| 1. |
- Danese, E., et al.
(författare)
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Impact of the CYP4F2 p.V433M Polymorphism on Coumarin Dose Requirement: Systematic Review and Meta-Analysis
- 2012
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Ingår i: Clinical Pharmacology and Therapeutics. - : Springer Science and Business Media LLC. - 1532-6535 .- 0009-9236. ; 92:6, s. 746-756
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Forskningsöversikt (refereegranskat)abstract
- A systematic review and a meta-analysis were performed to quantify the accumulated information from genetic association studies investigating the impact of the CYP4F2 rs2108622 (p.V433M) polymorphism on coumarin dose requirement. An additional aim was to explore the contribution of the CYP4F2 variant in comparison with, as well as after stratification for, the VKORC1 and CYP2C9 variants. Thirty studies involving 9,470 participants met prespecified inclusion criteria. As compared with CC-homozygotes, T-allele carriers required an 8.3% (95% confidence interval (CI): 5.6-11.1%; P < 0.0001) higher mean daily coumarin dose than CC homozygotes to reach a stable international normalized ratio (INR). There was no evidence of publication bias. Heterogeneity among studies was present (I-2 = 43%). Our results show that the CYP4F2 p.V433M polymorphism is associated with interindividual variability in response to coumarin drugs, but with a low effect size that is confirmed to be lower than those contributed by VKORC1 and CYP2C9 polymorphisms.
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| 2. |
- Tagetti, A., et al.
(författare)
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A genetic risk score for hypertension is associated with risk of thoracic aortic aneurysm
- 2019
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Ingår i: Journal of Human Hypertension. - : Springer Science and Business Media LLC. - 0950-9240 .- 1476-5527. ; 33:9, s. 658-663
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Tidskriftsartikel (refereegranskat)abstract
- A genetic risk score (GRS) based on 29 single nucleotide polymorpysms (SNPs) associated with high blood pressure (BP) was prospectively associated with development of hypertension, stroke and cardiovascular events. The aim of the present study was to evaluate the impact of this GRS on the incidence of aortic disease, including aortic dissection (AD), rupture or surgery of a thoracic (TAA) or abdominal (AAA) aortic aneurysm. More than 25,000 people from the Swedish Malmo Diet and Cancer Study had information on at least 24 SNPs and were followed up for a median ≥ 18 years. The number of BP elevating alleles of each SNPs, weighted by their effect size in the discovery studies, was summed into a BP-GRS. In Cox regression models, adjusted for traditional cardiovascular risk factors including hypertension, we found significant associations of the BP-GRS, prospectively, with incident TAA (hazard ratio (HR) 1.64 (95% confidence interval (CI) 1.081–2.475 comparing the third vs. the first tertile; p = 0.020) but not with either AAA or aortic dissection. Calibration, discrimination and reclassification analyses show modest improvement in prediction using the BP-GRS in addition to the model which used only traditional risk factors. A GRS for hypertension associates with TAA suggesting a link between genetic determinants of BP and aortic disease. The effect size is small but the addition of more SNPs to the GRS might improve its discriminatory capability.
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| 3. |
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| 4. |
- Fava, Cristiano, et al.
(författare)
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Subjects heterozygous for genetic loss of function of the thiazide-sensitive cotransporter have reduced blood pressure
- 2008
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Ingår i: Human Molecular Genetics. - : Oxford University Press (OUP). - 0964-6906 .- 1460-2083. ; 17:3, s. 413-418
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Tidskriftsartikel (refereegranskat)abstract
- Gitelmans syndrome (GS) is an inherited recessive disorder caused by homozygous or compound heterozygous loss of function mutations of the NaCl cotransporter (NCCT) gene encoding the kidney-expressed NCCT, the pharmacological target of thiazide diuretics. An observational study estimated the prevalence of GS to 19/1 000 000, in Sweden, suggesting that similar to 1% of the population carries one mutant NCCT allele. As the phenotype of GS patients, who always carry two mutant alleles, is indistinguishable from that seen in patients treated with high-dose thiazide diuretics, we aimed at investigating whether subjects carrying one mutated NCCT allele have a phenotype resembling that of treatment with low-dose thiazide diuretics. We screened first-degree relatives of 18 of our patients with an established clinical end genetic diagnosis of GS for NCCT loss of function mutations and identified 35 healthy subjects carrying one mutant allele (GS-heterozygotes). Each GS-heterozygote was assigned a healthy control subject matched for age, BMI and sex. GS-heterozygotes had markedly lower blood pressure (systolic 103.3 +/- 16.4 versus 123.2 +/- 19.4 mmHg; diastolic 62.5 +/- 10.5 versus 73.1 +/- 9.4 mmHg; P < 0.001) than controls. There was no significant difference between the groups either in plasma concentration or urinary excretion rate of electrolytes, however, GS-heterozygotes had higher fasting plasma glucose concentration. Similar to patients being treated with low-dose thiazide diuretics, GS-heterozygotes have markedly lower blood pressure and slightly higher fasting plasma glucose compared with control subjects. Our findings suggest that GS-heterozygotes, the prevalence of which can be estimated to 1%, are partially protected from hypertension through partial genetic loss of function of the NCCT. However, as our study had a case-control design, it is important to underline that any potential effects on population blood pressure and risk of future cardiovascular disease need to be examined in prospective and population-based studies.
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| 5. |
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| 6. |
- Fava, Cristiano, et al.
(författare)
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Vanin-1 T26I polymorphism, hypertension and cardiovascular events in two large urban-based prospective studies in Swedes.
- 2011
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Ingår i: Nutrition Metabolism and Cardiovascular Diseases. - : Elsevier BV. - 1590-3729 .- 0939-4753.
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND AND AIMS: Vanin-1 (gene name VNN1) is an enzyme with pantetheinase activity generating the amino-thiol cysteamine which is implicated in the regulation of red-ox status through its effect on glutathione. We tested the hypothesis that the rs2294757 VNN1 T26I polymorphism could affect blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events. METHODS AND RESULTS: The VNN1 T26I polymorphism was genotyped in 5664 participants of the cardiovascular cohort of the "Malmö Diet and Cancer" (MDC-CVA) study and successively in 17874 participants of the "Malmö Preventive project"(MPP). The incidence of cardiovascular events was monitored for an average of nearly 12 years of follow-up in the MDC-CVA and for 25 years in the MPP. Both before and after adjustment for sex, age and BMI in the MDC-CVA the polymorphism had a mild lowering effect on diastolic BP and hypertension, especially in females. However in MPP no effect on BP phenotypes was detectable. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events in the MDC-CVA was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the VNN1 T26I variant in determining BP level and incident ischemic events.
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| 7. |
- Montagnana, Martina, et al.
(författare)
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The Pro12Ala polymorphism of the PPARG gene is not associated with the metabolic syndrome in an urban population of middle-aged Swedish individuals.
- 2008
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Ingår i: Diabetic Medicine: A journal of the British Diabetic Association. - : Wiley. - 1464-5491. ; 25:8, s. 902-908
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: To determine if the common Pro12Ala polymorphism (rs1801282) of the peroxisome proliferator-activated receptor (PPARG) gene is associated with the metabolic syndrome (MetS) or with its individual components in middle-aged Swedish individuals. METHODS: MetS was defined according to the National Cholesterol Education Program/Adult Panel III (NCEP/ATP III), the International Diabetes Federation (IDF) and the European Group for the Study of Insulin Resistance (EGIR) criteria in a population-based sample of nearly 5000 subjects participating in the Malmö Diet and Cancer-cardiovascular arm. RESULTS: Of the subjects included in the analysis, 21.8, 29.4 and 20.4% had MetS according to the NCEP/ATP III, IDF and EGIR (only in subjects without diabetes) definitions, respectively. The Pro12Ala was not associated with MetS or with its individual components. These results were similar when patients with diabetes were excluded. Hypertensive and obese ala-carriers had lower fasting glucose and hypertensive ala-carriers also had lower level triglycerides (P < 0.05). CONCLUSIONS: Our data do not support a major role for the Pro12Ala variant of the PPARG gene in MetS and its individual components. The modest difference in triglyceride and glucose levels, restricted to hypertensive and obese subjects in our cohort, suggests that the polymorphism has a minor effect on glucose and lipid metabolism, particularly in individuals at risk for gluco-metabolic disturbances.
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