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- Heard-Costa, Nancy L, et al.
(författare)
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NRXN3 is a novel locus for waist circumference : a genome-wide association study from the CHARGE Consortium
- 2009
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Ingår i: PLoS genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 5:6, s. e1000539-
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Tidskriftsartikel (refereegranskat)abstract
- Central abdominal fat is a strong risk factor for diabetes and cardiovascular disease. To identify common variants influencing central abdominal fat, we conducted a two-stage genome-wide association analysis for waist circumference (WC). In total, three loci reached genome-wide significance. In stage 1, 31,373 individuals of Caucasian descent from eight cohort studies confirmed the role of FTO and MC4R and identified one novel locus associated with WC in the neurexin 3 gene [NRXN3 (rs10146997, p = 6.4×10−7)]. The association with NRXN3 was confirmed in stage 2 by combining stage 1 results with those from 38,641 participants in the GIANT consortium (p = 0.009 in GIANT only, p = 5.3×10−8 for combined analysis, n = 70,014). Mean WC increase per copy of the G allele was 0.0498 z-score units (0.65 cm). This SNP was also associated with body mass index (BMI) [p = 7.4×10−6, 0.024 z-score units (0.10 kg/m2) per copy of the G allele] and the risk of obesity (odds ratio 1.13, 95% CI 1.07–1.19; p = 3.2×10−5 per copy of the G allele). The NRXN3 gene has been previously implicated in addiction and reward behavior, lending further evidence that common forms of obesity may be a central nervous system-mediated disorder. Our findings establish that common variants in NRXN3 are associated with WC, BMI, and obesity.
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| 2. |
- Vasan, Ramachandran S, et al.
(författare)
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Genetic variants associated with cardiac structure and function : a meta-analysis and replication of genome-wide association data
- 2009
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Ingår i: Journal of the American Medical Association (JAMA). - : American Medical Association (AMA). - 0098-7484 .- 1538-3598. ; 302:2, s. 168-178
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Echocardiographic measures of left ventricular (LV) structure and function are heritable phenotypes of cardiovascular disease. OBJECTIVE: To identify common genetic variants associated with cardiac structure and function by conducting a meta-analysis of genome-wide association data in 5 population-based cohort studies (stage 1) with replication (stage 2) in 2 other community-based samples. DESIGN, SETTING, AND PARTICIPANTS: Within each of 5 community-based cohorts comprising the EchoGen consortium (stage 1; n = 12 612 individuals of European ancestry; 55% women, aged 26-95 years; examinations between 1978-2008), we estimated the association between approximately 2.5 million single-nucleotide polymorphisms (SNPs; imputed to the HapMap CEU panel) and echocardiographic traits. In stage 2, SNPs significantly associated with traits in stage 1 were tested for association in 2 other cohorts (n = 4094 people of European ancestry). Using a prespecified P value threshold of 5 x 10(-7) to indicate genome-wide significance, we performed an inverse variance-weighted fixed-effects meta-analysis of genome-wide association data from each cohort. MAIN OUTCOME MEASURES: Echocardiographic traits: LV mass, internal dimensions, wall thickness, systolic dysfunction, aortic root, and left atrial size. RESULTS: In stage 1, 16 genetic loci were associated with 5 echocardiographic traits: 1 each with LV internal dimensions and systolic dysfunction, 3 each with LV mass and wall thickness, and 8 with aortic root size. In stage 2, 5 loci replicated (6q22 locus associated with LV diastolic dimensions, explaining <1% of trait variance; 5q23, 12p12, 12q14, and 17p13 associated with aortic root size, explaining 1%-3% of trait variance). CONCLUSIONS: We identified 5 genetic loci harboring common variants that were associated with variation in LV diastolic dimensions and aortic root size, but such findings explained a very small proportion of variance. Further studies are required to replicate these findings, identify the causal variants at or near these loci, characterize their functional significance, and determine whether they are related to overt cardiovascular disease.
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| 5. |
- Ingelsson, Erik, et al.
(författare)
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Altered blood pressure progression in the community and its relation to clinical events.
- 2008
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Ingår i: Archives of Internal Medicine. - 0003-9926 .- 1538-3679. ; 168:13, s. 1450-1457
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Tidskriftsartikel (refereegranskat)abstract
- Background Long-term blood pressure (BP) progression and its importance as a predictor of clinical outcome have not been well characterized across different periods. Methods We evaluated period trends for 3 BP variables (long-term slope and mean BP during a baseline period of 16 years, and last baseline value) in an earlier period (1953- 1971, n = 1644, mean participant age, 61 years) and in a later period (1971-1990, n = 1040, mean participant age, 58 years) in participants in the Framingham Heart Study who initially did not have hypertension. In addition, we explored the relation of BP to cardiovascular disease incidence and all-cause mortality in the 2 periods, each with up to 16 years of follow-up. Results Long-term slope, mean, and last baseline BP measurements were significantly lower in the later period (P < ;. 001). Rates of hypertension control (BP < , 140/90 mmHg) were higher in the later vs the earlier period (32% vs 23%, P < ;. 001). Multivariate hazard ratios for the relation of BP to outcomes were generally lower in the later period, this was statistically significant for the relation of last baseline BP to all-cause mortality (hazard ratio for 1-SD increase in systolic BP, 1.02 vs 1.25, P=.03, hazard ratio for diastolic BP, 1.00 vs 1.23, P=. 04). Conclusions We found evidence that BP levels in the community have changed over time, coinciding with improved rates of hypertension control and attenuation of BP-mortality relations. These findings are consistent with the hypothesis that hypertension treatment in the community has altered the natural history of BP progression and its relation to clinical outcome.
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| 6. |
- Ingelsson, Erik, et al.
(författare)
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Associations of serum adiponectin with skeletal muscle morphology and insulin sensitivity
- 2009
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Ingår i: Journal of Clinical Endocrinology and Metabolism. - : The Endocrine Society. - 0021-972X .- 1945-7197. ; 94:3, s. 953-957
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Tidskriftsartikel (refereegranskat)abstract
- CONTEXT: Skeletal muscle morphology and function are strongly associated with insulin sensitivity. OBJECTIVE: The objective of the study was to test the hypothesis that circulating adiponectin is associated with skeletal muscle morphology and that adiponectin mediates the relation of muscle morphology to insulin sensitivity. DESIGN, SETTINGS, AND PARTICIPANTS: This was a cross-sectional investigation of 461 men aged 71 yr, participants of the community-based Uppsala Longitudinal Study of Adult Men study. MAIN OUTCOME MEASURES: Measures included serum adiponectin, insulin sensitivity measured with euglycemic insulin clamp technique, and capillary density and muscle fiber composition determined from vastus lateralis muscle biopsies. RESULTS: In multivariable linear regression models (adjusting for age, physical activity, fasting glucose, and pharmacological treatment for diabetes), serum adiponectin levels rose with increasing capillary density (beta, 0.30 per 50 capillaries per square millimeter increase; P = 0.041) and higher proportion of type I muscle fibers (beta, 0.27 per 10% increase; P = 0.036) but declined with a higher proportion of type IIb fibers (beta, -0.39 per 10% increase; P = 0.014). Using bootstrap methods to examine the potential role of adiponectin in associations between muscle morphology and insulin sensitivity and the associations of capillary density (beta difference, 0.041; 95% confidence interval 0.001, 0.085) and proportion of type IIb muscle fibers (beta difference, -0.053; 95% confidence interval -0.107, -0.002) with insulin sensitivity were significantly attenuated when adiponectin was included in the models. CONCLUSIONS: Circulating adiponectin concentrations were higher with increasing skeletal muscle capillary density and in individuals with higher proportion of slow oxidative muscle fibers. Furthermore, our results indicate that adiponectin could be a partial mediator of the relations between skeletal muscle morphology and insulin sensitivity.
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| 7. |
- Ingelsson, Erik, et al.
(författare)
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Circulating retinol-binding protein 4, cardiovascular risk factors and prevalent cardiovascular disease in elderly
- 2009
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Ingår i: Atherosclerosis. - : Elsevier BV. - 0021-9150 .- 1879-1484. ; 206:1, s. 239-244
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: Our aim was to examine relations of serum retinol-binding protein 4 (RBP4) to cardiovascular risk factors, and prevalent metabolic syndrome (MetS) and cardiovascular disease (CVD) in a large community-based sample of elderly. METHODS: We evaluated cross-sectional relations of serum RBP4 to cardiovascular risk factors including anthropometrical measures, blood pressure, lipid measures, fasting glucose and insulin, body fat distribution including truncal fat by dual-energy x-ray absorptiometry (DXA), homeostasis model assessment insulin resistance (HOMA-IR) and prevalent MetS in one thousand eight 70-year old participants (50% women) of the Prospective Investigation of the Vasculature in Uppsala Seniors (PIVUS), and in five hundred seven 82-year old men from Uppsala Longitudinal Study of Adult Men (ULSAM). In ULSAM, we also examined associations with prevalent CVD. RESULTS: RBP4 concentrations were positively correlated with serum triglycerides (r=0.30; P<0.0001 in both samples), whereas correlations with body mass index (BMI), waist circumference, sagittal abdominal diameter, total and truncal fat mass, total cholesterol, fasting glucose and HOMA-IR were weak. In multivariable-adjusted models, RBP-4 was associated with MetS (odds ratio (OR), 1.16 and 1.33; 95% confidence interval (CI), 0.99-1.37 and 1.05-1.67 per 1-standard deviation (SD) increase in PIVUS and ULSAM, respectively), and prior cerebrovascular disease (OR, 1.37; 95% CI, 1.00-1.88 per 1-SD increase in ULSAM), but not with prior myocardial infarction. CONCLUSION: In elderly, RBP4 concentrations were associated with MetS and its components in both sexes, and prior cerebrovascular disease in men. These findings are consistent with the hypothesis that circulating RBP4 could be a marker of metabolic complications and possibly also atherosclerosis and overt CVD.
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| 8. |
- Newton-Cheh, Christopher, et al.
(författare)
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Association of common variants in NPPA and NPPB with circulating natriuretic peptides and blood pressure
- 2009
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Ingår i: Nature Genetics. - : Springer Science and Business Media LLC. - 1546-1718 .- 1061-4036. ; 41:3, s. 348-353
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Tidskriftsartikel (refereegranskat)abstract
- We examined the association of common variants at the NPPA-NPPB locus with circulating concentrations of the natriuretic peptides, which have blood pressure-lowering properties. We genotyped SNPs at the NPPA-NPPB locus in 14,743 individuals of European ancestry, and identified associations of plasma atrial natriuretic peptide with rs5068 (P = 8 x 10(-70)), rs198358 (P = 8 x 10(-30)) and rs632793 (P = 2 x 10(-10)), and of plasma B-type natriuretic peptide with rs5068 (P = 3 x 10(-12)), rs198358 (P = 1 x 10(-25)) and rs632793 (P = 2 x 10(-68)). In 29,717 individuals, the alleles of rs5068 and rs198358 that showed association with increased circulating natriuretic peptide concentrations were also found to be associated with lower systolic (P = 2 x 10(-6) and 6 x 10(-5), respectively) and diastolic blood pressure (P = 1 x 10(-6) and 5 x 10(-5)), as well as reduced odds of hypertension (OR = 0.85, 95% CI = 0.79-0.92, P = 4 x 10(-5); OR = 0.90, 95% CI = 0.85-0.95, P = 2 x 10(-4), respectively). Common genetic variants at the NPPA-NPPB locus found to be associated with circulating natriuretic peptide concentrations contribute to interindividual variation in blood pressure and hypertension.
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| 9. |
- Sundström, Johan, et al.
(författare)
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Circulating biomarkers of extracellular matrix remodeling and risk of atherosclerotic events
- 2006
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Ingår i: Current Opinion in Lipidology. - : Ovid Technologies (Wolters Kluwer Health). - 0957-9672 .- 1473-6535. ; 17:1, s. 45-53
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Tidskriftsartikel (refereegranskat)abstract
- PURPOSE OF REVIEW: Disturbances of the synthesis and breakdown of the extracellular matrix of arterial walls have emerged as key features of the atherosclerotic process. Altered levels of circulating extracellular matrix markers have frequently been observed in relation to manifestations of atherosclerotic disease and its risk factors. RECENT FINDINGS: Research has been focused on the matrix-degrading metalloproteinases, their tissue inhibitors, and procollagen peptides. The most promising matrix metalloproteinase is matrix metalloproteinase-9, which has been observed to predict rapid coronary artery narrowing, ischemic heart disease incidence, abdominal aortic aneurysm expansion, worse outcome in stroke patients, and cardiovascular death. The use of tissue inhibitors of metalloproteinases for prognostication is uncertain thus far. The procollagen marker with most prognostic potential is the marker for type III collagen turnover rate, the N-terminal propeptide PIIINP, higher levels of which predict an adverse outcome after a myocardial infarction and in chronic heart failure, and portend abdominal aortic aneurysm expansion and risk of rupture. Also, the marker for type I collagen synthesis, the C-terminal propeptide PICP, predicts adverse outcomes following myocardial infarction and in chronic heart failure. Extracellular matrix remodeling is also a promising therapeutic target, being favorably affected by several conventional cardiovascular drugs and select dietary interventions. Synthetic matrix metalloproteinase inhibitors are also under development. SUMMARY: Circulating matrix markers have emerged as candidate biomarkers for predicting risk of subsequent atherosclerotic events. Future large longitudinal observational and intervention studies will determine the role of matrix biomarkers in diagnosis and prognostication, and as targets for intervention in cardiovascular diseases.
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