| 1. |
- Scuteri, Angelo, et al.
(author)
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Arterial stiffness and influences of the metabolic syndrome: A cross-countries study.
- 2014
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In: Atherosclerosis. - : Elsevier BV. - 1879-1484 .- 0021-9150. ; 233:2, s. 654-660
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Journal article (peer-reviewed)abstract
- Specific clusters of metabolic syndrome (MetS) components impact differentially on arterial stiffness, indexed as pulse wave velocity (PWV). Of note, in several population-based studies participating in the MARE (Metabolic syndrome and Arteries REsearch) Consortium the occurrence of specific clusters of MetS differed markedly across Europe and the US. The aim of the present study was to investigate whether specific clusters of MetS are consistently associated with stiffer arteries in different populations. We studied 20,570 subjects from 9 cohorts representing 8 different European countries and the US participating in the MARE Consortium. MetS was defined in accordance with NCEP ATPIII criteria as the simultaneous alteration in ≥3 of the 5 components: abdominal obesity (W), high triglycerides (T), low HDL cholesterol (H), elevated blood pressure (B), and elevated fasting glucose (G). PWV measured in each cohort was "normalized" to account for different acquisition methods. MetS had an overall prevalence of 24.2% (4985 subjects). MetS accelerated the age-associated increase in PWV levels at any age, and similarly in men and women. MetS clusters TBW, GBW, and GTBW are consistently associated with significantly stiffer arteries to an extent similar or greater than observed in subjects with alteration in all the five MetS components - even after controlling for age, sex, smoking, cholesterol levels, and diabetes mellitus - in all the MARE cohorts. In conclusion, different component clusters of MetS showed varying associations with arterial stiffness (PWV).
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| 2. |
- Scuteri, Angelo, et al.
(author)
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Metabolic syndrome across Europe: Different clusters of risk factors
- 2015
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In: European Journal of Preventive Cardiology. - : Oxford University Press (OUP). - 2047-4881 .- 2047-4873. ; 22:4, s. 486-491
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Journal article (peer-reviewed)abstract
- Background: Metabolic syndrome (MetS) remains a controversial entity. Specific clusters of MetS components - rather than MetS per se - are associated with accelerated arterial ageing and with cardiovascular (CV) events. To investigate whether the distribution of clusters of MetS components differed cross-culturally, we studied 34,821 subjects from 12 cohorts from 10 European countries and one cohort from the USA in the MARE (Metabolic syndrome and Arteries REsearch) Consortium. Methods: In accordance with the ATP III criteria, MetS was defined as an alteration three or more of the following five components: elevated glucose (G), fasting glucose >= 110 mg/dl; low HDL cholesterol, <40mg/dl for men or <50 mg/dl for women; high triglycerides (T), >= 150 mg/dl; elevated blood pressure (B), >= 130/ >= 85 mmHg; abdominal obesity (W), waist circumference >102 cm for men or >88 cm for women. Results: MetS had a 24.3% prevalence (8468 subjects: 23.9% in men vs. 24.6% in women, p < 0.001) with an age-associated increase in its prevalence in all the cohorts. The age-adjusted prevalence of the clusters of MetS components previously associated with greater arterial and CV burden differed across countries (p < 0.0001) and in men and women (p < 0.0001). In details, the cluster TBW was observed in 12% of the subjects with MetS, but was far more common in the cohorts from the UK (32.3%), Sardinia in Italy (19.6%), and Germany (18.5%) and less prevalent in the cohorts from Sweden (1.2%), Spain (2.6%), and the USA (2.5%). The cluster GBW accounted for 12.7% of subjects with MetS with higher occurrence in Southern Europe (Italy, Spain, and Portugal: 31.4, 18.4, and 17.1% respectively) and in Belgium (20.4%), than in Northern Europe (Germany, Sweden, and Lithuania: 7.6, 9.4, and 9.6% respectively). Conclusions: The analysis of the distribution of MetS suggested that what follows under the common definition of MetS is not a unique entity rather a constellation of cluster of MetS components, likely selectively risky for CV disease, whose occurrence differs across countries.
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| 3. |
- Erzurumluoglu, A. Mesut, et al.
(author)
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Meta-analysis of up to 622,409 individuals identifies 40 novel smoking behaviour associated genetic loci
- 2020
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In: Molecular Psychiatry. - : Nature Publishing Group. - 1359-4184 .- 1476-5578. ; 25:10, s. 2392-2409
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Journal article (peer-reviewed)abstract
- Smoking is a major heritable and modifiable risk factor for many diseases, including cancer, common respiratory disorders and cardiovascular diseases. Fourteen genetic loci have previously been associated with smoking behaviour-related traits. We tested up to 235,116 single nucleotide variants (SNVs) on the exome-array for association with smoking initiation, cigarettes per day, pack-years, and smoking cessation in a fixed effects meta-analysis of up to 61 studies (up to 346,813 participants). In a subset of 112,811 participants, a further one million SNVs were also genotyped and tested for association with the four smoking behaviour traits. SNV-trait associations with P < 5 × 10-8 in either analysis were taken forward for replication in up to 275,596 independent participants from UK Biobank. Lastly, a meta-analysis of the discovery and replication studies was performed. Sixteen SNVs were associated with at least one of the smoking behaviour traits (P < 5 × 10-8) in the discovery samples. Ten novel SNVs, including rs12616219 near TMEM182, were followed-up and five of them (rs462779 in REV3L, rs12780116 in CNNM2, rs1190736 in GPR101, rs11539157 in PJA1, and rs12616219 near TMEM182) replicated at a Bonferroni significance threshold (P < 4.5 × 10-3) with consistent direction of effect. A further 35 SNVs were associated with smoking behaviour traits in the discovery plus replication meta-analysis (up to 622,409 participants) including a rare SNV, rs150493199, in CCDC141 and two low-frequency SNVs in CEP350 and HDGFRP2. Functional follow-up implied that decreased expression of REV3L may lower the probability of smoking initiation. The novel loci will facilitate understanding the genetic aetiology of smoking behaviour and may lead to the identification of potential drug targets for smoking prevention and/or cessation.
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| 4. |
- Evangelou, Evangelos, et al.
(author)
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Genetic analysis of over 1 million people identifies 535 new loci associated with blood pressure traits.
- 2018
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 50:10, s. 1412-1425
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Journal article (peer-reviewed)abstract
- High blood pressure is a highly heritable and modifiable risk factor for cardiovascular disease. We report the largest genetic association study of blood pressure traits (systolic, diastolic and pulse pressure) to date in over 1 million people of European ancestry. We identify 535 novel blood pressure loci that not only offer new biological insights into blood pressure regulation but also highlight shared genetic architecture between blood pressure and lifestyle exposures. Our findings identify new biological pathways for blood pressure regulation with potential for improved cardiovascular disease prevention in the future.
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| 5. |
- Kanoni, Stavroula, et al.
(author)
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Implicating genes, pleiotropy, and sexual dimorphism at blood lipid loci through multi-ancestry meta-analysis.
- 2022
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In: Genome biology. - : Springer Science and Business Media LLC. - 1474-760X .- 1465-6906 .- 1474-7596. ; 23:1
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Journal article (peer-reviewed)abstract
- Genetic variants within nearly 1000 loci are known to contribute to modulation of blood lipid levels. However, the biological pathways underlying these associations are frequently unknown, limiting understanding of these findings and hindering downstream translational efforts such as drug target discovery.To expand our understanding of the underlying biological pathways and mechanisms controlling blood lipid levels, we leverage a large multi-ancestry meta-analysis (N=1,654,960) of blood lipids to prioritize putative causal genes for 2286 lipid associations using six gene prediction approaches. Using phenome-wide association (PheWAS) scans, we identify relationships of genetically predicted lipid levels to other diseases and conditions. We confirm known pleiotropic associations with cardiovascular phenotypes and determine novel associations, notably with cholelithiasis risk. We perform sex-stratified GWAS meta-analysis of lipid levels and show that 3-5% of autosomal lipid-associated loci demonstrate sex-biased effects. Finally, we report 21 novel lipid loci identified on the X chromosome. Many of the sex-biased autosomal and X chromosome lipid loci show pleiotropic associations with sex hormones, emphasizing the role of hormone regulation in lipid metabolism.Taken together, our findings provide insights into the biological mechanisms through which associated variants lead to altered lipid levels and potentially cardiovascular disease risk.
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| 6. |
- Lunetta, Kathryn L., et al.
(author)
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Rare coding variants and X-linked loci associated with age at menarche
- 2015
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 6
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Journal article (peer-reviewed)abstract
- More than 100 loci have been identified for age at menarche by genome-wide association studies; however, collectively these explain only similar to 3% of the trait variance. Here we test two overlooked sources of variation in 192,974 European ancestry women: low-frequency proteincoding variants and X-chromosome variants. Five missense/nonsense variants (in ALMS1/LAMB2/TNRC6A/TACR3/PRKAG1) are associated with age at menarche (minor allele frequencies 0.08-4.6%; effect sizes 0.08-1.25 years per allele; P<5 x 10(-8)). In addition, we identify common X-chromosome loci at IGSF1 (rs762080, P = 9.4 x 10(-13)) and FAAH2 (rs5914101, P = 4.9 x 10(-10)). Highlighted genes implicate cellular energy homeostasis, post-transcriptional gene silencing and fatty-acid amide signalling. A frequently reported mutation in TACR3 for idiopathic hypogonatrophic hypogonadism (p.W275X) is associated with 1.25-year-later menarche (P = 2.8 x 10(-11)), illustrating the utility of population studies to estimate the penetrance of reportedly pathogenic mutations. Collectively, these novel variants explain similar to 0.5% variance, indicating that these overlooked sources of variation do not substantially explain the 'missing heritability' of this complex trait.
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| 7. |
- McCarthy, Shane, et al.
(author)
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A reference panel of 64,976 haplotypes for genotype imputation
- 2016
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 48:10, s. 1279-1283
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Journal article (peer-reviewed)abstract
- We describe a reference panel of 64,976 human haplotypes at 39,235,157 SNPs constructed using whole-genome sequence data from 20 studies of predominantly European ancestry. Using this resource leads to accurate genotype imputation at minor allele frequencies as low as 0.1% and a large increase in the number of SNPs tested in association studies, and it can help to discover and refine causal loci. We describe remote server resources that allow researchers to carry out imputation and phasing consistently and efficiently.
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| 8. |
- Nilsson, Peter M., et al.
(author)
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Characteristics of healthy vascular ageing in pooled population-based cohort studies : the global Metabolic syndrome and Artery REsearch Consortium
- 2018
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In: Journal of Hypertension. - 1473-5598. ; 36:12, s. 2340-2349
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Journal article (peer-reviewed)abstract
- OBJECTIVE: Arterial ageing is characterized by increasing arterial stiffness as measured by pulse wave velocity (PWV). This process is enhanced in participants with early vascular ageing (EVA), but slowed in participants with healthy vascular ageing (HVA). We aimed to describe characteristics of EVA and HVA in a transcontinental study including 11 cohorts.METHODS: In all, 18 490 participants from the global MARE Consortium, free of cardiovascular disease, participated with data on PWV and cardiometabolic risk factors. We defined HVA as the lowest 10% and EVA as the highest 10% of the standardized PWV distribution, adjusted for age intervals. HVA individuals were compared with the 90% of non-HVA individuals with ANCOVA, adjusted for age, sex and hypertension.RESULTS: The 1723 HVA participants were at the same age as the rest of the population, more likely women (59.4 vs 57.0%), and with significantly lower levels of established cardiovascular risk factors (blood pressure, lipids, glucose). Similarly, the prevalence rate of obesity, diabetes mellitus, hypertension and the metabolic syndrome was lower in the HVA participants. In the presence of similar levels of cardiovascular risk factors, HVA participants in the 50-64 years of age group presented lower PWV 5.8 (SD 0.5) vs. 7.4 (1.4) m/s (P < 0.0001) than control individuals in the 35-49 years of age group, corresponding to an estimated difference in chronological age of 14 years.CONCLUSION: Participants with healthy vascular ageing (HVA), belonging to the lowest end of the PWV distribution, are in general characterized by an up to 14 years estimated younger biological (vascular) age than those with higher PWV values, and have lower levels of risk factors.
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| 9. |
- Ntalla, Ioanna, et al.
(author)
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Multi-ancestry GWAS of the electrocardiographic PR interval identifies 202 loci underlying cardiac conduction
- 2020
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In: Nature Communications. - : Springer Science and Business Media LLC. - 2041-1723. ; 11:1
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Journal article (peer-reviewed)abstract
- The electrocardiographic PR interval reflects atrioventricular conduction, and is associated with conduction abnormalities, pacemaker implantation, atrial fibrillation (AF), and cardiovascular mortality. Here we report a multi-ancestry (N=293,051) genome-wide association meta-analysis for the PR interval, discovering 202 loci of which 141 have not previously been reported. Variants at identified loci increase the percentage of heritability explained, from 33.5% to 62.6%. We observe enrichment for cardiac muscle developmental/contractile and cytoskeletal genes, highlighting key regulation processes for atrioventricular conduction. Additionally, 8 loci not previously reported harbor genes underlying inherited arrhythmic syndromes and/or cardiomyopathies suggesting a role for these genes in cardiovascular pathology in the general population. We show that polygenic predisposition to PR interval duration is an endophenotype for cardiovascular disease, including distal conduction disease, AF, and atrioventricular pre-excitation. These findings advance our understanding of the polygenic basis of cardiac conduction, and the genetic relationship between PR interval duration and cardiovascular disease. On the electrocardiogram, the PR interval reflects conduction from the atria to ventricles and also serves as risk indicator of cardiovascular morbidity and mortality. Here, the authors perform genome-wide meta-analyses for PR interval in multiple ancestries and identify 141 previously unreported genetic loci.
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| 10. |
- Scott, Robert A., et al.
(author)
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Large-scale association analyses identify new loci influencing glycemic traits and provide insight into the underlying biological pathways
- 2012
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In: Nature Genetics. - : Springer Science and Business Media LLC. - 1061-4036 .- 1546-1718. ; 44:9, s. 991-1005
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Journal article (peer-reviewed)abstract
- Through genome-wide association meta-analyses of up to 133,010 individuals of European ancestry without diabetes, including individuals newly genotyped using the Metabochip, we have increased the number of confirmed loci influencing glycemic traits to 53, of which 33 also increase type 2 diabetes risk (q < 0.05). Loci influencing fasting insulin concentration showed association with lipid levels and fat distribution, suggesting impact on insulin resistance. Gene-based analyses identified further biologically plausible loci, suggesting that additional loci beyond those reaching genome-wide significance are likely to represent real associations. This conclusion is supported by an excess of directionally consistent and nominally significant signals between discovery and follow-up studies. Functional analysis of these newly discovered loci will further improve our understanding of glycemic control.
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