| 1. |
- Craddock, Nick, et al.
(författare)
-
Genome-wide association study of CNVs in 16,000 cases of eight common diseases and 3,000 shared controls
- 2010
-
Ingår i: Nature. - : Springer Science and Business Media LLC. - 0028-0836 .- 1476-4687. ; 464:7289, s. 713-720
-
Tidskriftsartikel (refereegranskat)abstract
- Copy number variants (CNVs) account for a major proportion of human genetic polymorphism and have been predicted to have an important role in genetic susceptibility to common disease. To address this we undertook a large, direct genome-wide study of association between CNVs and eight common human diseases. Using a purpose-designed array we typed,19,000 individuals into distinct copy-number classes at 3,432 polymorphic CNVs, including an estimated similar to 50% of all common CNVs larger than 500 base pairs. We identified several biological artefacts that lead to false-positive associations, including systematic CNV differences between DNAs derived from blood and cell lines. Association testing and follow-up replication analyses confirmed three loci where CNVs were associated with disease-IRGM for Crohn's disease, HLA for Crohn's disease, rheumatoid arthritis and type 1 diabetes, and TSPAN8 for type 2 diabetes-although in each case the locus had previously been identified in single nucleotide polymorphism (SNP)-based studies, reflecting our observation that most common CNVs that are well-typed on our array are well tagged by SNPs and so have been indirectly explored through SNP studies. We conclude that common CNVs that can be typed on existing platforms are unlikely to contribute greatly to the genetic basis of common human diseases.
|
|
| 2. |
- Steer, Peter, et al.
(författare)
-
Acute elevations of medium- and long-chain fatty acids have different impacts on endothelium-dependent vasodilation in humans
- 2003
-
Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 38:1, s. 15-19
-
Tidskriftsartikel (refereegranskat)abstract
- It has previously been shown that acute elevation of long-chain fatty acids (LCFA) impairs endothelium-dependent vasodilation (EDV) in humans. In this study, we tested the hypothesis that an elevation of both medium-chain fatty acids (MCFA) and LCFA affects the endothelium differently from LCFA elevation alone. Ten healthy volunteers received an intravenous infusion of Structolipid (structured TG, MCFA/LCFA ratio 1:1) and heparin for 2 h, while another 10 subjects received an infusion of Intralipid (LCFA only) and heparin. EDV and endothelium-independent vasodilation (EIDV) were studied in the forearm after local administration of methacholine chloride (2 and 4 microg/min) and sodium nitroprusside (5 and 10 microg/min). Forearm blood flow was determined by venous occlusion plethysmography. Intralipid and heparin increased circulating FA levels from 0.2 +/- 0.1 to 1.4 +/- 0.5 mmol/L (P < 0.001) and reduced EDV by 20% (P < 0.01). Although Structolipid and heparin increased circulating FA levels to a similar extent (from 0.4 +/- 0.1 to 1.8 +/- 0.4 mmol/L after 2 h), EDV was not significantly changed. EIDV increased slightly during both interventions (P < 0.05). In conclusion, an acute elevation of LCFA attenuated EDV, whereas an elevation of both MCFA and LCFA did not influence EDV. Thus, FA composition seems to be of importance for EDV in healthy humans.
|
|
| 3. |
- Steer, Peter, et al.
(författare)
-
Cardiac and vascular structure and function are related to lipid peroxidation and metabolism
- 2002
-
Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 37:3, s. 231-236
-
Tidskriftsartikel (refereegranskat)abstract
- The present study investigated possible relationships between left ventricular mass, intima-media thickness of the carotid artery (IMT), total arterial compliance, and lipid status in a population sample of 58 apparently healthy subjects aged 20 to 69. By stepwise multiple regression analysis, including age, blood pressure, and smoking, left ventricular mass index, measured by M-mode echocardiography, increased by 13.0 g/m2 for each 1 standard deviation (SD = 0.11 microM, r = 0.60, P< 0.01) increase in plasma malondialdehyde and 9.50 g/m2 per SD increase in plasma 8-iso-prostaglandin F2alpha in women only (SD = 8.88 ng/L, r = 0.44, P = 0.01). Each 1-SD (SD = 0.27 g/L) increase in apolipoprotein B was associated with a 63 microm increase in IMT (r = 0.47, P = 0.014) and a 0.27 mL/min/m2/mm Hg (r = -0.60, P < 0.01) decrease in stroke index/pulse pressure ratio, reflecting total arterial compliance in women. In men, each 1-SD increase in the proportion of stearic acid (18:0) in serum cholesterol esters (SD = 0.12 percent units) reduced the transmitral E/A ratio, measured by Doppler echocardiography, reflecting left ventricular diastolic function, by 0.10 units (r = -0.29, P < 0.05). Thus, important cardiovascular characteristics, such as left ventricular mass, left ventricular diastolic function, carotid IMT, and total arterial compliance, were independently predicted by indices of lipid metabolism and peroxidation in apparently healthy subjects.
|
|
| 4. |
- Steer, Peter, et al.
(författare)
-
Endothelial vasodilatory function is predicted by circulating apolipoprotein B and HDL in healthy humans
- 2002
-
Ingår i: Lipids. - : Wiley. - 0024-4201 .- 1558-9307. ; 37:12, s. 1135-1140
-
Tidskriftsartikel (refereegranskat)abstract
- Endothelium-dependent vasodilation (EDV), LDL particle size, and antibodies against oxidized LDL (oxLDLab) have been shown to be related to the development of atherosclerosis and cardiovascular disease. In this study, we investigated whether LDL particle size, oxLDLab, apolipoproteins, and lipoproteins are related to endothelial vasodilatory function in a population sample of 58 apparently healthy subjects aged 20 to 69 yr. EDV and endothelium-independent vasodilation (EIDV) were studied in the forearm during local administration of methacholine chloride (2 and 4 microg/min) or sodium nitroprusside (5 and 10 microg/min). Forearm blood flow was determined with venous occlusion plethysmography. In multiple stepwise regression analyses, neither oxLDLab nor small LDL particles were significantly predictive of endothelial vasodilatory function. Instead, a high level of apolipoprotein B (apoB) was an independent predictor of both attenuated EDV and EIDV (r = -0.43, P < 0.01, and r = -0.34, P < 0.05, respectively). HDL cholesterol, on the other hand, was the only lipid variable that was significantly related to the EDV to EIDV ratio, an index of endothelial vasodilatory function (r = 0.35, P < 0.01). The inverse associations between apoB and both EDV and EIDV indicate that apoB might be an early marker of structural vascular changes in healthy subjects, whereas HDL seems to be more specifically related to endothelial vasodilatory function.
|
|
| 5. |
- Steer, Peter, et al.
(författare)
-
Endothelial vasodilatory function is related to the proportions of saturated fatty acids and alpha-linolenic acid in young men, but not in women
- 2003
-
Ingår i: European Journal of Clinical Investigation. - : Wiley. - 0014-2972 .- 1365-2362. ; 33:5, s. 390-396
-
Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Fatty acid composition of serum lipids is associated with cardiovascular disease. As attenuated endothelium-dependent vasodilation (EDV) is an early event in atherosclerosis, we investigated the relationships between endothelial vasodilatory function and the proportion of serum fatty acids, reflecting dietary fat quality, in 74 healthy men and women, aged 20-30 years. DESIGN: Endothelium-dependent vasodilation and endothelium-independent vasodilation (EIDV) was studied in the forearm during local administration of methacholine (2 and 4 micro g min-1) and nitroprusside (5 and 10 micro g min-1). Forearm blood flow was determined with venous occlusion plethysmography. An endothelial function index was calculated as the EDV/EIDV ratio. RESULTS: The endothelial function index was inversely related to the total proportion of saturated fatty acids (r = -0.41, P < 0.05), in particular lauric and myristic acid (r = -0.37 and r = -0.36, respectively, P < 0.05 for both), and was positively related to the proportion of alpha-linolenic acid (r = 0.45, P < 0.01) in men only. Total serum nonesterified fatty acid (NEFA) concentration was not significantly related to endothelial vasodilatory function. By multiple stepwise regression analysis, including age, blood pressure, body mass index, and serum cholesterol, triglyceride and NEFA as confounders, myristic acid and alpha-linolenic acid were independent predictors of the endothelial function index in men only (r = -0.39 and r = 0.47, respectively, P < 0.01 for both). CONCLUSIONS: We conclude that serum fatty acid composition predicts endothelial vasodilatory dysfunction independently of serum NEFA and cholesterol levels in young, healthy men in their third decade of life, whereas fatty acid composition seems to be less important in women at this age. As a result of the large number of analyses performed, these findings need to be verified by other studies.
|
|
| 6. |
- Steer, Peter
(författare)
-
Lipids and Endothelium-Dependent Vasodilation
- 2003
-
Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- Impaired endothelium-dependent vasodilation (EDV) is associated with atherosclerotic cardiovascular disease as well as several of its risk factors. The aim of the present thesis was to investigate how lipids influence EDV in the vascular bed of the human forearm. Apolipoprotein B was inversely associated with both EDV and endothelium-independent vasodilation (EIDV) in healthy subjects aged 20-69 years. HDL cholesterol was associated with the EDV to EIDV ratio (EFI). Small LDL particles and antibodies against oxidized LDL were not associated with endothelial vasodilatory function. The EFI in young, healthy subjects was positively associated with alpha-linolenic acid proportion, but inversely associated with myristic acid in men only. Eicosapentaenoic acid was positively associated with EDV, whereas dihomo-gamma-linolenic acid was inversely associated with both EDV and EIDV in men. Acute elevation of long-chain fatty acids with Intralipid®/heparin infusion in young, healthy subjects impaired EDV after 2 h. This impairment could be prevented by co-infusing vitamin C, diclophenac or L-arginine. Acute elevation of both medium-chain and long-chain fatty acids during Structolipid®/heparin infusion did not impair EDV. An ordinary meal (34 E% fat) transiently attenuated EDV at 1 hour. No attenuation in EDV was observed after meals containing 20 and 3 E% fat. These findings show that the endothelial vasodilatory function is associated with fatty acid profile in serum in the fasting state and during acute fatty acid elevation, as well as with apolipoprotein B and HDL cholesterol. Furthermore, lowering dietary fat content to 20 E% or less preserves endothelial vasodilatory function and might therefore protect against atherosclerosis.
|
|
| 7. |
- Steer, Peter, et al.
(författare)
-
The effect of a mixed meal on endothelium-dependent vasodilation is dependent on fat content in healthy humans
- 2003
-
Ingår i: Clinical Science. - 0143-5221 .- 1470-8736. ; 105:1, s. 81-87
-
Tidskriftsartikel (refereegranskat)abstract
- Impaired endothelium-dependent vasodilation (EDV) is an early marker of atherosclerosis. The aim of the present study was to investigate how meals with different fat contents influence endothelial vasodilatory function. A total of 26 young, healthy men and women aged 20-30 years ingested an ordinary Western meal [34 energy% (E%) fat, n =10], or isocaloric meals with low-fat (20 E%, n =8), or minimal-fat (3 E%, n =8) content. EDV was assessed as forearm blood flow (FBF) during local administration of 4 microg/min methacholine chloride (Mch-FBF) and endothelium-independent vasodilation as FBF during administration of 10 microg/min sodium nitroprusside (SNP-FBF) at baseline and 1 and 2 h after each meal. FBF was determined by venous occlusion plethysmography. An endothelial function index (EFI) was calculated as the Mch-FBF/SNP-FBF ratio. Both Mch-FBF and the EFI were decreased at 1 h after the 34 E% fat meal ( P <0.01 and P <0.05 respectively), but approached fasting levels after 2 h. Mch-FBF and EFI did not change significantly in the group consuming the 20 E% fat meal, but increased in the 3 E% fat group ( P <0.01 and P <0.05 compared with baseline for Mch-FBF and EFI respectively). SNP-FBF was not significantly affected by any of the meals. In conclusion, low-fat meals did not attenuate EDV, in contrast with an ordinary Western meal, which transiently impaired EDV. Our findings indicate that a dietary fat content of 20 E% or less might be beneficial to endothelial vasodilatory function.
|
|
| 8. |
- Steer, Peter, et al.
(författare)
-
Vitamin C, diclophenac and L-arginine protect endothelium-dependent vasodilation against elevated circulating fatty acid levels in humans
- 2003
-
Ingår i: Atherosclerosis. - 0021-9150 .- 1879-1484. ; 168:1, s. 65-72
-
Tidskriftsartikel (refereegranskat)abstract
- An acute elevation of circulating non-esterified fatty acids (NEFAs) has previously been shown to impair endothelium-dependent vasodilation (EDV). In this study, we investigated if local administration of vitamin C (n=8, 18 mg/min), L-arginine (n=8, 12.5 mg/min), or the cyclooxygenase (COX) inhibitor diclophenac (n=8, 0.5 mg/min) can counteract the endothelial dysfunction seen during infusion of Intralipid plus heparin (n=10). EDV and endothelium-independent vasodilation (EIDV) were studied in the forearm after local administration of methacholine chloride (Mch; 2 and 4 microg/min) and sodium nitroprusside (SNP; 5 and 10 microg/min). Forearm blood flow (FBF) was determined with venous occlusion plethysmography. Intralipid and heparin increased circulating NEFA levels sevenfold and impaired EDV (P<0.001 vs baseline). Concomitant administration of L-arginine or diclophenac abolished the NEFA-induced impairment in EDV. Concomitant vitamin C administration actually improved EDV (P<0.05 vs baseline). NEFA elevation increased EIDV (P<0.01), but this effect was not significant after L-arginine or diclophenac infusions. In conclusion, an acute elevation of circulating NEFAs led to impaired EDV. Administration of L-arginine, vitamin C or COX inhibition abolished this effect, suggesting that NEFAs might interact with endothelial vasodilatory function through multiple mechanisms.
|
|
| 9. |
- Zaitlen, Noah, et al.
(författare)
-
Informed Conditioning on Clinical Covariates Increases Power in Case-Control Association Studies
- 2012
-
Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 8:11
-
Tidskriftsartikel (refereegranskat)abstract
- Genetic case-control association studies often include data on clinical covariates, such as body mass index (BMI), smoking status, or age, that may modify the underlying genetic risk of case or control samples. For example, in type 2 diabetes, odds ratios for established variants estimated from low-BMI cases are larger than those estimated from high-BMI cases. An unanswered question is how to use this information to maximize statistical power in case-control studies that ascertain individuals on the basis of phenotype (case-control ascertainment) or phenotype and clinical covariates (case-controlcovariate ascertainment). While current approaches improve power in studies with random ascertainment, they often lose power under case-control ascertainment and fail to capture available power increases under case-control-covariate ascertainment. We show that an informed conditioning approach, based on the liability threshold model with parameters informed by external epidemiological information, fully accounts for disease prevalence and non-random ascertainment of phenotype as well as covariates and provides a substantial increase in power while maintaining a properly controlled falsepositive rate. Our method outperforms standard case-control association tests with or without covariates, tests of gene x covariate interaction, and previously proposed tests for dealing with covariates in ascertained data, with especially large improvements in the case of case-control-covariate ascertainment. We investigate empirical case-control studies of type 2 diabetes, prostate cancer, lung cancer, breast cancer, rheumatoid arthritis, age-related macular degeneration, and end-stage kidney disease over a total of 89,726 samples. In these datasets, informed conditioning outperforms logistic regression for 115 of the 157 known associated variants investigated (P-value = 1x10(-9)). The improvement varied across diseases with a 16% median increase in chi(2) test statistics and a commensurate increase in power. This suggests that applying our method to existing and future association studies of these diseases may identify novel disease loci.
|
|
