Analysis of ductal carcinoma in situ by self-reported race reveals molecular differences related to outcome.

BACKGROUND: Ductal carcinoma in situ (DCIS) is a non-obligate precursor to invasive breast cancer (IBC). Studies have indicated differences in DCIS outcome based on race or ethnicity, but molecular differences have not been investigated. METHODS: We examined the molecular profile of DCIS by self-reported race (SRR) and outcome groups in Black (n = 99) and White (n = 191) women in a large DCIS case-control cohort study with longitudinal follow up. RESULTS: Gene expression and pathway analyses suggested that different genes and pathways are involved in diagnosis and ipsilateral breast outcome (DCIS or IBC) after DCIS treatment in White versus Black women. We identified differences in ER and HER2 expression, tumor microenvironment composition, and copy number variations by SRR and outcome groups. CONCLUSIONS: Our results suggest that different molecular mechanisms drive initiation and subsequent ipsilateral breast events in Black versus White women.

Risk of Parkinson's disease and depression severity in different populations: A two-sample Mendelian randomization analysis.

BACKGROUND: Depression is widely recognized as a common non-motor symptom of Parkinson's disease (PD). Across different studies, the reported prevalence of depression in PD varies widely, ranging from 2.7% to 90%, but it is unclear whether this association is due to genetic or acquired factors. Whether there is a causal relationship remains unknown. The aim of this study was to use a two-sample Mendelian randomization (MR) approach to investigate the causal effect of PD on depression. METHODS: Analyses were conducted separately for individuals of European and East Asian ancestry using publicly available summary data from genome-wide association studies. Depression was divided into two categories: ever depressed for a whole week and major depressive disorder (MDD). PD data were used as the exposure and were obtained from the International Parkinson's Disease Genomics Consortium and the BioBank Japan PheWeb, while depression data were used as the outcome and were obtained from the ntegrative Epidemiology Unit (IEU) Open GWAS Project(A public GWAS database） and the Psychiatric Genomics Consortium. The influence of PD on depression was assessed using inverse variance weighted (IVW), weighted median, MR-Egger, and weighted mode methods. Heterogeneity and pleiotropy were tested, and the results were validated using FinnGen GWAS data from version R9. RESULTS: In individuals of European ancestry, there was a causal relationship between PD and ever depressed for a whole week (IVW method, odds ratio [OR] = 0.990; 95% CI, 0.984-0.996; p = .002), but no causal relationship was observed between PD and MDD (IVW method, OR = 0.974; 95% CI, 0.942-1.009; p = .141). In individuals of East Asian ancestry, no causal relationship was observed between PD and ever depressed for a whole week (IVW method, OR = 1.001; 95% CI, 0.829-1.209; p = .990) and between PD and MDD (IVW method, OR = 1.017; 95% CI, 0.982-1.052; p = .342). The results of the three additional analysis methods were similar to those of the IVW method, and there was no heterogeneity according to Cochran's Q-test. There was no evidence of pleiotropy based on MR-Egger intercept test and MR-PRESSO. The FinnGen validation dataset supported these findings. The results are stable and reliable. CONCLUSION: The observed increase in depression among PD patients could potentially be attributed to modifiable acquired factors. Consequently, there is an urgent need to strengthen the management of PD patients in order to prevent the development of depression in the future.

Polygenic risk score portability for common diseases across genetically diverse populations.

BACKGROUND: Polygenic risk scores (PRS) derived from European individuals have reduced portability across global populations, limiting their clinical implementation at worldwide scale. Here, we investigate the performance of a wide range of PRS models across four ancestry groups (Africans, Europeans, East Asians, and South Asians) for 14 conditions of high-medical interest. METHODS: To select the best-performing model per trait, we first compared PRS performances for publicly available scores, and constructed new models using different methods (LDpred2, PRS-CSx and SNPnet). We used 285 K European individuals from the UK Biobank (UKBB) for training and 18 K, including diverse ancestries, for testing. We then evaluated PRS portability for the best models in Europeans and compared their accuracies with respect to the best PRS per ancestry. Finally, we validated the selected PRS models using an independent set of 8,417 individuals from Biobank of the Americas-Genomelink (BbofA-GL); and performed a PRS-Phewas. RESULTS: We confirmed a decay in PRS performances relative to Europeans when the evaluation was conducted using the best-PRS model for Europeans (51.3% for South Asians, 46.6% for East Asians and 39.4% for Africans). We observed an improvement in the PRS performances when specifically selecting ancestry specific PRS models (phenotype variance increase: 1.62 for Africans, 1.40 for South Asians and 0.96 for East Asians). Additionally, when we selected the optimal model conditional on ancestry for CAD, HDL-C and LDL-C, hypertension, hypothyroidism and T2D, PRS performance for studied populations was more comparable to what was observed in Europeans. Finally, we were able to independently validate tested models for Europeans, and conducted a PRS-Phewas, identifying cross-trait interplay between cardiometabolic conditions, and between immune-mediated components. CONCLUSION: Our work comprehensively evaluated PRS accuracy across a wide range of phenotypes, reducing the uncertainty with respect to which PRS model to choose and in which ancestry group. This evaluation has let us identify specific conditions where implementing risk-prioritization strategies could have practical utility across diverse ancestral groups, contributing to democratizing the implementation of PRS.

The causality between use of glucocorticoids and risk of pancreatitis: a Mendelian randomization study.

Background and aim: To date, the association between glucocorticoid use and the risk of pancreatitis remains controversial. The aim of this study was the investigation of this possible relationship. Methods: We carried out a two-sample Mendelian randomization (MR) analysis using GWAS data from European ancestry, East Asian descendants and the FinnGen Biobank Consortium to evaluate this potential causal relationship. Genetic variants associated with glucocorticoid use were selected based on genome-wide significance (p < 5×10-8). Results: Our MR analysis of European ancestry data revealed no significant causal relationship between glucocorticoid use and AP (IVW: OR=1.084, 95% CI= 0.945-1.242, P=0.249; MR-Egger: OR=1.049, 95% CI= 0.686-1.603, P=0.828; weighted median: OR=1.026, 95% CI= 0.863-1.219, P=0.775) or CP (IVW: OR=1.027, 95% CI= 0.850-1.240, P=0.785; MR-Egger: OR= 1.625, 95% CI= 0.913-2.890, P= 0.111; weighted median: OR= 1.176, 95% CI= 0.909-1.523, P= 0.218). Sensitivity analyses, including MR-Egger and MR-PRESSO, indicated no evidence of pleiotropy or heterogeneity, confirming the robustness of our findings. Multivariable MR analysis adjusted for alcohol consumption, BMI, cholelithiasis and C-reactive protein levels supported these findings. Replicated analysis was performed on datasets from the FinnGen Biobank Consortium and East Asian descendants, and similar results were obtained. Conclusions: This MR analysis suggests that there is no causal association between glucocorticoid use and the risk of pancreatitis.

Role of Selected Genetic Polymorphisms in the Development of Rheumatoid Arthritis in a British White Population.

BACKGROUND: Rheumatoid arthritis (RA) is a complex autoimmune disease that negatively affects synovial joints, leading to the deterioration of movement and mobility of patients. This chronic disease is considered to have a strong genetic inheritance, with genome-wide association studies (GWAS) highlighting many genetic loci associated with the disease. Moreover, numerous confounding and non-genetic factors also contribute to the risk of the disease. AIMS: This study investigates the association of selected genetic polymorphisms with rheumatoid arthritis risk and develops a polygenic risk score (PRS) based on selected genes. METHODS: A case-control study recruited fully consenting participants from the East Midlands region of the UK. DNA samples were genotyped for a range of polymorphisms and genetic associations were calculated under several inheritance models. PRS was calculated at crude (unweighted) and weighted levels, and its associations with clinical parameters were determined. RESULTS: There were significant associations with the risk of RA at six genetic markers and their associated risk alleles (TNRF2*G, TRAF1*A, PTPN22*T, HLA-DRB1*G, TNFα*A, and IL4-590*T). The TTG haplotype at the VDR locus increased the risk of RA with an OR of 3.05 (CI 1.33-6.98, p = 0.009). The GA haplotype of HLADRB1-TNFα-308 was a significant contributor to the risk of RA in this population (OR = 2.77, CI 1.23-6.28, p = 0.01), although linkage disequilibrium was low. The polygenic risk score was significantly higher in cases over controls in both unweighted (mean difference = 1.48, t285 = 5.387, p < 0.001) and weighted (mean difference = 2.75, t285 = 6.437, p < 0.001) results. CONCLUSION: Several genetic loci contribute to the increased risk of RA in the British White sample. The PRS is significantly higher in those with RA and can be used for clinical applications and personalised prevention of disease.

Whole-Exome Analysis for Polish Caucasian Patients with Retinal Dystrophies and the Creation of a Reference Genomic Database for the Polish Population.

We present the results of the first study of a large cohort of patients with inherited retinal dystrophies (IRD) performed for the Polish population using whole-exome sequencing (WES) in the years 2016-2019. Moreover, to facilitate such diagnostic analyses and enable future application of gene therapy and genome editing for IRD patients, a Polish genomic reference database (POLGENOM) was created based on whole-genome sequences of healthy Polish Caucasian nonagenarians and centenarians. The newly constructed database served as a control, providing a comparison for variant frequencies in the Polish population. The diagnostic yield for the selected group of IRD patients reached 64.9%. The study uncovered the most common pathogenic variants in ABCA4 and USH2A in the European population, along with several novel causative variants. A significant frequency of the ABCA4 complex haplotype p.(Leu541Pro; Ala1038Val) was observed, as well as that of the p.Gly1961Glu variant. The first VCAN causative variant NM_004385.5:c.4004-2A>G in Poland was found and described. Moreover, one of the first patients with the RPE65 causative variants was identified, and, in consequence, could receive the dedicated gene therapy. The availability of the reference POLGENOM database enabled comprehensive variant characterisation during the NGS data analysis, confirming the utility of a population-specific genomic database for enhancing diagnostic accuracy. Study findings suggest the significance of genetic testing in elder patients with unclear aetiology of eye diseases. The combined approach of NGS and the reference genomic database can improve the diagnosis, management, and future treatment of IRDs.

No Evidence That Vitamin D Levels or Deficiency Are Associated with the Risk of Open-Angle Glaucoma in Individuals of European Ancestry: A Mendelian Randomisation Analysis.

BACKGROUND: Glaucoma is the second leading cause of blindness worldwide, with intraocular pressure as the only known modifiable risk factor. Vitamin D has been proposed to influence intraocular pressure and decrease retinal ganglion cell degeneration. Based on these findings, vitamin D has been suggested to prevent or reduce the severity of primary open-angle glaucoma (POAG), which is the most common form. METHODS: We applied two-sample Mendelian randomisation (MR) analyses to data from the SUNLIGHT consortium and the UK Biobank to assess the causal effect of vitamin D levels and vitamin D deficiency on primary open-angle glaucoma (POAG). MR analysis, including sensitivity tests using other GWAS summary statistics from FinnGen, was also performed. We also investigated the association between single nucleotide polymorphisms (SNPs) on genes involved in vitamin D metabolic pathways and POAG. RESULTS: We found no statistical evidence that vitamin D levels (OR = 1.146, 95% CI 0.873 to 1.504, p = 0.326) or vitamin D deficiency (OR = 0.980 (95% CI 0.928 to 1.036, p = 0.471) causally affect the risk of developing POAG. Sensitivity analyses, including the use of a more relaxed p-value threshold, and use of winter-measured samples only, replication in the FinnGen dataset, and exploration of specific genetic markers also showed no evidence of association between SNPs for genes involved in key steps of vitamin D metabolism and POAG. CONCLUSIONS: These results indicate that vitamin D may not be a significant factor in modifying POAG risk, challenging the hypothesis that vitamin D supplementation could be effective in reducing POAG risk. Further research should focus on identifying other potential risk factors for POAG prevention strategies.

Local Ancestry Inference Based on Population-Specific Single-Nucleotide Polymorphisms-A Study of Admixed Populations in the 1000 Genomes Project.

Human populations have interacted throughout history, and a considerable portion of modern human populations show evidence of admixture. Local ancestry inference (LAI) is focused on detecting the genetic ancestry of chromosomal segments in admixed individuals and has wide applications. In this work, we proposed a new LAI method based on population-specific single-nucleotide polymorphisms (SNPs) and applied it in the analysis of admixed populations in the 1000 Genomes Project (1KGP). Based on population-specific SNPs in a sliding window, we computed local ancestry information vectors, which are moment estimators of local ancestral proportions, for two haplotypes of an admixed individual and inferred the local ancestral origins. Then we used African (AFR), East Asian (EAS), European (EUR) and South Asian (SAS) populations from the 1KGP and indigenous American (AMR) populations from the Human Genome Diversity Project (HGDP) as reference populations and conducted the proposed LAI analysis on African American populations and American populations in the 1KGP. The results were compared with those obtained by RFMix, G-Nomix and FLARE. We demonstrated that the existence of alleles in a chromosomal region that are specific to a particular reference population and the absence of alleles specific to the other reference populations provide reasonable evidence for determining the ancestral origin of the region. Contemporary AFR, AMR and EUR populations approximate ancestral populations of the admixed populations well, and the results from RFMix, G-Nomix and FLARE largely agree with those from the Ancestral Spectrum Analyzer (ASA), in which the proposed method was implemented. When admixtures are ancient and contemporary reference populations do not satisfactorily approximate ancestral populations, the performances of RFMix, G-Nomix and FLARE deteriorate with increased error rates and fragmented chromosomal segments. In contrast, our method provides fair results.

Exploring the relationship between gut microbiota and breast cancer risk in European and East Asian populations using Mendelian randomization.

BACKGROUND: Several studies have explored the potential link between gut microbiota and breast cancer; nevertheless, the causal relationship between gut microbiota and breast cancer remains unclear. METHODS: We utilized summary statistics from genome-wide association studies (GWAS) of the gut microbiome from the MiBioGen project with summary data from GWAS on breast cancer from the FinnGen consortium and the IEU database, with the IEU data sourced from the Biobank Japan. Preliminary statistical analyses were conducted using inverse variance weighting (IVW), supplemented by various sensitivity analysis methods, including MR-Egger regression, weighted median, weighted mode, simple median, and simple mode, to ensure the robustness of our findings. Heterogeneity and pleiotropy were assessed to avoid misleading conclusions caused by unconsidered confounders or non-specific effects of genetic variants, ensuring that the results reflect a genuine causal relationship. RESULTS: In European populations, four types of gut microbiota were associated with breast cancer. The genus Erysipelatoclostridium was positively associated with the risk of breast cancer, with an odds ratio (OR) of 1.21 (95% confidence interval [CI] 1.083-1.358), false discovery rate (FDR) = 0.0039. The class Coriobacteriia, order Coriobacteriales, and family Coriobacteriaceae, which belong to the same phylogenetic system, showed a consistent inversely association with breast cancer risk, with an OR of 0.757 (95% CI 0.616-0.930), FDR = 0.0281. In East Asian populations, three types of gut microbiota were related to breast cancer. The Eubacterium ruminantium group was positively associated with breast cancer risk, with an OR of 1.259 (95% CI 1.056-1.499), FDR = 0.0497. The families Porphyromonadaceae and Ruminococcaceae were inversely associated with breast cancer risk, with ORs of 0.304 (95% CI 0.155-0.596), FDR = 0.0005, and 0.674 (95% CI 0.508-0.895), FDR = 0.03173, respectively. However, these two taxa had limited instrumental variables, restricting the statistical power and potentially affecting the interpretation of the results. CONCLUSION: This MR analysis demonstrated a probable causal link between specific gut microbiota and breast cancer. This study, through Mendelian randomization analysis comparing European and East Asian populations, reveals that gut microbiota may influence breast cancer risk differently across populations, providing potential directions for developing targeted prevention and treatment methods.

Association between inflammatory bowel disease and osteoporosis in European and East Asian populations: exploring causality, mediation by nutritional status, and shared genetic architecture.

Background: While previous research has established an association between inflammatory bowel disease (IBD) and osteoporosis (OP), the nature of this association in different populations remains unclear. Objective: Our study used linkage disequilibrium scores(LDSC) regression analysis and Mendelian randomization(MR) to assess the genetic correlation and causal relationship between IBD and OP in European and East Asian populations. Methods: We performed separate genetic correlation and causal analyses for IBD and OP in European and East Asian populations, used the product of coefficients method to estimate the mediating effect of nutritional status on the causal relationship, and used multi-trait analysis to explore the biological mechanisms underlying the IBD-nutrition-OP causal pathway. Results: Our analysis revealed a significant genetic correlation and causal relationship between IBD and OP in the European population. Conversely, no such correlation or causal relationship was observed in the East Asian population. Mediation analysis revealed a significant mediating effect of nutritional status on the causal pathway between IBD and OP in the European population. Multi-trait analysis of the IBD-nutrition-OP causal pathway identified MFAP2, ATP13A2, SERPINA1, FTO and VCAN as deleterious variants. Conclusion: Our findings establish a genetic correlation and causal relationship between IBD and OP in the European population, with nutritional status playing a crucial mediating role.

Maternal smoking DNA methylation risk score associated with health outcomes in offspring of European and South Asian ancestry.

Background: Maternal smoking has been linked to adverse health outcomes in newborns but the extent to which it impacts newborn health has not been quantified through an aggregated cord blood DNA methylation (DNAm) score. Here, we examine the feasibility of using cord blood DNAm scores leveraging large external studies as discovery samples to capture the epigenetic signature of maternal smoking and its influence on newborns in White European and South Asian populations. Methods: We first examined the association between individual CpGs and cigarette smoking during pregnancy, and smoking exposure in two White European birth cohorts (n=744). Leveraging established CpGs for maternal smoking, we constructed a cord blood epigenetic score of maternal smoking that was validated in one of the European-origin cohorts (n=347). This score was then tested for association with smoking status, secondary smoking exposure during pregnancy, and health outcomes in offspring measured after birth in an independent White European (n=397) and a South Asian birth cohort (n=504). Results: Several previously reported genes for maternal smoking were supported, with the strongest and most consistent association signal from the GFI1 gene (6 CpGs with p<5 × 10-5). The epigenetic maternal smoking score was strongly associated with smoking status during pregnancy (OR = 1.09 [1.07, 1.10], p=5.5 × 10-33) and more hours of self-reported smoking exposure per week (1.93 [1.27, 2.58], p=7.8 × 10-9) in White Europeans. However, it was not associated with self-reported exposure (p>0.05) among South Asians, likely due to a lack of smoking in this group. The same score was consistently associated with a smaller birth size (-0.37±0.12 cm, p=0.0023) in the South Asian cohort and a lower birth weight (-0.043±0.013 kg, p=0.0011) in the combined cohorts. Conclusions: This cord blood epigenetic score can help identify babies exposed to maternal smoking and assess its long-term impact on growth. Notably, these results indicate a consistent association between the DNAm signature of maternal smoking and a small body size and low birth weight in newborns, in both White European mothers who exhibited some amount of smoking and in South Asian mothers who themselves were not active smokers. Funding: This study was funded by the Canadian Institutes of Health Research Metabolomics Team Grant: MWG-146332.

MIR124-3 and NKX6-1 hypermethylation profiles accurately predict metachronous gastric lesions in a Caucasian population.

BACKGROUND: Early gastric cancer is treated endoscopically, but patients require surveillance due to the risk of metachronous gastric lesions (MGLs). Epigenetic alterations, particularly aberrant DNA methylation in genes, such as MIR124-3, MIR34b/c, NKX6-1, EMX1, MOS and CDO1, have been identified as promising biomarkers for MGL in Asian populations. We aimed to determine whether these changes could predict MGL risk in intermediate-risk Caucasian patients. METHODS: This case-cohort study included 36 patients who developed MGL matched to 48 patients without evidence of MGL in the same time frame (controls). Multiplex quantitative methylation-specific PCR was performed using DNA extracted from the normal mucosa adjacent to the primary lesion. The overall risk of progression to MGL was assessed using Kaplan-Meier and Cox proportional hazards model analyses. RESULTS: MIR124-3, MIR34b/c and NKX6-1 were successfully analyzed in 77 samples. MIR124-3 hypermethylation was detected in individuals who developed MGL (relative quantification 78.8 vs 50.5 in controls, p = 0.014), particularly in females and Helicobacter pylori-negative patients (p = 0.021 and p = 0.0079, respectively). This finding was further associated with a significantly greater risk for MGL development (aHR = 2.31, 95% CI 1.03-5.17, p = 0.042). Similarly, NKX6-1 was found to be hypermethylated in patients with synchronous lesions (relative quantification 7.9 vs 0.0 in controls, p = 0.0026). A molecular-based methylation model incorporating both genes was significantly associated with a threefold increased risk for MGL development (aHR = 3.10, 95% CI 1.07-8.95, p = 0.037). CONCLUSIONS: This preliminary study revealed an association between MIR124-3 and NKX6-1 hypermethylation and the development of MGL in a Western population. These findings may represent a burden reduction and a greener approach to patient care.

APOL1 polymorphisms are not influencing acute coronary syndrome risk in Czech males.

BACKGROUND: The highest mortality and morbidity worldwide is associated with atherosclerotic cardiovascular disease (ASCVD), which has in background both environmental and genetic risk factors. Apolipoprotein L1 (APOL1) variability influences the risk of ASCVD in Africans, but little is known about the APOL1 and ASCVD in other ethnic groups. METHODS: To investigate the role of APOL1 and ASCVD, we have genotyped four (rs13056427, rs136147, rs10854688 and rs9610473) APOL1 polymorphisms in a group of 1541 male patients with acute coronary syndrome (ACS) and 1338 male controls. RESULTS: Individual APOL1 polymorphisms were not associated with traditional CVD risk factors such as smoking, hypertension or diabetes prevalence, with BMI values or plasma lipid levels. Neither individual polymorphisms nor haplotypes were associated with an increased risk of ACS nor did they predict total or cardiovascular mortality over the 10.2 ± 3.9 years of follow-up. CONCLUSIONS: We conclude that APOL1 genetic variability has no major effect on risk of ACS in Caucasians.

Deciphering the mediating role of CXCL10 in hypothyroidism-induced idiopathic pulmonary fibrosis in European ancestry: a Mendelian randomization study.

Background: Idiopathic pulmonary fibrosis (IPF) is a lethal lung disease characterized by progressive fibrosis, leading to impaired gas exchange and high mortality. The etiology of IPF is complex, with potential links to autoimmune disorders such as hypothyroidism. This study explores the relationship between hypothyroidism and IPF, focusing on the mediating role of plasma proteins. Methods: A two-sample Mendelian randomization (MR) approach was employed to determine the impact of hypothyroidism on IPF and the mediating role of 4,907 plasma proteins, all in individuals of European ancestry. Sensitivity analyses, external validation, and reverse causality tests were conducted to ensure the robustness of the findings. Additionally, the function of causal SNPs was evaluated through gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses. Conclusion: The findings suggest that hypothyroidism, through altered plasma protein expression, particularly CXCL10, may contribute to the pathogenesis of IPF. This novel insight highlights the potential of CXCL10 as a therapeutic target in IPF, especially in patients with hypothyroidism. The study emphasizes the need for further research into the complex interplay between autoimmune disorders and IPF, with a view towards developing targeted interventions for IPF management.

Genome-wide analyses of neonatal jaundice reveal a marked departure from adult bilirubin metabolism.

Jaundice affects almost all neonates in their first days of life and is caused by the accumulation of bilirubin. Although the core biochemistry of bilirubin metabolism is well understood, it is not clear why some neonates experience more severe jaundice and require treatment with phototherapy. Here, we present the first genome-wide association study of neonatal jaundice to date in nearly 30,000 parent-offspring trios from Norway (cases ≈ 2000). The alternate allele of a common missense variant affecting the sequence of UGT1A4 reduces the susceptibility to jaundice five-fold, which replicated in separate cohorts of neonates of African American and European ancestries. eQTL colocalization analyses indicate that the association may be driven by regulation of UGT1A1 in the intestines, but not in the liver. Our results reveal marked differences in the genetic variants involved in neonatal jaundice compared to those regulating bilirubin levels in adults, suggesting distinct genetic mechanisms for the same biological pathways.

Causal associations between insulin and Lp(a) levels in Caucasian population: a Mendelian randomization study.

BACKGROUND: Numerous observational studies have demonstrated that circulating lipoprotein(a) [Lp(a)] might be inversely related to the risk of type 2 diabetes (T2D). However, recent Mendelian randomization (MR) studies do not consistently support this association. The results of in vitro research suggest that high insulin concentrations can suppress Lp(a) levels by affecting apolipoprotein(a) [apo(a)] synthesis. This study aimed to identify the relationship between genetically predicted insulin concentrations and Lp(a) levels, which may partly explain the associations between low Lp(a) levels and increased risk of T2D. METHODS: Independent genetic variants strongly associated with fasting insulin levels were identified from meta-analyses of genome-wide association studies in European populations (GWASs) (N = 151,013). Summary level data for Lp(a) in the population of European ancestry were acquired from a GWAS in the UK Biobank (N = 361,194). The inverse-variance weighted (IVW) method approach was applied to perform two-sample summary-level MR. Robust methods for sensitivity analysis were utilized, such as MR‒Egger, the weighted median (WME) method, MR pleiotropy residual sum and outlier (MR-PRESSO), leave-one-out analysis, and MR Steiger. RESULTS: Genetically predicted fasting insulin levels were negatively associated with Lp(a) levels (ß = - 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (ß = - 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (ß = - 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a). CONCLUSION: Our MR study provides robust evidence supporting the association between genetically predicted increased insulin concentrations and decreased concentrations of Lp(a). These findings suggest that hyperinsulinaemia, which typically accompanies T2D, can partially explain the inverse relationship between low Lp(a) concentrations and an increased risk of T2D.

Opioid use disorder risk alleles in self-reported assigned African American/Afro-Caribbean and European biogeographical genetic ancestry groups and in males and females.

The influence of genetic variants related to opioid use disorder (OUD) was evaluated using multiple logistic regression analysis in self-reported assigned African American/Afro-Caribbean and European biogeographical ancestry groups (BGAGs) and by sex. From a sample size of 1301 adult patients (>18 years of age) seen in emergency departments of three medical centers in Ohio, six variants were found to be associated with OUD. Two of the variants, rs2740574 (CYP3A4) and rs324029 (DRD3), were included in the analysis having met criteria of at least five subjects for each BGAG, variant carrier status, and OUD status combinations. Variant carriers in the African/Afro-Caribbean BGAG had slightly lower predicted probabilities of OUD. Variant carriers in the European BGAG had slightly higher predicted probabilities of OUD. Relative to sex, all the six variants met evaluation criteria (five subjects for all sex, variant, and OUD status combinations). No statistically significant interactions were found between a given variant, BGAGs and sex. Findings suggest variant testing relative to OUD risk can be applied across BGAGs and sex, however, studies in larger populations are needed.

Single-nuclei sequencing of uterine serous carcinoma reveals racial differences in immune signaling.

Significant racial disparities exist between Black and White patients with uterine serous carcinoma (USC). While the reasons for these disparities are unclear, several studies have demonstrated significantly different rates of driver mutations between racial groups, including TP53. However, limited research has investigated the transcriptional differences of tumors or the composition of the tumor microenvironment (TME) between these groups. Here, we report the single-nuclei RNA-sequencing profiles of primary USC tumors from diverse racial backgrounds. We find that there are significant differences between the tumors of Black and White patients. Tumors from Black patients exhibited higher expression of specific genes associated with aggressiveness, such as PAX8, and axon guidance and synaptic signaling pathways. We also demonstrated that T cell populations are reduced in the tumor tissue compared to matched benign, while anti-inflammatory macrophage populations are retained within the TME. Furthermore, we investigated the connection between PAX8 overexpression and immunosuppression in USC through regulation of several cytokines and chemokines. Notably, we show that PAX8 activity can influence macrophage gene expression and protein secretion. These studies provide a detailed understanding of the USC transcriptome and TME, and identify differences in tumor biology from patients of different racial backgrounds.

Increased Frequency of Angiotensin-Converting Enzyme D Allele in Asian Patients With Chronic Obstructive Pulmonary Disease: An Updated Meta-Analysis.

At present, the angiotensin-converting enzyme (ACE) I/D polymorphism was considered to be associated to the pathogenesis of chronic obstructive pulmonary disease (COPD). However, the association between it and the risk of COPD in different ethnic groups is still unclear. The purpose of this study is to conduct an updated meta-analysis of the association between them; collect literatures published before 10 February 2023 by searching PubMed, Embase, MEDLINE, CBM, CNKI, Wanfang, and VIP Chinese scientific databases; and display the analysis results by drawing forest plots. At the same time, publication bias, sensitivity analysis, and trial sequential analysis (TSA) were performed to evaluate the stability and reliability of the results. In the overall population, the result of the DD versus II model showed the association with the risk of COPD ([OR] = 1.30, 95% CI [1.08, 1.56]), and there were no associations in other genetic models (p > 0.05). In Caucasians, the results of all genetic models showed no associations (p > 0.05). In Asians, the results of D versus I, DD versus II, and DD versus II + ID models showed the associations with the risk of COPD (D vs. I: [OR] = 1.48, 95% CI [1.14, 1.93]; DD vs. II: [OR] = 2.04, 95% CI [1.53, 2.72]; DD vs. II + ID: [OR] = 2.19, 95% CI [1.45, 3.29]), while the results of ID versus II and DD + ID versus II models showed no associations (p > 0.05). Therefore, the D allele and "DD" genotype variation of the ACE I/D gene polymorphism are associated with susceptibility to COPD in Asians but not in Caucasians.

Epigenetic and genetic risk of Alzheimer disease from autopsied brains in two ethnic groups.

Genetic variants and epigenetic features both contribute to the risk of Alzheimer's disease (AD). We studied the AD association of CpG-related single nucleotide polymorphisms (CGS), which act as a hub of both the genetic and epigenetic effects, in Caribbean Hispanics (CH) and generalized the findings to Non-Hispanic Whites (NHW). First, we conducted a genome-wide, sliding-window-based association with AD, in 7,155 CH and 1,283 NHW participants. Next, using data from the dorsolateral prefrontal cortex in 179 CH brains, we tested the cis- and trans-effects of AD-associated CGS on brain DNA methylation to mRNA expression. For the genes with significant cis- and trans-effects, we investigated their enriched pathways. We identified six genetic loci in CH with CGS dosage associated with AD at genome-wide significance levels: ADAM20 (Score = 55.19, P = 4.06 × 10-8), the intergenic region between VRTN and SYNDIG1L (Score = - 37.67, P = 2.25 × 10-9), SPG7 (16q24.3) (Score = 40.51, P = 2.23 × 10-8), PVRL2 (Score = 125.86, P = 1.64 × 10-9), TOMM40 (Score = - 18.58, P = 4.61 × 10-8), and APOE (Score = 75.12, P = 7.26 × 10-26). CGSes in PVRL2 and APOE were also significant in NHW. Except for ADAM20, CGSes in the other five loci were associated with CH brain methylation levels (mQTLs) and CGSes in SPG7, PVRL2, and APOE were also mQTLs in NHW. Except for SYNDIG1L (P = 0.08), brain methylation levels in the other five loci affected downstream mRNA expression in CH (P < 0.05), and methylation at VRTN and TOMM40 were also associated with mRNA expression in NHW. Gene expression in these six loci were also regulated by CpG sites in genes that were enriched in the neuron projection and glutamatergic synapse pathways (FDR < 0.05). DNA methylation at all six loci and mRNA expression of SYNDIG1 and TOMM40 were significantly associated with Braak Stage in CH. In summary, we identified six CpG-related genetic loci associated with AD in CH, harboring both genetic and epigenetic risks. However, their downstream effects on mRNA expression maybe ethnic specific and different from NHW.