Genetic Risk Research Articles

An Integrative Migraine Polygenic Risk Score Is Associated with Age at Onset But Not Chronification.

Background/Objective: Genome-wide association studies (GWASs) demonstrate a complex genetic landscape for migraine risk. Migraine polygenic risk scores (PRSs) developed from GWAS data may have utility for predicting disease course. We analyzed the strength of association between an integrative migraine PRS and age at onset and chronification. Methods: In this retrospective clinical/genetic case-control study, PGS004799 was calculated for adults with European ancestry from two real-world community cohorts. In the DodoNA cohort, 1653 treated, deeply phenotyped migraine cases, diagnosed using International Classification of Headache Disorders 3rd edition criteria, were followed for a mean (range) of 2.3 (1-10) years and compared to 3460 controls (without migraine diagnosis). In the GHI cohort, 2443 cases were identified using the first migraine ICD code as a proxy for migraine onset and compared to 8576 controls (without migraine ICD codes). PRS associations with age at onset (DodoNA) or first migraine ICD code (GHI) and chronification (DodoNA) were evaluated. Results: In both cohorts, PRS was higher in cases (DodoNA mean (range) cases: 0.82 (0.07-1.76), controls: 0.78 (0.04-1.56); t (5111) = -6.1, p = 1.4 × 10-9, GHI: cases: 0.79 (0.003-1.68), controls: 0.75 (-0.06-1.53); t (11,017) = -7.69, p = 1.6 × 10-14), and a higher PRS was associated with earlier onset in females (HR [95% CI] DodoNA: 2.1 [1.6-2.6, p < 0.001; GHI: 1.8 [1.4-2.1], p < 0.001) and in males (DodoNA: 2.5 [1.3-4.7], p = 0.005; GHI: 1.6 [1.1-2.6], p = 0.027). PRS was not different in cases with or without chronification (t (1651) = -1.67, p = 0.094) and was not associated with earlier chronification (1.2 [0.8-1.6], p = 0.424). Conclusions: Higher genetic risk was associated with earlier onset and increased risk of migraine well into adulthood, but not with chronification. This suggests that the PRS quantifies genetic susceptibility that is distinct from factors influencing disease course.

Clinical management model for impulse control disorders in Parkinson's disease.

Over the last decade, we have gained a better understanding of impulse control disorder in Parkinson's disease (PD-ICD), a medication complication in PD. Researchers were aware of its complexity and took efforts to learn more about its diagnostic and treatment possibilities. Nevertheless, clinical management for it is currently neglected. We conducted a narrative overview of literature published from 2012 to October 2023 on various aspects of clinical management for PD-ICD. A potential "susceptibility-catalytic-stress" model in the development of PD-ICD was proposed and a profile encoding predictors for PD-ICD was created. Based on these predictors, some methods for prediction were recently developed for better prediction, such as the polymorphic dopamine genetic risk score and the clinic-genetic ICD-risk score. A variety of treatment options, including dose reduction of dopamine receptor agonists (DAs), DAs removal, DAs switch, and add-on therapy, are investigated with inconsistent reports. Based on current findings, we developed a clinical management model prototype centered on prevention, consisting of prediction, prevention, follow-up and monitoring, therapy, and recurrence prevention, for clinical reference, and further proposed 4 key clinical management principles, including standardization, prediction centered, persistence, and whole course.

Polygenic risk score for prediction of atrial fibrillation according to presence of the hypertrophic cardiomyopathy

Abstract Background The significance of genetic predisposition in predicting atrial fibrillation (AF) is well recognized, yet its role in hypertrophic cardiomyopathy (HCM) patients remains less clear. Objective In this study, we aimed to elucidate the impact of genetic risk on the development of AF in both HCM and non-HCM patients. Methods This retrospective analysis examined 1,180 HCM patients (mean age 61.1±7.1, 63.0% male) and 476,238 non-HCM patients (mean age 57.0±8.1, 45.3% male) from the UK Biobank. Participants were stratified based on their validated polygenic risk score (PRS) for AF: the bottom 10% constituted the low genetic risk group, the top 10% comprised the high genetic risk group, and the remainder fell into the intermediate genetic risk group. We assessed the incidence of AF and major cardiovascular events and analyzed predictors, including genetic risk. Results Among HCM patients, no significant differences in baseline characteristics were observed based on genetic risk, except for the rate of CIED implantation (P=0.036). Conversely, among non-HCM patients, variations in age, gender, and comorbidities were noted according to genetic risk. The HCM patients were categorized into three groups based on risk, with respective AF incidence rates of 2.4, 3.6, and 5.4 events per 100 person-years, respectively. In non-HCM patients, the incidence of AF per 100 person-years was 0.2, 0.5, and 1.0, respectively. Genetic risk emerged as a significant predictor of AF in both HCM and non-HCM patients, although with a higher hazard ratio observed in non-HCM patient (HR, 2.51; 95% CI, 1.59–3.98 vs. HR, 4.77; 95% CI, 4.47–5.09) (P=0.003 for interaction). In non-HCM patients, predictors of AF included age, male sex, body mass index, smoking history, and a history of hypertension, diabetes, heart failure, stroke, and myocardial infarction, in addition to PRS. However, in HCM patients, only age, diabetes, and a history of stroke were identified as independent predictors of AF. Moreover, high genetic risk was significantly associated with the risk of major adverse cardiovascular events. Conclusions In conclusion, our study indicates associations between genetic predisposition and AF occurrence in both HCM and non-HCM patients.

Genetic and lifestyle risks for coronary artery disease and risk of incident dementia

Abstract Background Lifestyle risk factors for coronary artery disease (CAD) have been associated with neurodegeneration and dementia. Whether an underlying genetic risk for the development of CAD further increases this risk, however, remains unclear. Purpose To examine whether an increased genetic risk for CAD is associated with an increased risk of dementia, and to investigate whether lifestyle factors modify these associations. Methods A prospective cohort study of 457,353 participants of European ancestry without dementia at baseline (mean [SD], age 57 [8] years; 55% were female) was conducted within the UK Biobank study. Exposures were a genome-wide polygenic risk score (PRS) for CAD and a modified version of the American Heart Association’s Life’s Essential 8 (LE8) cardiovascular health score comprising four biological (BMI, BP, lipids, glucose) and four lifestyle (smoking status, diet, physical activity, and sleep duration) risk factors previously linked to both CAD and dementia. Dementia diagnoses were obtained from death register and inpatient records. Results 9,337 cases of all-cause dementia were observed over a median 13.9-year follow-up. There were no significant interactions between genetic risk for CAD and lifestyle factors for all-cause dementia, or any other dementia subtype. After adjusting for potential demographic confounders, a higher genetic risk for CAD was associated with elevated risk of developing all-cause dementia (hazard ratio (HR) per 1-SD increase in PRS = 1.08 [95% CI, 1.05-1.10]), Alzheimer’s disease (HR 1.08 [1.03-1.12]), and vascular dementia (HR 1.13 [1.06-1.19]). An unfavourable LE8 cardiovascular health score was also associated with an increased risk of developing all-cause dementia (HR 1.05 [1.02-1.08]), predominantly through its association with vascular dementia (HR 1.14 [1.06-1.22]), as we found no evidence for any associations between LE8 and Alzheimer’s disease (HR 1.00 [0.97-1.02]). Conclusion These findings indicate that a high genetic risk for CAD is associated with an increased risk of developing major dementia subtypes. Regardless of this underlying genetic risk, however, our results suggest that lifestyle interventions designed to reduce the risk of CAD may also reduce one’s risk of developing dementia, particularly in those with underlying vascular pathology.

Circulating ketone bodies, genetic predisposition, and incident atrial fibrillation

Abstract Background Ketone bodies (KB) are essential alternative fuel sources for the myocardium. However, the evidence on the level of circulating KB and heart disorders is inconsistent. Whether the total and individual KB are associated with risk of onset atrial fibrillation (AF) in the general population and in individuals with different genetic susceptibilities to AF are still unclear. Purpose To examine the association between circulating KB and AF risk and to further test whether genetic risk could modify the above association. Methods In the UK Biobank, 247,304 participants (mean age 56.5, 45.3% men) with available data on KB and without baseline AF were included. The concentrations of KB, including β-hydroxybutyrate (β-OHB), acetoacetate, and acetone, were measured using nuclear magnetic resonance, and the values of KB were increased by one and then log10-transformed for analyses. The genetic risk of AF was based on the standard polygenic risk score. The definitions of AF were based on the ICD-10 code I48, which was linked to primary care, hospital admission electronic health records and death records. Cox proportional hazard model was used to estimate the hazard ratio (HR) with 95% confidence interval (CI). Results During a median follow-up of 13.8 years, 16,936 cases of onset of AF were recorded. After adjusting for age, sex, race, Townsend index, education, alcohol intake frequency, smoking status, healthy diet, metabolic equivalent, body mass index, systolic blood pressure (SBP), total cholesterol, estimated glomerular filtration rate, cardiovascular diseases, and diabetes, elevated total KB, β-OHB, acetoacetate, and acetone were all with the risk of AF (HR, 95% CI per 10-fold increase: 1.20, 1.13-1.28; 1.13, 1.07-1.19; 1.12, 1.06-1.18; and 1.78, 1.57-2.01, respectively). The highest risk of AF was observed among individuals at high genetic risk to AF and had the highest quartile of total KB (HR 2.91, 95% CI 2.66-3.19). Participants who had low genetic risk were more susceptible to high total KB for incident AF (p for interaction = 0.036). The associations of total KB, β-OHB, and acetone with AF risk were more prominent for men (HR, 95% CI per 10-fold increase: 1.32, 1.22-1.44; 1.22, 1.14-1.31; 2.01, 1.72-2.36) than for women (p for interaction &amp;lt;0.05). The association between total KB and AF risk was strengthened in individuals &amp;lt;60 years, current smokers, and those with SBP&amp;lt;130 mmHg (p for interaction = 0.033, 0.021, and 0.017, respectively). Conclusions Circulating KB concentrations were associated with AF risk, with acetone showing the strongest relationship with AF. Individuals at low genetic risk were more susceptible to the level of total KB for incident AF. Our findings suggest that KB may be a biomarker, particularly for identifying individuals without AF at baseline who are at low genetic risk. The additive value of plasma KB to a risk prediction score warrants further investigation.

Association between genetic predisposition of AF and the risk of ischemic stroke and thromboembolism

Abstract Background Ischemic stroke and thromboembolism are the major complications of atrial fibrillation (AF), however, its association with genetic background of AF remains unclear. To investigate the association between genetic predisposition of AF underlying common variants and the risk of ischemic stroke and thromboembolism. Methods We included unrelated individuals with non-valvular AF from UK biobank. The polygenic risk scores of AF (PRSAF) was calculated for each individual using the effect weight from a previous study which has been validated in both European and mixed-ancestry population[1, 2]. The SNPs from the original score were lifted over to GRCh38 and 6514708 of 6730541 were available in the UK biobank genotype data. The clinical data was defined by ICD-10 code. The primary endpoint is ischemic stroke or thromboembolism resulting in hospitalization after first AF diagnosis. Results A total of 28810 unrelated patients were included in the study. Among them, 4064 had PRSAF over 90th percentile of the general population, and were considered having high genetic risk. The rest 18746 with per SD increase in PRSAF lower than 90th percentile of the general population were considered having lower genetic risk. Generally, age and sex adjusted model demonstrated that per standard deviation change in PRSAF is associated with 9% increase in the risk of stroke or thromboembolism (HR=1.09, 95%CI: 1.03-1.14), and patients with high genetic risk was associated with 15% increase in the risk of stroke or thromboembolism (HR=1.15, 95%CI: 1.02-1.31).The result remained stable when further adjusted for clinical risk factors (1.09, 95%CI: 1.04-1.15 per SD increase in PRSAF) and competing risk of death (1.10, 95%CI: 1.05-1.16 per SD increase in PRSAF). There was no interaction between CHA2DS2-VASc score risk stratification and the per SD increase in PRSAF (P interaction = 0.751, Figure 1A). However, the association between per SD increase in PRSAF and the event tended to be affected by age at AF onset (HR = 1.02 95%CI: 0.94, 1.11 for early onset AF; HR = 1.12 95%CI: 1.05, 1.19 for non-early onset AF, P for interaction = 0.062, Figure 1B). Multi-variate COX regression including PRSAF, components of CHA2DS2-VASc score, and other AF risk factors revealed that history of stroke/thromboembolism, age over 65 years, hypertension, diabetes and high AF genetic risk were significantly associated with the outcome (Figure 1C). To evaluate the importance of these risk factors, average population attributable fraction for 10-year risk of stroke/thromboembolism in the study population was calculated, indicating that genetic risk of AF is responsible for 3.26% (0.89%-5.63%) of the events (Figure 1D). Conclusion Genetic predisposition of AF underlying common variants is associated with ischemic stroke and thromboembolism independent of clinical risk factors. But its role in different AF populations, like early onset AF, remains further investigation.Figure 1

Interaction of polychlorinated biphenyls exposure, lifestyle and genetic risk in dyslipidemia

Abstract Background Polychlorinated biphenyls (PCBs) are endocrine-disrupting chemicals that have been associated with various adverse health conditions. However, the interaction effects between PCBs, lifestyle, and/or genetic susceptibility on dyslipidemias are still unknown. Methods Six serum PCBs including PCB-28, 101, 118, 138, 153, and 180 were determined in 3,845 participants from the Wuhan-Zhuhai cohort. Dyslipidemias, including hyper-total cholesterol (HyperTC), hyper-triglyceride (HyperTG), hyper-low density lipoprotein cholesterol (HyperLDL-C), and hypo-high density lipoprotein cholesterol (HypoHDL-C) were classified based on serum lipids levels, which were examined by an automatic biochemical analyzer. Besides, we constructed lipid-specific polygenic risk scores (PRS) and healthy lifestyle scores, and used Logistic regression models to explore the relationships of serum PCBs, lifestyle, and PRS with dyslipidemias. Results We observed that all six PCB congeners were positively associated with the prevalence of dyslipidemias to varying degrees. In particular, dose-response manners were observed between ΣPCB levels and odds ratios (ORs) of HyperTC, HyperTG, and HyperLDL-C, respectively. Besides, we found that PRSs and unhealthy lifestyles were both positively associated with dyslipidemias. For the combined effect of ΣPCB, lifestyle, and PRS, participants with high ΣPCB, unfavorable lifestyle, and high genetic risk had the highest odds of HyperTC (2.285; 1.533, 3.417), HyperTG (7.944; 5.169, 12.329), and HyperLDL-C (3.523; 2.311, 5.394) when compared with those with low ΣPCB, healthy lifestyle, and low genetic risk. Conclusions Our study provided evidence that PCB exposure potentially increases the prevalence of dyslipidemias, which may be exacerbated by genetic susceptibility and unhealthy lifestyles. Key messages • Our results highlighted the importance of reducing PCB exposure, adopting healthy lifestyles for the prevention of dyslipidemia. • Our work might facilitate the emergence of reducing or regulating PCB pollution to control blood lipids and the resultant dyslipidemia epidemic.

Longitudinal associations between accelerometry-assessed sleep clusters and obesity in adolescence and young adulthood: the German GINIplus and LISA birth cohorts study

Abstract Background Some studies have identified diverse sleep patterns in adolescents and adults by considering multidimensional objective sleep parameters. However, whether sleep patterns are consistent from adolescence to young adulthood and their long-term associations with obesity remain unknown. Purpose This study aimed to investigate the longitudinal associations of objectively measured and clustering-identified sleep patterns with body mass index (BMI) and overweight/obesity in adolescence and young adulthood, and to test whether these associations change over time or are modified by genetic risk. Methods A total of 1973 participants wearing 7-day accelerometers in either 15-year (n=1347, aged 14.3-16.4 years) and/or 20-year (n=1262, aged 19.5-22.4 years) follow-ups of German GINIplus and LISA birth cohorts were included. Sleep clusters were identified by K-means cluster analysis on 12 accelerometry-assessed sleep characteristics at each follow-up. BMI and overweight/obesity were measured by physical exams or self-/parent-reported questionnaires. Multivariable linear and logistic regression models with generalized estimating equations were tested. The interaction effects with time of follow-ups and polygenic risk scores (PRS, n=1087) for BMI were further examined. Results Although sleep characteristics changed from adolescence to young adulthood, such as shorter total sleep time (mean 7.2 to 6.6 hours), the consistent five sleep clusters were classified in both periods: good sleep, delayed sleep phase, sleep irregularity and variability, fragmented sleep, and prolonged sleep latency. Compared to the "good sleep" cluster, the "prolonged sleep latency" cluster showed significant associations with higher BMI (β=0.56, 95% confidence interval (CI) = [0.06, 1.05]) and increased odds of overweight/obesity (odds ratio (OR)=1.55, 95%CI= [1.02, 2.34]). PRS was associated with higher BMI (β=0.65, 95%CI= [0.39, 0.91]) and overweight/obesity (OR=1.52, 95%CI= [1.15, 2.00]), with no significant gene-sleep cluster interaction effect. Only among males, the interaction effects with time of follow-ups on overweight/obesity were observed in the "delayed sleep phase", "sleep irregularity and variability", and "fragmented sleep" clusters (p-interaction &amp;lt;0.05), showing more harmful effects with increasing age. Conclusions Five sleep patterns were identified consistently across adolescence and young adulthood, and the "prolonged sleep latency" pattern was associated with higher BMI and overweight/obesity, independent of genetic risk. For young adult males, "delayed sleep phase", "sleep irregularity and variability" and "fragmented sleep" patterns seemed to have more unfavorable impacts on overweight/obesity.

Measurement invariance of the Center for Epidemiological Studies-Depression scale and associations with genetic risk in older adults.

As populations are aging, it needs to be ensured that valid depression rating scales are available across old adulthood. Center for Epidemiological Studies-Depression scale (CES-D) is a common depression rating scale, however, few studies have assessed its validity in individuals with age over 90 and/or cognitive impairment. We examined the factor structures of 20-, 15-, and 8-item CES-D scales, their measurement invariance for age and cognition, and associations with genetic risk of depression. Participants were from a population-based older Finnish Twin Cohort study including 71-79-year-olds from the MEMTWIN II (n = 1034 for exploratory and n = 664 for confirmatory factor analyses) and 90+ year-olds from the NONAGINTA (n = 134, confirmatory factor analyses) sub-studies. Associations of polygenic risk score of major depressive disorder (MDD-PRS) with CES-D scales were examined in MEMTWIN II. Exploratory factor analyses (n = 1034) suggested four- (CES-D 20) and three-factor (CES-D 8) structures and these models fit well in confirmatory analyses (n = 664). Unidimensional models had good (CES-D 15 & 20) or fair fit (CES-D 8). Results supported scalar invariance of all CES-D versions for age and cognitive status. Higher MDD-PRS was associated with more depressive symptoms in different CES-D versions. Different CES-D versions are adequate for measuring depressive symptoms across age groups and cognitive spectrum in old age. Genetic risk of depression predicts depressive symptoms even in old age.

Socioeconomic deprivation and atrial fibrillation risk: an observational and gene-environment interaction analysis

Abstract Background The association between socioeconomic deprivation and incident atrial fibrillation (AF) is debated, along with limited evidence on how genetic predisposition to AF interacts with socioeconomic deprivation and AF risk. Purpose To evaluate the association and gene-environmental interaction between socioeconomic deprivation and the risk of incident AF. Methods From the UK Biobank prospective cohort, we selected participants who were free from previous AF. Participants with missing values and those who did not pass the genetic quality control were excluded. As an indicator of socioeconomic deprivation, we utilised the indices of multiple deprivation (IMD), which is calculated from scores of multiple socioeconomic factors, including crime, education, employment, health, housing, income, and living environment. Participants were divided into 3 groups by IMD; the top 20% as high IMD (most deprived), the bottom 20% as low IMD, and 20-80% as mid IMD. Using a polygenic risk score (PRS) for AF generated using a Bayesian approach applied to external genome-wide association study data, the interaction between genetic risk and socioeconomic deprivation was assessed. The primary endpoint was incident AF during a median of 13.7 years of follow-up. Results A total of 377,386 (aged 56.5±8.1 years, 45.2% male) were analysed. The high IMD group (n=85,108) was younger and had a higher proportion of comorbidities than the mid or low-IMD groups. An increase in IMD as a continuous variable was significantly associated with an increased risk of incident AF. The high IMD group showed a significantly increased risk of AF (multivariable-adjusted hazard ratio [aHR]=1.12, 95% confidence interval=1.07-1.17, P&amp;lt;0.001) compared with the low IMD group (incidence rate 7.7 vs. 4.8/1,000 person-year). All components of IMD except housing score significantly increased the risk of incident AF (aHR ranged from 1.07 to 1.15). Within each IMD group, higher AF PRS groups were significantly associated with an increased risk of incident AF with the low AF PRS group as a reference, showing aHRs of 1.50 for mid-PRS and 2.57 for high-PRS in the low IMD group, 1.60 and 2.65 in the mid-IMD group, and 1.55 and 2.33 in the high IMD group, respectively (all P&amp;lt;0.001). The impact of socioeconomic deprivation was attenuated in participants with high AF PRS (P for interaction=0.042), mainly driven by the interaction effect of crime (P for interaction [Pi]=0.005), employment deprivation (Pi=0.005), and health deprivation scores (Pi=0.043). Conclusion Socioeconomically deprived individuals had a significantly higher risk of AF, and the effect was partially modified by genetic predisposition to AF. A personalised approach to applying AF screening for high-risk individuals may be more efficacious. Legal measures and policies to enhance public health by alleviating socioeconomic inequalities are needed to mitigate AF risk and improve cardiovascular health outcomes.

Increased risk for thoracic and abdominal aortic aneurysm in the relatives of abdominal aorta aneurysm patients

Abstract Introduction Genetic susceptibilities in aneurysm genes are risk factors for developing aneurysms of the aorta. This translates to a high aneurysm prevalence in relatives of aortic aneurysm patients. For relatives of abdominal aorta aneurysm (AAA) patients, guidelines recommend abdominal ultrasound screening for early detection and management, while for relatives of thoracic aorta aneurysm patients (TAA), transthoracic ultrasound of the ascending aorta and aortic root is recommended. Neither of these guidelines are designed to detect aneurysms in the whole aorta. The incidence of TAA in relatives of AAA index-patients is unknown and may determine whether abdominal ultrasound screening is sufficient for relatives of AAA patients or whether whole aorta screening should be recommended. Furthermore, focused screening of high risk relatives of aneurysm patients may improve the yield of aneurysm detection now that population frequencies are declining. Methods Whole aorta non-contrast CTs of relatives of AAA index-patients were collected retrospectively in a tertiary referral (2016 to 2021). Family history and DNA testing of AAA index-patients were used to classify relatives into high genetic risk (familial disease and/or pathogenic/likely pathogenic variant (P/LP) in an aneurysm gene) or unknown genetic risk (no familial disease or no P/LP detected). TAA were defined as ascending diameters ≥ 45mm or descending diameters ≥ 40mm. Thoracic aortic dilatations (TAD) were defined as ascending diameters of 40-45 mm or descending diameters of 35-40 mm. Abdominal diameters ≥30mm were classified as AAA and diameters between 25-29 mm as abdominal dilatations (AAD). References 1-3. Results CT scans (n=301 relatives, 47% male, age 58(50-65)) showed 34% aortic aneurysms and/or dilatations versus 14% in the general population (age adjusted, p&amp;lt;0.001). TAA was 28-times more frequent (2%, p&amp;lt;0001) and AAA 3 times more frequent (8%, p&amp;lt;0.001) than in the general population. Thoracic and abdominal dilatations occurred in 18% and 17% of relatives. Overall, males were 4 times more likely to have an aneurysm than females (p&amp;lt;0.05). Aneurysms and dilatations occurred at the same rate in relatives with or without a family history or a P/LP in an aneurysm gene. These results endorse total aorta screening for relatives of all AAA patients rather than restricting screening to the abdominal aorta. Conclusions Relatives of AAA patients had a high risk for thoracic and abdominal aneurysms as well as dilatations. This indicates that imaging of the whole aorta will improve early detection of aortic aneurysms in relatives both with and without a family history of aneurysms.

Blood pressure polygenic risk scores associate with resistant hypertension in individuals with type 1 diabetes

Abstract Background Hypertension is a major risk factor of global disease burden, but treatment goals are often not met. A subset of individuals with hypertension is affected by treatment-resistant hypertension (RHTN), and they suffer from increased cardiovascular morbidity and mortality. Early identification of individuals at risk of RHTN could lead to more efficient antihypertensive drug treatment. Purpose The aim of this study was to investigate whether polygenic risk scores (PRS) for systolic (SBP) and diastolic blood pressure (DBP) predict RHTN in individuals with or without type 1 diabetes (T1D). Methods We performed association analyses between PRSs and RHTN in two Finnish cohorts: The Finnish Diabetic Nephropathy Study (FinnDiane) and the Finnish individuals of the LIFE Study (LIFE-Fin). FinnDiane is an ongoing, observational nationwide study aiming to identify genetic and clinical risk factors for complications of T1D. We included data from 778 adults (476 with RHTN and 302 with controlled hypertension). LIFE is a randomized, double-blind study evaluating long-term effects of losartan compared with atenolol in patients with signs of left ventricular hypertrophy. We used SBP and DBP data from 378 Finnish individuals (173 with RHTN and 205 with controlled hypertension) at the four-year visit of the study. In FinnDiane, RHTN was defined as SBP ≥130 or DBP ≥85 mmHg and the use of three or more antihypertensive drugs, or SBP &amp;lt;130 and DBP &amp;lt;85 mmHg and the use of four or more antihypertensive drugs. In LIFE-Fin, RHTN was defined as SBP ≥140 or DBP ≥90 mmHg and the use of three or more antihypertensive drugs. Controlled hypertension was defined as the use of three or fewer antihypertensive drugs and SBP &amp;lt;130 and DBP &amp;lt;85 mmHg in FinnDiane, and as SBP &amp;lt;140 and DBP &amp;lt;90 mmHg in LIFE-Fin. We calculated a PRS for each participant using genome-wide association study data for 1,098,015 genetic variants; the variant-specific data were derived from UK Biobank based PRS-CS-method computed PRSs (1). Results We observed significant associations of SBP and DBP PRSs with RHTN in FinnDiane (OR 1.56 [1.30; 1.87], P = 1.8e-6, and OR 1.25 [1.04; 1.50], P = 0.02, per one-SD increase of the PRS value) when adjusted for age, sex, estimated glomerular filtration rate and body mass index. The association between SBP PRS and RHTN remained significant when T1D individuals with or without albuminuria were analysed separately. Neither SBP nor DBP PRSs were significantly associated with RHTN in LIFE-Fin. Conclusion Higher SBP PRSs associate with higher risk of RHTN in individuals with T1D, with or without albuminuria, but not in nondiabetic individuals with hypertension. It remains to be investigated whether general blood pressure genetics contribute to RHTN in the general population.

Long-term effects of arsenic on glucose-insulin homeostasis: A gene-environment interaction study

Abstract Background Arsenic exposure and genetic factors are associated with an increased risk of type 2 diabetes, yet study of environment-gene interaction on glucose-insulin homeostasis remains scarce. We aimed to investigate the associations and interactions of urinary total arsenic (UTAs) and genetic susceptibility with glucose-insulin homeostasis through a longitudinal epidemiological study. Methods A total of 6136 observations (3063 participants) from the baseline, 3-year follow-up, and 6-year follow-up of the Wuhan-Zhuhai cohort were included in this study. In each study period, we repeatedly measured UTAs, fasting plasma glucose (FPG), fasting plasma insulin (FPI), and homeostasis model-assessed insulin resistance (HOMA-IR) and β-cell function (HOMA-β). Polygenic risk scores (PRSs) specific for all traits were constructed by corresponding genome-wide association summary statistics. Linear mixed models were used to assess associations and interactions of UTAs and PRSs with four indicators of glucose-insulin homeostasis. Results After adjustment for all covariates, the βs (95% CIs) for the annual growth rates of FPG, FPI, and HOMA-IR were 0.020 (0.008, 0.032), 0.007 (0.002, 0.013), and 0.011 (0.004, 0.017), respectively, associated with each ln-unit increase in UTAs. Compared to subjects with the first-quartile PRS and low UTAs, participants with the fourth-quartile PRS and high UTAs had a 0.029 (0.012, 0.047) or 0.032 (0.012, 0.051) ln-unit increase in the annual growth rate of FPI or HOMA-IR, respectively. UTAs and PRS had significant interactions on the longitudinal progressive increases of FPI and HOMA-IR (P interaction &amp;lt; 0.05). Conclusions Arsenic exposure and genetic variants are significantly synergistic risk factors for dysregulation and progressive deterioration of glucose-insulin homeostasis. Our findings emphasize the importance of reducing arsenic exposure to maintain normal glucose-insulin metabolism, especially for those at higher genetic risk. Key messages • Arsenic exposure was associated with annual increased rates of FPG, FPI, and HOMA-IR. • Arsenic exposure and trait-specific PRSs are synergistic risk factors for glucose-insulin homeostasis impairment.

Implementation of polygenic risk scores in secondary prevention of (breast) cancer

Abstract Utilizing polygenic risk scores to inform secondary prevention of breast cancer via population screening programs is one of the pioneering applications of genomics in public health applications. Over the last decade, polygenic risk scores for breast cancer have been developed and validated in various European populations (AUC ± 0.63, OR per Z unit ± 1.6, depending on the population). In some countries, the polygenic risk score has been integrated with decision modeling tools, such as CanRisk in the Netherlands, and low-level implementation into health and care systems has started. Implementation strategies vary, but generally consider initial implementation into high-risk populations, such as breast cancer families, in specialized clinical setting, such as academic medical centres, or specialized cancer clinics, referring relatives of patients to population screening based on comprehensive risk modelling, including polygenic risk scores. This route may be followed by other disease fields as well. The presentations outlines the current evidence and considerations on breast cancer genetic risk modelling, clinical pilot studies and the outline of step-wise implementation of such models to benefit secondary prevention programs. We start from the perspective of a single hospital, to the needed steps to upscale to national populations, both in diversity of these populations, as the throughput of genetic testing and counselling, until the harmonization and recalibration of various European healthcare models. We draw from examples of the Genotyping on all patients (GOALL), building cancer health platforms (CanHeal) and Genome of Europe (GoE) consortia.

Long-term weight change in midlife, cardiac magnetic resonance parameters, risk of atrial fibrillation: a large prospective cohort study

Abstract Background Although obesity is a well-established risk factor for atrial fibrillation (AF), the relationship between weight change and the risk of AF remains controversial. Furthermore, the extent to which obesity-associated AF risk is mediated by cardiac remodeling is unclear. Purpose We aimed to evaluate the impacts of obesity and weight change on the risk of atrial fibrillation, and the role of cardiac remodeling in obesity-AF association. Methods This is a population-based prospective cohort of UK Biobank participants recruited from 2006 to 2010. A total of 490,969 participants and 19,634 participants were included for BMI and BMI change analysis, respectively. Body mass index (BMI) was assessed at baseline and follow-up assessment (2012-2013). Cardiovascular measurements were derived from cardiovascular magnetic resonance. Cox proportional hazard models were used to assess the associations of obesity and change in BMI with AF. The nonlinear associations of BMI and BMI change with AF were tested using a restricted cubic spine (RCS). Mediation analysis was conducted to quantify the role of cardiac remodeling in the association between obesity and AF. Results Among the 490,969 participants included (mean age: 56.4 ± 8.1 years, 54.9% women), 33,297 incident AF cases were observed during a median follow-up of 14.0 years. Overweight (hazard ratio [HR], 1.12, 95% confidence interval [CI] 1.09-1.15, P &amp;lt; 0.001) and obesity (1.73, 1.68-1.78, P &amp;lt; 0.001) significantly increased the risk of AF, particularly in men, those with age &amp;lt; 60 years and low genetic risk. During a median follow-up of 4.43 years, 1,217 (6.2%) participants experienced &amp;gt; 2% BMI loss per year and 1,318 (6.7%) participants experienced &amp;gt; 2% BMI gain per year. Compared to stable BMI, BMI loss was associated with a lower risk of AF (0.75, 0.57-0.99, P = 0.039). In addition, we found that BMI loss from obesity to overweight was associated with a reduced risk of AF (0.74, 0.54-1.02, P = 0.069) compared with maintaining baseline BMI category. Participants with stable obesity had a higher risk of AF (1.81, 1.52-2.16, P &amp;lt; 0.001) than those with stable normal weight. In addition, RCS indicated BMI had a J-shaped association with AF while BMI change had a linear association with AF. Mediation analyses revealed that left ventricular myocardial mass, left atrial maximum volume, and left atrial minimum volume were the three strongest mediating factors between obesity and AF, with a mediated proportion of 85.28%, 64.43%, and 55.89% of the total effect, respectively. Conclusion BMI decrease over 2% per year was associated with a lower risk of AF, especially in those changing from obesity to overweight. Left ventricular myocardial mass plays a central role in mediating obesity-related AF. Our findings support weight management at the population level to mitigate the growing epidemic of AF and ways targeting left ventricular myocardial mass are waiting to be further explored.Associations of BMI, BMI change with AFThe mediating role of cardiac remodeling

Functional genomics implicates natural killer cells in the pathogenesis of ankylosing spondylitis

Multiple lines of evidence indicate that ankylosing spondylitis (AS) is a lymphocyte-driven disease. However, which lymphocyte populations are critical in AS pathogenesis is not known. In this study, we aimed to identify the key cell types mediating the genetic risk in AS using an unbiased functional genomics approach. We integrated genome-wide association study (GWAS) data with epigenomic and transcriptomic datasets of human immune cells. To quantify enrichment of cell type-specific open chromatin or gene expression in AS risk loci, we used three published methods - LDSC-SEG, SNPsea, scDRS - that have successfully identified relevant cell types in other diseases. Natural killer (NK) cell-specific open chromatin regions are significantly enriched in heritability for AS, compared to other immune cell types such as T cells, B cells, and monocytes. This finding was consistent between two AS GWAS. Using RNA-seq data, we validated that genes in AS risk loci are enriched in NK cell-specific gene expression. Using the human Space-Time Gut Cell Atlas, we also found significant upregulation of AS-associated genes predominantly in NK cells. We performed co-localization analyses between GWAS risk loci and genetic variants associated with gene expression (eQTL) to find putative target genes. This revealed four AS risk loci affecting regulation of candidate target genes in NK cells: two known loci, ERAP1 and TNFRSF1A, and two under-studied loci, ENTR1 (aka SDCCAG3) and B3GNT2. Our findings suggest that NK cells may play a crucial role in AS development and highlight four putative target genes for functional follow-up in NK cells.

Progress in understanding the genetic underpinning of coronary artery disease: from genotype to phenotype

Abstract Background The functional dissection of genetic risk opens the door to strategies for pharmacological manipulation of molecular and cellular processes implicated in human diseases, including coronary artery disease (CAD). Aim To assess the relationship between a set of single nucleotide polymorphisms previously associated with CAD and coronary artery calcium (CAC) score in an asymptomatic population from Portugal. Methods Prospective study in a cohort of 1,284 subjects aged 59.3±8.9 years, 73.6% males without apparent CAD. The CAC score was performed by cardiac computed tomography and reported as Agatston units according to the Hoff nomogram. Anthropometric, conventional, and biochemical risk factors were evaluated. Thirty-three single nucleotide polymorphisms were genotyped by TaqMan real-time PCR. Bivariate and multivariate logistic regression analysis estimated variables associated with the CAC score. Results After bivariate analysis, PHACTR1 rs1332844 C&amp;gt;T, a downstream regulator of the endothelin-1 gene, showed a significant association with CAC score (p=0.015), together with CDKN2B-AS1 variants rs4977574 A&amp;gt;G in the locus 9p21.3 (p=0.002) and rs1333049 G&amp;gt;C (p=0.010). MTHFD1L gene encodes a mitochondrial enzyme responsible for homocysteine remethylating in methionine, and rs6922269 G&amp;gt;A showed protection against artery calcification (p=0.013). After multivariate logistic regression, PHACTR1 rs1332844 (CT+TT) (p=0.009) and CDKN2B-AS1 rs4977574 A&amp;gt;G (GG) (p=0.002) remained in the equation as independently associated with arterial calcification, together with male sex (p=0.039), age (p&amp;lt;0.0001), hypertension (p=0.001), diabetes (p&amp;lt;0.0001), smoking status (p&amp;lt;0.0001) and obesity (p=0.020). MTHFD1L rs6922269 AA also remained as significant protection from arterial calcification (p=0.027). Conclusion The present work showed two genetic variants, PHACTR1 and CDKN2B-AS1, linked to arterial wall calcification, herewith clinical and environmental risk factors. MTHFD1L showed protection. Understanding the genetic basis of vessel calcification can enable lifestyle changes or pharmacologic therapy to attenuate risk before the disease becomes clinic. More research in this field is critical to understanding the genetic basis of CAD through an intermediate phenotype, coronary arterial wall calcification.

Long-term changes in frailty and incident atrial fibrillation: multicenter prospective cohort study

Abstract Background Atrial fibrillation is the most common sustained cardiac arrhythmia and is prevalent among the elderly. Previous findings indicated a higher prevalence of AF in frail adults and frailty prevalent in AF patients. However, the association between dynamic changes of frailty and risk of new-onset AF is unclear. Purpose We aimed to investigate the associations of long-term changes in frailty with incident AF. Its associations with heart failure (HF), coronary heart disease (CHD), and stroke were also evaluated as a secondary aim. Methods Over 50,000 participants from UK Biobank cohort were included, with available frailty index (FI) data and free of AF, HF, CHD or stroke in both baseline and final follow-up assessments. Participants were categorized into nonfrailty, prefrailty and frailty based on their FI scores. Changes of frailty status from baseline to final follow-up assessment included alleviation, maintenance, and aggravation. Thus, transitions of frailty status included 7 categories: nonfrailty maintenance, nonfrailty aggravation (nonfrailty to prefrailty or frailty), prefrailty alleviation (prefrailty to nonfrailty), prefrailty maintenance, prefrailty aggravation (prefrailty to frailty), frailty alleviation (frailty to prefrailty or nonfrailty), and frailty maintenance. FI in baseline and follow-ups are used to calculate the trajectories of frailty (ΔFI). Cox proportional hazard models were used. Results Compared with nonfrailty at baseline, the HRs (95% CI) of AF for prefrailty and frailty were 1.32 (1.29, 1.36) and 1.89 (1.83, 1.96) in the multivariable-adjusted model. During a median of 5.1 years of follow-up from the final assessment, 1729 cases of AF were recorded. Frailty trajectory analysis showed that even a 0.01 point/year increase in ΔFI was associated with 14% (95% CI 1.08-1.20) higher risk of AF, independent of baseline FI and the risk rose to 1.89 (1.45, 2.46) with per 0.05 point/year increase in ΔFI. This association was strengthened in low genetic risk of AF, but sex, age, smoking status, alcohol intake, obesity, hypertension, diabetes and cancer did not materially modify the associations. Moreover, compared with nonfrailty maintenance, sustained frailty had the highest risk of AF (HR 1.95, 1.61-2.36). Alleviation from frailty reduced the risk of AF by 30% (95%CI 0.53-0.94), compared to sustained frailty. These associations were similar in HF and CHD, however, not significant in stroke. Conclusions Middle aged and elderly people, including those with diabetes, obesity and hypertension, may gain substantial benefits in risk of AF, HF and CHD by becoming less frail or maintaining nonfrailty, irrespective of past frailty status and established risk factors, delivering public health implications for the necessity of early identification and timely interventions of frailty in heart health management.

Innovative Approaches for Personalized Cardiovascular Prevention: the INNOPREV multicentric trial

Abstract Background Cardiovascular diseases (CVD) represent a major global health concern, requiring innovative primary prevention strategies. Personalized prevention, through the use of digital technologies and genetic risk scores (PRS), holds promise but requires further investigation to assess clinical efficacy. Consequently, the INNOPREV trial aims to investigate the efficacy of PRS and/or digital technologies in the uptake of CV preventive behaviors uptakes. Methods The INNOPREV trial is a multicenter randomized controlled trial conducted in Italy across three hospital centers in Rome, Catania, and Palermo. It aims to recruit 1020 participants aged 40-69 with a high 10-year CVD risk. Participants are allocated to traditional CVD risk assessment, or genetic testing, or digital interventions, or a combination of both. The study involves comprehensive CV risk assessments at baseline and follow-up visits at one, five, and twelve months. Data analysis will utilize mixed-effects models to analyze longitudinally collected data and explore potential moderators and mediators of behavior change. Results Preliminary results indicate good progress in recruitment, which currently stands at 250 participants (25% of expected). Recruited females have a mean age of 59 ± 6 years, while males have a mean age of 58 ± 6 years. Currently, PRS analyses indicate that 77% of participants have intermediate scores, and 23% have low scores. Follow-up will be essential to evaluate the efficacy of the proposed interventions. Conclusions We expect that the INNOPREV trial will provide evidence towards integration of innovative approaches based on PRS and digital devices, in the traditional preventive approaches for CVDs. Expectations are high based on the limited effectiveness of the current approaches in CV risk reduction based on lifestyle advice. Key messages • INNOPREV trial examines PRS and digital technology for CVD prevention, aiming to enhance preventive efficacy. Initial findings suggest promising potential for innovative CVD prevention strategies. • The INNOPREV trial aims to investigate the efficacy of personalized prevention strategies, including PRS and digital technologies, in improving cardiovascular preventive behaviors.

The genetic architecture of exercise-induced ventricular ectopy

Abstract Background Previously, we have shown that the frequency of exercise-induced premature ventricular contractions (PVCs) during and after exercise are associated with increased risk of major adverse cardiovascular events in asymptomatic individuals from the UK Biobank study1. The underlying mechanisms are, however, unclear. Several electrocardiographic markers associated with arrhythmogenesis have a known hereditary component, but the genetic underpinnings of exercise-induced ventricular ectopy have not been investigated. Purpose Our aim was to explore the genetic basis of premature ventricular ectopy during and after exercise and unveil plausible candidate genes and biological mechanisms. Methods We conducted a genome-wide association study (GWAS) for PVC frequency during exercise and recovery in &amp;gt;44,000 asymptomatic individuals of European ancestry without known cardiovascular disease from the UK Biobank study. As the distribution of PVC frequency is highly skewed (e.g. absence of negative values and excess of zero values), we first applied Gaussian transformation. Simulation studies were performed to justify that this approach would lead to valid inference. In the GWAS model, we included sex, age, UK Biobank genotyping array, and the first 10 genetic principal components as covariates. Statistical power was boosted by joint analysis of exercise and recovery PVC traits using multi-trait analysis of GWAS (MTAG)2. Genetic risk scores were constructed in independent samples from UK Biobank (N=341,948) and were tested for association with heart failure and life-threatening ventricular arrhythmias. Results We identified 4 loci for PVC frequency during exercise, and 1 locus for PVC frequency during recovery (Picture 1). Candidate genes included CRIM1, FLNC, and BAG3 for which mutations have been linked in the pathogenesis of (arrhythmogenic) cardiomyopathy. Subjects in the top 10% of the genetic risk scores had a significantly higher risk of heart failure and life-threatening ventricular arrhythmias compared to the bottom 90%, (odds ratio (OR) (95% confidence interval): 1.14 (1.08 – 1.20), p &amp;lt; 0.001; and 1.13 (1.02 – 1.24), p &amp;lt; 0.001, respectively). Conclusions Ventricular ectopic burdens during exercise and recovery have a significant heritable component. Candidate genes highlight a possible shared genetic background with inherited cardiomyopathy and a genetic risk score was associated with heart failure and ventricular arrhythmias. These findings substantial advance our understanding of the genetic basis of exercise-induced ventricular ectopy in a population-based cohort without cardiovascular disease.Miami plot of ventricular ectopic burden