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| 3. |
- Franceschini, N., et al.
(författare)
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GWAS and colocalization analyses implicate carotid intima-media thickness and carotid plaque loci in cardiovascular outcomes
- 2018
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Ingår i: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 9:1
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Tidskriftsartikel (refereegranskat)abstract
- Carotid artery intima media thickness (cIMT) and carotid plaque are measures of subclinical atherosclerosis associated with ischemic stroke and coronary heart disease (CHD). Here, we undertake meta-analyses of genome-wide association studies (GWAS) in 71,128 individuals for cIMT, and 48,434 individuals for carotid plaque traits. We identify eight novel susceptibility loci for cIMT, one independent association at the previously-identified PINX1 locus, and one novel locus for carotid plaque. Colocalization analysis with nearby vascular expression quantitative loci (cis-eQTLs) derived from arterial wall and metabolic tissues obtained from patients with CHD identifies candidate genes at two potentially additional loci, ADAMTS9 and LOXL4. LD score regression reveals significant genetic correlations between cIMT and plaque traits, and both cIMT and plaque with CHD, any stroke subtype and ischemic stroke. Our study provides insights into genes and tissue-specific regulatory mechanisms linking atherosclerosis both to its functional genomic origins and its clinical consequences in humans. © 2018, The Author(s).
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| 4. |
- Surendran, Praveen, et al.
(författare)
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Discovery of rare variants associated with blood pressure regulation through meta-analysis of 1.3 million individuals
- 2020
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Ingår i: Nature Genetics. - : Nature Publishing Group. - 1061-4036 .- 1546-1718. ; 52:12, s. 1314-1332
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Tidskriftsartikel (refereegranskat)abstract
- Genetic studies of blood pressure (BP) to date have mainly analyzed common variants (minor allele frequency > 0.05). In a meta-analysis of up to similar to 1.3 million participants, we discovered 106 new BP-associated genomic regions and 87 rare (minor allele frequency <= 0.01) variant BP associations (P < 5 x 10(-8)), of which 32 were in new BP-associated loci and 55 were independent BP-associated single-nucleotide variants within known BP-associated regions. Average effects of rare variants (44% coding) were similar to 8 times larger than common variant effects and indicate potential candidate causal genes at new and known loci (for example, GATA5 and PLCB3). BP-associated variants (including rare and common) were enriched in regions of active chromatin in fetal tissues, potentially linking fetal development with BP regulation in later life. Multivariable Mendelian randomization suggested possible inverse effects of elevated systolic and diastolic BP on large artery stroke. Our study demonstrates the utility of rare-variant analyses for identifying candidate genes and the results highlight potential therapeutic targets.
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| 5. |
- Tagetti, Angela, et al.
(författare)
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Intakes of omega-3 polyunsaturated fatty acids and blood pressure change over time: Possible interaction with genes involved in 20-HETE and EETs metabolism.
- 2015
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Ingår i: Prostaglandins & other Lipid Mediators. - : Elsevier BV. - 1098-8823. ; 120:May 16, s. 126-133
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Tidskriftsartikel (refereegranskat)abstract
- A high intake of omega-3 polyunsaturated fatty acids (ω-3 PUFAs), has been associated with reduced levels of blood pressure (BP). Their antihypertensive action may be due to the reduction of the ω-6/ω-3 ratio and the resulting competitive effect of ω-3 as compared to arachidonic acid (an ω-6 PUFA) as a substrate of cytochrome P450 (CYP450) enzymes involved in the production of vasoactive mediators. Some functional polymorphisms (SNPs), in genes which encode for the same enzymes, were associated with hypertension and ischemic stroke in the Malmö Diet and Cancer (MDC), a Swedish urban-based longitudinal study. The aim of this study was to evaluate the effect of the intake of different types of PUFAs on BP change over time (Δ-BP; mean follow-up 16.6±1.5 years; n=3.550 with complete phenotypic data), also considering the interaction with SNPs in genes involved in their metabolism via CYP450.
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| 6. |
- Fava, Cristiano, et al.
(författare)
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24-hour Ambulatory Blood Pressure is Linked to Chromosome 18q21-22 and Genetic Variation of NEDD4L Associates with Cross-Sectional and Longitudinal Blood Pressure in Swedes.
- 2006
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Ingår i: Kidney International. - : Elsevier BV. - 1523-1755 .- 0085-2538. ; 70:3, s. 562-569
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Tidskriftsartikel (refereegranskat)abstract
- Numerous linkage studies have indicated chromosome 18q21–22 as a locus of importance for blood pressure regulation. This locus harbors the neural precursor cell expressed developmentally downregulated 4-like (NEDD4L) gene, which is instrumental for the regulation of the amiloride-sensitive epithelial sodium channel (ENaC). In a linkage study of 16 markers (including two single nucleotide polymorphism markers located within the NEDD4L gene) on chromosome 18 between 70–104 cM and ambulatory blood pressure (ABP), in 118 families, the strongest evidence of linkage was found for 24 h and day-time systolic ABP at the NEDD4L locus (82.25 cM) (P=0.0014). In a large population sample (n=4001), we subsequently showed that a NEDD4L gene variant (rs4149601), which by alternative splicing leads to varying expression of a functionally crucial C2 domain, was associated with diastolic blood pressure (DBP) (P=0.03) and DBP progression over time (P=0.04). A genotype combination of the rs4149601 and an intronic NEDD4L marker (rs2288774) was associated with systolic blood pressure (SBP) (P=0.01), DBP (P=0.04), and progression of both SBP (P=0.03) and DBP (P=0.05) over time. A quantitative transmission disequilibrium test in the family material of the rs4149601 supported this NEDD4L variant as being at least partially causative of the linkage result. In conclusion, our findings suggest that the chromosome 18 linkage peak at 82.25 cM is explained by genetic NEDD4L variation affecting cross-sectional and longitudinal blood pressure, possibly as a consequence of altered NEDD4L interaction with ENaC.
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| 7. |
- Fava, Cristiano, et al.
(författare)
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A genetic risk score for hypertension associates with the risk of ischemic stroke in a Swedish case-control study
- 2015
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Ingår i: European Journal of Human Genetics. - : Springer Science and Business Media LLC. - 1018-4813 .- 1476-5438. ; 23
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Tidskriftsartikel (refereegranskat)abstract
- Genetic risk scores (GRS), summing up the total effect of several single-nucleotide polymorphisms (SNPs) in genes associated with either coronary risk or cardiovascular risk factors, have been tested for association with ischemic stroke with conflicting results. Recently an association was found between a GRS based on 29 SNPs discovered by genome-wide association studies and hypertension. The aim of our study was to investigate the possible association of the same GRS with ischemic stroke on top of other ‘traditional risk factors’, also testing its potential improvement in indices of discrimination and reclassification, in a Swedish case–control study. Twenty-nine SNPs were genotyped in 3677 stroke cases and 2415 controls included in the Lund Stroke Register (LSR), the Malmö Diet and Cancer (MDC) study and the Sahlgrenska Academy Study on Ischemic Stroke (SAHLSIS). The analysis was conducted in the combined sample, and separately for the three studies. After adjustment for hypertension, diabetes mellitus and smoking habits, the GRS was associated with ischemic stroke in the combined sample (OR (95% CI) 1.086 (1.029–1.147) per SD increase in the GRS P=0.003) with similar trends in all three samples: LSR (1.050 (0.967–1.140); P=0.25), MDC (1.168 (1.060–1.288); P=0.002) and SAHLSIS (1.124 (0.997–1.267); P=0.055). Measures of risk discrimination and reclassification improved marginally using the GRS. A blood pressure GRS is independently associated with ischemic stroke risk in three Swedish case–control studies, however, the effect size is low and adds marginally to prediction of stroke on top of traditional risk factors including hypertension.
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| 8. |
- Fava, Cristiano, et al.
(författare)
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A Variant Upstream of the CDH13 Adiponectin Receptor Gene and Metabolic Syndrome in Swedes.
- 2011
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Ingår i: American Journal of Cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 108, s. 1432-1437
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Tidskriftsartikel (refereegranskat)abstract
- Metabolic syndrome (MetS) constitutes a worldwide epidemic burst accounting for billions of cardiovascular disease events and deaths. The genetic basis of MetS is largely unknown. The rs11646213 T → A polymorphism maps at 16q23.3 upstream of the CDH13 gene codifying for cadherin-13 (also known as T-cadherin or H-cadherin), which is considered a vascular adiponectin receptor. This and other single-nucleotide polymorphisms have been associated with hypertension and adiponectin level in separate studies. The aim of the present study was to evaluate the effect of the CDH13 rs11646213 T → A polymorphism on individual components of MetS and on MetS. The polymorphism was genotyped in the cardiovascular cohort of the Malmö Diet and Cancer Study (n = 4,942) and successively in the Malmö Preventive Project (n = 17,675) cohort at baseline and after an average of 23 years of follow-up (reinvestigation). Four different definitions of MetS were applied to these cohorts. In the cardiovascular arm, CDH13 rs11646213 AA homozygotic women showed a trend toward higher triglycerides and lower high-density lipoprotein cholesterol and presented a higher MetS score (composite sum of MetS phenotypes). MetS (Adult Treatment Panel III definition) was more prevalent in AA homozygotic women compared to T-carriers, a result confirmed in the Malmö Preventive Project cohort at baseline and at reinvestigation with an increased risk from 19% to 45% in AA homozygotic women. In conclusion, the CDH13 rs11646213 T > A polymorphism was consistently associated with MetS in Swedish women recruited in 2 large cohorts. In light of the role of cadherin-13 as a vascular receptor for adiponectin, our study supports the genetic basis for the role of adiponectin in MetS pathogenesis.
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| 9. |
- Fava, Cristiano, et al.
(författare)
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Association between adducin-1 G460W variant and blood pressure in Swedes is dependent on interaction with body mass index and gender.
- 2007
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Ingår i: American Journal of Hypertension. - : Oxford University Press (OUP). - 1941-7225 .- 0895-7061. ; 20:9, s. 981-989
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Tidskriftsartikel (refereegranskat)abstract
- Background: The W allele of the G460W polymorphism in the adducin-1 gene has been occasionally associated with increased blood pressure (BP). The aim of this study was to test whether the G460W variant is associated with BP levels and BP progression rate and whether G460W associations with BP are affected by sex, body mass index (BMI), or age. Methods: The G460W polymorphism was genotyped in the population-based Malmo Diet and Cancer-cardiovascular arm (MDC-CVA; n = 6103), of whom 53% had also been examined 11 +/- 4.4 years earlier in the Malmo Preventive Project (MPP). Results: Among subjects without antihypertensive treatment (AHT) in the MDC-CVA (n = 5009), there was no difference between carriers (38%) and noncarriers (62%) of the W allele in systolic BP (139.2 +/- 18.2 v 139.2 +/- 18.5 mm Hg; P = .99) or diastolic BP (85.9 +/- 9.1 v 86.1 +/- 9.2 mm Hg; P = .49). In subjects free from AHT in the MPP and MDC (n = 2637) there was no difference between carriers (38%) and noncarriers (62%) in progression of systolic BP (2.0 +/- 2.5 v 2.0 +/- 2.7 mm Hg/year; P = .45) or diastolic BP (0.59 +/- 1.6 v 0.56 +/- 1.5 mm Hg/year; P = .66) from MPP to MDC. At MDC-CVA BP was influenced by interaction between the G460W and BMI (P = .02 for systolic BP and P = .002 for diastolic BP) and by interaction between G460W and sex (P = .03 for systolic BP and P = .02 for diastolic BP), a result further confirmed by stratified analysis showing that female carriers of the W allele belonging to the upper tertile of BMI had increased systolic BP (146.1 +/- 18.6 v 141.2 +/- 18.6 mm Hg; P < .001), diastolic BP (88.7 +/- 8.7 v 86.1 +/- 8.7 mm Hg; P < .001), and prevalence of hypertension (72.5% v 61.8 %; P = .001). Conclusions: Our data suggest that the G460W polymorphism influences BP when BMI and sex are taken into account.
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| 10. |
- Fava, Cristiano, et al.
(författare)
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Cardiovascular consequences of a polygenetic component of blood pressure in an urban-based longitudinal study: the Malmö Diet and Cancer.
- 2014
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Ingår i: Journal of Hypertension. - 1473-5598. ; 32:7, s. 1424-1428
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Tidskriftsartikel (refereegranskat)abstract
- A recently published genome wide association study identified 29 single nucleotide polymorphisms (SNPs) influencing blood pressure (BP). Case-control studies suggest that a genetic risk score (GRS) based on these 29 SNPs affect the risk of cardiovascular disease (CVD), but its role for CVD at population level is unknown. Here, we prospectively evaluate the impact of this polygenetic BP component on CVD morbidity and mortality in a large urban-based middle-aged population.
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