| 1. |
- Kilarski, Laura L., et al.
(författare)
-
Meta-analysis in more than 17,900 cases of ischemic stroke reveals a novel association at 12q24.12
- 2014
-
Ingår i: Neurology. - 1526-632X .- 0028-3878. ; 83:8, s. 678-685
-
Tidskriftsartikel (refereegranskat)abstract
- Objectives: To perform a genome-wide association study (GWAS) using the Immunochip array in 3,420 cases of ischemic stroke and 6,821 controls, followed by a meta-analysis with data from more than 14,000 additional ischemic stroke cases. Methods: Using the Immunochip, we genotyped 3,420 ischemic stroke cases and 6,821 controls. After imputation we meta-analyzed the results with imputed GWAS data from 3,548 cases and 5,972 controls recruited from the ischemic stroke WTCCC2 study, and with summary statistics from a further 8,480 cases and 56,032 controls in the METASTROKE consortium. A final in silico "look-up" of 2 single nucleotide polymorphisms in 2,522 cases and 1,899 controls was performed. Associations were also examined in 1,088 cases with intracerebral hemorrhage and 1,102 controls. Results: In an overall analysis of 17,970 cases of ischemic stroke and 70,764 controls, we identified a novel association on chromosome 12q24 (rs10744777, odds ratio [OR] 1.10 [1.07-1.13], p = 7.12 x 10(-11)) with ischemic stroke. The association was with all ischemic stroke rather than an individual stroke subtype, with similar effect sizes seen in different stroke subtypes. There was no association with intracerebral hemorrhage (OR 1.03 [0.90-1.17], p = 0.695). Conclusion: Our results show, for the first time, a genetic risk locus associated with ischemic stroke as a whole, rather than in a subtype-specific manner. This finding was not associated with intracerebral hemorrhage.
|
|
| 2. |
- Rothwell, Peter M., et al.
(författare)
-
Long-term effect of aspirin on colorectal cancer incidence and mortality: 20-year follow-up of five randomised trials
- 2010
-
Ingår i: The Lancet. - 1474-547X. ; 376:9754, s. 1741-1750
-
Tidskriftsartikel (refereegranskat)abstract
- Background High-dose aspirin (>= 500 mg daily) reduces long-term incidence of colorectal cancer, but adverse effects might limit its potential for long-term prevention. The long-term effectiveness of lower doses (75-300 mg daily) is unknown. We assessed the effects of aspirin on incidence and mortality due to colorectal cancer in relation to dose, duration of treatment, and site of tumour. Methods We followed up four randomised trials of aspirin versus control in primary (Thrombosis Prevention Trial, British Doctors Aspirin Trial) and secondary (Swedish Aspirin Low Dose Trial, UK-TA Aspirin Trial) prevention of vascular events and one trial of different doses of aspirin (Dutch TIA Aspirin Trial) and established the effect of aspirin on risk of colorectal cancer over 20 years during and after the trials by analysis of pooled individual patient data. Results In the four trials of aspirin versus control (mean duration of scheduled treatment 6.0 years), 391 (2.8%) of 14 033 patients had colorectal cancer during a median follow-up of 18.3 years. Allocation to aspirin reduced the 20-year risk of colon cancer (incidence hazard ratio [HR] 0.76, 0.60-0.96, p=0.02; mortality HR 0.65, 0.48-0.88, p=0.005), but not rectal cancer (0.90, 0.63-1.30, p=0.58; 0.80, 0.50-1.28, p=0.35). Where subsite data were available, aspirin reduced risk of cancer of the proximal colon (0.45, 0.28-0.74, p=0.001; 0.34, 0.18-0.66, p=0.001), but not the distal colon (1.10, 0.73-1.64, p=0.66; 1.21, 0.66-2.24, p=0.54; for incidence difference p=0.04, for mortality difference p=0.01). However, benefit increased with scheduled duration of treatment, such that allocation to aspirin of 5 years or longer reduced risk of proximal colon cancer by about 70% (0.35, 0.20-0.63; 0.24, 0.11-0.52; both p<0.0001) and also reduced risk of rectal cancer (0.58, 0.36-0.92, p=0.02; 0.47, 0.26-0.87, p=0.01). There was no increase in benefit at doses of aspirin greater than 75 mg daily, with an absolute reduction of 1.76% (0.61-2.91; p=0.001) in 20-year risk of any fatal colorectal cancer after 5-years scheduled treatment with 75-300 mg daily. However, risk of fatal colorectal cancer was higher on 30 mg versus 283 mg daily on long-term follow-up of the Dutch TIA trial (odds ratio 2.02, 0.70-6.05, p=0.15). Interpretation Aspirin taken for several years at doses of at least 75 mg daily reduced long-term incidence and mortality due to colorectal cancer. Benefit was greatest for cancers of the proximal colon, which are not otherwise prevented effectively by screening with sigmoidoscopy or colonoscopy.
|
|
| 3. |
- Traylor, Matthew, et al.
(författare)
-
A Novel MMP12 Locus Is Associated with Large Artery Atherosclerotic Stroke Using a Genome-Wide Age-at-Onset Informed Approach.
- 2014
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 10:7
-
Tidskriftsartikel (refereegranskat)abstract
- Genome-wide association studies (GWAS) have begun to identify the common genetic component to ischaemic stroke (IS). However, IS has considerable phenotypic heterogeneity. Where clinical covariates explain a large fraction of disease risk, covariate informed designs can increase power to detect associations. As prevalence rates in IS are markedly affected by age, and younger onset cases may have higher genetic predisposition, we investigated whether an age-at-onset informed approach could detect novel associations with IS and its subtypes; cardioembolic (CE), large artery atherosclerosis (LAA) and small vessel disease (SVD) in 6,778 cases of European ancestry and 12,095 ancestry-matched controls. Regression analysis to identify SNP associations was performed on posterior liabilities after conditioning on age-at-onset and affection status. We sought further evidence of an association with LAA in 1,881 cases and 50,817 controls, and examined mRNA expression levels of the nearby genes in atherosclerotic carotid artery plaques. Secondly, we performed permutation analyses to evaluate the extent to which age-at-onset informed analysis improves significance for novel loci. We identified a novel association with an MMP12 locus in LAA (rs660599; p = 2.5×10-7), with independent replication in a second population (p = 0.0048, OR(95% CI) = 1.18(1.05-1.32); meta-analysis p = 2.6×10-8). The nearby gene, MMP12, was significantly overexpressed in carotid plaques compared to atherosclerosis-free control arteries (p = 1.2×10-15; fold change = 335.6). Permutation analyses demonstrated improved significance for associations when accounting for age-at-onset in all four stroke phenotypes (p<0.001). Our results show that a covariate-informed design, by adjusting for age-at-onset of stroke, can detect variants not identified by conventional GWAS.
|
|
| 4. |
- van der Harst, Pim, et al.
(författare)
-
Seventy-five genetic loci influencing the human red blood cell
- 2012
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 492:7429, s. 369-375
-
Tidskriftsartikel (refereegranskat)abstract
- Anaemia is a chief determinant of global ill health, contributing to cognitive impairment, growth retardation and impaired physical capacity. To understand further the genetic factors influencing red blood cells, we carried out a genome-wide association study of haemoglobin concentration and related parameters in up to 135,367 individuals. Here we identify 75 independent genetic loci associated with one or more red blood cell phenotypes at P < 10(-8), which together explain 4-9% of the phenotypic variance per trait. Using expression quantitative trait loci and bioinformatic strategies, we identify 121 candidate genes enriched in functions relevant to red blood cell biology. The candidate genes are expressed preferentially in red blood cell precursors, and 43 have haematopoietic phenotypes in Mus musculus or Drosophila melanogaster. Through open-chromatin and coding-variant analyses we identify potential causal genetic variants at 41 loci. Our findings provide extensive new insights into genetic mechanisms and biological pathways controlling red blood cell formation and function.
|
|
