Pharmacogenomics study of thiazide diuretics and QT interval in multi-ethnic populations: the cohorts for heart and aging research in genomic epidemiology.

Thiazide diuretics, commonly used antihypertensives, may cause QT interval (QT) prolongation, a risk factor for highly fatal and difficult to predict ventricular arrhythmias. We examined whether common single-nucleotide polymorphisms (SNPs) modified the association between thiazide use and QT or its component parts (QRS interval, JT interval) by performing ancestry-specific, trans-ethnic and cross-phenotype genome-wide analyses of European (66%), African American (15%) and Hispanic (19%) populations (N=78 199), leveraging longitudinal data, incorporating corrected standard errors to account for underestimation of interaction estimate variances and evaluating evidence for pathway enrichment. Although no loci achieved genome-wide significance (P<5 × 10-8), we found suggestive evidence (P<5 × 10-6) for SNPs modifying the thiazide-QT association at 22 loci, including ion transport loci (for example, NELL1, KCNQ3). The biologic plausibility of our suggestive results and simulations demonstrating modest power to detect interaction effects at genome-wide significant levels indicate that larger studies and innovative statistical methods are warranted in future efforts evaluating thiazide-SNP interactions.

European and Mediterranean hydroclimate responses to tropical volcanic forcing over the last millennium.

Volcanic eruptions have global climate impacts, but their effect on the hydrologic cycle is poorly understood. We use a modified version of superposed epoch analysis, an eruption year list collated from multiple datasets, and seasonal paleoclimate reconstructions (soil moisture, precipitation, geopotential heights, and temperature) to investigate volcanic forcing of spring and summer hydroclimate over Europe and the Mediterranean over the last millennium. In the western Mediterranean, wet conditions occur in the eruption year and the following 3 years. Conversely, northwestern Europe and the British Isles experience dry conditions in response to volcanic eruptions, with the largest moisture deficits in post-eruption years 2 and 3. The precipitation response occurs primarily in late spring and early summer (April-July), a pattern that strongly resembles the negative phase of the East Atlantic Pattern. Modulated by this mode of climate variability, eruptions force significant, widespread, and heterogeneous hydroclimate responses across Europe and the Mediterranean.

Non-response to (statin) therapy: the importance of distinguishing non-responders from non-adherers in pharmacogenetic studies.

PURPOSE: In pharmacogenetic research, genetic variation in non-responders and high responders is compared with the aim to identify the genetic loci responsible for this variation in response. However, an important question is whether the non-responders are truly biologically non-responsive or actually non-adherent? Therefore, the aim of this study was to describe, within the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER), characteristics of both non-responders and high responders of statin treatment in order to possibly discriminate non-responders from non-adherers. METHODS: Baseline characteristics of non-responders to statin therapy (≤10 % LDL-C reduction) were compared with those of high responders (>40 % LDL-C reduction) through a linear regression analysis. In addition, pharmacogenetic candidate gene analysis was performed to show the effect of excluding non-responders from the analysis. RESULTS: Non-responders to statin therapy were younger (p = 0.001), more often smoked (p < 0.001), had a higher alcohol consumption (p < 0.001), had lower LDL cholesterol levels (p < 0.001), had a lower prevalence of hypertension (p < 0.001), and had lower cognitive function (p = 0.035) compared to subjects who highly responded to pravastatin treatment. Moreover, excluding non-responders from pharmacogenetic studies yielded more robust results, as standard errors decreased. CONCLUSION: Our results suggest that non-responders to statin therapy are more likely to actually be non-adherers, since they have more characteristics that are viewed as indicators of high self-perceived health and low disease awareness, possibly making the subjects less adherent to study medication. We suggest that in pharmacogenetic research, extreme non-responders should be excluded to overcome the problem that non-adherence is investigated instead of non-responsiveness.

Genetic contributions to variation in general cognitive function: a meta-analysis of genome-wide association studies in the CHARGE consortium (N=53949).

General cognitive function is substantially heritable across the human life course from adolescence to old age. We investigated the genetic contribution to variation in this important, health- and well-being-related trait in middle-aged and older adults. We conducted a meta-analysis of genome-wide association studies of 31 cohorts (N=53,949) in which the participants had undertaken multiple, diverse cognitive tests. A general cognitive function phenotype was tested for, and created in each cohort by principal component analysis. We report 13 genome-wide significant single-nucleotide polymorphism (SNP) associations in three genomic regions, 6q16.1, 14q12 and 19q13.32 (best SNP and closest gene, respectively: rs10457441, P=3.93 × 10(-9), MIR2113; rs17522122, P=2.55 × 10(-8), AKAP6; rs10119, P=5.67 × 10(-9), APOE/TOMM40). We report one gene-based significant association with the HMGN1 gene located on chromosome 21 (P=1 × 10(-6)). These genes have previously been associated with neuropsychiatric phenotypes. Meta-analysis results are consistent with a polygenic model of inheritance. To estimate SNP-based heritability, the genome-wide complex trait analysis procedure was applied to two large cohorts, the Atherosclerosis Risk in Communities Study (N=6617) and the Health and Retirement Study (N=5976). The proportion of phenotypic variation accounted for by all genotyped common SNPs was 29% (s.e.=5%) and 28% (s.e.=7%), respectively. Using polygenic prediction analysis, ~1.2% of the variance in general cognitive function was predicted in the Generation Scotland cohort (N=5487; P=1.5 × 10(-17)). In hypothesis-driven tests, there was significant association between general cognitive function and four genes previously associated with Alzheimer's disease: TOMM40, APOE, ABCG1 and MEF2C.

Drug-gene interactions and the search for missing heritability: a cross-sectional pharmacogenomics study of the QT interval.

Variability in response to drug use is common and heritable, suggesting that genome-wide pharmacogenomics studies may help explain the 'missing heritability' of complex traits. Here, we describe four independent analyses in 33 781 participants of European ancestry from 10 cohorts that were designed to identify genetic variants modifying the effects of drugs on QT interval duration (QT). Each analysis cross-sectionally examined four therapeutic classes: thiazide diuretics (prevalence of use=13.0%), tri/tetracyclic antidepressants (2.6%), sulfonylurea hypoglycemic agents (2.9%) and QT-prolonging drugs as classified by the University of Arizona Center for Education and Research on Therapeutics (4.4%). Drug-gene interactions were estimated using covariable-adjusted linear regression and results were combined with fixed-effects meta-analysis. Although drug-single-nucleotide polymorphism (SNP) interactions were biologically plausible and variables were well-measured, findings from the four cross-sectional meta-analyses were null (Pinteraction>5.0 × 10(-8)). Simulations suggested that additional efforts, including longitudinal modeling to increase statistical power, are likely needed to identify potentially important pharmacogenomic effects.

Comparison of arterial and venous blood gases and the effects of analysis delay and air contamination on arterial samples in patients with chronic obstructive pulmonary disease and healthy controls.

BACKGROUND: Arterial blood gases (ABGs) are often sampled incorrectly, leading to a 'mixed' or venous sample. Delays in analysis and air contamination are common. OBJECTIVES: We measured the effects of these errors in patients with chronic obstructive pulmonary disease (COPD) exacerbations and controls. METHODS: Arterial and venous samples were analyzed from 30 patients with COPD exacerbation and 30 controls. Venous samples were analysed immediately and arterial samples separated into non-air-contaminated and air-contaminated specimens and analysed at 0, 30, 60, 90 and 180 min. RESULTS: Mean venous pH was 7.371 and arterial pH was 7.407 (p < 0.0001). There was a correlation between venous and arterial pH (r = 0.5347, p < 0.0001). The regression equation to predict arterial pH was: arterial pH = 4.2289 + 0.43113 · venous pH. There were no clinically significant differences in arterial PO2 associated with analysis delay. A statistically significant decline in pH was detected at 30 min in patients with COPD exacerbation (p = 0.0042) and 90 min in controls (p < 0.0001). A clinically significant decline in pH emerged at 73 min in patients with COPD exacerbation and 87 min in controls. Air contamination was associated with a clinically significant increase in PO2 in all samples, including those that were immediately analyzed. CONCLUSIONS: Arterial and venous pH differ significantly. Venous pH cannot accurately replace arterial pH. Temporal delays in ABG analysis result in a significant decline in measured pH. ABGs should be analysed within 30 min. Air contamination leads to an immediate increase in measured PO2, indicating that air-contaminated ABGs should be discarded.

Are elevated circulating intercellular adhesion molecule 1 levels more strongly predictive of diabetes than vascular risk? Outcome of a prospective study in the elderly.

AIMS/HYPOTHESIS: The aim of this prospective study was to determine whether circulating intercellular adhesion molecule (ICAM) 1, as a potential surrogate of 'endothelial activation', is more strongly associated with risk of vascular events than with incident diabetes. METHODS: We related baseline ICAM-1 levels to vascular events (866 CHD and stroke events in 5,685 participants) and incident diabetes (292 in 4,945 without baseline diabetes) in the elderly over 3.2 years of follow-up. RESULTS: ICAM-1 levels correlated positively with triacylglycerol but negatively with LDL- and HDL-cholesterol. ICAM-1 levels were higher in those who developed diabetes (388.6 +/- 1.42 vs 369.4 +/- 1.39 ng/ml [mean+/-SD], p = 0.011) and remained independently associated with new-onset diabetes (HR 1.84, 95% CI 1.26-2.69, p = 0.0015 per unit increase in log[ICAM-1] after adjusting for classical risk factors and C-reactive protein). By contrast, ICAM-1 levels were not significantly (p = 0.40) elevated in those who had an incident vascular event compared with those who remained event-free, and corresponding adjusted risk associations were null (HR 0.98, 95% CI 0.80-1.22, p = 0.89) in analyses adjusted for other risk factors. CONCLUSIONS/INTERPRETATION: We show that elevated ICAM-1 levels are associated with risk of incident diabetes in the elderly at risk, despite no association with incident cardiovascular disease risk. We suggest that perturbations in circulating ICAM-1 levels are aligned more towards diabetes risk.

Lymphotoxin-alpha C804A polymorphism is a risk factor for stroke. The PROSPER study.

Inflammation plays a prominent role in the development of atherosclerosis, which is the most important risk factor for vascular events. Lymphotoxin-alpha (LTA) is a pro-inflammatory cytokine and is found to be expressed in atherosclerotic lesions. We investigated the association between the C804A polymorphism within the LTA gene and coronary and cerebrovascular events in 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER). The primary endpoint was the combined endpoint of death from coronary heart disease, non-fatal myocardial infarction, and clinical stroke. Secondary endpoints were the coronary and cerebrovascular components separately. All associations were assessed with a Cox-proportional hazards model adjusted for sex, age, pravastatin use, and country. Our overall analysis showed a significant association between the C804A polymorphism and the primary endpoint (p = 0.03). After stratification for gender, this association was found only in males. Furthermore, we found that the association between the C804A polymorphism and the primary endpoint was mainly attributable to clinical strokes (p = 0.02). The C804A polymorphism in the LTA gene associates with clinical stroke, especially in men. But further research is warranted to confirm our results.

Genetic variation in the interleukin-1 beta-converting enzyme associates with cognitive function. The PROSPER study.

Inflammation is thought to play an important role in the development of cognitive decline and dementia in old age. The interleukin-1 signalling pathway may play a prominent role in this process. The gene encoding for interleukin-1 beta-converting enzyme (ICE) is likely to influence IL-1 beta levels. Inhibition of ICE decreases the age-related increase in IL-1 beta levels and may therefore improve memory function. We assessed whether genetic variation in the ICE gene associates with cognitive function in an elderly population. All 5804 participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) were genotyped for the 10643GC, 9323GA, 8996AG and 5352GA polymorphisms in the ICE gene. Cross-sectional associations between the polymorphisms and cognitive function were assessed with linear regression. Longitudinal associations between polymorphisms, haplotypes and cognitive function were assessed with linear mixed models. All associations were adjusted for sex, age, education, country, treatment with pravastatin and version of test where appropriate. Subjects carrying the variants 10643C and 5352A allele had significantly lower IL-1 beta production levels (P < 0.01). Furthermore, we demonstrated that homozygous carriers of the 10643C and the 5352A allele performed better on all executive function tests at baseline and during follow-up compared to homozygous carriers of the wild-type allele (all P < 0.02). The haplotype with two variants present (10643C and 5352A) was associated with better executive function (all P < 0.02) compared to the reference haplotype without variants. For memory function the same trend was observed, although not significant. Genetic variation in the ICE gene is associated with better performance on cognitive function and lower IL-1 beta production levels. This suggests that low levels of IL-1 beta are protective for memory and learning deficits. Inhibition of ICE may therefore be an important therapeutic target for maintaining cognitive function in old age.

Genetic variation in the interleukin-10 gene promoter and risk of coronary and cerebrovascular events: the PROSPER study.

Proinflammatory cytokines, like interleukin-6 (IL-6) and tumor necrosis factor-alpha (TNF-alpha), are implicated in the development of atherosclerosis. The role of anti-inflammatory cytokines, like IL-10, is largely unknown. We investigated the association of four single nucleotide polymorphisms (SNPs) in the promoter region of the IL-10 gene (4259AG, -1082GA, -592CA, and -2849GA), with coronary and cerebrovascular disease in participants of the PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) trial. All associations were assessed with Cox proportional hazards models adjusted for sex, age, pravastatin use, and country. Haplotype analysis of the four SNPs showed a significant association between haplotype 4 (containing the -592A variant allele) and risk of coronary events (P = 0.019). Moreover, analysis of separate SNPs found a significant association between -2849AA carriers with incident stroke (HR (95%CI) 1.50 (1.04-2.17), P value = 0.02). Our study suggests that not only proinflammatory processes contribute to atherosclerosis, but that also anti-inflammatory cytokines may play an important role.

Healthy ageing: ageing safely.

The population of the developed world is steadily ageing. In the European Union, approximately 22% of persons are over 60 years of age and this is projected to increase to more than 27% by the year 2020. This has major implications for health care resources and the productive workforce. Ageing is accompanied by a decline in the physiological reserve of all organ systems, compromising homeostasis and resistance to disease. Thus, when disease develops in the elderly it has an increased impact on organ systems not directly involved. This places older people at risk for multiple simultaneous pathologies. Treatment often requires polypharmacy, which often is accompanied by drug interactions and adverse reactions. The pattern of sequential and comorbid disease often means that the later years of life are associated with an accumulating toll of disability, which in turn consumes a high proportion of health-care resources. The major goal of health care in the elderly should be to compress morbidity into the end of the normal lifespan. To achieve this, it will be necessary to redefine our approaches to treatment in the elderly and to develop an evidence base to inform this process.

The design of a prospective study of Pravastatin in the Elderly at Risk (PROSPER). PROSPER Study Group. PROspective Study of Pravastatin in the Elderly at Risk.

The PROspective Study of Pravastatin in the Elderly at Risk (PROSPER) is a randomized, double-blind, placebo-controlled trial designed to test the hypothesis that treatment with pravastatin will diminish risk of subsequent major vascular events in a cohort of men and women (70 to 82 years old) with preexisting vascular disease or significant risk of developing this condition. Five thousand eight hundred four men and women in addition to receiving advice on diet and smoking, have been randomized equally to treatment with 40 mg pravastatin/day or matching placebo in 3 centers (Cork, Ireland, Glasgow, Scotland, and Leiden, The Netherlands). Following an average 3.5-year intervention period, a primary assessment will be made of the influence of this therapy on major vascular events (a combination of coronary heart disease, death, nonfatal myocardial infarction, and fatal and nonfatal stroke). A number of additional analyses will also be conducted on the individual components of the primary end point, on men, on women, and on subjects with and without previous evidence of vascular disease. Finally, an assessment will be made of the effects of treatment on cognitive function, disability, hospitalization or institutionalization, vascular mortality, and all-cause mortality.

Methemoglobinemia following ingestion of a monolinuron/paraquat herbicide (Gramonol)

A 59-year-old man ingested a mouthful of Gramonol with suicidal intent and was admitted to a local hospital six and a half hours later. It was noted that he looked "ashen grey" and was centrally cyanosed. The methemoglobin and plasma paraquat concentrations performed on arrival at the Regional Poisons Treatment Unit eight hours after paraquat ingestion were 52% and 1100 micrograms/L respectively; the administration of methylene blue reversed methemoglobinemia within two hours. The patient suffered extensive paraquat-induced oral, and probably esophageal, ulceration and developed multiple organ (particularly renal, respiratory and hepatic) failure and died some 10 days later. This is the most severe case of Gramonol poisoning reported both in terms of the amount of paraquat ingested and the concentration of methemoglobin formed. We believe that the methemoglobinemia in this patient was caused by monolinuron not paraquat.

Tree ring correlation between prehistoric landslides and abrupt tectonic events in Seattle, washington.

Radiocarbon ages of submerged trees on landslide deposits in Lake Washington, Seattle, indicate that the most recent slides in three separate areas may have occurred simultaneously about 1000 years ago. Tree ring crossdating shows that seven bark-bearing trees from one of these recent slides and a tree 23 kilometers to the northwest in a probable tsunami deposit on the shore of Puget Sound died in the same season of the same year. The close coincidence among the most recent lake landslides, a probable tsunami, abrupt subsidence, and other possible seismic events gives evidence for a strong prehistoric earthquake in the Seattle region.

Recommendation on sampling, transport, and storage for the determination of the concentration of ionized calcium in whole blood, plasma, and serum. IFC Scientific Division, Working Group on Ion-Selective Electrodes (WGSE).

The substance concentration of ionized calcium (cCa 2+) in blood, plasma, or serum preanalytically may be affected by pH changes of the sample, calcium binding by heparin, and dilution by the anticoagulant solution. pH changes in whole blood can be minimized by anaerobic sampling to avoid loss of CO 2, by measuring as soon as possible, or by storing the sample in iced water to avoid lactic acid formation. cCa 2+ and pH should be determined simultaneously. Plasma or serum: If centrifuged in a closed tube and measured immediately, the pH of the sample will be close to the original value. If there has been a delay between centrifugation and measurement, causing substantial loss of CO 2, equilibration of the sample with a gas mixture corresponding to pCO 2 = 5.3 kPa prior to the measurement is recommended. Conversion of the measured values to cCa 2+ (7.4) is only valid if the pH is in the range 7.2-7.6. Ca 2+ binding by heparin can be minimized by using either of the following: 1) a final concentration of sodium or lithium heparinate of 15 IU/mL blood or less; or 2) calcium-titrated heparin with a final concentration of less than 50 IU/mL blood. Dilution effect can be avoided by use of dry heparin in capillaries or syringes.(ABSTRACT TRUNCATED AT 250 WORDS)

International Federation of Clinical Chemistry (IFCC), scientific division: IFCC recommendation on sampling transport and storage for the determination of the concentration of ionized calcium in whole blood, plasma and serum.

The substance concentration of ionized calcium (cCa2+) in blood, plasma or serum preanalytically may be affected by pH changes of the sample, calcium binding by heparin, and dilution by the anticoagulant solution. pH changes in whole blood can be minimized by anaerobic sampling to avoid loss of CO2, by measuring as soon as possible or by storing the sample in iced water to avoid lactic acid formation. cCa2+ and pH should be determined simultaneously.