were adjusted for baseline BMI/weight (as appropriate), age, sex, and 15 principal ancestry components. Results: Among 128 adolescents (73% female, mean age 17.2 ± 2.0 years and baseline BMI 51.6 ± 1.6 kg/m2; BMI GRS range -1.70 to 2.42), mean 6- and 12-month (n=121) BMI reductions were 13.6 ± 4.0 and 16.6 ± 5.7 kg/m2, respectively. A 1-unit increase in the BMI GRS was associated with a statistically significantly 5.85 kg higher baseline weight (p=0.045); however, it was not statistically significantly associated with baseline BMI (p=0.135). A 1-unit increase in BMI GRS was associated with a 0.76 kg/m2 greater 6-month BMI reduction (p=0.030); however, not with 12-month BMI change. LCA identified 4 distinct response trajectory categories based on 10-year %BMI change: (1; worst response) +1.7 ± 19.0%, (2) -10.1 ± 9.5%, (3) -29.0 ± 10.9%, and (4; best response) -48.5 ± 7.6%. The BMI GRS was not statistically significantly different between 10-year non-responders (categories 1-2; n=71) and responders (categories 3-4; n=57). When assessing response by BMI GRS quartile, compared to those in the lowest BMI GRS quartile those in the highest quartile had a 1.93 kg/m2 (3.56%) greater 6-month BMI reduction (p=0.026); however, no other statistically significant associations were found. Conclusion: Following MBS, a higher BMI GRS was associated with greater 6-month, however not 12-month, BMI reduction, and a BMI GRS did not significantly differentiate 10-year non-responders with responders. Further research is needed to elucidate potential predictors of response to MBS in adolescents with obesity. Presentation: Sunday, July 13, 2025

BackgroundImmune tolerance induction (ITI) is the only treatment to eradicate inhibitors in people with severe hemophilia A (SHA). Successful ITI restores factor VIII (FVIII) tolerance. ITI is demanding and successful in approximately 70% of people.ObjectivesIdentifying predictors of ITI outcome is essential to guide clinical decision making. We aimed to identify genetic predictors of ITI success in people with SHA and inhibitors who underwent ITI.MethodsThis observational multicenter study included people with SHA who underwent ITI, between 2015 and 2023. Clinical and patient data, including FVIII gene (F8) mutation type, and DNA samples were collected. Successful ITI was defined by a negative inhibitor titer and an adequate response to FVIII concentrates. By employing a global screening array, the associations between ITI success and F8 genotype and 216 candidate predictors, including single nucleotide polymorphisms and human leukocyte antigen variants, CA dinucleotide short tandem repeat polymorphisms in the IL10 promoter region, and FCGR2/3 gene locus variations, were analyzed.ResultsOf 204 participants, 147 (72.1%) achieved ITI success. The majority (52.0%) of participants had F8 intron 22 inversion. None of the candidate single nucleotide polymorphisms/human leukocyte antigen variants, IL10 CA dinucleotide short tandem repeats, or FCGR2/3 gene locus variations were associated with ITI success. F8 large deletions were negatively associated with ITI success (odds ratio, 0.15; 95% CI, 0.04-0.51; P = .002).ConclusionOur study of 204 people with SHA identified F8 large deletions as a predictor of ITI failure. Pooling cohorts may allow the identification of additional genetic predictors of ITI success in the future.

This study aimed to investigate the association between fat mass and obesity-associated (FTO) gene Single Nucleotide Polymorphisms (SNPs) and the risk of type 2 diabetes (T2DM) in older Iranian adults, addressing the limited data available for older populations in the Middle East. We analyzed 2,192 older adults from the Bushehr Elderly Health program in southern Iran. T2DM was defined using American Diabetes Association ADA criteria. The Illumina Global Screening Array was used to genotype FTO SNPs. In our analysis, 1,146 SNPs were examined for association with type 2 diabetes using generalized linear models under additive, dominant, and recessive models, controlling for age and sex, following quality control and linkage disequilibrium pruning. False discovery rate (FDR) correction was applied, with significance set at PFDR < 0.05. Among 2,192 elderly participants, 34% had type 2 diabetes. Although none of the examined FTO SNPs showed a statistically significant association with T2DM after FDR correction, the lowest P value was observed for rs16952649 under the additive model (P ≈ 0.002). Known risk alleles, such as rs1421085 (C allele: 42% vs. 43% in Europeans) and rs9940128 (A allele: 45% vs. 44%), were present at similar frequencies to European populations. Ethnic-specific genetic patterns were also observed in the Bushehr cohort. T2DM was not significantly associated with FTO variants, indicating context-dependent effects that were probably influenced by adiposity. The necessity of population-specific genetic research is highlighted by these findings. The online version contains supplementary material available at 10.1007/s40200-025-01721-6.

Hydatidosis, caused by Echinococcus granulosus, is a neglected zoonotic disease with significant public health implications in endemic regions, such as in Cusco, Peru. Genetic factors influencing susceptibility to infection and responses to albendazole, the primary treatment, remain unclear. Thus, this study aimed to investigates genetic polymorphisms associated with hydatidosis susceptibility and albendazole metabolism in the Cusco region. Hence, a cross-sectional study was conducted using 20 individuals from endemic areas. Peripheral blood samples were collected for genomic DNA extraction, followed by single-nucleotide polymorphism (SNP) genotyping using the Illumina Global Screening Array. Polymorphisms in genes related to immunity (interleukin 10 (IL10), interleukin 17A (IL17A), vitamin D receptor (VDR), interferon gamma (IFNG), forkhead box P3 (FOXP3), interleukin 4 (IL4), tumor necrosis factor (TNF), toll-like receptor 4 (TLR4), cytotoxic T-lymphocyte antigen 4 (CTLA4), mannose-binding lectin 2 (MBL2), interleukin 12B (IL12B), and transforming growth factor-beta 1 (TGFB1)) and drug metabolism genes (cytochrome P450 family 3 subfamily A member 4 (CYP3A4), cytochrome P450 family 2 subfamily B member 6 (CYP2B6), cytochrome P450 family 1 subfamily A member 2 (CYP1A2), ATP-binding cassette subfamily B member 1 (ABCB1), solute carrier organic anion transporter family member 1B1 (SLCO1B1), and cytochrome P450 family 2 subfamily E member 1 (CYP2E1)) were analyzed. High-frequency alleles were identified in six SNPs associated with susceptibility to Echinococcus granulosus: IL10 rs1800896 (77.5%), IL17A rs2275913 (97.5%), IFNG rs2779249 (92.5%), FOXP3 rs11568821 (97.5%), TGFB1 rs1800469 (80.0%), and VDR rs2228570 (87.5%). Likewise, elevated allele frequencies were observed for two SNPs potentially involved in albendazole metabolism: CYP3A4 rs2740574 (87.5%) and CYP2B6 rs2266780 (97.5%). A comparative analysis with other populations revealed significant differences in SNP frequencies in the Cusco population, both in SNPs related to susceptibility (IL17A rs2275913, VDR rs2228570, and TGFB1 rs1800469; p < 0.001) and pharmacogenetic-related SNPs (CYP2B6 rs2266782, SLCO1B1 rs4149056, and CYP2E1 rs8330; p < 0.05), suggesting the existence of unique local genetic patterns. These findings underscore the importance of pharmacogenetic screening to optimize albendazole therapy and support precision medical approaches for hydatidosis management in endemic regions. Further studies with larger cohorts are required to confirm these associations.