Clinical Trial Service Unit

About: Clinical Trial Service Unit is a based out in . It is known for research contribution in the topics: Population & Stroke. The organization has 428 authors who have published 1387 publications receiving 181920 citations.

Polymorphisms in the WNK1 Gene Are Associated with Blood Pressure Variation and Urinary Potassium Excretion

Abstract: WNK1 - a serine/threonine kinase involved in electrolyte homeostasis and blood pressure (BP) control - is an excellent candidate gene for essential hypertension (EH). We and others have previously reported association between WNK1 and BP variation. Using tag SNPs (tSNPs) that capture 100% of common WNK1 variation in HapMap, we aimed to replicate our findings with BP and to test for association with phenotypes relating to WNK1 function in the British Genetics of Hypertension (BRIGHT) study case-control resource (1700 hypertensive cases and 1700 normotensive controls). We found multiple variants to be associated with systolic blood pressure, SBP (7/28 tSNPs min-p=0.0005), diastolic blood pressure, DBP (7/28 tSNPs min-p=0.002) and 24 hour urinary potassium excretion (10/28 tSNPs min-p=0.0004). Associations with SBP and urine potassium remained significant after correction for multiple testing (p=0.02 and p=0.01 respectively). The major allele (A) of rs765250, located in intron1,demonstrated the strongestevidencefor associationwithSBP,effect size3.14 mmHg(95%CI:1.23–4.9), DBP1.9 mmHg (95%CI:0.7–3.2) and hypertension, odds ratio (OR: 1.3 [95%CI: 1.0–1.7]).We genotyped this variant in six independent populations (n=14,451) and replicated the association between rs765250 and SBP in a meta-analysis (p=7610 23 ,c ombined with BRIGHT data-set p=2610 24 , n=17,851). The associations of WNK1 with DBP and EH were not confirmed. Haplotype analysis revealed striking associations with hypertension and BP variation (global permutation p,10 27 ). We identified several common haplotypes to be associated with increased BP and multiple low frequency haplotypes significantly associated with lower BP (.10 mmHg reduction) and risk for hypertension (OR,0.60). Our data indicates that multiple rare and commonWNK1 variants contribute to BP variation and hypertension, and provide compelling evidence to initiate further genetic and functional studies to explore the role of WNK1 in BP regulation and EH.

Diet, smoking and lung cancer: a case-control study of 1000 cases and 1500 controls in South-West England.

Abstract: We have examined the relationship between diet and lung cancer in a case–control study of 982 cases of lung cancer and 1486 population controls in south-west England in which subjects were interviewed personally about their smoking habits and their consumption of foods and supplements rich in retinol or carotene. Analyses were performed for 15 dietary variables, including intake of pre-formed retinol and carotene. There were significant associations (P< 0.01) with lung cancer risk for 13 of the variables, eight of which remained after adjustment for smoking. When the 15 variables were considered simultaneously, independent significant associations remained for 5: pre-formed retinol (increased risk), and fish liver oil, vitamin pills, carrots and tomato sauce (decreased risk). It is unlikely that all five associations represent biological effects, or that they can all be explained by residual confounding by smoking, or by biases. We conclude that there is at least one as yet unidentified factor that is causally related to lung cancer risk and of considerable importance in terms of attributable risk in this population. © 2001 Cancer Research Campaign http://www.bjcancer.com

The Seascale cluster: a probable explanation.

Abstract: Seldom, if ever, can so few cases of disease have caused so much work and so much public concern for such a long time as the seven cases of leukaemia that occurred in young people under 25 years of age who lived in Seascale during the period 1955Ð1983. The expected number cannot be calculated precisely, but the excess under 10 years of age was about tenfold (five against 0.5 expected) and there can be no doubt that this ÔSeascale clusterÕ, as it has come to be called, constitutes a most unusual happening. The cluster was discovered by journalists from Yorkshire Television in 1983 in the course of enquiries into the mortality from cancer near Sellafield and was the subject of a television programme (Urquhart et al, 1984). It led to the appointment of a review committee under Sir Douglas Black, which advised the following year that there was sufficient evidence of an unusual incidence of disease to deserve intensive investigation of its cause (Black, 1984). Many studies have consequently been undertaken over the last 15 years, most of which have included non-HodgkinÕs lymphoma (NHL) with lymphoblastic leukaemia as, at young ages, there is no clear biological difference between them. The answer that the Black Committee sought has, however, proved elusive. Now with the most recent report by Dickinson and Parker in this issue (pp. 144Ð151) it may be thought that the answer has already been found. The occurrence of a cluster of cancers that are among those most easily produced by ionizing radiation in a village 3 km from Sellafield, the principal nuclear reprocessing plant in the UK, led many people to suspect that it was a direct effect of environmental pollution with radioactive waste and this was the first explanation considered by the Black Committee and the Committee on Medical Aspects of Radiation in the Environment (COMARE) that was set up by the Department of Health to oversee the recommended research and to review its findings. The idea was, however, quickly shown to be untenable (Black, 1984). For knowledge of the discharges from the plant showed that the doses that people were likely to have received were far too small to have caused such a large excess of cases, the maximum estimate of their likely effect being a 15% chance of producing one case (COMARE, 1986). This conclusion was later fortified by measurements of Pu and 137Cs in the bodies of exposed people, which showed that the models that had been used to estimate the doses people received had, for the most part, overestimated them (Popplewell et al, 1988; Stather et al, 1988). With the further information available 10 years later, COMARE (1996) concluded that the doses Seascale residents received that were attributable to discharges from Sellafield were less than 10% of their total dose and about 200 times too small to account for the observed excess of leukaemia and NHL. Alternative explanations consequently had to be considered and one was suggested by Gardner et al (1990) as a result of two studies. One was thought to show that an excess risk of leukaemia was seen only in children who were born in Seascale and not in those who went to school there but were born elsewhere (Gardner et al, 1987a, 1987b) and the other that the risk of the disease in West Cumbria was associated with the fathersÕ employment at Sellafield before the children were conceived (Gardner et al, 1990). The excess risk with the fatherÕs employment was not great (a relative risk of 1.97 based on nine cases), but the risk was greatest with the highest cumulative dose that the father had received (relative risk for 100 mSv or more 6.24, 95% confidence limits 1.51Ð25.76) and a significant doseÐresponse relationship was observed with the dose estimated to have been received in the 6 months immediately prior to the childÕs conception, when, for much of the time, the more radio-sensitive spermatids, relevant to the childÕs conception, would have been exposed. Gardner et alÕs (1990) idea was never attractive to radiobiologists who knew that no such effect had been observed in the children of the survivors of the Hiroshima and Nagasaki atomic explosions and that animal experiments did not support the idea that chronic low dose exposure would be much more hazardous than moderate doses given acutely and it was soon dispelled by the results of human studies elsewhere over the next few years. The evidence has been reviewed by Doll et al (1994), Little et al (1995) and COMARE (1996) and the conclusion reached that the hypothesis that irradiation of the testis caused any detectable risk of leukaemia in subsequent offspring could not be sustained. It did not accord with what was known of radiation genetics or of the hereditability of childhood leukaemia. It was not supported by the relationship observed between menÕs exposure to ionizing radiation and the risk of leukaemia in their offspring in the survivors of the atomic bomb explosions in Japan or in nuclear workers in Ontario, in Scotland, or in Cumbria other than in Seascale. It made no contribution to another cluster in young persons in Egremont, 7 km north of Sellafield (Wakeford and Parker, 1996) and could not account for the excess recorded near Dounreay in Scotland nor near two nuclear sites in the south of England, nor even for the whole of the cluster observed in Seascale, which as Kinlen (1993) showed was not limited to children born there. In these circumstances, it seemed that the association that was observed by Gardner et al (1990) between paternal irradiation and leukaemia in young people born and resident in the West Cumbrian Health District was most readily explained by chance, a conclusion that has subsequently been supported by the results of two large surveys of the risk of cancer in the offspring of nuclear workers, neither of which has provided any evidence for such an association outside the original confines of the Seascale cluster (Draper et al, 1997; Roman et al, 1999). What then can be the explanation for the occurrence of the Seascale cluster itself? To some statisticians, cognisant of the many clusters that, like the one in Seascale, had been defined post hoc

The cancer burden in the United Kingdom in 2007 due to radiotherapy.

Abstract: The number of long-term cancer survivors in the general population of the UK is substantial and increasing rapidly. Many cancer survivors have been treated with radiotherapy but the likely number of radiotherapy-related second cancers has not previously been estimated. We used estimates of the numbers of cancer survivors in the UK at the beginning of 2007, in conjunction with estimates of the relative risk of a second primary cancer associated with previous radiotherapy from the United States Surveillance Epidemiology and End Results (SEER) programme, to estimate the numbers of incident cancers in the UK in 2007 that were associated with radiotherapy for a previous cancer and that may have been caused by it. We estimated that 1,346 cases of cancer, or about 0.45% of the 298,000 new cancers registered in the UK in 2007, were associated with radiotherapy for a previous cancer. The largest numbers of radiotherapy-related second cancers were lung cancer (23.7% of the total), oesophageal cancer (13.3%), and female breast cancer (10.6%); 54% of radiotherapy-related second cancers were in individuals aged 75 or over. The highest percentages of second cancers related to radiotherapy were among survivors of Hodgkin's disease and cancers of the oral cavity and pharynx and cervix uteri; over 15% of second cancers among these survivors were associated with radiotherapy for the first cancer. These calculations, which involve a number of assumptions and approximations, provide a reasonable, if conservative, estimate of the fraction of incident cancers in the UK that are attributable to past radiation therapy.

Association of CETP Gene Variants With Risk for Vascular and Nonvascular Diseases Among Chinese Adults.

Abstract: Importance Increasing levels of high-density lipoprotein (HDL) cholesterol through pharmacologic inhibition of cholesteryl ester transfer protein (CETP) is a potentially important strategy for prevention and treatment of cardiovascular disease (CVD). Objective To use genetic variants in theCETPgene to assess potential risks and benefits of lifelong lower CETP activity on CVD and other outcomes. Design, Setting, and Participants This prospective biobank study included 151 217 individuals aged 30 to 79 years who were enrolled from 5 urban and 5 rural areas of China from June 25, 2004, through July 15, 2008. All participants had baseline genotype data, 17 854 of whom had lipid measurements and 4657 of whom had lipoprotein particle measurements. Median follow-up of 9.2 years (interquartile range, 8.2-10.1 years) was completed January 1, 2016, through linkage to health insurance records and death and disease registries. Exposures FiveCETPvariants, including an East Asian loss-of-function variant (rs2303790), combined in a genetic score weighted to associations with HDL cholesterol levels. Main Outcomes and Measures Baseline levels of lipids and lipoprotein particles, cardiovascular risk factors, incidence of carotid plaque and predefined major vascular and nonvascular diseases, and a phenome-wide range of diseases. Results Among the 151 217 individuals included in this study (58.4% women and 41.6% men), the mean (SD) age was 52.3 (10.9) years. Overall, the mean (SD) low-density lipoprotein (LDL) cholesterol level was 91 (27) mg/dL; HDL cholesterol level, 48 (12) mg/dL.CETPvariants were strongly associated with higher concentrations of HDL cholesterol (eg, 6.1 [SE, 0.4] mg/dL perrs2303790-Gallele;P = 9.4 × 10−47) but were not associated with lower LDL cholesterol levels. Within HDL particles, cholesterol esters were increased and triglycerides reduced, whereas within very low-density lipoprotein particles, cholesterol esters were reduced and triglycerides increased. When scaled to 10-mg/dL higher levels of HDL cholesterol, theCETPgenetic score was not associated with occlusive CVD (18 550 events; odds ratio [OR], 0.98; 95% CI, 0.91-1.06), major coronary events (5767 events; OR, 1.08; 95% CI, 0.95-1.22), myocardial infarction (3118 events; OR, 1.14; 95% CI, 0.97-1.35), ischemic stroke (13 759 events; OR, 0.94; 95% CI, 0.86-1.02), intracerebral hemorrhage (6532 events; OR, 0.94; 95% CI, 0.83-1.06), or other vascular diseases or carotid plaque. Similarly,rs2303790was not associated with any vascular diseases or plaque. No associations with nonvascular diseases were found other than an increased risk for eye diseases withrs2303790(4090 events; OR, 1.43; 95% CI, 1.13-1.80;P = .003). Conclusions and Relevance CETPvariants were associated with altered HDL metabolism but did not lower LDL cholesterol levels and had no significant association with risk for CVD. These results suggest that in the absence of reduced LDL cholesterol levels, increasing HDL cholesterol levels by inhibition of CETP may not confer significant benefits for CVD.