Studies Of European Populations Research Articles

A novel EYA1 splicing mutation in a Chinese branchio-oto syndrome family with functional analysis and reproductive intervention.

Branchio-oto syndrome (BOS) is a group of autosomal dominant genetic diseases, multisystem disorders excluding renal anomalies. There are clinical heterogeneity and ethnic diversity in BOS, which reported in more studies in European populations than in Asian populations, with a prevalence rate of approximately 1/40000. As the most common disease-causing gene, the mutation types of EYA1 range from missense to various frameshift, splicing and nonsense variants. Although splicing mutations are one of the important factors in the disease, existed research has paid less attention to the novel mutations causing aberrant RNA splicing and their pathogenic mechanisms. Reproductive interventions that actively block the transmission of the disease to future generations have also not been reported. We had collected research samples from a three-generation Chinese family with BOS. Whole exome sequencing was applied for the screening of candidate causing gene. Minigene assay was performed to identify the aberrant splicing products, and molecular biology techniques were used to analyze the pathogenicity of potentially mistranslated proteins. pre-implantation genetic testing (PGT) has been employed to prevent hearing loss in this family based on SNP analysis. A novel mutation EYA1:c.1598-2AG>TA was identified by whole-exome sequencing and classified as harmful refer to ACMG's evidence. An aberrant RNA splicing was verified and suggested that might prematurely terminates the translation of EYA1 protein, through the minigene assay. The EYA1 truncated protein presented unstable and difficultly translocated to the nucleus, also impaired EYA1-SIX1 interactions in cytological experiments. PGT helped the proband give birth to a healthy boy. A novel splicing variant of EYA1 gene was identified in this study, and the potential molecular pathogenic mechanism was elucidated by several functional experiments. On basis above findings, we successfully implemented the first instance of using PGT to ensure the birth of a healthy offspring free from this genetic disorder.

Incidence and survival trends in small bowel adenocarcinoma (SBA) from 2000-2019 in the United States.

801 Background: SBA is a rare, poorly understood gastrointestinal malignancy. Adenocarcinomas are often grouped with other small bowel cancer histologies in epidemiologic and outcomes reports, which limits the ability to detect SBA-specific trends. Recent studies in European populations show increasing SBA incidence, but there are limited published data in American cohorts. Identifying trends in SBA can improve understanding of the population most at risk for developing SBA. This study describes U.S. trends in SBA incidence and outcomes from 2000 to 2019. Methods: Using the 2022 SEER research-limited dataset, we identified SBA cases and measured the incidence change from 2000-2019. We built linear regression models to evaluate changes in annual incidence by groups, including sex, race, and age of diagnosis, separately. We then compared the overall incidence and trends between subgroups. We investigated overall survival (OS) through the SEER research case listings for SBA patients diagnosed during the study period. Results: An average of 0.67 cases/100,000 SBA cases were reported annually from 2000-2019, with a median diagnosis age of 69 years. SBA incidence has increased annually by 0.3% per year from 2000-2019 (p=0.05). From 2000-2019, men were at a higher risk for SBA compared to women (p=0.02). In men, SBA cases increased at a rate of 0.004 cases/100,000/year from 2000-2019 (p=0.01) and a nonsignificant decrease in women of 0.00012 cases/100,000/year. There were no statistically significant differences in incidence or the change in incidence of SBA by race. The age-adjusted incidence was significantly higher each year between 2000 and 2019 in the > 70 cohort compared to the <70 cohort (p=0.02). Cases of SBA increased at a rate of 0.02 cases/100,000/year in adults >70 years (p=0.02). There were no differences in incidence rates in patients <70 years. There was no significant difference in OS for patients diagnosed with SBA in 2000, 2005, 2010, 2015, and 2019 (p=0.21). Conclusions: The overall annual incidence of SBA is increasing in the U.S. population. The most significant rate increases are in men and adults older than 70. In the SEER population, trends in SBA contrast with the recent rise of colorectal cancer in the young adult population, highlighting the unique nature of SBA compared to other gastrointestinal malignancies. Additionally, survival outcomes in patients diagnosed with SBA have remained stable over the past 20 years, while other malignancies have shown improvement in the same period. The small cohort size and the lack of a universal U.S. cancer registry limited this evaluation. Improved reporting of SBA cases and further research to identify risk factors are urgently needed to reduce the growing impact of SBA.

Abstract TMP63: Genetic investigation for cerebral small vessel disease genes in patients with spontaneous intracerebral hemorrhage

Objectives: Spontaneous intracerebral hemorrhage (ICH) is caused by the rupture of small arterioles due to cerebral small vessel disease (SVD), commonly with hypertensive arteriolosclerosis (HTA) or cerebral amyloid angiopathy (CAA). Several genes associated with SVD or ICH have been reported in studies of European populations, but it is unclear whether these genes are associated with ICH in the Japanese cohort. The aim of this study was to assess genetic variants associated with SVD in patients with ICH. Methods: We analyzed 920 patients with primary ICH and genetic data available from an ongoing, prospective, cohort study. ICH was diagnosed according to CLASsification system for ICH (CLAS-ICH) by stroke neurologists, and mixed-SVD was classified as HTA. We focused on the 27 genes previously identified in SVD ( APOE, CETP, PMF1, SLC25A44, TRHDE, APP, NOTCH3, COL4A1, COL4A2, PARVB, FOXC1, FOXF2, TREX1, ZCCHC14, WDR12, ICA1L, GCH1, SH2B3, ACOX1, UNC13D, TRIM65, TRIM47, WBP2, PLEKHG1, EFEMP1, VCAN, HTRA1 ) to investigate their association with the ICH phenotypes (ICH subtypes [HTA-ICH vs. CAA-ICH], hematoma location [non-lobar vs. lobar], modified Rankin Scale (mRS) at 90d [0-4 vs. 5-6]). Variants with minor allele frequency ≥0.05 were analyzed. Trend test was used to assess the association, and the significance level was defined as false discovery rate (FDR) <0.1. The reference allele was defined as a base allele of odds ratio (OR). Results: Characteristics of 920 patients with ICH are mean age 71 ± 13 years, 59% men, HTA-ICH vs. CAA-ICH:88% vs. 10%, non-lobar vs. lobar: 74% vs. 26%, and mRS 0-4 vs. 5-6: 78% vs. 22%. We assessed the 667 variants in 27 genes. In CAA-ICH vs HTA-ICH, two variants on APP (amyloid-β protein precursor) gene showed significance. One was rs2830008 (NM_000484:c.865+2696A>G, OR=2.67, p=5.9×10 -6 , FDR=0.039) and the other was rs73163761 (NM_000484:c.866-7085C>T, OR=2.59, p=1.9×10 -4 , FDR=0.064). These 2 variants were in linkage equilibrium (r 2 =0.93). The alternative allele frequencies of rs2830008: T>C and rs73163761: G>A were 0.182 vs. 0.077 and 0.166 vs. 0.071 in CAA-ICH vs. HTA-ICH, respectively, with the HTA-ICH frequencies aligning with those of the general population (0.081, 0.072, respectively). No significant association was observed for other phenotypes. Conclusion: We found that 2 variants on APP genes were associated with CAA-ICH in the Japanese ICH cohort, confirming the link to amyloid β pathology.

Progression from outpatient referral to spinal surgery in an Australian cohort with degenerative spinal disease.

Degenerative spine disease (DSD) encompasses a range of conditions with increasing prevalence and a significant burden of disease. Patients with DSD are often referred to a neurosurgery clinic with lengthy waiting times from referral to consultation. The reported proportion of referred patients who undergo spinal surgery varies from 20.05% to 54% in heterogenous study populations from predominantly North American and European study populations. These rates do not correlate with institutional data in the Australian public hospital system and there is limited Australian data in the literature. This retrospective study aimed to quantify the proportion of patients referred to a neurosurgery clinic who progressed to elective spinal surgery and explore predictors for surgery based on referral contents. All patients referred for DSD to a single tertiary centre between 1/1/16 and 31/12/22 were included. Referrals for spinal pathology due to trauma, infection or tumour were excluded. Patient demographics, clinical presentation and imaging findings contained in the outpatient referral were recorded. Outcomes, including progression to surgery, were also recorded. Univariate and multivariate analysis was performed to determine predictive factors for surgery. Of 5189 referrals, only 471 (9.1%) underwent surgery. Only 4.7% had surgery at our institution with the remaining 4.4% undergoing surgery elsewhere. Referrals from neurologists, rheumatologists and referrals specifying limb weakness or sensory change, were more likely to progress to surgery, although these predictors were only present in 0.7 - 3.9% of referrals. Axial pain negatively predicted surgery. To our knowledge, this is the only study in an Australian population to analyse the outcome of DSD referrals to neurosurgery clinic, based on referral contents alone. The vast majority of patients do not require surgery. Though there are a few predictive factors, progression to surgery cannot reliably be predicted from the referral, highlighting the opportunity to improve patient outcomes and healthcare utilisation for patients with DSD.

The mediating effects of mobile phone use on ADHD and educational outcomes: a two-step Mendelian randomisation study.

This study investigates the potential mediating role of mobile phone screen time in the causal relationships between Attention-deficit/hyperactivity disorder (ADHD) and educational attainment. Our analysis explores both the effect of ADHD on educational outcomes and the reverse, i.e., the influence of educational attainment on ADHD risk. A two-sample Mendelian randomisation (MR) analysis was conducted using genetic instruments from genome-wide association studies (GWAS) of European populations. We employed a two-step MR approach to assess the causal effects between ADHD, mobile phone screen time (both frequency and duration), and educational outcomes, including years of full-time education and college completion. Data from public genome-wide association studies encompassing European populations with sample sizes ranging from 55,374 to 470,941 were utilised. We found significant causal associations between childhood ADHD and educational attainment, partially mediated by mobile phone screen time. Childhood ADHD was negatively linked to years of full-time education (IVW: OR = 0.93, 95% CI = 0.90-0.97, p = 0.000) and college completion (IVW: OR = 0.97, 95% CI = 0.95-0.98, p = 0.000). Mobile phone use frequency mediated 19.3% of the effect on full-time education (β = -0.158) and 11.9% on college completion (β = -0.084). The duration of phone use mediated 64.8% of the effect on college completion (β = -0.054). When ADHD was the outcome, phone use duration mediated -22.45% of full-time education effects (β = 0.426) and -19.62% of college completion (β = 0.433). Different MR models reveal the complex mediation role of mobile phone use frequency and duration between ADHD and educational attainment, varying by educational outcome type. Frequency mediates the link between childhood ADHD and full-time education/college completion, while duration significantly impacts ADHD when higher education is the outcome. The notable mediation effect of duration on ADHD underscores the need for further study into screen time's influence on ADHD and academic achievement across stages.

Resting Heart Rate and Incident Atrial Fibrillation in Black Adults in the Jackson Heart Study

Resting heart rate (RHR) is a widely available measure of cardiovascular fitness that has been associated with several cardiovascular outcomes. RHR has previously been associated with the risk of atrial fibrillation (AF) among individuals of European ancestry, but little is known about this association in Black adults. To evaluate the association between RHR and incident AF in a large community-based sample of Black adults, independently of established risk factors. This cohort study uses data from the Jackson Heart Study, a prospective community-based cohort in Jackson, Mississippi. Participants without prevalent AF were included and were monitored for new-onset AF during follow-up, from 2000 through 2016. Data analysis was performed from August 1 to December 11, 2023. RHR was assessed from resting 12-lead electrocardiograms performed at examination 1 (2000-2004) and examination 3 (2009-2013). AF was identified from study electrocardiograms, hospitalization discharge diagnosis codes, and Medicare claims diagnosis codes. Cox regression was used to evaluate the association between baseline (examination 1) RHR and incident AF, adjusting for established AF risk factors. Among 4965 Black adults eligible for analysis, the mean (SD) age was 55 (13) years, 1830 (37%) were male, and the mean (SD) RHR at baseline was 65 (11) beats per minute (bpm). During a median (IQR) 14 (12-15) years of follow-up, there were 458 incident AF events, resulting in an incident rate of 7.5 per 1000 person-years (95% CI, 6.8-8.2 incidents per 1000 person-years). Each 10-bpm higher RHR was associated with a 9% higher risk of incident AF after adjustment for AF risk factors (hazard ratio, 1.09; 95% CI, 1.00-1.19). In a sensitivity analysis that excluded individuals with prior heart failure, prior myocardial infarction, and antiarrhythmic medication use at baseline, the hazard ratio was 1.14 (95% CI, 1.02-1.28). There was little evidence of effect modification of these associations by age, sex, body mass index, hypertension, or physical activity level. In this large prospective cohort study of Black adults, elevated baseline RHR was associated with increased risk of incident AF, consistent with findings from previous studies of European ancestry populations. Future research should focus on determining whether RHR can be used to screen patients at high risk of AF.

No genetic causality between appendectomy and gastrointestinal cancers: a Mendelian randomization study and meta-analysis in European population

The impact of appendectomy on the risk of gastrointestinal cancers remains unknown. We aimed to systematically estimate the causal relationship between appendectomy and gastrointestinal cancers in the European population using two-sample Mendelian randomization (TSMR) study methods and meta-analysis. As part of the discovery cohort analysis, we identified independent genetic variants strongly associated with appendectomy from the UK Biobank (50,105 cases) to serve as instrumental variables (IVs). Summary-level data for gastrointestinal cancers were obtained from the FinnGen study. As the replication cohort, IVs associated with appendectomy were extracted in the FinnGen study (28,601 cases). The data for gastrointestinal cancers were obtained from the UK Biobank. Finally, meta-analyses were conducted to evaluate the combined causal effects of the MR results. We found no causal relationship between appendectomy and gastrointestinal cancers in both the discovery and replication cohorts. Finally, the meta-analysis revealed no causal association between appendectomy and gastrointestinal cancers. Our findings suggest no causal relationship exists between appendectomy and gastrointestinal cancers in the European population. This genetic evidence supports the conclusion from other observational studies that appendectomy does not affect the risk of gastrointestinal cancers in the European population.

Blood pressure and cardiovascular risk in relation to birth weight and urinary sodium: an individual-participant meta-analysis of European family-based population studies

Abstract Background While the relation of salt intake with blood pressure (BP) is linear, it is U-shaped for mortality and cardiovascular disease (CVD). Purpose This individual-participant meta-analysis explored whether the relation of hypertension, death or CVD with 24 h urinary sodium excretion (UVNA) or sodium-to-potassium (UNAK) ratio was modified by birth weight. Methods Families were randomly enrolled in the Flemish Study on Genes, Environment and Health Outcomes (1985-2004) and the European Project on Genes in Hypertension (1999-2001). Categories of birth weight, UVNA and UNAK (≤2500, >2500-4000, >4000 g; <2.3, 2.3-4.6 and >4.6 g; and <1, 1-2 , >2, respectively) were coded using deviation-from-mean coding and analyzed by Kaplan-Meier survival functions and linear and Cox regression. Results The study population was subdivided into the Outcome (n=1945), Hypertension (n=1460) and BP cohorts (n=1039) to analyze the incidence of mortality and cardiovascular endpoints, hypertension and BP changes as function of UVNA changes. The prevalence of low/medium/high birth weight in the Outcome Cohort was 5.8/84.5/9.7%. Over 16.7 years (median), rates were 4.9%, 8.0% and 27.1% for mortality, CVD and hypertension, respectively, but were not associated with birth weight. Multivariable-adjusted hazard ratios were not significant for any endpoint in any of the BW, UVNA and UNAK strata. Adult body weight tracked with birth weight (P<0.0001). The partial r in the low birth weight group associating changes from baseline to follow-up in UVNA and systolic BP was 0.68 (P=0.023), but not significant in other birth weight groups. Conclusion This study did not substantiate its prior hypothesis, but showed tracking of adult with birth weight and suggest that low birth weight increases salt sensitivity.Figure 1Figure 2

Sex estimation using metrics of the innominate: A test of the DSP2 method.

Sex estimation is a critical component of the biological profile, and forensic anthropologists may use a variety of sex estimation methods depending upon the degree of completeness and state of preservation of the skeletal remains being analyzed. The innominate is widely accepted to be the most sexually dimorphic skeletal element. The Diagnose Sexuelle Probabiliste (DSP) method, which uses 10 measurements of the innominate, was introduced in 2005 and updated as DSP2 in 2017. While DSP2 has been reported to have high classification accuracy rates in studies of South American and European populations, the method has not been widely tested in US samples, and few US practitioners incorporate this method into their casework. The goal of this study was to test the reliability and accuracy of DSP2 using a large, modern sample from the US (n = 174). Two observers, blinded from demographic information associated with each specimen, collected the DSP2 metrics. Intra- and interobserver error analyses showed acceptable levels of agreement for all measurements, except for IIMT. Classification accuracies exceeded 95%, with minimal sex bias, for both observers and using various measurement combinations; however, an inclusivity sex bias occurred with more males reaching the 0.95 posterior probability threshold required by DSP2 to provide a sex classification estimate. Based on its high accuracy, forensic anthropologists in the US may consider incorporating DSP2 into their casework, although we recommend excluding IIMT and using SPU with caution. Additional methods will continue to be needed when the posterior probability threshold is not reached.

Interactions Between Eleven Sleep-Related Characteristics and Diabetic Nephropathy: A Bidirectional Mendelian Randomization Study in European Population.

Observational studies often report disturbed sleep patterns in individuals with diabetic nephropathy (DN). The possible causal relationship behind these connections remains unknown. This research assessed the possible cause-and-effect relationship between eleven sleep-related characteristics and the risk of developing DN using a two-sample Mendelian randomization (MR) study. This study employed a two-sample bidirectional MR analytical approach. Genetic data for eleven sleep-related characteristics were acquired from the genome-wide association studies (GWAS) database of individuals of European ancestry which involve scanning complete sets of DNA, or genomes. GWAS summary data for DN included 4,111 DN cases and 308,539 controls. Instrumental variables were single nucleotide polymorphisms strongly linked to sleep-related characteristics. The main analysis used the random-effects inverse variance weighted (IVW) approach, with validation through sensitivity testing. MR analysis revealed that a higher genetic predisposition for sleep efficiency reduced the chance of developing DN (odds ratio [OR]: 0.384; 95% confidence interval [CI] 0.205-0.717; p=0.003). Genetic susceptibility to DN was associated with a higher likelihood of experiencing more sleep episodes (OR: 1.015; 95% CI 1.003-1.028; p=0.016). Sensitivity analysis confirmed the robustness of these correlations. No significant connections were found between other genetically predicted sleep characteristics and the likelihood of developing DN. Our research indicates that a genetic predisposition for better sleep efficiency is linked to a lower risk of developing DN. There is also evidence suggesting that genetic predisposition to DN may directly impact sleep episodes. Further research is needed to explore the molecular mechanisms underlying these findings.

The Association between Non-Alcohol Liver Fatty Disease and Coronary Artery Calcification: A Two-Sample Mendelian Randomization Study.

Although prior observational studies have suggested that patients with non-alcohol fatty liver disease (NAFLD) may have a higher risk of coronary artery calcification (CAC), these findings remain controversial. This study aimed to explore the causal association between NAFLD and CAC at genetic level by two-sample Mendelian randomization (MR) analysis. Utilizing summary-level data from multiple large-scale genome-wide association studies (GWAS) in European populations, a two-sample MR analysis was initially conducted to explore the potential causal association between NAFLD and CAC. The results of the MR analysis were pooled through random-effect meta-analysis. The inverse variance weighting (IVW) method served as the primary approach for MR analysis. Additionally, the weighted median, MR-Egger and MR-pleiotropy residual sum and outlier (MR-PRESSO) methods was applied for sensitivity analysis. Summary-level data on liver fatty content was utilized for validation analysis, while summary-level data on cirrhosis served as positive control, further ensuring the validity and robustness of our findings. Reverse MR analysis was performed to assess the association between CAC and NAFLD, employing instrument variables derived from CAC. The MR analysis indicated that genetically predicted NAFLD had no effects on the risk of CAC (Beta: 0.01, 95% CI: -0.02 to 0.03, P = 0.74). Likewise, the reverse MR analysis found no significant genetic association between CAC and NAFLD (OR: 1.00, 95% CI: 0.96 to 1.06, P = 0.88). Validation analysis yielded consistent results, showing no significant association between fatty liver content and CAC. Our two-sample MR analysis did not support that there is a causal association between NAFLD and CAC at genetic level. The association between NAFLD and CAC reported in some previous observational studies may rely on NAFLD complicated with metabolic disorders, rather than being directly linked to the hepatic steatosis.

Modifiable factors mediating the effects of educational attainment on gestational diabetes mellitus: A two-step Mendelian randomization study.

Although there is currently a wealth of evidence to indicate that maternal educational attainment is associated with gestational diabetes mellitus (GDM), the specific modifiable risk factors that mediate the causal relationship between these two variables have yet to be identified. To identify the specific modifiable risk factors that mediate the causal relationship between the level of maternal education and GDM. Mendelian randomization (MR) was conducted using data from genome-wide association studies of European populations. We initially performed a two-sample MR analysis using data on genetic variants associated with the duration of education as instruments, and subsequently adopted a two-step MR approach using metabolic and lifestyle factors as mediators to examine the mechanisms underlying the relationship between the level of maternal education and risk of developing GDM. In addition, we calculated the proportions of total causal effects mediated by identified metabolic and lifestyle factors. A genetically predicted higher educational attainment was found to be associated with a lower risk of developing GDM (OR: 0.71, 95%CI: 0.60-0.84). Among the metabolic factors assessed, four emerged as potential mediators of the education-GDM association, which, ranked by mediated proportions, were as follows: Waist-to-hip-ratio (31.56%, 95%CI: 12.38%-50.70%), body mass index (19.20%, 95%CI: 12.03%-26.42%), high-density lipoprotein cholesterol (12.81%, 95%CI: 8.65%-17.05%), and apolipoprotein A-1 (7.70%, 95%CI: 4.32%-11.05%). These findings proved to be robust to sensitivity analyses. Our findings indicate a causal relationship between lower levels of maternal education and the risk of developing GDM can be partly explained by adverse metabolic profiles.

Causal links between immune cells and asthma: Insights from a Mendelian Randomization analysis

Objectives Recent studies suggest immunophenotypes may play a role in asthma, but their causal relationship has not been thoroughly examined. Methods We used single nucleotide polymorphism (SNP)-derived instrumental variables. Summary data from 731 immune cell profiles and asthma cases were analyzed from genome-wide association studies (GWAS) of European populations. Mendelian Randomization (MR) analyses included inverse variance weighted (IVW), weighted median, and MR–Egger methods. Pleiotropy was assessed using the MR-Egger intercept and MR pleiotropy residual sum and outlier (MR-PRESSO) tests. Reverse MR analysis explored bidirectional causation between asthma and immunophenotypes. All statistical analyses were conducted using R software. Results MR analysis identified 108 immune signatures potentially contributing to asthma. Two immunophenotypes were significantly associated with asthma risk: CD4+ secreting Treg cells in allergic asthma (ORIVW = 1.078; 95% CI: 1.036–1.122; PIVW = 0.0002) and IgD + CD38− %lymphocyte cells in non-allergic asthma (ORIVW = 1.123; 95% CI: 1.057–1.194; PIVW = 0.0002). Conclusions This study highlights the causal associations between specific immunophenotypes and asthma risk, providing new insights into asthma pathogenesis.

Causal Associations between Tea Consumption and Rapid Eye Movement Sleep Behavior Disorder: A Mendelian Randomization Study

Introduction: Previous studies have shown that tea consumption may have a protective effect against neurodegenerative diseases. However, the exact causal relationship between tea consumption and the precursor stages of certain neurodegenerative diseases, namely, REM sleep behavior disorder (RBD), remains unclear. To evaluate the causal association between tea consumption and RBD, we employed a Mendelian randomization study. Methods: We identified genetic instrumental variables that are significantly associated with tea consumption through genome-wide association studies (GWAS) in European populations. Bidirectional two-sample Mendelian randomization was utilized to determine the causal relationship between tea consumption and RBD, while sensitivity analyses were further employed to evaluate the robustness of the results. The multivariate Mendelian randomization method was used to assess the influence of relevant confounding factors on the results. Results: In the MR analysis using the inverse-variance weighting method, a significant causal relationship between tea consumption and RBD was observed (OR = 0.046, 95% CI: 0.004–0.563, p = 0.016). The consistency of findings across maximum likelihood, MR Pleiotropy RESidual Sum and Outlier, and multivariate MR after adjusting for potential confounding further supports this causal association. Sensitivity analyses revealed no evidence of heterogeneity or pleiotropy. Conclusions: The findings of our study demonstrate a robust causal association between tea consumption and RBD, indicating that tea consumption may serve as a protective factor against the development of RBD.

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

BackgroundNumerous 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.MethodsIndependent 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.ResultsGenetically predicted fasting insulin levels were negatively associated with Lp(a) levels (β = − 0.15, SE = 0.05, P = 0.003). The sensitivity analysis revealed that WME (β = − 0.26, SE = 0.07, P = 0.0002), but not MR‒Egger (β = − 0.22, SE = 0.13, P = 0.11), supported a causal relationship between genetically predisposed insulin levels and Lp(a).ConclusionOur 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.

Meat consumption and incident type 2 diabetes: an individual-participant federated meta-analysis of 1·97 million adults with 100 000 incident cases from 31 cohorts in 20 countries

Meat consumption could increase the risk of type 2 diabetes. However, evidence is largely based on studies of European and North American populations, with heterogeneous analysis strategies and a greater focus on red meat than on poultry. We aimed to investigate the associations of unprocessed red meat, processed meat, and poultry consumption with type 2 diabetes using data from worldwide cohorts and harmonised analytical approaches. This individual-participant federated meta-analysis involved data from 31 cohorts participating in the InterConnect project. Cohorts were from the region of the Americas (n=12) and the Eastern Mediterranean (n=2), European (n=9), South-East Asia (n=1), and Western Pacific (n=7) regions. Access to individual-participant data was provided by each cohort; participants were eligible for inclusion if they were aged 18 years or older and had available data on dietary consumption and incident type 2 diabetes and were excluded if they had a diagnosis of any type of diabetes at baseline or missing data. Cohort-specific hazard ratios (HRs) and 95% CIs were estimated for each meat type, adjusted for potential confounders (including BMI), and pooled using a random-effects meta-analysis, with meta-regression to investigate potential sources of heterogeneity. Among 1 966 444 adults eligible for participation, 107 271 incident cases of type 2 diabetes were identified during a median follow-up of 10 (IQR 7-15) years. Median meat consumption across cohorts was 0-110 g/day for unprocessed red meat, 0-49 g/day for processed meat, and 0-72 g/day for poultry. Greater consumption of each of the three types of meat was associated with increased incidence of type 2 diabetes, with HRs of 1·10 (95% CI 1·06-1·15) per 100 g/day of unprocessed red meat (I2=61%), 1·15 (1·11-1·20) per 50 g/day of processed meat (I2=59%), and 1·08 (1·02-1·14) per 100 g/day of poultry (I2=68%). Positive associations between meat consumption and type 2 diabetes were observed in North America and in the European and Western Pacific regions; the CIs were wide in other regions. We found no evidence that the heterogeneity was explained by age, sex, or BMI. The findings for poultry consumption were weaker under alternative modelling assumptions. Replacing processed meat with unprocessed red meat or poultry was associated with a lower incidence of type 2 diabetes. The consumption of meat, particularly processed meat and unprocessed red meat, is a risk factor for developing type 2 diabetes across populations. These findings highlight the importance of reducing meat consumption for public health and should inform dietary guidelines. The EU, the Medical Research Council, and the National Institute of Health Research Cambridge Biomedical Research Centre.

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.

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.

Associations between modifiable risk factors and hepatocellular carcinoma: a trans-ancestry Mendelian randomization study

BackgroundPotentially modifiable risk factors for hepatocellular carcinoma (HCC) have been investigated in observational epidemiology studies in East Asian and European populations, whereas the causal associations of most of these risk factors remain unclear.MethodsWe collected genome-wide association summary statistics of 22 modifiable risk factors in East Asians and 33 risk factors in Europeans. Genetic summary statistics of HCC were sourced from the Biobank Japan study (1,866 cases and 195,745 controls) for East Asians, and the deCODE genetics study (406 cases and 49,302 controls) and the UK Biobank (168 cases and 372 016 controls) for Europeans. Two-sample Mendelian randomization (MR) analyses were performed independently for East Asian and European populations.ResultsIn East Asians, genetically predicted alcohol frequency, ever drinkers, aspartate aminotransferase (AST), hypothyroidism, chronic hepatitis B, and chronic hepatitis C, metabolic dysfunction-associated steatotic liver disease (MASLD), and autoimmune hepatitis were significantly associated with an increased HCC risk (P < 0.05/22). Among European population, alanine transaminase, AST, MASLD, percent liver fat, and liver iron content were significantly associated with a higher risk of HCC (P < 0.05/33). The replication dataset and meta-analysis further confirmed these results.ConclusionsAlthough East Asian and European populations have different factors for HCC, their common modifiable risk factors AST and MASLD for HCC, offer valuable insights for targeted intervention strategies to mitigate society burden of HCC.

Three-dimensional morphometric and volumetric analysis of maxillary sinuses.

The maxillary sinus is a pyramid-shaped cavity with varying shapes, sizes, and capacities. Its dimensions grow gradually and develop until early adulthood. Anatomical knowledge of the maxillary sinus is essential to understanding sinonasal disorders, planning surgical procedures and preventing complications. Awareness of the sinus's proximity to critical structures helps avoid injuries during surgery. The European, Korean, and Sri Lankan population study parameters show varying results and do not necessarily apply to the Indian population. The standard morphometric data of the maxillary sinus is scanty in the Indian population. The study aimed to determine the volume and morphometry of the maxillary sinus along with gender differences in the Eastern population of the Indian. A retrospective cross-sectional study was conducted using cone beam computed tomography data of maxillary sinuses of 100 normal individuals. The data were analysed after the three-dimensional reconstruction of digital imaging and communications in medicine (DICOM) images with the help of DICOM to print and Geomagic freeform software in the Anatomy department. The different linear morphometric variables and volume of the maxillary sinus were studied. SPSS version 27.0. was utilised for statistical analyses. The mean values of Antero-posterior diameter, Transverse diameter, Craniocaudal diameters, the height of ostium from the floor and volume of the maxillary sinus in males on the right side are 36.61 mm, 20.7 mm, 40.31 mm, 26.02 mm and 16055.24 mm³ and on the left side are 37.17 mm, 20.17 mm, 40.73 mm, 26.91 mm and 15712.66 mm³ whereas in females the values on the right side are 38.10 mm, 21.56 mm, 38.96 mm, 25.81 mm and 14687.78 mm³ and on left side are 38.23 mm, 21.53 mm, 38.48 mm, 25.28 mm and 14203.13 mm3 respectively. The side-to-side parameter differences were non-significant within the male and female groups, respectively. The females had significantly (p < 0.05) larger transverse diameters than males in both the right and left maxillary sinuses. The males tend to have a slightly larger mean craniocaudal diameter than females, but the difference was found statistically significant (p < 0.05) only in the left maxillary sinus. The gender differentiation based on the measured parameters of bilateral maxillary sinus accuracy rate was 89.4% in males and 61.8% in females. These parameters serve as a standard or reference point, allowing radiologists and surgeons to compare individual patient scans to population averages and aid in better clinical outcomes. The mean values of different parameters of the maxillary sinus may be utilised to differentiate various suspected sinus pathologies, which is helpful for functional endoscopic sinus surgery. Gender differentiation can be done more accurately by forensic experts using Maxillary sinus transverse diameter bilaterally, followed by craniocaudal diameter of the left side sinus for predicting the gender of an unknown maxilla.