| 1. |
- Fava, Cristiano, et al.
(author)
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A Variant Upstream of the CDH13 Adiponectin Receptor Gene and Metabolic Syndrome in Swedes.
- 2011
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In: American Journal of Cardiology. - : Elsevier BV. - 1879-1913 .- 0002-9149. ; 108, s. 1432-1437
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Journal article (peer-reviewed)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.
(author)
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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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In: American Journal of Hypertension. - : Oxford University Press (OUP). - 1941-7225 .- 0895-7061. ; 20:9, s. 981-989
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Journal article (peer-reviewed)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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| 3. |
- Fava, Cristiano, et al.
(author)
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Chromosome 2q12, the ADRA2B I/D polymorphism and metabolic syndrome.
- 2009
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In: Journal of Hypertension. - 1473-5598. ; 27, s. 1794-1803
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Journal article (peer-reviewed)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.
(author)
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Determinants of kidney function in Swedish families: role of heritable factors.
- 2008
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In: Journal of Hypertension. - 1473-5598. ; 26:9, s. 1773-1779
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Journal article (peer-reviewed)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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| 5. |
- Fava, Cristiano, et al.
(author)
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From circulating biomarkers to genomics and imaging in the prediction of cardiovascular events in the general population.
- 2012
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In: Annals of Medicine. - : Informa UK Limited. - 1365-2060 .- 0785-3890. ; 44:5, s. 433-447
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Journal article (peer-reviewed)abstract
- Abstract Cardiovascular disease (CVD) is the leading cause of death and disability worldwide. In the last decades numerous markers have been considered and investigated for the prediction of CV events, but only a few of them resulted in improved global risk assessment beyond traditional risk factors when incorporated into coronary evaluation scores. Recent genetic studies have pointed out a few but consistent loci or genes which are independently associated with CV risk. The idea is fascinating that these genetic markers could lead to improved individual CV risk assessment and tailored pharmacological interventions. In this brief review we will not make a systematic review of all non-genetic and genetic markers of CV risk but we will try to make a brief overview of the most interesting ones with the aim to underline potential 'pros' and 'cons' of their implementation in clinical practice.
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| 6. |
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| 7. |
- Fava, Cristiano, et al.
(author)
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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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In: Pharmacogenetics & Genomics. - 1744-6872. ; 20:2, s. 94-103
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Journal article (peer-reviewed)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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| 8. |
- Fava, Cristiano, et al.
(author)
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Novel mutations in the SLC12A3 gene causing Gitelman's syndrome in Swedes
- 2007
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In: DNA Sequence. - : Informa UK Limited. - 1029-2365 .- 1042-5179. ; 18:5, s. 395-399
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Journal article (peer-reviewed)abstract
- PURPOSE: Gitelman's syndrome (GS) is an inherited autosomal recessive disorder due to loss of function mutations in the SLC12A3 gene encoding the Na-Cl co-transporter (NCCT), the target of thiazide diuretics. The defective function of the NCCT, which normally is expressed in the apical membrane of the distal convolute tubule in the kidney, leads to mild hypotension, hypokalemia, hyperreninemic hyperaldosteronism, mild metabolic alkalosis, hypomagnesemia and hypocalciuria. Up to now, more than 100 mutations of the SLC12A3 gene have been described in GS patients. METHODS: We have collected 30 patients from Sweden with a clinical diagnosis of GS and undertaken a mutation screening by SSCP and successive sequencing of the 26 exons and intronic boundaries. Both mutations were identified in most (n = 28, 93%) and at least one mutation was identified in all patients. RESULTS: We found 22 different mutations evenly distributed throughout the gene, 11 of which have not been described previously. The new variants include 8 missense mutations (Glu68Lys, His69Asn, Argl45His, Vall53Met, Gly230Asp, Gly342Ala, Val677Leu and Gly867Ser), 1 insertion (c.834_835insG on exon 6) and 2 splice-site mutations (c.2667 + lT>G substitution in splicing donor site after exon 22, c.1569-1G>A substitution in the splicing acceptor site before exon 13). CONCLUSION: In Swedish patients with the clinical features of GS, disease-causing mutations in the SLC12A3 gene were identified in most patients. The spectrum of GS mutations is wide making full mutation screening of the SLC12A3 gene necessary to confirm the diagnosis.
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| 9. |
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| 10. |
- Fava, Cristiano, et al.
(author)
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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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In: Hypertension. - 1524-4563.
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Journal article (peer-reviewed)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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