1. |
- 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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2. |
- 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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3. |
- Fava, Cristiano, et al.
(författare)
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Chromosome 2q12, the ADRA2B I/D polymorphism and metabolic syndrome.
- 2009
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Ingår i: Journal of Hypertension. - 1473-5598. ; 27, s. 1794-1803
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: To test whether a previously hypertension-linked 23 cM region on chromosome 2 is linked to the metabolic syndrome (MetS) or its individual components, and whether a common I/D polymorphism of the adrenergic receptor 2b (ADRA2B) gene, mapping in that region, is associated with the same traits. METHODS: We conducted fine mapping of the hypertension-linked region on chromosome 2 spanning between 107 and 130 cM using 11 informative polymorphic markers in 260 healthy white siblings belonging to 118 nuclear families. Variance-component linkage analysis was performed for each MetS component and a composite sum of MetS phenotypes as quantitative trait after adjustment for significant covariates using 'Solar software package'. Successively, the I/D polymorphism of the ADRA2B gene was genotyped in 5283 patients in the Malmö Diet and Cancer-cardiovascular arm, seeking for association with the MetS using standard definitions and separately, with its individual components. RESULTS: For 24-h pulse pressure and waist/hip ratio, LOD [logarithm of the odds (to the base 10)] scores of more than two were found between 107 and 122 cM on chromosome 2. For the composite sum of MetS phenotypes, LOD score of more than 1 was found between 116 and 120 cM. There was no difference between carriers and noncarriers of the D-allele of the ADRA2B gene in MetS prevalence but D-carriers were associated with significantly higher levels of diastolic blood pressure. CONCLUSION: Our results suggest that chromosome 2 could harbor one or more genes implied in blood pressure homeostasis and MetS development. The ADRA2B I/D polymorphism is not consistently associated with MetS and metabolic/anthropometric parameters but with diastolic blood pressure in an urban-based population of middle-aged Swedes.
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4. |
- Fava, Cristiano, et al.
(författare)
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Determinants of kidney function in Swedish families: role of heritable factors.
- 2008
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Ingår i: Journal of Hypertension. - 1473-5598. ; 26:9, s. 1773-1779
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Tidskriftsartikel (refereegranskat)abstract
- The aim of this study was to evaluate the determinants of kidney function and the role of heritable factors in a sample of 249 siblings free from known cardiovascular disease and without antihypertensive drugs belonging to 110 families. Four different measures and estimates of kidney function were considered. Blood pressure was recorded during 24 h by ambulatory blood pressure monitoring. Heritability was estimated with and without adjustment for significant covariates.In multivariate analysis, in addition to age, sex, BMI, HDL-cholesterol, 24-h systolic and mean blood pressure, systolic nocturnal blood pressure dipping resulted independently related to serum creatinine, estimated Cockcroft-Gault-creatinine clearance and estimated by the modification of diet in renal disease-glomerular filtration rate. After full adjustment, the heritability values were 51% for the measured creatinine clearance (P < 0.01), 58% for the estimated Cockcroft-Gault-creatinine clearance (P < 0.001), 40% for the estimated by the modification of diet in renal disease-glomerular filtration rate (P < 0.001), but 8% (P = 0.34) for serum creatinine.Our data confirm that kidney function is partially under genetic control and that genetic variants of importance for this trait could be mapped. The association of the circadian rhythm of blood pressure with kidney function in this sample deserves further investigation.
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6. |
- Fava, Cristiano, et al.
(författare)
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Homozygosity for the EPHX2 K55R polymorphism increases the long-term risk of ischemic stroke in men: a study in Swedes.
- 2010
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Ingår i: Pharmacogenetics & Genomics. - 1744-6872. ; 20:2, s. 94-103
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVES: The soluble epoxide hydrolase (gene name EPHX2) is responsible for metabolism of 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. There are several functional polymorphisms in the EPHX2 gene: two of them, the K55R and R287Q, showing an altered metabolic activity in vitro, were associated with coronary heart disease and ischemic stroke in previous studies. The aim of this study was to evaluate the effect of four polymorphisms in the EPHX2 gene on blood pressure levels, hypertension prevalence, and risk of incident cardiovascular events in a large sample of middle-aged Swedes. METHODS: The incidence of cardiovascular events (coronary events, n = 274; ischemic stroke, n = 197) was monitored over 10 years of follow-up. RESULTS: In the whole population, all polymorphisms had no effect on the studied parameters but a positive interaction between male sex and three SNPs including the K55R was evident: male, but not female, EPHX2 R55R homozygotes had significantly higher crude and adjusted systolic blood pressure and higher hypertension prevalence with respect to K-carriers. Kaplan-Meier curves showed higher incidence of ischemic strokes in male R55R homozygotes with respect to K-carriers (P = 0.015 by log-rank test). After adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke in male R55R homozygotes remained significantly higher (hazard ratio: 4.8; 95% confidence interval: 1.2-19.9). CONCLUSION: The functional K55R polymorphism of the EPHX2 gene confers a higher risk of hypertension prevalence and increases the risk of incident ischemic stroke in male homozygotes. Additional studies are needed to confirm these data and to elucidate the interaction between sex and the EPHX2 K55R polymorphism.
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7. |
- Fava, Cristiano, et al.
(författare)
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Hypertension, cardiovascular risk and polymorphisms in genes controlling the cytochrome P450 pathway of arachidonic acid: A sex-specific relation?
- 2012
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Ingår i: Prostaglandins & other Lipid Mediators. - : Elsevier BV. - 1098-8823. ; 98:3-4, s. 75-85
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Tidskriftsartikel (refereegranskat)abstract
- Hypertension is a multifactorial disease in which the interplay of genetic and environmental factors that maintain blood pressure stable throughout life is altered. Cytochrome P450 (CYP)-derived metabolites of arachidonic acid such as epoxyeicosatrienoic acids (EETs) and 20-hydroxyeicosatetraenoic acid (20-HETE), active on vascular tone, endothelial function and renal sodium reapportion, have been identified as candidate mediators in the development of hypertension in several animal models, with remarkable sex-specific effect. Several SNPs, some recognized as functional, in human genes implicated in EETs/20-HETE biosynthesis and metabolism, such as CYP2J2 and CYP4A11, have been tested for association with blood pressure, hypertension and its long-term cardiovascular consequences in different populations, with conflicting results. A sex-specific effect, related to CYP4F2 polymorphisms and expression, has been observed in association studies. This finding indicates that altered 20-HETE bioactivity underlay the excess of hypertension and associated vascular events observed in men with respect to women and is consistent with the results from experimental models. Further epidemiological and mechanistic studies are required to confirm the effect of lipid mediators on blood pressure in humans and define the mechanisms of a putative sex-specific effect.
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8. |
- Fava, Cristiano, et al.
(författare)
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Prediction of Blood Pressure Changes Over Time and Incidence of Hypertension by a Genetic Risk Score in Swedes.
- 2012
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Ingår i: Hypertension. - 1524-4563.
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Tidskriftsartikel (refereegranskat)abstract
- Recent Genome-Wide Association Studies (GWAS) have pinpointed different single nucleotide polymorphisms consistently associated with blood pressure (BP) and hypertension prevalence. However, little data exist regarding single nucleotide polymorphisms predicting BP variation over time and hypertension incidence. The aim of this study was to confirm the association of a genetic risk score (GRS), based on 29 independent single nucleotide polymorphisms, with cross-sectional BP and hypertension prevalence and to challenge its prediction of BP change over time and hypertension incidence in >17 000 middle-aged Swedes participating in a prospective study, the Malmö Preventive Project, investigated at baseline and over a 23-year average period of follow-up. The GRS was associated with higher systolic and diastolic BP values both at baseline (β±SEM, 0.968±0.102 mm Hg and 0.585±0.064 mm Hg; P<1E-19 for both) and at reinvestigation (β±SEM, 1.333±0.161 mm Hg and 0.724±0.086 mm Hg; P<1E-15 for both) and with increased hypertension prevalence (odds ratio [95% CI], 1.192 [1.140-1.245] and 1.144 [1.107-1.183]; P<1E-15 for both). The GRS was positively associated with change (Δ) in BP (β±SEM, 0.033±0.008 mm Hg/y and 0.023±0.004 mm Hg/y; P<1E-04 for both) and hypertension incidence (odds ratio [95% CI], 1.110 [1.065-1.156]; P=6.7 E-07), independently from traditional risk factors. The relative weight of the GRS was lower in magnitude than obesity or prehypertension, but comparable with diabetes mellitus or a positive family history of hypertension. A C-statistics analysis does not show any improvement in the prediction of incident hypertension on top of traditional risk factors. Our data from a large cohort study show that a GRS is independently associated with BP increase and incidence of hypertension.
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9. |
- Fava, Cristiano, et al.
(författare)
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Serine/threonine kinase 39 is a candidate gene for primary hypertension especially in women: results from two cohort studies in Swedes.
- 2011
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Ingår i: Journal of Hypertension. - 1473-5598. ; 29, s. 484-491
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: As recently pinpointed by a genome-wide association study the serine/threonine kinase 39 (STK39) is a candidate gene for hypertension. This kinase is strongly implicated in sodium reabsorption by the kidney through its modulating effect on furosemide-sensitive and thiazide-sensitive channels. The aim of our study was to test the effects of the STK39 rs35929607A>G polymorphism on blood pressure (BP) levels and the prevalence and incidence of hypertension in middle-aged Swedes participating in two urban-based surveys in Malmö (Sweden). METHODS: The rs35929607A>G polymorphism was genotyped in 5634 participants included in the cardiovascular cohort of the 'Malmö Diet and Cancer-cardiovascular arm' (MDC-CVA) study and successively in 17 894 participants of the 'Malmö Preventive Project' (MPP) both at baseline and at reinvestigation after a mean of 23 years. The effect of the same single nucleotide polymorphism on salt sensitivity was tested in 39 participants of the Salt Reduction to Avoid Hypertension study. RESULTS: Both before and after adjustment for covariates, the functional rs35929607A>G polymorphism was associated with higher SBP and DBP values in the MDC-CVA, but not in the MPP. In both surveys, the polymorphism was associated with hypertension prevalence; after adjustment using the autosomal-dominant model, the odds ratio for hypertension ranged between 1.077 (MPP at baseline) and 1.151 (MDC-CVA) with P-value less than 0.05. After stratification for sex, the results remained statistically significant in women, but not in men. Carriers of the G-allele displayed an increase in salt sensitivity. CONCLUSION: Our results from two large cohort studies support previous evidence about the association of the STK39 rs35929607A>G variant with hypertension, especially in women. If further confirmed in successive studies, owing to its pivotal role in sodium reabsorption at the renal tubule level, STK39 might prove to be a suitable target for antihypertensive therapy. The greater effect of the STK39 rs35929607A>G polymorphism in women with respect to men deserves further investigation.
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10. |
- Fava, Cristiano, et al.
(författare)
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The common functional polymorphism -50G>T of the CYP2J2 gene is not associated with ischemic coronary and cerebrovascular events in an urban-based sample of Swedes.
- 2010
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Ingår i: Journal of Hypertension. - 1473-5598. ; 28:2, s. 294-299
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: CYP2J2 is responsible for the production of 5,6 8,9 11,12 and 14,15-epoxyeicosatrienoic acids, vasodilator and anti-inflammatory substances. It is abundantly expressed in human heart and also present in kidney and vasculature. Carriers of a common polymorphism, the CYP2J2-50G>T, rs890293, have reduced expression of CYP2J2 mRNA level in the heart putatively through the interference with a binding site for a transcription factor with consequently reduced circulating levels of CYP2J2 epoxygenase metabolites in vivo. AIM: The aim of the present study was to evaluate the effect of this functional polymorphism on blood pressure (BP) levels, hypertension prevalence, and risk of incident cardiovascular events in middle-aged Swedes. METHODS: The CYP2J2 polymorphism was genotyped in 5740 participants of the cardiovascular cohort of the 'Malmö Diet and Cancer' study. The incidence of cardiovascular events (coronary events, n = 261; ischemic stroke, n = 185) was monitored over 10 years of follow-up. RESULTS: In the whole population the polymorphism had no effect on BP and hypertension prevalence and no interaction was found between the polymorphism and sex, age or body mass index. Before and after adjustment for major cardiovascular risk factors, the hazard ratio for incident ischemic stroke and coronary events was not significantly different in carriers of different genotypes. CONCLUSIONS: Our data do not support a major role for the CYP2J2-50G>T variant in determining BP level and incident ischemic events. Other studies are needed to elucidate if other polymorphisms in the same gene could have a role in BP homeostasis or incidence of cardiovascular events.
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