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- Asselbergs, Folkert W., et al.
(author)
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Large-Scale Gene-Centric Meta-analysis across 32 Studies Identifies Multiple Lipid Loci
- 2012
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 91:5, s. 823-838
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Journal article (peer-reviewed)abstract
- Genome-wide association studies (GWASs) have identified many SNPs underlying variations in plasma-lipid levels. We explore whether additional loci associated with plasma-lipid phenotypes, such as high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C), total cholesterol (TC), and triglycerides (TGs), can be identified by a dense gene-centric approach. Our meta-analysis of 32 studies in 66,240 individuals of European ancestry was based on the custom similar to 50,000 SNP genotyping array (the ITMAT-Broad-CARe array) covering similar to 2,000 candidate genes. SNP-lipid associations were replicated either in a cohort comprising an additional 24,736 samples or within the Global Lipid Genetic Consortium. We identified four, six, ten, and four unreported SNPs in established lipid genes for HDL-C, LDL-C, TC, and TGs, respectively. We also identified several lipid-related SNPs in previously unreported genes: DGAT2, HCAR2, GPIHBP1, PPARG, and FTO for HDL-C; SOCS3, APOH, SPTY2D1, BRCA2, and VLDLR for LDL-C; SOCS3, UGT1A1, BRCA2, UBE3B, FCGR2A, CHUK, and INSIG2 for TC; and SERPINF2, C4B, GCK, GATA4, INSR, and LPAL2 for TGs. The proportion of explained phenotypic variance in the subset of studies providing individual-level data was 9.9% for HDL-C, 9.5% for LDL-C, 10.3% for TC, and 8.0% for TGs. This large meta-analysis of lipid phenotypes with the use of a dense gene-centric approach identified multiple SNPs not previously described in established lipid genes and several previously unknown loci. The explained phenotypic variance from this approach was comparable to that from a meta-analysis of GWAS data, suggesting that a focused genotyping approach can further increase the understanding of heritability of plasma lipids.
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- Tragante, Vinicius, et al.
(author)
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Gene-centric Meta-analysis in 87,736 Individuals of European Ancestry Identifies Multiple Blood-Pressure-Related Loci.
- 2014
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In: American Journal of Human Genetics. - : Elsevier BV. - 0002-9297. ; 94:3, s. 349-360
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Journal article (peer-reviewed)abstract
- Blood pressure (BP) is a heritable risk factor for cardiovascular disease. To investigate genetic associations with systolic BP (SBP), diastolic BP (DBP), mean arterial pressure (MAP), and pulse pressure (PP), we genotyped ∼50,000 SNPs in up to 87,736 individuals of European ancestry and combined these in a meta-analysis. We replicated findings in an independent set of 68,368 individuals of European ancestry. Our analyses identified 11 previously undescribed associations in independent loci containing 31 genes including PDE1A, HLA-DQB1, CDK6, PRKAG2, VCL, H19, NUCB2, RELA, HOXC@ complex, FBN1, and NFAT5 at the Bonferroni-corrected array-wide significance threshold (p < 6 × 10(-7)) and confirmed 27 previously reported associations. Bioinformatic analysis of the 11 loci provided support for a putative role in hypertension of several genes, such as CDK6 and NUCB2. Analysis of potential pharmacological targets in databases of small molecules showed that ten of the genes are predicted to be a target for small molecules. In summary, we identified previously unknown loci associated with BP. Our findings extend our understanding of genes involved in BP regulation, which may provide new targets for therapeutic intervention or drug response stratification.
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- Padmanabhan, Sandosh, et al.
(author)
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Genome-Wide Association Study of Blood Pressure Extremes Identifies Variant near UMOD Associated with Hypertension
- 2010
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In: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 6:10
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Journal article (peer-reviewed)abstract
- Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 59 region of Uromodulin (UMOD; rs13333226, combined P value of 3.6x10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95% CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.
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- Postmus, Iris, et al.
(author)
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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
- 2014
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In: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Journal article (peer-reviewed)abstract
- Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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- Rothwell, P. M., et al.
(author)
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Effects of beta blockers and calcium-channel blockers on within-individual variability in blood pressure and risk of stroke
- 2010
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In: The Lancet Neurology. - 1474-4422. ; 9:5, s. 469-480
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Journal article (peer-reviewed)abstract
- BACKGROUND: Analyses of some randomised trials show that calcium-channel blockers reduce the risk of stroke more than expected on the basis of mean blood pressure alone and that beta blockers are less effective than expected. We aimed to investigate whether the effects of these drugs on variability in blood pressure might explain these disparities in effect on stroke risk. METHODS: The Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm (ASCOT-BPLA) compared amlodipine-based regimens with atenolol-based regimens in 19 257 patients with hypertension and other vascular risk factors and the Medical Research Council (MRC) trial compared atenolol-based and diuretic-based regimens versus placebo in 4396 hypertensive patients aged 65-74 years. We expressed visit-to-visit variability of blood pressure during follow-up in the two trials as standard deviation (SD) and as transformations uncorrelated with mean blood pressure. For ASCOT-BPLA, we also studied within-visit variability and variability on 24 h ambulatory blood-pressure monitoring (ABPM). RESULTS: In ASCOT-BPLA, group systolic blood pressure (SBP) SD was lower in the amlodipine group than in the atenolol group at all follow-up visits (p<0.0001), mainly because of lower within-individual visit-to-visit variability. Within-visit and ABPM variability in SBP were also lower in the amlodipine group than in the atenolol group (all p<0.0001). Analysis of changes from baseline showed that variability decreased over time in the amlodipine group and increased in the atenolol group. The lower risk of stroke in the amlodipine group (hazard ratio 0.78, 95% CI 0.67-0.90) was partly attenuated by adjusting for mean SBP during follow-up (0.84, 0.72-0.98), but was abolished by also adjusting for within-individual SD of clinic SBP (0.99, 0.85-1.16). Findings were similar for coronary events. In the ABPM substudy, reduced variability in daytime SBP in the amlodipine group (p<0.0001) partly accounted for the reduced risk of vascular events, but reduced visit-to-visit variability in clinic SBP had a greater effect. In the MRC trial, group SD SBP and all measures of within-individual visit-to-visit variability in SBP were increased in the atenolol group compared with both the placebo group and the diuretic group during initial follow-up (all p<0.0001). Subsequent temporal trends in variability in blood pressure during follow-up in the atenolol group correlated with trends in stroke risk. INTERPRETATION: The opposite effects of calcium-channel blockers and beta blockers on variability of blood pressure account for the disparity in observed effects on risk of stroke and expected effects based on mean blood pressure. To prevent stroke most effectively, blood-pressure-lowering drugs should reduce mean blood pressure without increasing variability; ideally they should reduce both. FUNDING: None.
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- Rothwell, P. M., et al.
(author)
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Prognostic significance of visit-to-visit variability, maximum systolic blood pressure, and episodic hypertension
- 2010
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In: The Lancet. - 0140-6736. ; 375:9718, s. 895-905
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Journal article (peer-reviewed)abstract
- BACKGROUND: The mechanisms by which hypertension causes vascular events are unclear. Guidelines for diagnosis and treatment focus only on underlying mean blood pressure. We aimed to reliably establish the prognostic significance of visit-to-visit variability in blood pressure, maximum blood pressure reached, untreated episodic hypertension, and residual variability in treated patients. METHODS: We determined the risk of stroke in relation to visit-to-visit variability in blood pressure (expressed as standard deviation [SD] and parameters independent of mean blood pressure) and maximum blood pressure in patients with previous transient ischaemic attack (TIA; UK-TIA trial and three validation cohorts) and in patients with treated hypertension (Anglo-Scandinavian Cardiac Outcomes Trial Blood Pressure Lowering Arm [ASCOT-BPLA]). In ASCOT-BPLA, 24-h ambulatory blood-pressure monitoring (ABPM) was also studied. FINDINGS: In each TIA cohort, visit-to-visit variability in systolic blood pressure (SBP) was a strong predictor of subsequent stroke (eg, top-decile hazard ratio [HR] for SD SBP over seven visits in UK-TIA trial: 6.22, 95% CI 4.16-9.29, p<0.0001), independent of mean SBP, but dependent on precision of measurement (top-decile HR over ten visits: 12.08, 7.40-19.72, p<0.0001). Maximum SBP reached was also a strong predictor of stroke (HR for top-decile over seven visits: 15.01, 6.56-34.38, p<0.0001, after adjustment for mean SBP). In ASCOT-BPLA, residual visit-to-visit variability in SBP on treatment was also a strong predictor of stroke and coronary events (eg, top-decile HR for stroke: 3.25, 2.32-4.54, p<0.0001), independent of mean SBP in clinic or on ABPM. Variability on ABPM was a weaker predictor, but all measures of variability were most predictive in younger patients and at lower (
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