Showing papers by "Ioanna Tzoulaki published in 2011"

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure is a heritable trait(1) influenced by several biological pathways and responsive to environmental stimuli. Over one billion people worldwide have hypertension (>= 140 mm Hg systolic blood pressure or >= 90 mm Hg diastolic blood pressure)(2). Even small increments in blood pressure are associated with an increased risk of cardiovascular events(3). This genome-wide association study of systolic and diastolic blood pressure, which used a multi-stage design in 200,000 individuals of European descent, identified sixteen novel loci: six of these loci contain genes previously known or suspected to regulate blood pressure (GUCY1A3-GUCY1B3, NPR3-C5orf23, ADM, FURIN-FES, GOSR2, GNAS-EDN3); the other ten provide new clues to blood pressure physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke and coronary artery disease, but not kidney disease or kidney function. We also observed associations with blood pressure in East Asian, South Asian and African ancestry individuals. Our findings provide new insights into the genetics and biology of blood pressure, and suggest potential novel therapeutic pathways for cardiovascular disease prevention.

Association between C reactive protein and coronary heart disease: mendelian randomisation analysis based on individual participant data

Abstract: Objective To use genetic variants as unconfounded proxies of C reactive protein concentration to study its causal role in coronary heart disease. Design Mendelian randomisation meta-analysis of ind ...

Blood Pressure Loci Identified with a Gene-Centric Array

Abstract: Raised blood pressure (BP) is a major risk factor for cardiovascular disease. Previous studies have identified 47 distinct genetic variants robustly associated with BP, but collectively these explain only a few percent of the heritability for BP phenotypes. To find additional BP loci, we used a bespoke gene-centric array to genotype an independent discovery sample of 25,118 individuals that combined hypertensive case-control and general population samples. We followed up four SNPs associated with BP at our p < 8.56 × 10(-7) study-specific significance threshold and six suggestively associated SNPs in a further 59,349 individuals. We identified and replicated a SNP at LSP1/TNNT3, a SNP at MTHFR-NPPB independent (r(2) = 0.33) of previous reports, and replicated SNPs at AGT and ATP2B1 reported previously. An analysis of combined discovery and follow-up data identified SNPs significantly associated with BP at p < 8.56 × 10(-7) at four further loci (NPR3, HFE, NOS3, and SOX6). The high number of discoveries made with modest genotyping effort can be attributed to using a large-scale yet targeted genotyping array and to the development of a weighting scheme that maximized power when meta-analyzing results from samples ascertained with extreme phenotypes, in combination with results from nonascertained or population samples. Chromatin immunoprecipitation and transcript expression data highlight potential gene regulatory mechanisms at the MTHFR and NOS3 loci. These results provide candidates for further study to help dissect mechanisms affecting BP and highlight the utility of studying SNPs and samples that are independent of those studied previously even when the sample size is smaller than that in previous studies.

Predicting Death: An Empirical Evaluation of Predictive Tools for Mortality

Abstract: Background The ability to predict death is crucial in medicine, and many relevant prognostic tools have been developed for application in diverse settings. We aimed to evaluate the discriminating performance of predictive tools for death and the variability in this performance across different clinical conditions and studies. Methods We used Medline to identify studies published in 2009 that assessed the accuracy (based on the area under the receiver operating characteristic curve [AUC]) of validated tools for predicting all-cause mortality. For tools where accuracy was reported in 4 or more assessments, we calculated summary accuracy measures. Characteristics of studies of the predictive tools were evaluated to determine if they were associated with the reported accuracy of the tool. Results A total of 94 eligible studies provided data on 240 assessments of 118 predictive tools. The AUC ranged from 0.43 to 0.98 (median [interquartile range], 0.77 [0.71-0.83]), with only 23 of the assessments reporting excellent discrimination (10%) (AUC, >0.90). For 10 tools, accuracy was reported in 4 or more assessments; only 1 tool had a summary AUC exceeding 0.80. Established tools showed large heterogeneity in their performance across different cohorts (I 2 range, 68%-95%). Reported AUC was higher for tools published in journals with lower impact factor (P = .01), with larger sample size (P = .01), and for those that aimed to predict mortality among the highest-risk patients (P = .002) and among children (P Conclusions Most tools designed to predict mortality have only modest accuracy, and there is large variability across various diseases and populations. Most proposed tools do not have documented clinical utility.

Prognostic effect size of cardiovascular biomarkers in datasets from observational studies versus randomised trials: meta-epidemiology study

Abstract: Objective To compare the reported effect sizes of cardiovascular biomarkers in datasets from observational studies with those in datasets from randomised controlled trials. Design Review of meta-analyses. Study selection Meta-analyses of emerging cardiovascular biomarkers (not part of the Framingham risk score) that included datasets from at least one observational study and at least one randomised controlled trial were identified through Medline (last update, January 2011). Data extraction Study-specific risk ratios were extracted from all identified meta-analyses and synthesised with random effects for (a) all studies, and (b) separately for observational and for randomised controlled trial populations for comparison. Results 31 eligible meta-analyses were identified. For seven major biomarkers (C reactive protein, non-HDL cholesterol, lipoprotein(a), post-load glucose, fibrinogen, B-type natriuretic peptide, and troponins), the prognostic effect was significantly stronger in datasets from observational studies than in datasets from randomised controlled trials. For five of the biomarkers the effect was less than half as strong in the randomised controlled trial datasets. Across all 31 meta-analyses, on average datasets from observational studies suggested larger prognostic effects than those from randomised controlled trials; from a random effects meta-analysis, the estimated average difference in the effect size was 24% (95% CI 7% to 40%) of the overall biomarker effect. Conclusions Cardiovascular biomarkers often have less promising results in the evidence derived from randomised controlled trials than from observational studies.

Use of reclassification for assessment of improved prediction: an empirical evaluation

Abstract: BACKGROUND An increasing number of studies evaluate the ability of predictors to change risk stratification and alter medical decisions, i.e. reclassification performance. We examined the reported design and analysis of recent studies of reclassification and the robustness of their claims for improved reclassification. METHODS Two independent investigators searched PubMed and citations to the article that introduced the currently most popular reclassification metric (net reclassification index, NRI) to identify studies performing reclassification analysis (January 2006-January 2010). We focused on articles that included any analyses comparing the performance of a baseline predictive model vs the baseline model plus some additional predictor for a prospectively assessed outcome. We recorded information on the baseline model used, outcomes assessed, choice of risk thresholds and features of reclassification analyses. RESULTS Of 58 baseline models used in 51 eligible papers, only 14 (24%) were previously described, used as described and had same outcomes as originally intended. Calibration was examined in 53% of the studies. Sixteen studies (31%) provided a reference for the choice of risk thresholds and only six used the previously proposed categories or justified the use of alternative thresholds. Only 14 studies (27%) stated that the chosen risk thresholds had different therapeutic intervention implications. NRI was calculated in 38 studies and was smaller in studies with adequately referenced or justified risk thresholds vs others (P < 0.0001). CONCLUSIONS Reclassification studies would benefit from more rigorous methodological standards; otherwise claims for improved reclassification may remain spurious.

Genetic variants in novel pathways influence blood pressure and cardiovascular disease risk

Abstract: Blood pressure (BP) is a heritable trait1 influenced by multiple biological pathways and is responsive to environmental stimuli. Over one billion people worldwide have hypertension (BP ≥140 mm Hg systolic [SBP] or ≥90 mm Hg diastolic [DBP])2. Even small increments in BP are associated with increased risk of cardiovascular events3. This genome-wide association study of SBP and DBP, which used a multi-stage design in 200,000 individuals of European descent, identified 16 novel loci: six of these loci contain genes previously known or suspected to regulate BP (GUCY1A3-GUCY1B3; NPR3-C5orf23; ADM; FURIN-FES; GOSR2; GNAS-EDN3); the other 10 provide new clues to BP physiology. A genetic risk score based on 29 genome-wide significant variants was associated with hypertension, left ventricular wall thickness, stroke, and coronary artery disease, but not kidney disease or kidney function. We also observed associations with BP in East Asian, South Asian, and African ancestry individuals. Our findings provide new insights into the genetics and biology of BP, and suggest novel potential therapeutic pathways for cardiovascular disease prevention. Genetic approaches have advanced the understanding of biological pathways underlying inter-individual variation in BP. For example, studies of rare Mendelian BP disorders have identified multiple defects in renal sodium handling pathways4. More recently two genomewide association studies (GWAS), each of >25,000 individuals of European-ancestry, identified 13 loci associated with SBP, DBP, and hypertension5,6. We now report results of a new meta-analysis of GWAS data that includes staged follow-up genotyping to identify additional BP loci. Primary analyses evaluated associations between 2.5 million genotyped or imputed single nucleotide polymorphisms (SNPs) and SBP and DBP in 69,395 individuals of European ancestry from 29 studies (Supplementary Materials Sections 1–3, Supplementary Tables 1– 2). Following GWAS meta-analysis, we conducted a three-stage validation experiment that made efficient use of available genotyping resources, to follow up top signals in up to 133,661 additional individuals of European descent (Supplementary Fig. 1 and Supplementary Materials Section 4). Twenty-nine independent SNPs at 28 loci were significantly associated with SBP, DBP, or both in the meta-analysis combining discovery and follow up data (Fig. 1, Table 1, Supplementary Figs 2–3, Supplementary Tables 3–5). All 29 SNPs attained association P <5×10−9, an order of magnitude beyond the standard genome-wide significance level for a single stage experiment (Table 1). Sixteen of these 29 associations were novel (Table 1). Two associations were near the FURIN and GOSR2 genes; prior targeted analyses of variants in these genes suggested they Note added in proof: Since this manuscript was submitted, Kato et al published a BP GWAS in East Asians that identified a SNP highly correlated to the SNP we report at the NPR3-c5orf23 locus28. Author contributions Full author contributions and roles are listed in the Supplementary Materials Section 19. NIH Public Access Author Manuscript Nature. Author manuscript; available in PMC 2012 May 01. Published in final edited form as: Nature. ; 478(7367): 103–109. doi:10.1038/nature10405. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript may be BP loci7,8. At the CACNB2 locus we validated association for a previously reported6 SNP rs4373814 and detected a novel independent association for rs1813353 (pairwise r2 =0.015 in HapMap CEU). Of our 13 previously reported associations5,6, only the association at PLCD3 was not supported by the current results (Supplementary Table 4). Some of the associations are in or near genes involved in pathways known to influence BP (NPR3, GUCY1A3-GUCY1B3, ADM, GNAS-EDN3, NPPA-NPPB, and CYP17A1; Supplementary Fig. 4). Twenty-two of the 28 loci did not contain genes that were a priori strong biological candidates. As expected from prior BP GWAS results, the effects of the novel variants on SBP and DBP were small (Fig. 1 and Table 1). For all variants, the observed directions of effects were concordant for SBP, DBP, and hypertension (Fig. 1, Table 1, Supplementary Fig. 3). Among the genes at the genome-wide significant loci, only CYP17A1, previously implicated in Mendelian congenital adrenal hyperplasia and hypertension, is known to harbour rare variants that have large effects on BP9. We performed several analyses to identify potential causal alleles and mechanisms. First, we looked up the 29 genome-wide significant index SNPs and their close proxies (r2>0.8) among cis-acting expression SNP (eSNP) results from multiple tissues (Supplementary Materials Section 5). For 13/29 index SNPs, we found association between nearby eSNP variants and expression level of at least one gene transcript (10−4 > p > 10−51, Supplementary Table 6). In 5 cases, the index BP SNP and the best eSNP from a genomewide survey were identical, highlighting potential mediators of the SNP-BP associations. Second, because changes in protein sequence are strong a priori candidates to be functional, we sought non-synonymous coding SNPs that were in high LD (r2 >0.8) with the 29 index SNPs. We identified such SNPsat 8 loci (Table 1, Supplementary Materials Section 6, Supplementary Table 7). In addition we performed analyses testing for differences in genetic effect according to body mass index (BMI) or sex, and analyses of copy number variants, pathway enrichment, and metabolomic data, but we did not find any statistically significant results (Supplementary Materials Sections 7–9, Supplementary Tables 8–10). We evaluated whether the BP variants we identified in Europeans were associated with BP in individuals of East Asian (N=29,719), South Asian (N=23,977), and African (N=19,775) ancestries (Table 1, Supplementary Tables 11–13). We found significant associations in individuals of East Asian ancestry for SNPs at 9 loci and in individuals of South Asian ancestry for SNPs at 6 loci; some have been reported previously (Supplementary Tables 12 and 15). The lack of significant association for individual SNPs may reflect small sample sizes, differences in allele frequencies or LD patterns, imprecise imputation for some ancestries using existing reference samples, or a genuinely different underlying genetic architecture. Because of limited power to detect effects of individual variants in the smaller non-European samples, we created genetic risk scores for SBP and DBP incorporating all 29 BP variants weighted according to effect sizes observed in the European samples. In each non-European ancestry group, risk scores were strongly associated with SBP (P=1.1×10−40 in East Asian, P=2.9×10−13 in South Asian, P=9.8×10−4 in African ancestry individuals) and DBP (P=2.9×10−48, P=9.5×10−15, and P=5.3×10−5, respectively; Supplementary Table 13). We also created a genetic risk score to assess association of the variants in aggregate with hypertension and with clinical measures of hypertensive complications including left ventricular mass, left ventricular wall thickness, incident heart failure, incident and prevalent stroke, prevalent coronary artery disease (CAD), kidney disease, and measures of kidney function, using results from other GWAS consortia (Table 2, Supplementary Materials Sections 10–11, Supplementary Table 14). The risk score was weighted using the average of Page 2 Nature. Author manuscript; available in PMC 2012 May 01. N IH PA Athor M anscript N IH PA Athor M anscript N IH PA Athor M anscript SBP and DBP effects for the 29 SNPs. In an independent sample of 23,294 women10, an increase of 1 standard deviation in the genetic risk score was associated with a 21% increase in the odds of hypertension (95% CI 19%–28%; Table 2, Supplementary Table 14). Among individuals in the top decile of the risk score, the prevalence of hypertension was 29% compared with 16% in the bottom decile (odds ratio 2.09, 95% CI 1.86–2.36). Similar results were observed in an independent hypertension case-control sample (Table 2). In our study, individuals in the top compared to bottom quintiles of genetic risk score differed by 4.6 mm Hg SBP and 3.0 mm Hg DBP, differences that approach population-averaged BP treatment effects for a single antihypertensive agent11. Epidemiologic data have shown that differences in SBP and DBP of this magnitude, across the population range of BP, are associated with an increase in cardiovascular disease risk3. Consistent with this and in line with findings from randomized trials of BP-lowering medication in hypertensive patients12,13, the genetic risk score was positively associated with left ventricular wall thickness (P=6.0×10−6), occurrence of stroke (P=3.3×10−5) and CAD (P=8.1×10−29). The same genetic risk score was not, however, significantly associated with chronic kidney disease or measures of kidney function, even though these renal outcomes were available in a similar sample size as for the other outcomes (Table 2). The absence of association with kidney phenotypes could be explained by a weaker causal relation of BP with kidney phenotypes than with CAD and stroke. This finding is consistent with the mismatch between observational data that show a positive association of BP with kidney disease, and clinical trial data that show inconsistent evidence of benefit of BP lowering on kidney disease prevention in patients with hypertension14. Thus, several lines of evidence converge to suggest that BP elevation may in part be a consequence rather than a cause of sub-clinical kidney disease. Our discovery meta-analysis (Supplementary Fig. 2) suggests an excess of modestly significant (10−5

Relationship of dietary cholesterol to blood pressure: the INTERMAP study.

Abstract: ObjectiveA direct relationship of dietary cholesterol to blood pressure of men has been reported in a few observational studies from the USA. It is not clear whether this association prevails consistently, for example, in populations with varied dietary habits, across ethnic groups, and sexes. Cross

Relation of Urinary Calcium and Magnesium Excretion to Blood Pressure The International Study of Macro- and Micro-Nutrients and Blood Pressure and the International Cooperative Study on Salt, Other Factors, and Blood Pressure

Abstract: Data indicate an inverse association between dietary calcium and magnesium intakes and blood pressure (BP); however, much less is known about associations between urinary calcium and magnesium excretion and BP in general populations. The authors assessed the relation of BP to 24-hour excretion of calcium and magnesium in 2 cross-sectional studies. The International Study of Macro- and Micro-Nutrients and Blood Pressure (INTERMAP) comprised 4,679 persons aged 40–59 years from 17 population samples in China, Japan, the United Kingdom, and the United States, and the International Cooperative Study on Salt, Other Factors, and Blood Pressure (INTERSALT) comprised 10,067 persons aged 20–59 years from 52 samples around the world. Timed 24-hour urine collections, BP measurements, and nutrient data from four 24-hour dietary recalls (INTERMAP) were collected. In multiple linear regression analyses, urinary calcium excretion was directly associated with BP. After adjustment for multiple confounders (including weight, height, alcohol intake, calcium intake, urinary sodium level, and urinary potassium intake), systolic BP was 1.9 mm Hg higher per each 4.1 mmol per 24 hours (2 standard deviations) of higher urinary calcium excretion (associations were smaller for diastolic BP) in INTERMAP. Qualitatively similar associations were observed in INTERSALT analyses. Associations between magnesium excretion and BP were small and nonsignificant for most of the models examined. The present data suggest that altered calcium homoeostasis, as exhibited by increased calcium excretion, is associated with higher BP levels.