Maarten Leusink

Adult height, coronary heart disease and stroke: a multi-locus Mendelian randomization meta-analysis

Abstract Background: We investigated causal effect of completed growth, measured by adult height, on coronary heart disease (CHD), stroke and cardiovascular traits, using instrumental variable (IV) Mendelian randomization meta-analysis. Methods: We developed an allele score based on 69 single nucleotide polymorphisms (SNPs) associated with adult height, identified by the IBCCardioChip, and used it for IV analysis against cardiovascular risk factors and events in 21 studies and 60 028 participants. IV analysis on CHD was supplemented by summary data from 180 height-SNPs from the GIANT consortium and their corresponding CHD estimates derived from CARDIoGRAMplusC4D. Results: IV estimates from IBCCardioChip and GIANT-CARDIoGRAMplusC4D showed that a 6.5-cm increase in height reduced the odds of CHD by 10% [odds ratios 0.90; 95% confidence intervals (CIs): 0.78 to 1.03 and 0.85 to 0.95, respectively],which agrees with the estimate from the Emerging Risk Factors Collaboration (hazard ratio 0.93; 95% CI: 0.91 to 0.94). IV analysis revealed no association with stroke (odds ratio 0.97; 95% CI: 0.79 to 1.19). IV analysis showed that a 6.5-cm increase in height resulted in lower levels of body mass index (P < 0.001), triglycerides (P < 0.001), non high-density (non-HDL) cholesterol (P < 0.001), C-reactive protein (P = 0.042), and systolic blood pressure (P = 0.064) and higher levels of forced expiratory volume in 1 s and forced vital capacity (P < 0.001 for both). Conclusions: Taller individuals have a lower risk of CHD with potential explanations being that taller people have a better lung function and lower levels of body mass index, cholesterol and blood pressure.

Seventeen years of statin pharmacogenetics: a systematic review

AIM We evaluated the evidence of pharmacogenetic associations with statins in a systematic review. METHODS Two separate outcomes were considered of interest: modification of low-density lipoprotein cholesterol (LDL-C) response and modification of risk for cardiovascular events. RESULTS In candidate gene studies, 141 loci were claimed to be associated with LDL-C response. Only 5% of these associations were positively replicated. In addition, six genome-wide association studies of LDL-C response identified common SNPs in APOE, LPA, SLCO1B1, SORT1 and ABCG2 at genome-wide significance. None of the investigated SNPs consistently affected the risk reduction for cardiovascular events. CONCLUSION Only five genetic loci were consistently associated with LDL-C response. However, as effect sizes are modest, there is no evidence for the value of genetic testing in clinical practice.

Robust association of the LPA locus with low-density lipoprotein cholesterol lowering response to statin treatment in a meta-analysis of 30 467 individuals from both randomized control trials and observational studies and association with coronary artery disease outcome during statin treatment

Objectives The LPA single-nucleotide polymorphism rs10455872 has been associated with low-density lipoprotein cholesterol (LDLc) lowering response to statins in several randomized control trials (RCTs) and is a known coronary artery disease (CAD) marker. However, it is unclear what residual risk of CAD this marker may have during statin treatment. Methods Using electronic medical records linked to the GoDARTS genotyped population, we identified over 8000 patients on statins in Tayside, Scotland. Results We replicated the findings of the RCTs, with the G allele of rs10455872 being associated with a 0.10 mmol/l per allele poorer reduction in LDLc in response to statin treatment, and conducted a meta-analysis with previously published RCTs (P=1.46×10−29, n=30 467). We showed an association between rs10455872 and CAD in statin-treated individuals and have replicated this finding in the Utrecht Cardiovascular Pharmacogenetics study (combined odds ratio 1.41, 95% confidence interval 1.17–1.68, P=4.5×10−5, n=8822) suggesting that statin treatment does not abrogate this well-established genetic risk for CAD. Furthermore, in a Cox proportional hazards model with LDLc measured time dependently, we demonstrated that the relationship between CAD and rs10455872 was independent of LDLc during statin treatment. Conclusion Individuals with the G allele of rs10455872, which represents approximately one in seven patients, have a higher risk of CAD than the majority of the population even after treatment with statins; and therefore represent a vulnerable group requiring an alternative medication in addition to statin treatment.

Pharmacogenetic analysis of GLCCI1 in three north European pediatric asthma populations with a reported use of inhaled corticosteroids

BACKGROUND GLCCI1 rs37972 has previously been associated with decreased lung function improvement upon treatment with inhaled corticosteroids (ICS) in asthmatics. AIM To assess whether variation in rs37972 is associated with altered ICS efficacy in north European asthmatic children and young adults with a reported use of ICS. PATIENTS & METHODS rs37972 was genotyped in three cohort studies of asthmatic children with a reported use of ICS. As an indicator for asthma exacerbations, asthma-related hospital visits and oral corticosteroid use were studied. Asthma control was assessed using a questionnaire. RESULTS rs37972 T allele was not significantly associated with an increased risk of oral corticosteroid use (summary odds ratio: 1.20; 95% CI: 0.99-1.45), an increased risk of asthma-related hospital visits (summary odds ratio: 1.07; 95% CI: 0.89-1.29), uncontrolled symptoms (summary odds ratio: 1.01; 95% CI: 0.75-1.36) or higher ICS dosages (summary β: 0.01, 95% CI: -0.06-0.08). CONCLUSION Variation in GLCCI1 rs37972 genotype does not seem to affect ICS efficacy in north European asthmatic children. Original submitted 26 November 2013; Revision submitted 13 February 2014.

ST13 polymorphisms and their effect on exacerbations in steroid-treated asthmatic children and young adults

The clinical response to inhaled corticosteroids (ICS) is associated with single nucleotide polymorphisms (SNPs) in various genes. This study aimed to relate variations in genes in the steroid pathway and asthma susceptibility genes to exacerbations in children and young adults treated with ICS.

Cholesteryl Ester Transfer Protein Polymorphisms, Statin Use, and Their Impact on Cholesterol Levels and Cardiovascular Events

The association of nonfunctional variants of the cholesteryl ester transfer protein (CETP) with efficacy of statins has been a subject of debate. We evaluated whether three functional CETP variants influence statin efficacy. The effect of CETP genotype on achieved levels of high‐density lipoprotein cholesterol (HDLc), low‐density lipoprotein cholesterol (LDLc), and total cholesterol during statin treatment was estimated by meta‐analysis of the linear regression outcomes of three studies (11,021 individuals). The effect of these single‐nucleotide polymorphisms (SNPs) on statin response in protecting against myocardial infarction (MI) was estimated by meta‐analysis of statin × SNP interaction terms from logistic regression in five studies (16,570 individuals). The enhancer SNP rs3764261 significantly increased HDLc by 0.02 mmol/l per T allele (P = 6 × 10–5) and reduced protection against MI by statins (interaction odds ratio (OR) = 1.19 per T allele; P = 0.04). Focusing on functional CETP variants, we showed that in carriers of the rs3764261 T variant, HDLc increased more during statin treatment, and protection against MI by statins appeared to be reduced as compared with those in noncarriers.

Association Claims in the Sequencing Era

Since the completion of the Human Genome Project, the field of human genetics has been in great flux, largely due to technological advances in studying DNA sequence variation. Although community-wide adoption of statistical standards was key to the success of genome-wide association studies, similar standards have not yet been globally applied to the processing and interpretation of sequencing data. It has proven particularly challenging to pinpoint unequivocally disease variants in sequencing studies of polygenic traits. Here, we comment on a number of factors that may contribute to irreproducible claims of association in scientific literature and discuss possible steps that we can take towards cultural change.

Genetic variation in uncontrolled childhood asthma despite ICS treatment

Genetic variation may partly explain asthma treatment response heterogeneity. We aimed to identify common and rare genetic variants associated with asthma that was not well controlled despite inhaled corticosteroid (ICS) treatment. Data of 110 children was collected in the Children Asthma Therapy Optimal trial. Associations of genetic variation with measures of lung function (FEV1%pred), airway hyperresponsiveness (AHR) to methacholine (Mch PD20) and treatment response outcomes were analyzed using the exome chip. The 17q12-21 locus (containing ORMDL3 and GSMDB) previously associated with childhood asthma was investigated separately. Single-nucleotide polymorphisms (SNPs) in the 17q12-21 locus were found nominally associated with the outcomes. The strongest association in this region was found for rs72821893 in KRT25 with FEV1%pred (P=3.75*10−5), Mch PD20 (P=0.00095) and Mch PD20-based treatment outcome (P=0.006). No novel single SNPs or burden tests were significantly associated with the outcomes. The 17q12-21 region was associated with FEV1%pred and AHR, and additionally with ICS treatment response.

A genetic risk score is associated with statin-induced low-density lipoprotein cholesterol lowering

AIM To find new genetic loci associated with statin response, and to investigate the association of a genetic risk score (GRS) with this outcome. PATIENTS & METHODS In a discovery meta-analysis (five studies, 1991 individuals), we investigated the effects of approximately 50000 single nucleotide polymorphisms on statin response, following up associations with p < 1 × 10(-4) (three independent studies, 5314 individuals). We further assessed the effect of a GRS based on SNPs in ABCG2, LPA and APOE. RESULTS No new SNPs were found associated with statin response. The GRS was associated with reduced statin response: 0.0394 mmol/l per allele (95% CI: 0.0171-0.0617, p = 5.37 × 10(-4)). CONCLUSION The GRS was associated with statin response, but the small effect size (˜2% of the average low-density lipoprotein cholesterol reduction) limits applicability.

Adult derived genetic blood pressure scores and blood pressure measured in different body postures in young children.

Aims Several genes are related to blood pressure (BP) levels in adults, but it is largely unknown whether these genes also determine BP early in life. Methods Systolic BP (SBP) and diastolic BP (DBP) were measured in 720 5-year-old children from the WHeezing-Illnesses-STudy-LEidsche-Rijn (WHISTLER) birth cohort in sitting and supine positions using a semi-automatic oscillometric device. Illumina chip technology was used to genotype 18, 19, 11 and 12 single nucleotide polymorphisms associated with adult SBP, DBP, mean arterial pressure (MAP) and hypertension, respectively, in the children’s DNA and separate weighted genetic risk scores (GRSs) were constructed. The associations are reported as linear regression coefficients (mmHg BP in childhood/GRS score point) or odds ratios (highest childhood BP quintile/hypertension GRS score point). Results A higher GRS for SBP was related to higher supine SBP (0.37, 95% CI 0.01 to 0.7), but not to supine DBP (−0.05, 95% CI −0.4 to 0.3) or supine MAP (0.19, 95% CI −0.1 to 0.5). A higher GRS for DBP was related to a higher supine SBP (0.66, 95% CI 0.1 to 1.2), but not to supine DBP (−0.07, 95% CI −0.6 to 0.4) or supine MAP (0.28, 95% CI −0.2 to 0.7). With the sitting BP measurements, the GRSs for SBP and DBP were related to neither SBP nor DBP. No association was found between GRS for MAP and SBP, DBP or MAP. Hypertension GRS was not associated with a higher BP in children. Conclusions Higher scores for adult derived diastolic and systolic BP genes appear to be related to higher supine systolic BP at age 5 years.