Sarah Parish

Christian-Albrechts-Universität zu Kiel, Kiel, Schleswig-Holstein, Germany

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Publications (118)

  • File available · Data · Oct 2016
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    [Show abstract] [Hide abstract] ABSTRACT: Background and objectives Because there is substantial biologic intraindividual variation in albumin excretion, randomized trials of albuminuria-reducing therapies may need multiple urine samples to estimate daily urinary albumin excretion. Mailing spot urine samples could offer a convenient and cost-effective method to collect multiple samples, but urine albumin-to-creatinine ratio stability in samples stored at ambient temperatures for several days is unknown. Design, setting, participants, & measurements Patients with kidney disease provided fresh urine samples in two tubes (with and without boric acid preservative). Reference aliquots from each participant were analyzed immediately, whereas remaining aliquots were subject to different handling/storage conditions before analysis, including delayed processing for up to 7 days at three different storage temperatures (4 degrees C, 18 degrees C, and 30 degrees C), multiple freeze-thawcycles, and long-termfrozen storage at -80 degrees C, -40 degrees C, and -20 degrees C. We calculated the mean percentage change in urine albumin-to-creatinine ratio for each condition, and we considered samples stable if the 95% confidence interval was within a 65% threshold. Results Ninety-three patients provided samples with detectable albuminuria in the reference aliquot. Median (interquartile range) urine albumin-to-creatinine ratio was 87 (20-499) mg/g. The inclusion of preservative had minimal effect on fresh urine albumin-to-creatinine ratio measurements but reduced the changes in albumin and creatinine in samples subject to processing delay and storage conditions. The urine albumin-to-creatinine ratio was stable for 7 days in samples containing preservative at 4 degrees C and 18 degrees C and 2 days when stored at 30 degrees C. It was also stable in samples with preservative after three freeze-thaw cycles and in frozen storage for 6 months at -80 degrees C or -40 degrees C but not at -20 degrees C. Conclusions Mailed urine samples collected with preservative and received within 7 days if ambient temperature is <= 18 degrees C, or within 2 days if the temperature is higher but does not exceed 30 degrees C, are suitable for the measurement of urine albumin-to-creatinine ratio in randomized trials. Preserved samples frozen to -40 degrees C or -80 degrees C for 6 months before analysis also seem suitable.
    Full-text available · Article · Sep 2016 · Clinical Journal of the American Society of Nephrology
  • Yanting Shen · Yang Yang · Sarah Parish · [...] · David A. Clifton
    Conference Paper · Aug 2016
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Extended-release niacin with laropiprant did not significantly reduce the risk of major vascular events and increased the risk of serious adverse events in Heart Protection Study 2-Treatment of HDL to Reduce the Incidence of Vascular Events (HPS2-THRIVE), but its net effects on health and healthcare costs are unknown. Methods and results: 25 673 participants aged 50 to 80 years with previous cardiovascular disease were randomized to 2 g of extended-release niacin with 40 mg of laropiprant daily versus matching placebo, in addition to effective statin-based low-density lipoprotein cholesterol-lowering treatment. The net effects of niacin-laropiprant on quality-adjusted life years and hospital care costs (2012 UK £; converted into US $ using purchasing power parity index) during 4 years in HPS2-THRIVE were evaluated using estimates of the impact of serious adverse events on health-related quality of life and hospital care costs. During the study, participants assigned niacin-laropiprant experienced marginally but not statistically significantly lower survival (0.012 fewer years [standard error (SE) 0.007]), fewer quality-adjusted life years (0.023 [SE 0.007] fewer using UK EQ-5D scores; 0.020 [SE 0.006] fewer using US EQ-5D scores) and accrued greater hospital costs (UK £101 [SE £37]; US $145 [SE $53]). Stroke, heart failure, musculoskeletal events, gastrointestinal events, and infections were associated with significant decreases in health-related quality of life in both the year of the event and in subsequent years. All serious vascular and nonvascular events were associated with substantial increases in hospital care costs. Conclusions: In HPS2-THRIVE, the addition of extended-release niacin-laropiprant to statin-based therapy reduced quality of life-adjusted survival and increased hospital costs. Clinical trial registration: URL: http://clinicaltrials.gov. Unique identifier: NCT00461630.
    Article · Jul 2016 · Circulation Cardiovascular Quality and Outcomes
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    [Show abstract] [Hide abstract] ABSTRACT: Background: Lipoprotein-associated phospholipase A2 (Lp-PLA2) has been implicated in development of atherosclerosis; however, recent randomized trials of Lp-PLA2 inhibition reported no beneficial effects on vascular diseases. In East Asians, a loss-of-function variant in the PLA2G7 gene can be used to assess the effects of genetically determined lower Lp-PLA2 METHODS: PLA2G7 V279F (rs76863441) was genotyped in 91 428 individuals randomly selected from the China Kadoorie Biobank of 0.5 M participants recruited in 2004-08 from 10 regions of China, with 7 years' follow-up. Linear regression was used to assess effects of V279F on baseline traits. Logistic regression was conducted for a range of vascular and non-vascular diseases, including 41 ICD-10 coded disease categories. Results: PLA2G7 V279F frequency was 5% overall (range 3-7% by region), and 9691 (11%) participants had at least one loss-of-function variant. V279F was not associated with baseline blood pressure, adiposity, blood glucose or lung function. V279F was not associated with major vascular events [7141 events; odds ratio (OR) = 0.98 per F variant, 95% confidence interval (CI) 0.90-1.06] or other vascular outcomes, including major coronary events (922 events; 0.96, 0.79-1.18) and stroke (5967 events; 1.00, 0.92-1.09). Individuals with V279F had lower risks of diabetes (7031 events; 0.91, 0.84-0.98) and asthma (182 events; 0.53, 0.28-0.98), but there was no association after adjustment for multiple testing. Conclusions: Lifelong lower Lp-PLA2 activity was not associated with major risks of vascular or non-vascular diseases in Chinese adults. Using functional genetic variants in large-scale prospective studies with linkage to a range of health outcomes is a valuable approach to inform drug development and repositioning.
    Full-text available · Article · Jun 2016 · International Journal of Epidemiology
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    Full-text available · Article · Jan 2016 · Journal of the American College of Cardiology
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    [Show abstract] [Hide abstract] ABSTRACT: 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 x 10(-11) to 5.0 x 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 x 10(-6)). Our results provide new evidence for the role of DNA methylation in blood pressure regulation.
    Full-text available · Article · Sep 2015 · Nature Genetics
  • Robert Clarke · Derrick Bennett · Sarah Parish
    Article · Feb 2015 · American Journal of Clinical Nutrition
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    [Show abstract] [Hide abstract] ABSTRACT: 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.
    Full-text available · Article · Jan 2015 · Nature
  • D. Bennett · L. Li · I. Millwood · [...] · Z. Chen
    Conference Paper · Sep 2014
  • [Show abstract] [Hide abstract] ABSTRACT: Background: Patients with evidence of vascular disease are at increased risk for subsequent vascular events despite effective use of statins to lower the low-density lipoprotein (LDL) cholesterol level. Niacin lowers the LDL cholesterol level and raises the high-density lipoprotein (HDL) cholesterol level, but its clinical efficacy and safety are uncertain. Methods: After a prerandomization run-in phase to standardize the background statin-based LDL cholesterol-lowering therapy and to establish participants' ability to take extended-release niacin without clinically significant adverse effects, we randomly assigned 25,673 adults with vascular disease to receive 2 g of extended-release niacin and 40 mg of laropiprant or a matching placebo daily. The primary outcome was the first major vascular event (nonfatal myocardial infarction, death from coronary causes, stroke, or arterial revascularization). Results: During a median follow-up period of 3.9 years, participants who were assigned to extended-release niacin-laropiprant had an LDL cholesterol level that was an average of 10 mg per deciliter (0.25 mmol per liter as measured in the central laboratory) lower and an HDL cholesterol level that was an average of 6 mg per deciliter (0.16 mmol per liter) higher than the levels in those assigned to placebo. Assignment to niacin-laropiprant, as compared with assignment to placebo, had no significant effect on the incidence of major vascular events (13.2% and 13.7% of participants with an event, respectively; rate ratio, 0.96; 95% confidence interval [CI], 0.90 to 1.03; P=0.29). Niacin-laropiprant was associated with an increased incidence of disturbances in diabetes control that were considered to be serious (absolute excess as compared with placebo, 3.7 percentage points; P<0.001) and with an increased incidence of diabetes diagnoses (absolute excess, 1.3 percentage points; P<0.001), as well as increases in serious adverse events associated with the gastrointestinal system (absolute excess, 1.0 percentage point; P<0.001), musculoskeletal system (absolute excess, 0.7 percentage points; P<0.001), skin (absolute excess, 0.3 percentage points; P=0.003), and unexpectedly, infection (absolute excess, 1.4 percentage points; P<0.001) and bleeding (absolute excess, 0.7 percentage points; P<0.001). Conclusions: Among participants with atherosclerotic vascular disease, the addition of extended-release niacin-laropiprant to statin-based LDL cholesterol-lowering therapy did not significantly reduce the risk of major vascular events but did increase the risk of serious adverse events. (Funded by Merck and others; HPS2-THRIVE ClinicalTrials.gov number, NCT00461630.).
    Article · Jul 2014 · New England Journal of Medicine
  • Robert Clarke · Derrick Bennett · Sarah Parish · [...] · Francine Grodstein
    File available · Data · Jun 2014
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    Robert Clarke · Derrick Bennett · Sarah Parish · [...] · Francine Grodstein
    [Show abstract] [Hide abstract] ABSTRACT: Background: Elevated plasma homocysteine is a risk factor for Alzheimer disease, but the relevance of homocysteine lowering to slow the rate of cognitive aging is uncertain. Objective: The aim was to assess the effects of treatment with B vitamins compared with placebo, when administered for several years, on composite domains of cognitive function, global cognitive function, and cognitive aging. Design: A meta-analysis was conducted by using data combined from 11 large trials in 22,000 participants. Domain-based z scores (for memory, speed, and executive function and a domain-composite score for global cognitive function) were available before and after treatment (mean duration: 2.3 y) in the 4 cognitive-domain trials (1340 individuals); Mini-Mental State Examination (MMSE)–type tests were available at the end of treatment (mean duration: 5 y) in the 7 global cognition trials (20,431 individuals). Results: The domain-composite and MMSE-type global cognitive function z scores both decreased with age (mean ± SE: −0.054 ± 0.004 and −0.036 ± 0.001/y, respectively). Allocation to B vitamins lowered homocysteine concentrations by 28% in the cognitive-domain trials but had no significant effects on the z score differences from baseline for individual domains or for global cognitive function (z score difference: 0.00; 95% CI: −0.05, 0.06). Likewise, allocation to B vitamins lowered homocysteine by 26% in the global cognition trials but also had no significant effect on end-treatment MMSE-type global cognitive function (z score difference: −0.01; 95% CI: −0.03, 0.02). Overall, the effect of a 25% reduction in homocysteine equated to 0.02 y (95% CI: −0.10, 0.13 y) of cognitive aging per year and excluded reductions of >1 mo per year of treatment. Conclusion: Homocysteine lowering by using B vitamins had no significant effect on individual cognitive domains or global cognitive function or on cognitive aging.
    Full-text available · Article · Jun 2014 · American Journal of Clinical Nutrition
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    [Show abstract] [Hide abstract] ABSTRACT: Objectives Observational and genetic studies have shown that lipoprotein(a) [Lp(a)] levels and apolipoprotein(a) [apo(a)] isoform size are both associated with coronary heart disease (CHD) risk, but the relative independence of these risk factors remains unclear. Clarification of this uncertainty is relevant to the potential of future Lp(a)-lowering therapies for the prevention of CHD. Methods Plasma Lp(a) levels and apo(a) isoform size, estimated by the number of kringle IV (KIV) repeats, were measured in 995 patients with CHD and 998 control subjects. The associations between CHD risk and fifths of Lp(a) levels were assessed before and after adjustment for KIV repeats and, conversely, the associations between CHD risk and fifths of KIV repeats were assessed before and after adjustment for Lp(a) levels. ResultsIndividuals in the top fifth of Lp(a) levels had more than a 2-fold higher risk of CHD compared with those in the bottom fifth, and this association was materially unaltered after adjustment for KIV repeats [odds ratio (OR) 2.05, 95% confidence interval (CI) 1.38–3.04, P < 0.001). Furthermore, almost all of the excess risk was restricted to the two-fifths of the population with the highest Lp(a) levels. Individuals in the bottom fifth of KIV repeats had about a 2-fold higher risk of CHD compared with those in the top fifth, but this association was no longer significant after adjustment for Lp(a) levels (OR 1.13, 95% CI 0.77–1.66, P = 0.94). Conclusions The effect of KIV repeats on CHD risk is mediated through their impact on Lp(a) levels, suggesting that absolute levels of Lp(a), rather than apo(a) isoform size, are the main determinant of CHD risk.This article is protected by copyright. All rights reserved.
    Full-text available · Article · Dec 2013 · Journal of Internal Medicine
  • File available · Data · Aug 2013
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    [Show abstract] [Hide abstract] ABSTRACT: Statins are prescribed widely to lower plasma low-density lipoprotein (LDL) concentrations and cardiovascular disease risk and have been shown to have beneficial effects in a broad range of patients. However, statins are associated with an increased risk, albeit small, of clinical myopathy and type 2 diabetes. Despite evidence for substantial genetic influence on LDL concentrations, pharmacogenomic trials have failed to identify genetic variations with large effects on either statin efficacy or toxicity, and have produced little information regarding mechanisms that modulate statin response. Here we identify a downstream target of statin treatment by screening for the effects of in vitro statin exposure on genetic associations with gene expression levels in lymphoblastoid cell lines derived from 480 participants of a clinical trial of simvastatin treatment. This analysis identified six expression quantitative trait loci (eQTLs) that interacted with simvastatin exposure, including rs9806699, a cis-eQTL for the gene glycine amidinotransferase (GATM) that encodes the rate-limiting enzyme in creatine synthesis. We found this locus to be associated with incidence of statin-induced myotoxicity in two separate populations (meta-analysis odds ratio = 0.60). Furthermore, we found that GATM knockdown in hepatocyte-derived cell lines attenuated transcriptional response to sterol depletion, demonstrating that GATM may act as a functional link between statin-mediated lowering of cholesterol and susceptibility to statin-induced myopathy.
    Full-text available · Article · Aug 2013 · Nature
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