Objectives This study sought to determine whether variations in NOS1AP affect drug-induced long QT syndrome (LQTS). Background Use of antiarrhythmic drugs is limited by the high incidence of serious ...adverse events including QT prolongation and torsades de pointes. NOS1AP gene variants play a role in modulating QT intervals in healthy subjects and severity of presentation in LQTS. Methods This study carried out an association study using 167 single nucleotide polymorphisms (SNP) spanning the NOS1AP gene in 58 Caucasian patients experiencing drug-induced LQTS (dLQTS) and 87 Caucasian controls from the DARE (Drug-Induced Arrhythmia Risk Evaluation) study. Results The rs10800397 SNP was significantly associated with dLQTS (odds ratio OR: 3.3, 99.95% confidence interval CI: 1.0 to 10.8, p = 3.7 × 10–4 ). The associations were more pronounced in the subgroup of amiodarone users, in which 3 SNPs, including rs10800397, were significantly associated (most significant SNP: rs10919035: OR: 5.5, 99.95% CI: 1.1 to 27.9, p = 3.0 × 10–4 ). We genotyped rs10919035 in an independent replication cohort of 28 amiodarone dLQTS cases versus 173 control subjects (meta-analysis of both studies: OR: 2.81, 99.95% CI: 1.62 to 4.89, p = 2.4 × 10–4 ). Analysis of corrected QT interval among 74 control subjects from our dataset showed a similar pattern of significance over the gene region as the case-control analysis. This pattern was confirmed in 1,480 control subjects from the BRIGHT (British Genetics of Hypertension Study) cohort (top SNP from DARE: rs12734991 in meta-analysis: increase in corrected QT interval per C allele: 9.1 ± 3.2 ms, p = 1.7 × 10–4 ). Conclusions These results provide the first demonstration that common variations in the NOS1AP gene are associated with a significant increase in the risk of dLQTS. This study suggests that common variations in the NOS1AP gene may have relevance for future pharmacogenomic applications in clinical practice permitting safer prescription of drugs for vulnerable patients.
One important confounder in genome-wide association studies (GWASs) is population genetic structure, which may generate spurious associations if not properly accounted for. This may ultimately result ...in a biased polygenic risk score (PRS) prediction, especially when applied to another population. To explore this matter, we focused on principal component analysis (PCA) and asked whether a population genetics informed strategy focused on PCs derived from an external reference population helps in mitigating this PRS transferability issue. Throughout the study, we used two complex model traits, height and body mass index, and samples from UK and Estonian Biobanks. We aimed to investigate 1) whether using a reference population (1000G) for computation of the PCs adjusted for in the discovery cohort improves the resulting PRS performance in a target set from another population and 2) whether adjusting the validation model for PCs is required at all. Our results showed that any other set of PCs performed worse than the one computed on samples from the same population as the discovery dataset. Furthermore, we show that PC correction in GWAS cannot prevent residual population structure information in the PRS, also for non-structured traits. Therefore, we confirm the utility of PC correction in the validation model when the investigated trait shows an actual correlation with population genetic structure, to account for the residual confounding effect when evaluating the predictive value of PRS.
Low baroreflex sensitivity (BRS) was an established risk factor for cardiovascular disorders. We investigated determinants of BRS in a large sample from general population.
In a population-based ...study (n = 901), data were collected on BRS, arm cuff blood pressure (BP), and obesity indices including body mass index, waist-to-hip ratio, waist circumference, and percentage body fat (%BF). BRS was calculated by spectral analysis software based on continuously recorded spontaneous fluctuations in beat-to-beat finger BP for 10-15 minutes. Correlations and multivariable regression analyses were used to test associations of age, sex, obesity indices, and hypertension with BRS while considering effects of lifestyle factors (smoking, alcohol consumption, and physical activity).
In multivariable analysis, age, sex, %BF, and hypertension were independently associated with BRS. BRS decreased with -0.10 (95% confidence interval: -0.15 to -0.06) ms/mm Hg with each year of increase in age. Women had -1.55 (95% confidence interval: -2.28 to -0.73) ms/mm Hg lower mean BRS than men. The effects of %BF (per 10% increase) and hypertension on BRS were -0.55 (95% confidence interval: -0.97 to -0.13) ms/mm Hg and -1.23 (95% confidence interval: -1.92 to -0.46) ms/mm Hg, respectively. There was no evidence of associations between BRS and lifestyle factors. Age, age2, sex, and their interactions plus %BF and hypertension contributed 16.9% of total variance of BRS.
In this large general population study, we confirmed prior findings that age and sex were important factors associated with BRS and found %BF was more strongly related to less favorable BRS levels than body mass index.
Many adolescents start using tobacco, alcohol, and cannabis. Genetic vulnerability, parent characteristics in young adolescence, and interaction (GxE) and correlation (rGE) between these factors ...could contribute to the development of substance use. Using prospective data from the TRacking Adolescent Individuals’ Lives Survey (TRAILS; N = 1,645), we model latent parent characteristics in young adolescence to predict young adult substance use. Polygenic scores (PGS) are created based on genome-wide association studies (GWAS) for smoking, alcohol use, and cannabis use. Using structural equation modeling we model the direct, GxE, and rGE effects of parent factors and PGS on young adult smoking, alcohol use, and cannabis initiation. The PGS, parental involvement, parental substance use, and parent–child relationship quality predicted smoking. There was GxE such that the PGS amplified the effect of parental substance use on smoking. There was rGE between all parent factors and the smoking PGS. Alcohol use was not predicted by genetic or parent factors, nor by interplay. Cannabis initiation was predicted by the PGS and parental substance use, but there was no GxE or rGE. Genetic risk and parent factors are important predictors of substance use and show GxE and rGE in smoking. These findings can act as a starting point for identifying people at risk.
The identification of single-nucleotide polymorphisms (SNPs) in genes putatively related to pathophysiological processes in major depressive disorder (MDD) might improve both diagnosis and ...personalized treatment strategies eventually leading to more effective interventions. Considering the important role of the glucocorticoid receptor and the related FK506 binding protein 51 (FKBP51) in the pathophysiology of MDD, we aimed to investigate putative associations between variants of FKBP5, the coding gene of FKBP51, with antidepressant treatment resistance and MDD susceptibility.Nine common SNPs of the FKBP5 gene prioritized based on location and, putative or known functions were genotyped in Han Chinese population, including MDD patients with or without antidepressant-treatment resistance and healthy controls. Associations of FKBP5 SNPs with MDD susceptibility and treatment response were examined in the whole group of MDD patients, as well as in subgroups stratified by antidepressant treatment resistance, compared with healthy controls.In total, 181 Han Chinese patients with MDD and 80 healthy controls were recruited. No significant SNP or haplotype associations were observed in the whole patient group. There were nominal significant differences both for the haplotype block with SNPs in strong LD (r2 > 0.8, P = .040) and haplotype block with SNPs in moderate LD (r2 > 0.1, P = .017) between the haplotype distributions of patients with antidepressant treatment resistance (n = 81) and healthy controls, but both significances did not survive multiple testing correction. Furthermore, no specific haplotype could be observed causing a significant difference in any combination between all comparisons.No associations were observed of FKBP5 variants with MDD or antidepressant treatment response. The lack of associations might be due to the relatively small sample size of this study (power ranged from 0.100 to 0.752). A follow-up study will need larger, better phenotyped, and more homogeneous samples to draw a definitive conclusion regarding the involvement of this gene in MDD.
Recent studies suggest that smoking and lower educational attainment may have genetic influences in common. However, little is known about the mechanisms through which genetics contributes to ...educational inequalities in adolescent and young adult smoking. Common genetic liabilities may underlie cognitive skills associated with both smoking and education, such as IQ and effortful control, in line with indirect health-related selection explanations. Additionally, by affecting cognitive skills, genes may predict educational trajectories and hereby adolescents’ social context, which may be associated with smoking, consistent with social causation explanations. Using data from the Dutch TRAILS Study (N = 1581), we estimated the extent to which polygenic scores (PGSs) for ever smoking regularly (PGSSMOK) and years of education (PGSEDU) predict IQ and effortful control, measured around age 11, and whether these cognitive skills then act as shared predictors of smoking and educational level around age 16, 19, 22, and 26. Second, we assessed if educational level mediated associations between PGSs and smoking. Both PGSs were associated with lower effortful control, and PGSEDU also with lower IQ. Lower IQ and effortful control, in turn, predicted having a lower educational level. However, neither of these cognitive skills were directly associated with smoking behaviour after controlling for covariates and PGSs. This suggests that IQ and effortful control are not shared predictors of smoking and education (i.e., no indirect health-related selection related to cognitive skills). Instead, PGSSMOK and PGSEDU, partly through their associations with lower cognitive skills, predicted selection into a lower educational track, which in turn was associated with more smoking, in line with social causation explanations. Our findings suggest that educational differences in the social context contribute to associations between genetic liabilities and educational inequalities in smoking.
•Correlated genetic risk factors predict educational inequalities in smoking.•We studied the mechanisms linking genetics to educational differences in smoking.•Genes predicted cognitive skills in childhood, which predicted educational level.•A lower educational level in adolescence was in turn associated with more smoking.•The social context may drive associations between genetic liabilities and smoking.
Dupuytren disease (DD) is a common complex trait, with varying severity and incompletely understood cause. Genome-wide association studies (GWAS) have identified risk loci. In this article, we ...examine whether genetic risk profiles of DD in patients are associated with clinical variation and disease severity and with patient genetic risk profiles of genetically correlated traits, including body mass index (BMI), triglycerides, high-density lipoproteins, type 2 diabetes mellitus, and endophenotypes fasting glucose and glycated hemoglobin.
The authors used a well-characterized cohort of 1461 DD patients with available phenotypic and genetic data. Phenotype data include age at onset, recurrence, and family history of disease. Polygenic risk scores (PRSs) of DD, BMI, triglycerides, high-density lipoprotein, type 2 diabetes, fasting glucose, and hemoglobin A1c using various significance thresholds were calculated with PRSice using the most recent GWAS summary statistics. Control data from LifeLines were used to determine P value cutoffs for PRS generation explaining most variance.
The PRS for DD was significantly associated with a positive family history for DD, age at onset, disease onset before the age of 50, and recurrence. We also found a significant negative correlation between the PRSs for DD and BMI.
Although GWAS studies of DD are designed to identify genetic risk factors distinguishing case/control status, we show that the genetic risk profile for DD also explains part of its clinical variation and disease severity. The PRS may therefore aid in accurate prognostication, choosing initial treatment and in personalized medicine in the future.
Risk, III.
Ubiquitous non-persistent endocrine disrupting chemicals (EDCs) have inconsistent associations with cardiometabolic traits. Additionally, large-scale genome-wide association studies (GWASs) have ...yielded many genetic risk variants for cardiometabolic traits and diseases. This study aimed to investigate the associations between a wide range of EDC exposures (parabens, bisphenols, and phthalates) and 14 cardiometabolic traits and whether these are moderated by their respective genetic risk scores (GRSs). Data were from 1074 participants aged 18 years or older of the Lifelines Cohort Study, a large population-based biobank. GRSs for 14 cardiometabolic traits were calculated based on genome-wide significant common variants from recent GWASs. The concentrations of 15 EDCs in 24-hour urine were measured by isotope dilution liquid chromatography tandem mass spectrometry technology. The main effects of trait-specific GRSs and each of the EDC exposures and their interaction effects on the 14 cardiometabolic traits were examined in multiple linear regression. The present study confirmed significant main effects for all GRSs on their corresponding cardiometabolic trait. Regarding the main effects of EDC exposures, 26 out of 280 EDC-trait tests were significant with explained variances ranging from 0.43 % (MMP- estimated glomerular filtration rate (eGFR)) to 2.37 % (PrP-waist-hip ratio adjusted body mass index (WHRadjBMI)). We confirmed the association of MiBP and MBzP with WHRadjBMI and body mass index (BMI), and showed that parabens, bisphenol F, and many other phthalate metabolites significantly contributed to the variance of WHRadjBMI, BMI, high-density lipoprotein (HDL), eGFR, fasting glucose (FG), and diastolic blood pressure (DBP). Only one association between BMI and bisphenol F was nominally significantly moderated by the GRS explaining 0.36 % of the variance. However, it did not survive multiple testing correction. We showed that non-persistent EDC exposures exerted effects on BMI, WHRadjBMI, HDL, eGFR, FG, and DBP. However no evidence for a modulating role of GRSs was found.
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•Associations of 20 EDC levels with 14 cardiometabolic traits were investigated.•Weighted cardiometabolic GRSs were calculated based on the latest GWAS results.•All trait-specific GRSs associated with risk factors for cardiometabolic disease.•Phthalates particularly contributed to the variance of cardiometabolic traits.•Only the interaction of GRS with BPF on BMI was nominally significantly associated.
Previous studies have shown that skin autofluorescence (SAF), measured with an advanced glycation end product (AGE) reader, estimates the accumulation of AGEs in tissues. SAF is predictive of ...incident type 2 diabetes, cardiovascular disease (CVD), and CV mortality in the general population. Studies in diabetic mice have shown that activation of the receptor for AGEs in hematopoietic progenitor cells increases blood neutrophils and monocytes, impairing atherosclerosis regression. We asked whether SAF is associated with blood neutrophil and monocyte counts in the general population, and whether this was moderated by prediabetes, diabetes, and sex.
We examined the associations between SAF and blood neutrophil/monocyte counts in participants of the Lifelines cohort (n = 58,923: n = 24,382 men, and n = 34,541 women), a prospective population-based cohort from the North of the Netherlands, employing multivariable regression analyses.
SAF positively associated with blood neutrophil and monocyte counts in the whole cohort. The positive association between SAF and monocyte, but not neutrophil, counts was moderated by prediabetes and diabetes. Positive associations between SAF and blood neutrophil and monocyte counts were moderated by male sex. Moreover, three-way interaction analyses revealed that the positive associations between SAF and neutrophil and monocyte counts were moderated by prediabetes, but not diabetes, in male sex.
SAF is positively associated with blood neutrophil and monocyte counts in the general population, especially in men with prediabetes. This may contribute to the increased CV risk in men with prediabetes.
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•Skin autofluorescence (SAF) is positively associated with blood neutrophil and monocyte counts in the Lifelines cohort.•The association between SAF and blood monocyte, but not neutrophil, counts is moderated by prediabetes and diabetes.•The associations between SAF and blood neutrophil and monocyte counts are moderated by male sex.•The associations between SAF and blood neutrophil and monocyte counts are moderated by prediabetes in male sex.
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