The interaction between polyphenol intake and genes (MC4R, Cav-1, and Cry1) related to body homeostasis and cardiometabolic risk factors in overweight and obese women: a cross-sectional study.

Background: Cardiovascular disease (CVD), which is an important global health challenge, is expanding. One of the main factors in the occurrence of CVD is a high genetic risk. The interaction between genetic risk in CVD and nutrition is debatable. Polyphenols are one of the important dietary components that may have a protective role in people who have a high genetic risk score (GRS) for cardiometabolic risk factors. This study, conducted in overweight and obese women, examines the interaction between polyphenol intake and specific genes (MC4r, Cav-1, and Cry1) related to maintaining body balance and their interaction with cardiometabolic risk factors. Methods: This cross-sectional study included 391 women who were overweight or obese, aged 18 to 48 years, with a body mass index (BMI) between 25 and 40 kg/m2. Body composition was measured using the InBody 770 scanner. Total dietary polyphenol intake (TDPI) was assessed with a validated 147-item food frequency questionnaire (FFQ), and polyphenol intakes were determined using the Phenol-Explorer database. Serum samples underwent biochemical tests. The Genetic Risk Score (GRS) was calculated based on the risk alleles of three genes: MC4r, Cav-1, and Cry1. Results: The mean ± standard deviation (SD) age and BMI of women were 36.67 (9.1) years and 30.98 (3.9) kg/m2, respectively. The high GRS and high TDPI group had a significant negative interaction with fasting blood glucose (FBS) (p = 0.01). Individuals who had a high GRS and a high phenolic acid intake were found to have a significant negative interaction with Triglyceride (p = 0.04). Similarly, individuals with high GRS and a high intake of flavonoids had a significant negative interaction with TG (p < 0.01) and a significant positive interaction with High-density lipoprotein (HDL) (p = 0.01) in the adjusted model. Conclusion: According to our findings, those with a high GRS may have a protective effect on cardiometabolic risk factors by consuming high amounts of polyphenols. Further studies will be necessary in the future to validate this association.

Peer Social Genetic Effects and the Etiology of Substance Use Disorders, Major Depression, and Anxiety Disorder in a Swedish National Sample.

OBJECTIVE: There is growing interest in how peers' genotypes may influence health (i.e., peer social genetic effects). The authors sought to clarify the nature of peer social genetic effects on risk for drug use disorder, alcohol use disorder (AUD), major depression, and anxiety disorder. METHOD: Cox models were used with data from a population-based Swedish cohort (N=655,327). Outcomes were drug use disorder, AUD, major depression, and anxiety disorder registrations between ages 17 and 30 from medical, criminal, and pharmacy registries. The authors indexed peer social genetic effects with peers' family genetic risk scores (FGRSs) for the same disorders, which are personalized measures of genetic risk inferred from diagnoses in first- to fifth-degree relatives. RESULTS: Across disorders, peer FGRSs predicted increased risks of proband registration (hazard ratio range, 1.01-1.59), with stronger effects for drug use disorder and AUD than for major depression and anxiety disorder. Peer social genetic effects were stronger for school classmates than for geographically proximal peers, and for peers from upper secondary school (ages 16-19) versus peers from lower secondary school (ages 7-16). Peer social genetic effects remained significant following statistical control for sociodemographic confounders, whether peers were affected, and peers' FGRS for educational attainment. Peer social genetic effects were more pronounced for probands at higher genetic risk. CONCLUSIONS: The genetic makeup of adolescents' peers has long-reaching consequences on risks for drug use disorder, AUD, major depression, and anxiety disorder. Individuals at high genetic risk are more sensitive to social genetic effects. Alternative hypotheses such as sociodemographic stratification, exposure to affected peers, and genetic predispositions for educational attainment did not explain the risk associated with peer social genetic effects for substance use and psychiatric disorders.

The clinical utility of a glaucoma polygenic risk score in four population-based European-ancestry cohorts.

OBJECTIVE: We used a polygenic risk score (PRS) to identify high-risk groups for primary open-angle glaucoma (POAG) within population-based cohorts. DESIGN: Secondary analysis of four prospective population-based studies. PARTICIPANTS: We included four European-ancestry cohorts: the United States (US) based Nurses' Health Study (NHS), NHS2, and the Health Professionals Follow-up Study, and the Rotterdam Study (RS) in the Netherlands. The US cohorts included female nurses and male health professionals aged 55+ years. The RS included residents aged 45 years or older living in Rotterdam, the Netherlands. METHODS: PRS weights were estimated by applying the Lassosum method on imputed genotype and phenotype data from the UK-Biobank. This resulted in 144,020 variants, single nucleotide polymorphism (SNPs) and indels, with non-zero betas that we used to calculate a PRS in the target populations. Using multivariable Cox proportional hazard models, we estimated the relationship between the standardized PRS and relative risk for POAG. Additionally, POAG prediction was tested by calculating these models' concordance (Harrell's C-statistic). Finally, we assessed the association between PRS tertiles and glaucoma-related traits. MAIN OUTCOME MEASURES: The relative risk for POAG and Harrell's C-statistic (the equivalent of an area-under-the-curve for longitudinal models). RESULTS: Among 1,046 cases and 38,809‬ controls, the relative risk (95% confidence interval) for POAG for participants in the highest PRS quintile was 3.99 (3.08, 5.18) in the US cohorts, and 4.89 (2.93, 8.17) in the Rotterdam Study, compared with participants with median genetic risk (3rd quintile). In restricted cubic spline analyses, the relation between continuous PRS and POAG risk increased exponentially in the US and Rotterdam cohorts (Pspline<0.05). Combining age, sex, intraocular pressure >25 mmHg, and family history resulted in a meta-analyzed concordance of 0.75 (0.73, 0.75). Adding the PRS to this model improved the concordance to 0.82 (0.80, 0.84). In a meta-analysis of all cohorts, cases in the highest tertile had a larger cup-disc ratio at diagnosis, by 0.11 (0.07, 0.15), and a 2.07-fold increased risk of requiring glaucoma surgery (1.19, 3.60). CONCLUSIONS: Incorporating a PRS into a POAG predictive model improves identification concordance from 0.75 up to 0.82, supporting its potential for guiding more cost-effective screening strategies.

Genetic Risk Stratification of Primary Open-Angle Glaucoma in Japanese Individuals.

PURPOSE: To assess the impact of genetic risk estimation for primary open-angle glaucoma (POAG) in Japanese individuals. DESIGN: Cross-sectional analysis. PARTICIPANTS: Genetic risk scores (GRSs) were constructed based on a genome-wide association study (GWAS) of POAG in Japanese people. A total of 3625 Japanese individuals, including 1191 patients and 2434 controls (Japanese Tohoku), were used for the model selection. We also evaluated the discriminative accuracy of constructed GRSs in a dataset comprising 1034 patients and 1147 controls (the Japan Glaucoma Society Omics Group [JGS-OG] and the Genomic Research Committee of the Japanese Ophthalmological Society [GRC-JOS]) and 1900 participants from a population-based study (Hisayama Study). METHODS: We evaluated 2 types of GRSs: polygenic risk scores using the pruning and thresholding procedure and a GRS using variants associated with POAG in the GWAS of the International Glaucoma Genetics Consortium (IGGC). We selected the model with the highest areas under the receiver operating characteristic curve (AUC). In the population-based study, we evaluated the correlations between GRS and ocular measurements. MAIN OUTCOME MEASURE: Proportion of patients with POAG after stratification according to the GRS. RESULTS: We found that a GRS using 98 variants, which showed genome-wide significance in the IGGC, showed the best discriminative accuracy (AUC, 0.65). In the Japanese Tohoku, the proportion of patients with POAG in the top 10% individuals was significantly higher than that in the lowest 10% (odds ratio [OR], 6.15; 95% confidence interval [CI], 4.35-8.71). In the JGS-OG and GRC-JOS, we confirmed similar impact of POAG GRS (AUC, 0.64; OR [top vs. bottom decile], 5.81; 95% CI, 3.79-9.01). In the population-based study, POAG prevalence was significantly higher in the top 20% individuals of the GRS compared with the bottom 20% (9.2% vs. 5.0%). However, the discriminative accuracy was low (AUC, 0.56). The POAG GRS was correlated positively with intraocular pressure (r = 0.08: P = 4.0 × 10-4) and vertical cup-to-disc ratio (r = 0.11; P = 4.0 × 10-6). CONCLUSIONS: The GRS showed moderate discriminative accuracy for POAG in the Japanese population. However, risk stratification in the general population showed relatively weak discriminative performance. FINANCIAL DISCLOSURE(S): Proprietary or commercial disclosure may be found in the Footnotes and Disclosures at the end of this article.

Comparative analysis of genetic risk scores for predicting biochemical recurrence in prostate cancer patients after radical prostatectomy.

BACKGROUND: In recent years, Genome-Wide Association Studies (GWAS) has identified risk variants related to complex diseases, but most genetic variants have less impact on phenotypes. To solve the above problems, methods that can use variants with low genetic effects, such as genetic risk score (GRS), have been developed to predict disease risk. METHODS: As the GRS model with the most incredible prediction power for complex diseases has not been determined, our study used simulation data and prostate cancer data to explore the disease prediction power of three GRS models, including the simple count genetic risk score (SC-GRS), the direct logistic regression genetic risk score (DL-GRS), and the explained variance weighted GRS based on directed logistic regression (EVDL-GRS). RESULTS AND CONCLUSIONS: We used 26 SNPs to establish GRS models to predict the risk of biochemical recurrence (BCR) after radical prostatectomy. Combining clinical variables such as age at diagnosis, body mass index, prostate-specific antigen, Gleason score, pathologic T stage, and surgical margin and GRS models has better predictive power for BCR. The results of simulation data (statistical power = 0.707) and prostate cancer data (area under curve = 0.8462) show that DL-GRS has the best prediction performance. The rs455192 was the most relevant locus for BCR (p = 2.496 × 10-6) in our study.

Evidence of gene-nutrient interaction association with waist circumference, cross-sectional analysis.

BACKGROUND AND AIMS: Waist circumference (WC) is a significant indicator of body adiposity and is associated with increased mortality and morbidity of cardiovascular diseases. Although, single nutrient intake and candidate genes were previously associated with WC. Little is known about WC association with overall diet quality, genetic risk score and gene-nutrient interaction. This study aims to investigate the influence of overall diet quality and multiple WC-associated single nucleotide polymorphisms on WC. In addition to investigating gene-nutrient interaction association with WC. METHODS: This study explored cross-sectional data from two large sample-size studies, to provide reproducible results. As a representation of the UK population, the Airwave Health Monitoring Study (n = 6,502) and the UK-Biobank Cohort Study (n = 171,129) were explored for factors associated with WC. Diet quality was evaluated based on the Mellen Index for Dietary Approaches to Stop Hypertension (Mellen-DASH). The genetic risk score for WC (GRS-Waist) was calculated by screening the population genotype for WC-associated single nucleotide polymorphisms. Multivariate linear regression models were built to explore WC association with diet quality and genetic risk score. Gene-nutrient interaction was explored by introducing the interaction term (GRS-Waist X Mellen-DASH score) to multivariate linear regression analysis. RESULTS: The prevalence of high WC (Female > 80 cm, Male > 94 cm) was 46.5% and 51.7% in both populations. Diet quality and genetic risk score of WC were significantly associated with WC. There was no evidence of interaction between GRS-Waist, DASH diet scores and nutrient intake on WC. CONCLUSION: This study's findings provided reproducible results on waist circumference association with diet and genetics and tested the possibility of gene-nutrient interaction. These reproducible results are successful in building the foundation for using diet and genetics for early identification of those at risk of having high WC and WC-associated diseases. In addition, evidence on gene-diet interactions on WC is limited and lacks replication, therefore our findings may guide future research in investigating this interaction and investigating its application in precision nutrition.

Combination of risk alleles of PNPLA3, TM6SF2, and HSD17B13 of donors can predict recurrence of steatotic liver disease after liver transplantation.

AIMS: This study aimed to identify the genetic risk factors from donors or recipients that contribute to postliver transplantation (LT) steatotic liver disease (SLD), focusing on the genetic risk score (GRS) based on single nucleotide polymorphisms (SNPs) in SLD patients. METHODS: This retrospective study included 55 Japanese SLD recipients and their respective donors. Genotyping of PNPLA3, TM6SF2, and HSD17B13 was undertaken, and the combined GRS was calculated. The relationship between the GRS and the incidence of posttransplant SLD was also evaluated. RESULTS: The SLD recipients had a high prevalence of post-LT graft steatosis/steatohepatitis (76.4% and 58.2%, respectively). Although the recipients had a high frequency of risk alleles, there was no relationship between the number of risk alleles for each SNP and the incidence of posttransplant SLD. In contrast, an increased number of risk alleles for any SNP in the donor was correlated with high incidence rates of both post-LT steatosis and steatohepatitis. A multivariable analysis showed that a high donor GRS was an independent risk factor for graft steatosis (odds ratio 8.77; 95% CI, 1.94-52.94; p = 0.009). Similarly, a high donor GRS was an independent risk factor (odds ratio 6.76; 95% CI, 1.84-30.78; p = 0.007) for post-LT graft steatohepatitis. CONCLUSIONS: Donor risk alleles of PNPLA3, TM6SF2, and HSD17B13, rather than recipient risk alleles, have been implicated in the development of posttransplant SLD. The combination of these donor risk alleles into a GRS could predict the development of posttransplant SLD.

Effect of disclosing a polygenic risk score for coronary heart disease on adverse cardiovascular events: 10-year follow-up of the MI-GENES randomized clinical trial.

Background: The MI-GENES clinical trial (NCT01936675), in which participants at intermediate risk of coronary heart disease (CHD) were randomized to receive a Framingham risk score (FRSg, n=103), or an integrated risk score (IRSg, n=104) that additionally included a polygenic risk score (PRS), demonstrated that after 6 months, participants randomized to IRSg had higher statin initiation and lower low-density lipoprotein cholesterol (LDL-C). Objectives: In a post hoc 10-year follow-up analysis of the MI-GENES trial, we investigated whether disclosure of a PRS for CHD was associated with a reduction in adverse cardiovascular events. Methods: Participants were followed from randomization beginning in October 2013 until September 2023 to ascertain adverse cardiovascular events, testing for CHD, and changes in risk factors, by blinded review of electronic health records. The primary outcome was the time from randomization to the occurrence of the first major adverse cardiovascular event (MACE), defined as cardiovascular death, non-fatal myocardial infarction, coronary revascularization, and non-fatal stroke. Statistical analyses were conducted using Cox proportional hazards regression and linear mixed-effects models. Results: We followed all 203 participants who completed the MI-GENES trial, 100 in FRSg and 103 in IRSg (mean age at the end of follow-up: 68.2±5.2, 48% male). During a median follow-up of 9.5 years, 9 MACEs occurred in FRSg and 2 in IRSg (hazard ratio (HR), 0.20; 95% confidence interval (CI), 0.04 to 0.94; P=0.042). In FRSg, 47 (47%) underwent at least one test for CHD, compared to 30 (29%) in IRSg (HR, 0.51; 95% CI, 0.32 to 0.81; P=0.004). IRSg participants had a longer duration of statin therapy during the first four years post-randomization and a greater reduction in LDL-C for up to 3 years post-randomization. No significant differences between the two groups were observed for hemoglobin A1C, systolic and diastolic blood pressures, weight, and smoking cessation rate during follow-up. Conclusions: The disclosure of an IRS that included a PRS to individuals at intermediate risk for CHD was associated with a lower incidence of MACE after a decade of follow-up, likely due to a higher rate of initiation and longer duration of statin therapy, leading to lower LDL-C levels.

Genetic distance and ancestry proportion modify the association between maternal genetic risk score of type 2 diabetes and fetal growth.

BACKGROUND: Maternal genetic risk of type 2 diabetes (T2D) has been associated with fetal growth, but the influence of genetic ancestry is not yet fully understood. We aimed to investigate the influence of genetic distance (GD) and genetic ancestry proportion (GAP) on the association of maternal genetic risk score of T2D (GRST2D) with fetal weight and birthweight. METHODS: Multi-ancestral pregnant women (n = 1,837) from the NICHD Fetal Growth Studies - Singletons cohort were included in the current analyses. Fetal weight (in grams, g) was estimated from ultrasound measurements of fetal biometry, and birthweight (g) was measured at delivery. GRST2D was calculated using T2D-associated variants identified in the latest trans-ancestral genome-wide association study and was categorized into quartiles. GD and GAP were estimated using genotype data of four reference populations. GD was categorized into closest, middle, and farthest tertiles, and GAP was categorized as highest, medium, and lowest. Linear regression analyses were performed to test the association of GRST2D with fetal weight and birthweight, adjusted for covariates, in each GD and GAP category. RESULTS: Among women with the closest GD from African and Amerindigenous ancestries, the fourth and third GRST2D quartile was significantly associated with 5.18 to 7.48 g (weeks 17-20) and 6.83 to 25.44 g (weeks 19-27) larger fetal weight compared to the first quartile, respectively. Among women with middle GD from European ancestry, the fourth GRST2D quartile was significantly associated with 5.73 to 21.21 g (weeks 18-26) larger fetal weight. Furthermore, among women with middle GD from European and African ancestries, the fourth and second GRST2D quartiles were significantly associated with 117.04 g (95% CI = 23.88-210.20, p = 0.014) and 95.05 g (95% CI = 4.73-185.36, p = 0.039) larger birthweight compared to the first quartile, respectively. The absence of significant association among women with the closest GD from East Asian ancestry was complemented by a positive significant association among women with the highest East Asian GAP. CONCLUSIONS: The association between maternal GRST2D and fetal growth began in early-second trimester and was influenced by GD and GAP. The results suggest the use of genetic GD and GAP could improve the generalizability of GRS.

Addressing causal relationship between drinking behavior and metabolic syndrome: one-sample Mendelian randomization analysis.

AIMS: Alcohol drinking is associated with central obesity, hypertension, and hyperlipidemia, which further causes metabolic syndrome (MetS). However, prior epidemiological studies on such associations lack experimental evidence for a causal relationship. This study aims to explore the causal relationship between drinking behavior and MetS in Taiwan population by using Mendelian randomization (MR) analysis. METHODS: A cross-sectional study was conducted using the Taiwan Biobank database, which comprised 50 640 Han Chinese who were 30-70 years old without cancer from 2008 to 2020. In MR analysis, we constructed weighted and unweighted genetic risk scores by calculating SNP alleles significantly associated with alcohol drinking. We calculated odds ratios and 95% confidence interval (CI) by using a two-stage regression model. RESULTS: A total of 50 640 participants were included with a mean age of 49.5 years (SD: 1.67 years), 36.6% were men. The adjusted odds ratio (aOR) of MetS per 5% increase in the likelihood of genetic predisposition to drink based on weighted genetic risk score with adjustment was 1.11 (95% CI: 1.10, 1.12, P < .001). Analysis was also conducted by grouping the likelihood of genetic predisposition to drink based on quartiles with multivariate adjustment. Using Q1 as the reference group, the aORs of MetS for Q2, Q3, and Q4 were 1.19 (1.12, 1.27, p < .001), 1.31 (1.23, 1.40, p < .001), and 1.87 (1.75, 2.00, p < .001), respectively, for the weighted genetic risk score. CONCLUSIONS: This study shows a modest relationship between drinking behavior and MetS by using MR analysis.

Hospital-treated infectious diseases, genetic susceptibility and risk of type 2 diabetes: A population-based longitudinal study.

BACKGROUND: The longitudinal association between infectious diseases and the risk of type 2 diabetes (T2D) remains unclear. METHODS: Based on the UK Biobank, the prospective cohort study included a total of 396,080 participants without diabetes at baseline. We determined the types and sites of infectious diseases and incident T2D using the International Classification of Diseases 10th Revision codes (ICD-10). Time-varying Cox proportional hazard model was used to assess the association. Infection burden was defined as the number of infection episodes over time and the number of co-occurring infections. Genetic risk score (GRS) for T2D consisted of 424 single nucleotide polymorphisms. RESULTS: During a median of 9.04 [IQR, 8.3-9.7] years of follow-up, hospital-treated infectious diseases were associated with a greater risk of T2D (adjusted HR [aHR] 1.54 [95 % CI 1.46-1.61]), with risk difference per 10,000 individuals equal to 154.1 [95 % CI 140.7-168.2]. The heightened risk persisted after 5 years following the index infection. Bacterial infection with sepsis had the strongest risk of T2D (aHR 2.95 [95 % CI 2.53-3.44]) among different infection types. For site-specific analysis, bloodstream infections posed the greatest risk (3.01 [95 % CI 2.60-3.48]). A dose-response association was observed between infection burden and T2D risk within each GRS tertile (p-trend <0.001). High genetic risk and infection synergistically increased the T2D risk. CONCLUSION: Infectious diseases were associated with an increased risk of subsequent T2D. The risk showed specificity according to types, sites, severity of infection and the period since infection occurred. A potential accumulative effect of infection was revealed.

The role of genetically-influenced phospholipid transfer protein activity in lipoprotein metabolism and coronary artery disease.

BACKGROUND: Phospholipid transfer protein (PLTP) transfers surface phospholipids between lipoproteins and as such plays a role in lipoprotein metabolism, but with unclear effects on coronary artery disease (CAD) risk. We aimed to investigate the associations of genetically-influenced PLTP activity with 1-H nuclear magnetic resonance (1H-NMR) metabolomic measures and with CAD. Furthermore, using factorial Mendelian randomization (MR), we examined the potential additional effect of genetically-influenced PLTP activity on CAD risk on top of genetically-influenced low-density lipoprotein-cholesterol (LDL-C) lowering. METHODS: Using data from UK Biobank, genetic scores for PLTP activity and LDL-C were calculated and dichotomised based on the median, generating four groups with combinations of high/low PLTP activity and high/low LDL-C levels for the factorial MR. Linear and logistic regressions were performed on 168 metabolomic measures (N = 58,514) and CAD (N = 318,734, N-cases=37,552), respectively, with results expressed as ß coefficients (in standard deviation units) or odds ratios (ORs) and 95% confidence interval (CI). RESULTS: Irrespective of the genetically-influenced LDL-C, genetically-influenced low PLTP activity was associated with a higher HDL particle concentration (ß [95% CI]: 0.03 [0.01, 0.05]), smaller HDL size (-0.14 [-0.15, -0.12]) and higher triglyceride (TG) concentration (0.04 [0.02, 0.05]), but not with CAD (OR 0.99 [0.97, 1.02]). In factorial MR analyses, genetically-influenced low PLTP activity and genetically-influenced low LDL-C had independent associations with metabolomic measures, and genetically-influenced low PLTP activity did not show an additional effect on CAD risk. CONCLUSIONS: Low PLTP activity associates with higher HDL particle concentration, smaller HDL particle size and higher TG concentration, but no association with CAD risk was observed.

Characterizing the Relationship between Expression Quantitative Trait Loci (eQTLs), DNA Methylation Quantitative Trait Loci (mQTLs), and Breast Cancer Risk Variants.

PURPOSE: To assess the association of a polygenic risk score (PRS) for functional genetic variants with the risk of developing breast cancer. METHODS: Summary data-based Mendelian randomization (SMR) and heterogeneity in dependent instruments (HEIDI) were used to identify breast cancer risk variants associated with gene expression and DNA methylation levels. A new SMR-based PRS was computed from the identified variants (functional PRS) and compared to an established 313-variant breast cancer PRS (GWAS PRS). The two scores were evaluated in 3560 breast cancer cases and 3383 non-cancer controls and also in a prospective study (n = 10,213) comprising 418 cases. RESULTS: We identified 149 variants showing pleiotropic association with breast cancer risk (eQTLHEIDI > 0.05 = 9, mQTLHEIDI > 0.05 = 165). The discriminatory ability of the functional PRS (AUCcontinuous [95% CI]: 0.540 [0.526 to 0.553]) was found to be lower than that of the GWAS PRS (AUCcontinuous [95% CI]: 0.609 [0.596 to 0.622]). Even when utilizing 457 distinct variants from both the functional and GWAS PRS, the combined discriminatory performance remained below that of the GWAS PRS (AUCcontinuous, combined [95% CI]: 0.561 [0.548 to 0.575]). A binary high/low-risk classification based on the 80th centile PRS in controls revealed a 6% increase in cases using the GWAS PRS compared to the functional PRS. The functional PRS identified an additional 12% of high-risk cases but also led to a 13% increase in high-risk classification among controls. Similar findings were observed in the SCHS prospective cohort, where the GWAS PRS outperformed the functional PRS, and the highest-performing PRS, a combined model, did not significantly improve over the GWAS PRS. CONCLUSIONS: While this study identified potentially functional variants associated with breast cancer risk, their inclusion did not substantially enhance the predictive accuracy of the GWAS PRS.

Islet autoantibody frequency in relatives of children with type 1 diabetes who have a type 2 diabetes diagnosis.

AIM: This study aimed to evaluate characteristics of autoimmunity in individuals who have a type 2 diagnosis and are relatives of children with type 1 diabetes. METHODS: Pre-diagnosis samples (median 17 months before onset) from relatives who were later diagnosed with type 2 diabetes were measured for autoantibodies to glutamate decarboxylase 65 (GADA), islet antigen-2 (IA-2A), zinc transporter 8 (ZnT8A) and insulin (IAA) as well as the type 1 diabetes genetic risk score (GRS2). Associations between islet autoantibodies, insulin treatment and GRS2 were analysed using Fisher's exact and t-tests. RESULTS: Among 226 relatives (64% men; mean age at sampling 41 years; mean age 54 years at diagnosis), 32 (14%) were islet autoantibody-positive for at least one autoantibody more than a decade before diagnosis. Approximately half of these (n = 15) were treated with insulin. GADA-positivity was higher in insulin-treated relatives than in non-insulin-treated relatives (12/18 [67%] vs. 6/18 [33%], p < 0.001). IAA-positivity was observed in 13/32 (41%) of relatives with autoantibodies. GRS2 scores were increased in autoantibody-positive relatives (p = 0.032), but there was no clear evidence for a difference according to treatment (p = 0.072). CONCLUSION: This study highlights the importance of measuring islet autoantibodies, including IAA, in relatives of people with type 1 diabetes to avoid misdiagnosis.

T2DM/CKD genetic risk scores and the progression of diabetic kidney disease in T2DM subjects.

This study aimed at understanding the predictive potential of genetic risk scores (GRS) for diabetic kidney disease (DKD) progression in patients with type 2 diabetes mellitus (T2DM) and Major Cardiovascular Events (MCVE) and All-Cause Mortality (ACM) as secondary outcomes. We evaluated 30 T2DM and CKD GWAS-derived single nucleotide polymorphisms (SNPs) and their association with clinical outcomes in a central European cohort (n = 400 patients). Our univariate Cox analysis revealed significant associations of age, duration of diabetes, diastolic blood pressure, total cholesterol and eGFR with progression of DKD (all P < 0.05). However, no single SNP was conclusively associated with progression to DKD, with only CERS2 and SHROOM3 approaching statistical significance. While a single SNP was associated with MCVE - WSF1 (P = 0.029), several variants were associated with ACM - specifically CANCAS1, CERS2 and C9 (all P < 0.02). Our GRS did not outperform classical clinical factors in predicting progression to DKD, MCVE or ACM. More precisely, we observed an increase only in the area under the curve (AUC) in the model combining genetic and clinical factors compared to the clinical model alone, with values of 0.582 (95 % CI 0.487-0.676) and 0.645 (95 % CI 0.556-0.735), respectively. However, this difference did not reach statistical significance (P = 0.06). This study highlights the complexity of genetic predictors and their interplay with clinical factors in DKD progression. Despite the promise of personalised medicine through genetic markers, our findings suggest that current clinical factors remain paramount in the prediction of DKD. In conclusion, our results indicate that GWAS-derived GRSs for T2DM and CKD do not offer improved predictive ability over traditional clinical factors in the studied Czech T2DM population.

Efeitos de Longo Prazo do Implante Valvar Pulmonar e Evolução da Prótese em Pacientes com Tetralogia de Fallot Corrigida / Long-Term Effects of Pulmonary Valve Implantation and Prosthesis Evolution in Patients with Repaired Tetralogy of Fallot

Resumo Fundamento A regurgitação valvar pulmonar é uma importante complicação de longo prazo em pacientes com tetralogia de Fallot (TF). Objetivo O presente estudo tem como objetivo investigar os efeitos do implante valvar pulmonar (IVP) na anatomia e função do ventrículo direito (VD) e na evolução em longo prazo da prótese implantada em posição pulmonar. Métodos Uma análise de coorte retrospectiva e unicêntrica foi realizada em 56 pacientes consecutivos com TF submetidos a IVP. O estudo incluiu pacientes de ambos os gêneros, com idade ≥ 12 anos e compreendeu avaliação de dados clínicos e cirúrgicos, ressonância magnética cardiovascular pré e pós-operatória e dados ecocardiográficos obtidos mais de 1 ano após IVP. Resultados Após o IVP, houve uma diminuição significativa do volume sistólico final do VD indexado pela área de superfície corpórea (ASC), de 89 mL/ASC para 69 mL/ASC (p < 0,001) e do volume diastólico final indexado do VD, de 157 mL/ASC para 116 mL/ASC (p < 0,001). Além disso, houve aumento da fração de ejeção corrigida do VD [ FEVDc = fluxo pulmonar ajustado (fluxo pulmonar anterógrado − fluxo regurgitante) / volume diastólico final do VD ] de 23% para 35% (p < 0,001) e da fração de ejeção do ventrículo esquerdo de 58% para 60% (p = 0,008). No entanto, foi observado um aumento progressivo no gradiente de pico da válvula pulmonar ao longo do tempo, com 25% dos pacientes apresentando um gradiente superior a 60 mmHg. Próteses menores (tamanhos 19 a 23) foram associadas a um risco 4,3 vezes maior de gradiente > 60 mmHg em comparação com próteses maiores (tamanhos 25 a 27; p = 0,029; intervalo de confiança: 1,18 a 17,8). Conclusão Conforme esperado, o IVP demonstrou melhorias nos volumes e na função do VD. O acompanhamento e a vigilância a longo prazo são cruciais para avaliar a durabilidade da prótese e detectar potenciais complicações. O dimensionamento adequado das próteses é essencial para melhorar a longevidade da prótese.

Abstract Background Pulmonary valve regurgitation is a significant long-term complication in patients with tetralogy of Fallot (TOF). Objective This study aims to investigate the effects of pulmonary valve implantation (PVI) on the anatomy and function of the right ventricle (RV) and the long-term evolution of the implanted prosthesis in the pulmonary position. Methods A single-center retrospective cohort analysis was performed in 56 consecutive patients with TOF who underwent PVI. The study included patients of both sexes, aged ≥ 12 years, and involved assessing clinical and surgical data, pre- and post-operative cardiovascular magnetic resonance imaging, and echocardiogram data more than 1 year after PVI. Results After PVI, there was a significant decrease in RV end-systolic volume indexed by body surface area (BSA), from 89 mL/BSA to 69 mL/BSA (p < 0.001) and indexed RV end-diastolic volume, from 157 mL/BSA to 116 mL/BSA (p < 0.001). Moreover, there was an increase in corrected RV ejection fraction [ RVEFC = net pulmonary flow (pulmonary forward flow − regurgitant flow) / R V end-diastolic volume] from 23% to 35% (p < 0.001) and left ventricular ejection fraction from 58% to 60% (p = 0.008). However, a progressive increase in the peak pulmonary valve gradient was observed over time, with 25% of patients experiencing a gradient exceeding 60 mmHg. Smaller prostheses (sizes 19 to 23) were associated with a 4.3-fold higher risk of a gradient > 60 mmHg compared to larger prostheses (sizes 25 to 27; p = 0.029; confidence interval: 1.18 to 17.8). Conclusion As expected, PVI demonstrated improvements in RV volumes and function. Long-term follow-up and surveillance are crucial for assessing the durability of the prosthesis and detecting potential complications. Proper sizing of prostheses is essential for improved prosthesis longevity.

A polygenetic risk score combined with environmental factors better predict susceptibility to hepatocellular carcinoma in Chinese population.

AIMS: This study aimed to investigate environmental factors and genetic variant loci associated with hepatocellular carcinoma (HCC) in Chinese population and construct a weighted genetic risk score (wGRS) and polygenic risk score (PRS). METHODS: A case-control study was applied to confirm the single nucleotide polymorphisms (SNPs) and environmental variables linked to HCC in the Chinese population, which had been screened by meta-analyses. wGRS and PRS were built in training sets and validation sets. Area under the curve (AUC), net reclassification improvement (NRI), integrated discrimination improvement (IDI), Akaike information criterion (AIC), and Bayesian information criterion (BIC) were applied to evaluate the performance of the models. RESULTS: A total of 13 SNPs were included in both risk prediction models. Compared with wGRS, PRS had better accuracy and discrimination ability in predicting HCC risk. The AUC for PRS in combination with drinking history, cirrhosis, HBV infection, and family history of HCC in training sets and validation sets (AUC: 0.86, 95% CI: 0.84-0.89; AUC: 0.85, 95% CI: 0.81-0.89) increased at least 20% than the AUC for PRS alone (AUC: 0.63, 95% CI: 0.60-0.67; AUC: 0.65, 95% CI: 0.60-0.71). CONCLUSIONS: A novel model combining PRS with alcohol history, HBV infection, cirrhosis, and family history of HCC could be applied as an effective tool for risk prediction of HCC, which could discriminate at-risk individuals for precise prevention.

Sex-specific associations between air pollutants and asthma prevalence in Japanese adults: a population-based study.

This study investigated the association between air pollutants and asthma prevalence in male and female Japanese adults. In this retrospective cross-sectional analysis, annual mean exposure levels of air pollutants, specifically nitrogen dioxide (NO2) and particulate matter with a median aerodynamic diameter ≤2.5 µm (PM2.5), were assessed at a local monitoring site. Multivariable logistic regression models, adjusted for genetic and/or lifestyle factors, were used to explore the association between air pollutants and asthma, with stratification by sex. A total of 1,497 participants aged ≥40 years were included. Their mean age was 65.9 ± 12.4 years, with 847 being women. Overall, 91 participants were diagnosed with asthma. In the multivariable model, ambient exposure levels of NO2 and PM2.5 were significantly associated with asthma in women but not in men. This study highlights sex as a significant determinant of the link between air pollutants and asthma exacerbation, particularly among female Japanese adults.

Outdoor walking, genetic predisposition, and the risk of incident osteoporosis among older adults: A prospective large population-based cohort study.

This large-scale prospective study showed that a significant association between longer duration of daily outdoor walking and reduced osteoporosis risk was found among older adults, particularly among those with a low genetic predisposition to osteoporosis, which highlighted the importance of outdoor walking as a simple, cost-effective adjunct for preventing osteoporosis. PURPOSE: The available cross-sectional data and small-scale studies indicate that outdoor walking benefits bone metabolism. Nevertheless, there is a scarcity of comprehensive prospective research investigating the enduring correlation between outdoor walking and osteoporosis. This study aims to conduct a prospective analysis of the correlation between outdoor walking and osteoporosis while also examining potential variations influenced by genetic susceptibility to osteoporosis. METHODS: 24,700 older adults without osteoporosis at baseline were enrolled. These individuals were followed up until December 31, 2021, during which data on outdoor walking was gathered. The genetic risk score for osteoporosis was comprised of 14 single-nucleotide polymorphisms. RESULTS: 4,586 cases of osteoporosis were identified throughout a median follow-up period of 37.3 months. Those who walked outside for > 30 but ≤ 60 min per day had a hazard ratio (HR) of 0.83 (95% confidence interval (CI): 0.72-0.95) for incident osteoporosis, whereas those who walked outside for > 60 min per day had an HR of 0.60 (95% CI: 0.39-0.92). We found that osteoporosis risk exhibited a declining trend in individuals with low genetic risk. Individuals walking outside for > 60 min per day tended to have the lowest overall osteoporosis risk among those with high genetic risk. CONCLUSIONS: A significant negative correlation exists between an extended period of daily outdoor walking and osteoporosis incidence risk. This correlation is particularly pronounced among individuals with low genetic risk. The results above underscore the significance of outdoor walking as a simple and economical adjunct to public health programs to prevent osteoporosis.

Brugada syndrome in Japan and Europe: a genome-wide association study reveals shared genetic architecture and new risk loci.

BACKGROUND AND AIMS: Brugada syndrome (BrS) is an inherited arrhythmia with a higher disease prevalence and more lethal arrhythmic events in Asians than in Europeans. Genome-wide association studies (GWAS) have revealed its polygenic architecture mainly in European populations. The aim of this study was to identify novel BrS-associated loci and to compare allelic effects across ancestries. METHODS: A GWAS was conducted in Japanese participants, involving 940 cases and 1634 controls, followed by a cross-ancestry meta-analysis of Japanese and European GWAS (total of 3760 cases and 11 635 controls). The novel loci were characterized by fine-mapping, gene expression, and splicing quantitative trait associations in the human heart. RESULTS: The Japanese-specific GWAS identified one novel locus near ZSCAN20 (P = 1.0 × 10-8), and the cross-ancestry meta-analysis identified 17 association signals, including six novel loci. The effect directions of the 17 lead variants were consistent (94.1%; P for sign test = 2.7 × 10-4), and their allelic effects were highly correlated across ancestries (Pearson's R = .91; P = 2.9 × 10-7). The genetic risk score derived from the BrS GWAS of European ancestry was significantly associated with the risk of BrS in the Japanese population [odds ratio 2.12 (95% confidence interval 1.94-2.31); P = 1.2 × 10-61], suggesting a shared genetic architecture across ancestries. Functional characterization revealed that a lead variant in CAMK2D promotes alternative splicing, resulting in an isoform switch of calmodulin kinase II-δ, favouring a pro-inflammatory/pro-death pathway. CONCLUSIONS: This study demonstrates novel susceptibility loci implicating potentially novel pathogenesis underlying BrS. Despite differences in clinical expressivity and epidemiology, the polygenic architecture of BrS was substantially shared across ancestries.