| 621. |
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| 622. |
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| 623. |
- Burgess, S., et al.
(författare)
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Bayesian methods for meta-analysis of causal relationships estimated using genetic instrumental variables
- 2010
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Ingår i: Statistics in medicine. - : Wiley. - 1097-0258 .- 0277-6715. ; 29:12, s. 1298-311
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Tidskriftsartikel (refereegranskat)abstract
- Genetic markers can be used as instrumental variables, in an analogous way to randomization in a clinical trial, to estimate the causal relationship between a phenotype and an outcome variable. Our purpose is to extend the existing methods for such Mendelian randomization studies to the context of multiple genetic markers measured in multiple studies, based on the analysis of individual participant data. First, for a single genetic marker in one study, we show that the usual ratio of coefficients approach can be reformulated as a regression with heterogeneous error in the explanatory variable. This can be implemented using a Bayesian approach, which is next extended to include multiple genetic markers. We then propose a hierarchical model for undertaking a meta-analysis of multiple studies, in which it is not necessary that the same genetic markers are measured in each study. This provides an overall estimate of the causal relationship between the phenotype and the outcome, and an assessment of its heterogeneity across studies. As an example, we estimate the causal relationship of blood concentrations of C-reactive protein on fibrinogen levels using data from 11 studies. These methods provide a flexible framework for efficient estimation of causal relationships derived from multiple studies. Issues discussed include weak instrument bias, analysis of binary outcome data such as disease risk, missing genetic data, and the use of haplotypes.
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| 624. |
- Cirulli, Elizabeth T., et al.
(författare)
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A Missense Variant in PTPN22 is a Risk Factor for Drug-induced Liver Injury
- 2019
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Ingår i: Gastroenterology. - : W B SAUNDERS CO-ELSEVIER INC. - 0016-5085 .- 1528-0012. ; 156:6, s. 1707-1716
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: We performed genetic analyses of a multiethnic cohort of patients with idiosyncratic drug-induced liver injury (DILI) to identify variants associated with susceptibility.METHODS: We performed a genome-wide association study of 2048 individuals with DILI (cases) and 12,429 individuals without (controls). Our analysis included subjects of European (1806 cases and 10,397 controls), African American (133 cases and 1,314 controls), and Hispanic (109 cases and 718 controls) ancestry. We analyzed DNA from 113 Icelandic cases and 239,304 controls to validate our findings.RESULTS: We associated idiosyncratic DILI with rs2476601, a nonsynonymous polymorphism that encodes a substitution of tryptophan with arginine in the protein tyrosine phosphatase, nonreceptor type 22 gene (PTPN22) (odds ratio [OR] 1.44; 95% confidence interval [CI] 1.28-1.62; P = 1.2 x 10(-9) and replicated the finding in the validation set (OR 1.48; 95% CI 1.09-1.99; P =.01). The minor allele frequency showed the same effect size (OR > 1) among ethnic groups. The strongest association was with amoxicillin and clavulanate-associated DILI in persons of European ancestry (OR 1.62; 95% CI 1.32-1.98; P = 4.0 x 10(-6); allele frequency = 13.3%), but the polymorphism was associated with DILI of other causes (OR 1.37; 95% CI 1.21-1.56; P = 1.5 x 10(-6); allele frequency = 11.5%). Among amoxicillin-and clavulanate-associated cases of European ancestry, rs2476601 doubled the risk for DILI among those with the HLA risk alleles A* 02: 01 and DRB1* 15: 01.CONCLUSIONS: In a genome-wide association study, we identified rs2476601 in PTPN22 as a non-HLA variant that associates with risk of liver injury caused by multiple drugs and validated our finding in a separate cohort. This variant has been associated with increased risk of autoimmune diseases, providing support for the concept that alterations in immune regulation contribute to idiosyncratic DILI.
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| 625. |
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| 626. |
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| 627. |
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| 628. |
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| 629. |
- Dione, Mariama, 1987, et al.
(författare)
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Human low-threshold mechanoafferent responses to pure changes in friction controlled using an ultrasonic haptic device
- 2021
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 11:1
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Tidskriftsartikel (refereegranskat)abstract
- The forces that are developed when manipulating objects generate sensory cues that inform the central nervous system about the qualities of the object's surface and the status of the hand/object interaction. Afferent responses to frictional transients or slips have been studied in the context of lifting/holding tasks. Here, we used microneurography and an innovative tactile stimulator, the Stimtac, to modulate both the friction level of a surface, without changing the surface or adding a lubricant, and, to generate the frictional transients in a pure and net fashion. In three protocols, we manipulated: the frictional transients, the friction levels, the rise times, the alternation of phases of decrease or increase in friction to emulate grating-like stimuli. Afferent responses were recorded in 2 FAIs, 1 FAII, 2 SAIs and 3 SAIIs from the median nerve of human participants. Independently of the unit type, we observed that: single spikes were generated time-locked to the frictional transients, and that reducing the friction level reduced the number of spikes during the stable phase of the stimulation. Our results suggest that those frictional cues are encoded in all the unit types and emphasize the possibility to use the Stimtac device to control mechanoreceptor firing with high temporal precision.
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| 630. |
- Figtree, G. A., et al.
(författare)
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Novel estrogen receptor alpha promoter polymorphism increases ventricular hypertrophic response to hypertension
- 2007
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Ingår i: Journal of Steroid Biochemistry and Molecular Biology. - : Elsevier BV. - 0960-0760 .- 1879-1220. ; 103:2, s. 110-118
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Tidskriftsartikel (refereegranskat)abstract
- Given the strong genetic contribution to blood pressure and left ventricular hypertrophy (LVH), and the influence of estrogen on these parameters, we hypothesized that polymorphisms in the estrogen receptor alpha (ERα) promoter may influence LVH. Three novel polymorphisms were identified upstream of the ERα alternatively spliced exon 1E, within sequence which demonstrated significant promoter activity in vitro. Demonstration of ERα E isoform expression in human ventricle by RT-PCR supported a possible functional role for the 1E novel polymorphisms in estrogen signaling in the heart. Indeed, G > A (-721 E) was significantly associated with LVH after controlling for systolic blood pressure and sex in a healthy population (n = 74), contributing to 23% of interventricular septum (IVS) width variance (p < 0.001) and 9.4% of left ventricular mass index (LVMI) variance (p = 0.035). In a separate hypertensive cohort, male carriers of the A allele (n = 8) had a 17% increase in IVS (95% CI: 6-28%) and a 19% increase in LVMI (3-34%) compared to GG homozygotes (n = 84). We conclude that a novel polymorphism in the promoter of a cardiac mRNA splice isoform of ERα is associated with LVH.
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