| 1. |
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| 2. |
- Postmus, I., et al.
(författare)
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Meta-analysis of genome-wide association studies of HDL cholesterol response to statins
- 2016
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Ingår i: Journal of Medical Genetics. - : BMJ. - 0022-2593 .- 1468-6244. ; 53:12, s. 835-45
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Tidskriftsartikel (refereegranskat)abstract
- Background In addition to lowering low density lipoprotein cholesterol (LDL-C), statin therapy also raises high density lipoprotein cholesterol (HDL-C) levels. Interindividual variation in HDL-C response to statins may be partially explained by genetic variation. Methods and results We performed a meta-analysis of genome-wide association studies (GWAS) to identify variants with an effect on statin-induced high density lipoprotein cholesterol (HDL-C) changes. The 123 most promising signals with p<1x10(-4) from the 16 769 statin-treated participants in the first analysis stage were followed up in an independent group of 10 951 statin-treated individuals, providing a total sample size of 27 720 individuals. The only associations of genome-wide significance (p<5x10(-8)) were between minor alleles at the CETP locus and greater HDL-C response to statin treatment. Conclusions Based on results from this study that included a relatively large sample size, we suggest that CETP may be the only detectable locus with common genetic variants that influence HDL-C response to statins substantially in individuals of European descent. Although CETP is known to be associated with HDL-C, we provide evidence that this pharmacogenetic effect is independent of its association with baseline HDL-C levels.
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| 3. |
- Daniau, A. -L, et al.
(författare)
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predictability of biomass burning in response to climate changes
- 2012
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Ingår i: Global Biogeochemical Cycles. - 0886-6236 .- 1944-9224. ; 26, s. GB4007-
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Tidskriftsartikel (refereegranskat)abstract
- Climate is an important control on biomass burning, but the sensitivity of fire to changes in temperature and moisture balance has not been quantified. We analyze sedimentary charcoal records to show that the changes in fire regime over the past 21,000 yrs are predictable from changes in regional climates. Analyses of paleo-fire data show that fire increases monotonically with changes in temperature and peaks at intermediate moisture levels, and that temperature is quantitatively the most important driver of changes in biomass burning over the past 21,000 yrs. Given that a similar relationship between climate drivers and fire emerges from analyses of the interannual variability in biomass burning shown by remote-sensing observations of month-by-month burnt area between 1996 and 2008, our results signal a serious cause for concern in the face of continuing global warming.
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| 4. |
- McGurnaghan, S. J., et al.
(författare)
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Development and validation of a cardiovascular risk prediction model in type 1 diabetes
- 2021
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 64, s. 2001-2011
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis We aimed to report current rates of CVD in type 1 diabetes and to develop a CVD risk prediction tool for type 1 diabetes. Methods A cohort of 27,527 people with type 1 diabetes without prior CVD was derived from the national register in Scotland. Incident CVD events during 199,552 person-years of follow-up were ascertained using hospital admissions and death registers. A Poisson regression model of CVD was developed and then validated in the Swedish National Diabetes Register (n = 33,183). We compared the percentage with a high 10 year CVD risk (i.e., >= 10%) using the model with the percentage eligible for statins using current guidelines by age. Results The age-standardised rate of CVD per 100,000 person-years was 4070 and 3429 in men and women, respectively, with type 1 diabetes in Scotland, and 4014 and 3956 in men and women in Sweden. The final model was well calibrated (Hosmer- Lemeshow test p > 0.05) and included a further 22 terms over a base model of age, sex and diabetes duration (C statistic 0.82; 95% CI 0.81, 0.83). The model increased the base model C statistic foam 0.66 to 0.80, from 0.60 to 0.75 and from 0.62 to 0.68 in those aged <40, 40-59 and >= 60 years, respectively (alp values <0.005). The model required minimal calibration in Sweden and had a C statistic of 0.85. Under current guidelines, >90% of those aged 20-39 years and 100% of those >= 40 years with type 1 diabetes were eligible for statins, but it was not until age 65 upwards that 100% had a modelled risk of CVD >= 10% in 10 years. Conclusions/interpretation A prediction tool such as that developed here can provide individualised risk predictions. This 10 year CVD risk prediction tool could facilitate patient discussions regarding appropriate statin prescribing. Apart from 10 year risk, such discussions may also consider longer-term CVD risk, the potential for greater benefits from early vs later statin intervention. the potential impact on quality of life of an early CVD event and evidence on safety, all of which could influence treatment decisions, particularly in younger people with type 1 diabetes.
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| 5. |
- Pattaro, Cristian, et al.
(författare)
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Genome-Wide Association and Functional Follow-Up Reveals New Loci for Kidney Function
- 2012
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7390 .- 1553-7404. ; 8:3, s. e1002584-
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Tidskriftsartikel (refereegranskat)abstract
- Chronic kidney disease (CKD) is an important public health problem with a genetic component. We performed genomewide association studies in up to 130,600 European ancestry participants overall, and stratified for key CKD risk factors. We uncovered 6 new loci in association with estimated glomerular filtration rate (eGFR), the primary clinical measure of CKD, in or near MPPED2, DDX1, SLC47A1, CDK12, CASP9, and INO80. Morpholino knockdown of mpped2 and casp9 in zebrafish embryos revealed podocyte and tubular abnormalities with altered dextran clearance, suggesting a role for these genes in renal function. By providing new insights into genes that regulate renal function, these results could further our understanding of the pathogenesis of CKD.
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| 6. |
- Alkayyali, Sami, et al.
(författare)
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Common variant in the HMGA2 gene increases susceptibility to nephropathy in patients with type 2 diabetes.
- 2012
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 1432-0428 .- 0012-186X.
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Tidskriftsartikel (refereegranskat)abstract
- AIMS/HYPOTHESIS: Type 2 diabetes is a chronic metabolic disorder associated with devastating microvascular complications. Genome-wide association studies have identified more than 60 genetic variants associated with type 2 diabetes and/or glucose and insulin traits, but their role in the progression of diabetes is not established. The aim of this study was to explore whether these variants were also associated with the development of nephropathy in patients with type 2 diabetes. METHODS: We studied 28 genetic variants in 2,229 patients with type 2 diabetes from the local Malmö Scania Diabetes Registry (SDR) published during 2007-2010. Diabetic nephropathy (DN) was defined as micro- or macroalbuminuria and/or end-stage renal disease. Estimated glomerular filtration rate (eGFR) was assessed using the MDRD-4 formula. Replication genotyping of rs1531343 was performed in diabetic (Steno type 2 diabetes [n = 345], Genetics of Diabetes Audit and Research in Tayside Scotland [Go-DARTS] [n = 784]) and non-diabetic (Malmö Preventive Project [n = 2,523], Botnia study [n = 2,247]) cohorts. RESULTS: In the SDR, HMGA2 single-nucleotide polymorphism rs1531343 was associated with DN (OR 1.50, 95% CI 1.20, 1.87, p = 0.00035). In the combined analysis totalling 3,358 patients with type 2 diabetes (n = 1,233 cases, n = 2,125 controls), carriers of the C-allele had a 1.45-fold increased risk of developing nephropathy (95% CI 1.20, 1.75, p = 0.00010). Furthermore, the risk C-allele was associated with lower eGFR in patients with type 2 diabetes (n = 2,499, β ± SEM, -3.7 ± 1.2 ml/min, p = 0.002) and also in non-diabetic individuals (n = 17,602, β ± SEM, -0.008 ± 0.003 ml/min (log( e )), p = 0.006). CONCLUSIONS/INTERPRETATION: These data demonstrate that the HMGA2 variant seems to be associated with increased risk of developing nephropathy in patients with type 2 diabetes and lower eGFR in both diabetic and non-diabetic individuals and could thus be a common denominator in the pathogenesis of type 2 diabetes and kidney complications.
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| 7. |
- Chasman, Daniel I., et al.
(författare)
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Integration of genome-wide association studies with biological knowledge identifies six novel genes related to kidney function
- 2012
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 21:24, s. 5329-5343
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Tidskriftsartikel (refereegranskat)abstract
- In conducting genome-wide association studies (GWAS), analytical approaches leveraging biological information may further understanding of the pathophysiology of clinical traits. To discover novel associations with estimated glomerular filtration rate (eGFR), a measure of kidney function, we developed a strategy for integrating prior biological knowledge into the existing GWAS data for eGFR from the CKDGen Consortium. Our strategy focuses on single nucleotide polymorphism (SNPs) in genes that are connected by functional evidence, determined by literature mining and gene ontology (GO) hierarchies, to genes near previously validated eGFR associations. It then requires association thresholds consistent with multiple testing, and finally evaluates novel candidates by independent replication. Among the samples of European ancestry, we identified a genome-wide significant SNP in FBXL20 (P 5.6 10(9)) in meta-analysis of all available data, and additional SNPs at the INHBC, LRP2, PLEKHA1, SLC3A2 and SLC7A6 genes meeting multiple-testing corrected significance for replication and overall P-values of 4.5 10(4)2.2 10(7). Neither the novel PLEKHA1 nor FBXL20 associations, both further supported by association with eGFR among African Americans and with transcript abundance, would have been implicated by eGFR candidate gene approaches. LRP2, encoding the megalin receptor, was identified through connection with the previously known eGFR gene DAB2 and extends understanding of the megalin system in kidney function. These findings highlight integration of existing genome-wide association data with independent biological knowledge to uncover novel candidate eGFR associations, including candidates lacking known connections to kidney-specific pathways. The strategy may also be applicable to other clinical phenotypes, although more testing will be needed to assess its potential for discovery in general.
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| 8. |
- Parsa, Afshin, et al.
(författare)
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Common Variants in Mendelian Kidney Disease Genes and Their Association with Renal Function
- 2013
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Ingår i: Journal of the American Society of Nephrology. - 1046-6673 .- 1533-3450. ; 24:12, s. 2105-2117
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Tidskriftsartikel (refereegranskat)abstract
- Many common genetic variants identified by genome-wide association studies for complex traits map to genes previously linked to rare inherited Mendelian disorders. A systematic analysis of common single-nucleotide polymorphisms (SNPs) in genes responsible for Mendelian diseases with kidney phenotypes has not been performed. We thus developed a comprehensive database of genes for Mendelian kidney conditions and evaluated the association between common genetic variants within these genes and kidney function in the general population. Using the Online Mendelian Inheritance in Man database, we identified 731 unique disease entries related to specific renal search terms and confirmed a kidney phenotype in 218 of these entries, corresponding to mutations in 258 genes. We interrogated common SNPs (minor allele frequency >5%) within these genes for association with the estimated GFR in 74,354 European-ancestry participants from the CKDGen Consortium. However, the top four candidate SNPs (rs6433115 at LRP2, rs1050700 at TSC1, rs249942 at PALB2, and rs9827843 at ROBO2) did not achieve significance in a stage 2 meta-analysis performed in 56,246 additional independent individuals, indicating that these common SNPs are not associated with estimated GFR. The effect of less common or rare variants in these genes on kidney function in the general population and disease-specific cohorts requires further research.
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| 9. |
- Postmus, Iris, et al.
(författare)
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Pharmacogenetic meta-analysis of genome-wide association studies of LDL cholesterol response to statins.
- 2014
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Ingår i: Nature communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 5
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Tidskriftsartikel (refereegranskat)abstract
- Statins effectively lower LDL cholesterol levels in large studies and the observed interindividual response variability may be partially explained by genetic variation. Here we perform a pharmacogenetic meta-analysis of genome-wide association studies (GWAS) in studies addressing the LDL cholesterol response to statins, including up to 18,596 statin-treated subjects. We validate the most promising signals in a further 22,318 statin recipients and identify two loci, SORT1/CELSR2/PSRC1 and SLCO1B1, not previously identified in GWAS. Moreover, we confirm the previously described associations with APOE and LPA. Our findings advance the understanding of the pharmacogenetic architecture of statin response.
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| 10. |
- Shore, A. C., et al.
(författare)
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Measures of atherosclerotic burden are associated with clinically manifest cardiovascular disease in type 2 diabetes: a European cross-sectional study
- 2015
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Ingår i: Journal of Internal Medicine. - : Wiley. - 1365-2796 .- 0954-6820. ; 278:3, s. 291-302
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Tidskriftsartikel (refereegranskat)abstract
- BackgroundThere is a need to develop and validate surrogate markers of cardiovascular disease (CVD) in subjects with diabetes. The macrovascular changes associated with diabetes include aggravated atherosclerosis, increased arterial stiffness and endothelial dysfunction. The aim of this study was to determine which of these factors is most strongly associated with clinically manifest cardiovascular events. MethodsVascular changes were measured in a cohort of 458 subjects with type 2 diabetes (T2D) and CVD (myocardial infarction, stroke or lower extremity arterial disease), 527 subjects with T2D but without clinically manifest CVD and 515 subjects without T2D and with or without CVD. ResultsCarotid intima-media thickness (IMT) and ankle-brachial pressure index were independently associated with the presence of CVD in subjects with T2D, whereas pulse wave velocity and endothelial function provided limited independent additive information. Measurement of IMT in the carotid bulb provided better discrimination of the presence of CVD in subjects with T2D than measurement of IMT in the common carotid artery. The factors most significantly associated with increased carotid IMT in T2D were age, disease duration, systolic blood pressure, impaired renal function and increased arterial stiffness, whereas there were no or weak independent associations with metabolic factors and endothelial dysfunction. ConclusionsMeasures of atherosclerotic burden are associated with clinically manifest CVD in subjects with T2D. In addition, vascular changes that are not directly related to known metabolic risk factors are important in the development of both atherosclerosis and CVD in T2D. A better understanding of the mechanisms involved is crucial for enabling better identification of CVD risk in T2D.
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| 11. |
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| 12. |
- Aizawa, Kunihiko, et al.
(författare)
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Reservoir Pressure Integral Is Independently Associated With the Reduction in Renal Function in Older Adults
- 2022
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Ingår i: Hypertension. - 0194-911X. ; 79:10, s. 2364-2372
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Tidskriftsartikel (refereegranskat)abstract
- Background: Arterial hemodynamic parameters derived from reservoir-excess pressure analysis exhibit prognostic utility. Reservoir-excess pressure analysis may provide useful information about an influence of altered hemodynamics on target organ such as the kidneys. We determined whether the parameters derived from the reservoir-excess pressure analysis were associated with the reduction in estimated glomerular filtration rate in 542 older adults (69.4±7.9 years, 194 females) at baseline and after 3 years. Methods: Reservoir-excess pressure parameters, including reservoir pressure integral, excess pressure integral, systolic, and diastolic rate constants, were obtained by radial artery tonometry. Results: After 3 years, and in a group of 94 individuals (72.4±7.6 years, 26 females), there was an estimated glomerular filtration rate reduction of >5% per year (median reduction of 20.5% over 3 years). A multivariable logistic regression analysis revealed that higher baseline reservoir pressure integral was independently associated with a smaller reduction in estimated glomerular filtration rate after accounting for conventional cardiovascular risk factors and study centers (odds ratio: 0.660 [95% CIs, 0.494-0.883]; P=0.005). The association remained unchanged after further adjustments for potential confounders and baseline renal function (odds ratio: 0.528 [95% CIs, 0.351-0.794]; P=0.002). No other reservoir-excess pressure parameters exhibited associations with the reduction in renal function. Conclusions: This study demonstrates that baseline reservoir pressure integral was associated with the decline in renal function in older adults at 3-year follow-up, independently of conventional cardiovascular risk factors. This suggests that reservoir pressure integral may play a role in the functional decline of the kidneys.
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| 15. |
- Palmer, C. N. A., et al.
(författare)
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Paradoxical Lower Serum Triglyceride Levels and Higher Type 2 Diabetes Mellitus Susceptibility in Obese Individuals with the PNPLA3 148M Variant
- 2012
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 7:6
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Tidskriftsartikel (refereegranskat)abstract
- Background: Obesity is highly associated with elevated serum triglycerides, hepatic steatosis and type 2 diabetes (T2D). The I148M (rs738409) genetic variant of patatin-like phospholipase domain-containing 3 gene (PNPLA3) is known to modulate hepatic triglyceride accumulation, leading to steatosis. No association between PNPLA3 I148M genotype and T2D in Europeans has been reported. Aim of this study is to examine the relationship between PNPLA3 I148M genotypes and serum triglycerides, insulin resistance and T2D susceptibility by testing a gene-environment interaction model with severe obesity. Methods and Findings: PNPLA3 I148M was genotyped in a large obese cohort, the SOS study (n = 3,473) and in the Go-DARTS (n = 15,448), a T2D case-control study. Metabolic parameters were examined across the PNPLA3 I148M genotypes in participants of the SOS study at baseline and at 2- and 10-year follow up after bariatric surgery or conventional therapy. The associations with metabolic parameters were validated in the Go-DARTS study. Serum triglycerides were found to be lower in the PNPLA3 148M carriers from the SOS study at baseline and from the Go-DARTS T2D cohort. An increased risk for T2D conferred by the 148M allele was found in the SOS study (O.R. 1.09, 95% C.I. 1.01-1.39, P = 0.040) and in severely obese individuals in the Go-DARTS study (O. R. 1.37, 95% C.I. 1.13-1.66, P = 0.001). The 148M allele was no longer associated with insulin resistance or T2D after bariatric surgery in the SOS study and no association with the 148M allele was observed in the less obese (BMI<35) individuals in the Go-DARTS study (P for interaction = 0.002). This provides evidence for the obesity interaction with 148M allele and T2D risk in a large-scale cross-sectional and a prospective interventional study. Conclusions: Severely obese individuals carrying the PNPLA3 148M allele have lower serum triglyceride levels, are more insulin resistant and more susceptible to T2D. This study supports the hypothesis that obesity-driven hepatic lipid accumulation may contribute to T2D susceptibility.
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| 19. |
- Siddiqui, Moneeza Kalhan, et al.
(författare)
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CKM Glu83Gly Is Associated With Blunted Creatine Kinase Variation, but Not With Myalgia
- 2017
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Ingår i: Circulation. - 1942-325X .- 1942-3268. ; 10:4
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Glu83Gly (rs11559024) with constitutive creatine phosphokinase (CK) levels, CK variation, and inducibility. Given the diagnostic importance of CK in determining muscle damage, we tested the association of the variant with myalgia.METHODS AND RESULTS: ) lower for carriers of the variant, respectively. The variant was not associated with myalgia (odds ratio, 0.84; 95% confidence interval, 0.52-1.38).CONCLUSIONS: This study highlights that a genetic factor known to be associated with constitutive CK levels is also associated with CK variability and inducibility. This is discussed in the context of evidence to suggest that the variant has an impact on inducibility of CK by trauma through a previously reported case of a homozygous carrier. However, the lack of association between the variant and myalgia suggests that it cannot reliably be used as a biomarker for muscle symptoms.
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| 20. |
- van Zuydam, NR, et al.
(författare)
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A Genome-Wide Association Study of Diabetic Kidney Disease in Subjects With Type 2 Diabetes
- 2018
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Ingår i: Diabetes. - : American Diabetes Association. - 1939-327X .- 0012-1797. ; 67:7, s. 1414-1427
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Tidskriftsartikel (refereegranskat)abstract
- Identification of sequence variants robustly associated with predisposition to diabetic kidney disease (DKD) has the potential to provide insights into the pathophysiological mechanisms responsible. We conducted a genome-wide association study (GWAS) of DKD in type 2 diabetes (T2D) using eight complementary dichotomous and quantitative DKD phenotypes: the principal dichotomous analysis involved 5,717 T2D subjects, 3,345 with DKD. Promising association signals were evaluated in up to 26,827 subjects with T2D (12,710 with DKD). A combined T1D+T2D GWAS was performed using complementary data available for subjects with T1D, which, with replication samples, involved up to 40,340 subjects with diabetes (18,582 with DKD). Analysis of specific DKD phenotypes identified a novel signal near GABRR1 (rs9942471, P = 4.5 × 10−8) associated with microalbuminuria in European T2D case subjects. However, no replication of this signal was observed in Asian subjects with T2D or in the equivalent T1D analysis. There was only limited support, in this substantially enlarged analysis, for association at previously reported DKD signals, except for those at UMOD and PRKAG2, both associated with estimated glomerular filtration rate. We conclude that, despite challenges in addressing phenotypic heterogeneity, access to increased sample sizes will continue to provide more robust inference regarding risk variant discovery for DKD.
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| 21. |
- van Zuydam, Natalie, et al.
(författare)
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Genome-Wide Association Study of Peripheral Artery Disease
- 2021
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 14:5
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Tidskriftsartikel (refereegranskat)abstract
- Background: Peripheral artery disease (PAD) affects >200 million people worldwide and is associated with high mortality and morbidity. We sought to identify genomic variants associated with PAD overall and in the contexts of diabetes and smoking status. Methods: We identified genetic variants associated with PAD and then meta-analyzed with published summary statistics from the Million Veterans Program and UK Biobank to replicate their findings. Next, we ran stratified genome-wide association analysis in ever smokers, never smokers, individuals with diabetes, and individuals with no history of diabetes and corresponding interaction analyses, to identify variants that modify the risk of PAD by diabetic or smoking status. Results: We identified 5 genome-wide significant (P-association <= 5x10(-8)) associations with PAD in 449 548 (N-cases=12 086) individuals of European ancestry near LPA (lipoprotein [a]), CDKN2BAS1 (CDKN2B antisense RNA 1), SH2B3 (SH2B adaptor protein 3) - PTPN11 (protein tyrosine phosphatase non-receptor type 11), HDAC9 (histone deacetylase 9), and CHRNA3 (cholinergic receptor nicotinic alpha 3 subunit) loci (which overlapped previously reported associations). Meta-analysis with variants previously associated with PAD showed that 18 of 19 published variants remained genome-wide significant. In individuals with diabetes, rs116405693 at the CCSER1 (coiled-coil serine rich protein 1) locus was associated with PAD (odds ratio [95% CI], 1.51 [1.32-1.74], P-diabetes=2.5x10(-9), P-interactionwithdiabetes=5.3x10(-7)). Furthermore, in smokers, rs12910984 at the CHRNA3 locus was associated with PAD (odds ratio [95% CI], 1.15 [1.11-1.19], P-smokers=9.3x10(-10), P-interactionwithsmoking=3.9x10(-5)). Conclusions: Our analyses confirm the published genetic associations with PAD and identify novel variants that may influence susceptibility to PAD in the context of diabetes or smoking status.
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| 22. |
- van Zuydam, Natalie R., et al.
(författare)
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Genetic Predisposition to Coronary Artery Disease in Type 2 Diabetes Mellitus
- 2020
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Ingår i: Circulation. - : Lippincott Williams & Wilkins. - 2574-8300. ; 13:6, s. 640-648
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Coronary artery disease (CAD) is accelerated in subjects with type 2 diabetes mellitus (T2D).METHODS: To test whether this reflects differential genetic influences on CAD risk in subjects with T2D, we performed a systematic assessment of genetic overlap between CAD and T2D in 66 643 subjects (27 708 with CAD and 24 259 with T2D). Variants showing apparent association with CAD in stratified analyses or evidence of interaction were evaluated in a further 117 787 subjects (16 694 with CAD and 11 537 with T2D).RESULTS: None of the previously characterized CAD loci was found to have specific effects on CAD in T2D individuals, and a genome-wide interaction analysis found no new variants for CAD that could be considered T2D specific. When we considered the overall genetic correlations between CAD and its risk factors, we found no substantial differences in these relationships by T2D background.CONCLUSIONS: This study found no evidence that the genetic architecture of CAD differs in those with T2D compared with those without T2D.
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