The PHArmacogenetic study of Statins in the Elderly at risk (PHASE) is a genome wide association study in the PROspective Study of Pravastatin in the Elderly at risk for vascular disease (PROSPER) ...that investigates the genetic variation responsible for the individual variation in drug response to pravastatin. Statins lower LDL-cholesterol in general by 30%, however not in all subjects. Moreover, clinical response is highly variable and adverse effects occur in a minority of patients. In this report we first describe the rationale of the PROSPER/PHASE project and second show that the PROSPER/PHASE study can be used to study pharmacogenetics in the elderly.
The genome wide association study (GWAS) was conducted using the Illumina 660K-Quad beadchips following manufacturer's instructions. After a stringent quality control 557,192 SNPs in 5,244 subjects were available for analysis. To maximize the availability of genetic data and coverage of the genome, imputation up to 2.5 million autosomal CEPH HapMap SNPs was performed with MACH imputation software. The GWAS for LDL-cholesterol is assessed with an additive linear regression model in PROBABEL software, adjusted for age, sex, and country of origin to account for population stratification.
Forty-two SNPs reached the GWAS significant threshold of p = 5.0e-08 in 5 genomic loci (APOE/APOC1; LDLR; FADS2/FEN1; HMGCR; PSRC1/CELSR5). The top SNP (rs445925, chromosome 19) with a p-value of p = 2.8e-30 is located within the APOC1 gene and near the APOE gene. The second top SNP (rs6511720, chromosome 19) with a p-value of p = 5.22e-15 is located within the LDLR gene. All 5 genomic loci were previously associated with LDL-cholesterol levels, no novel loci were identified. Replication in WOSCOPS and CARE confirmed our results.
With the GWAS in the PROSPER/PHASE study we confirm the previously found genetic associations with LDL-cholesterol levels. With this proof-of-principle study we show that the PROSPER/PHASE study can be used to investigate genetic associations in a similar way to population based studies. The next step of the PROSPER/PHASE study is to identify the genetic variation responsible for the variation in LDL-cholesterol lowering in response to statin treatment in collaboration with other large trials.
Proprotein convertase subtilisin-like/kexin type 9 (PCSK9) is a protein involved in LDL-cholesterol metabolism. The single-nucleotide polymorphism (SNP) rs11591147 has been associated with lower ...LDL-cholesterol and a lower risk of coronary heart disease. Because PCSK9 has high affinity to the LDL receptor, inhibiting PCSK9 is a testable therapeutic target for lipid-lowering therapy. Currently, several approaches to inhibit PCSK9 are under development, but it is unknown what the effects of those inhibitors will be on cognition or noncardiovascular clinical events. In this study, we assessed the association between rs11591147 and cognitive performance, activities of daily living (ADL), and noncardiovascular clinical events within 5,777 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). Rs11591147 was associated with 10% to 16% lower LDL cholesterol levels (P = 3.62 × 10−12), but was not associated with cognitive performance, ADL, or noncardiovascular clinical events in the PROSPER study. Our findings suggest that lower cholesterol levels due to genetic variation in the PCSK9 gene are not associated with cognitive performance, functional status, or noncardiovascular clinical events.
Abstract Background and Aims Although guidelines recommend opportunistic screening for chronic kidney disease (CKD) in individuals with established risk factors, such as diabetes, hypertension, or ...cardiovascular disease, screening for CKD in these individuals remains suboptimal. This study aimed to evaluate the effectiveness of an additional systematic home-based albuminuria screening program in patients at risk for CKD in a primary care setting. Method A cross-sectional screening study was performed in 10 general practices and 5 pharmacies in the Netherlands between Nov 2021-Nov 2023. A random selection of patients aged 45-80 years with risk factors for CKD progression was invited for home-based albuminuria screening. These patients were registered at their general practitioner (GP) or at the pharmacy. Patients in the GP-group were identified based on the following risk factors: diabetes, cardiovascular disease, hypertension, hypercholesterolemia, or obesity. Patients were excluded in case of a normal albuminuria status (ACR (albumin-creatinine ratio) <3.0 mg/mmol) within 18 months prior to the screening. Patients in the pharmacy-group were identified based on drug prescriptions for the aforementioned risk factors in the last 6 months. Home-based albuminuria screening was performed using a urine collection device that was sent by post to a central laboratory for ACR measurement. If the test result was positive upon confirmation (i.e. ≥two tests ACR ≥3 mg/mmol), patients were invited for an elaborate visit in the general practice or pharmacy, to assess presence of CKD and cardiovascular risk factors. Main outcomes were participation rate and yield of the home-based albuminuria screening in the total study population and in both screening groups separately. Secondary outcomes were the yield of persistent albuminuria despite treatment with RAS-inhibition in both screening groups and the yield of previously undiagnosed albuminuria in the GP-group. Results We invited 6 380 patients (2 578 via pharmacy registries and 3 802 via GP registries), of whom 2 147 completed the home-based screening, corresponding to a participation rate of 33.7%. The participation rate among GP patients was 41.4% (1 575/3 802), compared to 22.2% (572/2 578) among pharmacy patients (P < .001). Albuminuria was confirmed in 8.5% (134/3 802) and 5.6% (32/2 578) of the participants in the GP- and pharmacy-group, respectively. Among participants in the GP-group, 59.7% (80/134) had a positive albuminuria test within one year prior to the screening; the remaining 40.3% either had no albuminuria test (or a normal albuminuria test within one year prior to the screening. Of those with increased albuminuria in the GP- and pharmacy-group, 85.8% (115/134) and 81.3% (26/32) attended the elaborate screening visit, respectively. In the GP-group, 72.2% (83/115) had an eGFR >60 and only 19.1% (22/115) an adequate blood pressure (<130/80 mmHg), compared to 69.2% (18/26) and 19.2% (5/26) in the pharmacy-group. Of the albuminuric participants in the GP- and pharmacy-group, respectively, 44.3% (51/115) and 23.1% (6/26) were not treated with RAS inhibition, and 94.8% (109/115) and 96.2% (25/26), respectively, were not treated with an SGLT2 inhibitor. Many patients were not aware of having albuminuria before participating in the systematic home-based screening program 42.6% (109/115) in the GP-group vs. 61.5% (16/26) in the pharmacy-group). Conclusion In conclusion, systematic albuminuria screening in the primary care setting when added to regular opportunistic screening has an acceptable participation rate and yield when performed via GPs, but is less effective when performed via pharmacies. It identifies patients with yet unknown albuminuria and most of the identified patients may benefit of initiation or optimization of albuminuria-lowering treatment. The introduction of such systematic albuminuria screening programs via GPs merits further study.
Thyroid dysfunction is an important public health problem, which affects 10% of the general population and increases the risk of cardiovascular morbidity and mortality. Many aspects of thyroid ...hormone regulation have only partly been elucidated, including its transport, metabolism, and genetic determinants. Here we report a large meta-analysis of genome-wide association studies for thyroid function and dysfunction, testing 8 million genetic variants in up to 72,167 individuals. One-hundred-and-nine independent genetic variants are associated with these traits. A genetic risk score, calculated to assess their combined effects on clinical end points, shows significant associations with increased risk of both overt (Graves' disease) and subclinical thyroid disease, as well as clinical complications. By functional follow-up on selected signals, we identify a novel thyroid hormone transporter (SLC17A4) and a metabolizing enzyme (AADAT). Together, these results provide new knowledge about thyroid hormone physiology and disease, opening new possibilities for therapeutic targets.
We carried out a trans-ancestry genome-wide association and replication study of blood pressure phenotypes among up to 320,251 individuals of East Asian, European and South Asian ancestry. We find ...genetic variants at 12 new loci to be associated with blood pressure (P = 3.9 × 10(-11) to 5.0 × 10(-21)). The sentinel blood pressure SNPs are enriched for association with DNA methylation at multiple nearby CpG sites, suggesting that, at some of the loci identified, DNA methylation may lie on the regulatory pathway linking sequence variation to blood pressure. The sentinel SNPs at the 12 new loci point to genes involved in vascular smooth muscle (IGFBP3, KCNK3, PDE3A and PRDM6) and renal (ARHGAP24, OSR1, SLC22A7 and TBX2) function. The new and known genetic variants predict increased left ventricular mass, circulating levels of NT-proBNP, and cardiovascular and all-cause mortality (P = 0.04 to 8.6 × 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
Blood pressure (BP) is a major risk factor for cardiovascular disease and more than 200 genetic loci associated with BP are known. Here, we perform a multi-stage genome-wide association study for BP ...(max N = 289,038) principally in East Asians and meta-analysis in East Asians and Europeans. We report 19 new genetic loci and ancestry-specific BP variants, conforming to a common ancestry-specific variant association model. At 10 unique loci, distinct non-rare ancestry-specific variants colocalize within the same linkage disequilibrium block despite the significantly discordant effects for the proxy shared variants between the ethnic groups. The genome-wide transethnic correlation of causal-variant effect-sizes is 0.898 and 0.851 for systolic and diastolic BP, respectively. Some of the ancestry-specific association signals are also influenced by a selective sweep. Our results provide new evidence for the role of common ancestry-specific variants and natural selection in ethnic differences in complex traits such as BP.
Human leukocyte telomere length (LTL) decreases with age and shorter LTL has previously been associated with increased prospective mortality. However, it is not clear whether LTL merely marks the ...health status of an individual by its association with parameters of immune function, for example, or whether telomere shortening also contributes causally to lifespan variation in humans.
We measured LTL in 870 nonagenarian siblings (mean age 93 years), 1580 of their offspring and 725 spouses thereof (mean age 59 years) from the Leiden Longevity Study (LLS).
We found that shorter LTL is associated with increased prospective mortality in middle (30-80 years; hazard ratio (HR)=0.75, P=0.001) and highly advanced age (≥90 years; HR=0.92, P=0.028), and show that this association cannot be explained by the association of LTL with the immune-related markers insulin-like growth factor 1 to insulin-like growth factor binding protein 3 molar ratio, C-reactive protein, interleukin 6, cytomegalovirus serostatus or white blood cell counts. We found no difference in LTL between the middle-aged LLS offspring and their spouses (β=0.006, P=0.932). Neither did we observe an association of LTL-associated genetic variants with mortality in a prospective meta-analysis of multiple cohorts (n=8165).
We confirm LTL to be a marker of prospective mortality in middle and highly advanced age and additionally show that this association could not be explained by the association of LTL with various immune-related markers. Furthermore, the approaches performed here do not further support the hypothesis that LTL variation contributes to the genetic propensity for longevity.
Smoking is an important cardiovascular disease risk factor, but the mechanisms linking smoking to blood pressure are poorly understood.
Data on 141 317 participants (62 666 never, 40 669 former, 37 ...982 current smokers) from 23 population-based studies were included in observational and Mendelian randomization meta-analyses of the associations of smoking status and smoking heaviness with systolic and diastolic blood pressure, hypertension, and resting heart rate. For the Mendelian randomization analyses, a genetic variant rs16969968/rs1051730 was used as a proxy for smoking heaviness in current smokers. In observational analyses, current as compared with never smoking was associated with lower systolic blood pressure and diastolic blood pressure and lower hypertension risk, but with higher resting heart rate. In observational analyses among current smokers, 1 cigarette/day higher level of smoking heaviness was associated with higher (0.21 bpm; 95% confidence interval 0.19; 0.24) resting heart rate and slightly higher diastolic blood pressure (0.05 mm Hg; 95% confidence interval 0.02; 0.08) and systolic blood pressure (0.08 mm Hg; 95% confidence interval 0.03; 0.13). However, in Mendelian randomization analyses among current smokers, although each smoking increasing allele of rs16969968/rs1051730 was associated with higher resting heart rate (0.36 bpm/allele; 95% confidence interval 0.18; 0.54), there was no strong association with diastolic blood pressure, systolic blood pressure, or hypertension. This would suggest a 7 bpm higher heart rate in those who smoke 20 cigarettes/day.
This Mendelian randomization meta-analysis supports a causal association of smoking heaviness with higher level of resting heart rate, but not with blood pressure. These findings suggest that part of the cardiovascular risk of smoking may operate through increasing resting heart rate.
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