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1.
PLoS One ; 14(11): e0224608, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31682633

RESUMO

PURPOSE AND METHODS: A meta-analysis using data from seven German population-based cohorts was performed by the German Epidemiological consortium of Peripheral Arterial Disease (GEPArD) to investigate whether one question about claudication is more efficient for PAD screening than established questionnaires. Claudication was defined on the basis of the answer to one question asking for pain in the leg during normal walking. This simple question was compared with established questionnaires, including the Edinburgh questionnaire. The associations of claudication with continuous ABI values and decreased ABI were analyzed by linear and logistic regression analysis, respectively. The results of the studies were pooled in a random effect meta-analysis, which included data from 27,945 individuals (14,052 women, age range 20-84 years). RESULTS: Meta-analysis revealed a significant negative association between claudication and ABI, which was stronger in men (ß = -0.07; 95%CI -0.10, -0.04) than in women (ß = -0.02; 95%CI -0.02, -0.01). Likewise, the presence of claudication symptoms was related to an increased odds of a decreased ABI in both men (Odds ratio = 5.40; 95%CI 4.20, 6.96) and women (Odds ratio = 1.99; 95%CI 1.58, 2.51). CONCLUSIONS: Asking only one question about claudication was able to identify many individuals with a high likelihood of a reduced ABI with markedly higher sensitivity and only slightly reduced specificity compared to more complex questionnaires. At least in men, this question should be established as first screening step.

3.
Kidney Int ; 96(2): 480-488, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-31248648

RESUMO

Damage of mitochondrial DNA (mtDNA) with reduction in copy number has been proposed as a biomarker for mitochondrial dysfunction and oxidative stress. Chronic kidney disease (CKD) is associated with increased mortality and risk of cardiovascular disease, but the underlying mechanisms remain incompletely understood. Here we investigated the prognostic role of mtDNA copy number for cause-specific mortality in 4812 patients from the German Chronic Kidney Disease study, an ongoing prospective observational national cohort study of patients with CKD stage G3 and A1-3 or G1-2 with overt proteinuria (A3) at enrollment. MtDNA was quantified in whole blood using a plasmid-normalized PCR-based assay. At baseline, 1235 patients had prevalent cardiovascular disease. These patients had a significantly lower mtDNA copy number than patients without cardiovascular disease (fully-adjusted model: odds ratio 1.03, 95% confidence interval [CI] 1.01-1.05 per 10 mtDNA copies decrease). After four years of follow-up, we observed a significant inverse association between mtDNA copy number and all-cause mortality, adjusted for kidney function and cardiovascular disease risk factors (hazard ratio 1.37, 95% CI 1.09-1.73 for quartile 1 compared to quartiles 2-4). When grouped by causes of death, estimates pointed in the same direction for all causes but in a fully-adjusted model decreased copy numbers were significantly lower only in infection-related death (hazard ratio 1.82, 95% CI 1.08-3.08). A similar association was observed for hospitalizations due to infections in 644 patients (hazard ratio 1.19, 95% CI 1.00-1.42 in the fully-adjusted model). Thus, our data support a role of mitochondrial dysfunction in increased cardiovascular disease and mortality risks as well as susceptibility to infections in patients with CKD.

4.
Eur Respir J ; 53(6)2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-31097517

RESUMO

Although chronic obstructive pulmonary disease (COPD) prevalence and mortality rates rise continuously, patients often remain undiagnosed, probably due to a lack of disease-related awareness. The aim of this study was to quantify public interest in COPD by analysing the frequency of web queries via Google.Data from 2004 to 2018 were collected using the search engine query data analysis tool Google Trends. The relative search volume of the topic "chronic obstructive pulmonary disease" was compared with the relative search volume of nine topics representing the major causes of death in high-income countries according to the World Health Organization.Our analysis showed highest relative search volumes for the topics "diabetes mellitus", followed by "stroke" and "breast cancer". The topic "chronic obstructive pulmonary disease" ranked eighth and its relative search volume clearly displayed a seasonal variation, with peaks in the first and the fourth quarter of the year.This analysis reveals that COPD is highly under-represented in the public interest, while real-world prevalence constantly rises, indicating that there is still an urgent need to raise the levels of awareness for COPD.

5.
Artigo em Inglês | MEDLINE | ID: mdl-31006013

RESUMO

BACKGROUND: There is little information in haemodialysis (HD) patients on whether temporal changes in serum calcium, phosphate or intact parathyroid hormone (iPTH) are associated with mortality. METHODS: We analysed associations of phosphate, total calcium and iPTH with all-cause and cardiovascular mortality in 8817 incident HD patients from the European second Analyzing Data, Recognizing Excellence and Optimizing Outcomes (AROii) cohort enrolled in 2007-09, which were prospectively followed for a median of 3 years, using time-dependent Cox proportional hazards models. We evaluated changes in risk over time depending on changes in phosphate, calcium or iPTH. RESULTS: The association of phosphate and iPTH with all-cause mortality was U-shaped, with the lowest risk ranges between 1.20 and 1.89 mmol/L for phosphate and between 239 and 710 ng/L for iPTH. For total calcium, the associations were J-shaped, with an increased risk for all-cause mortality at levels >2.36 mmol/L. Lowest risk ranges for cardiovascular mortality did not change markedly for all three parameters. If iPTH was below the lowest risk range at baseline (iPTH <239 ng/L), a subsequent increase in levels was associated with improved survival. For phosphate, an increase or decrease out of the lowest risk range was associated with increased mortality risk. For calcium, this was only the case when the values increased above the lowest risk range. CONCLUSION: In the AROii cohort, the ranges of bone mineral biomarkers associated with the lowest mortality ranges were largely consistent with the current Kidney Disease: Improving Global Outcomes chronic kidney disease-mineral and bone disorder guideline recommendations. Allowing a suppressed iPTH to increase was associated with a lower mortality, whereas shifts of phosphate or calcium outside the lowest risk range increased mortality.

6.
JAMA Cardiol ; 4(6): 575-579, 2019 Jun 01.
Artigo em Inglês | MEDLINE | ID: mdl-31017618

RESUMO

Importance: Genetic and epidemiologic data suggest that lipoprotein(a) (Lp[a]) is one of the strongest genetically determined risk factors for coronary heart disease (CHD). Specific therapies to lower Lp(a) are on the horizon, but the required reduction of Lp(a) to translate into clinically relevant lowering of CHD outcomes is a matter of debate. Objective: To estimate the required Lp(a)-lowering effect size that may be associated with a reduction of CHD outcomes compared with the effect size of low-density lipoprotein cholesterol (LDL-C)-lowering therapies. Design, Setting, and Participants: Genetic epidemiologic study using a mendelian randomization analysis to estimate the required Lp(a)-lowering effect size for a clinically meaningful effect on outcomes. We used the effect estimates for Lp(a) from a genome-wide association study (GWAS) and meta-analysis on Lp(a) published in 2017 of 5 different primarily population-based studies of European ancestry. All Lp(a) measurements were performed in 1 laboratory. Genetic estimates for 27 single-nucleotide polymorphisms on Lp(a) concentrations were used. Odds ratios for these 27 single-nucleotide polymorphisms associated with CHD risk were retrieved from a subsample of the CHD Exome+ consortium. Exposures: Genetic LPA score, plasma Lp(a) concentrations, and observations of statin therapies on CHD outcomes. Main Outcomes and Measures: Coronary heart disease. Results: The study included 13 781 individuals from the Lp(a)-GWAS-Consortium from 5 primarily population-based studies and 20 793 CHD cases and 27 540 controls from a subsample of the CHD Exome+ consortium. Four of the studies were similar in age distribution (means between 51 and 59 years), and 1 cohort was younger; mean age, 32 years. The frequency of women was similar between 51% and 55%. We estimated that the required reduction in Lp(a) effect size would be 65.7 mg/dL (95% CI, 46.3-88.3) to reach the same potential effect on clinical outcomes that can be reached by lowering LDL-C by 38.67 mg/dL (to convert to millimoles per liter, multiply by 0.0259). Conclusions and Relevance: This mendelian randomization analysis estimated a required Lp(a)-lowering effect size of 65.7 mg/dL to reach the same effect as a 38.67-mg/dL lowering of LDL-C. However, this estimate is determined by the observed effect estimates of single-nucleotide polymorphisms on Lp(a) concentrations and is therefore influenced by the standardization of the Lp(a) assay used. As a consequence, calculations of the required Lp(a)-lowering potential of a drug to be clinically effective might have been overestimated in the past.

7.
Eur J Med Genet ; 2018 Oct 29.
Artigo em Inglês | MEDLINE | ID: mdl-30385235

RESUMO

Ring chromosome 20 syndrome is a rare chromosomal disorder characterized by childhood-onset drug-resistant epilepsy, behavioral problems and variable cognitive impairment. While most cases occur sporadically, parent-to-child transmission of ring 20 mosaicism has only been reported in a few exceptional families. We identified a further family with mother-to-child transmission of ring 20 mosaicism. Detailed characterization of the ring chromosome showed a complete ring with preserved telomere repetitive sequences. SNP genotyping excluded mosaic uniparental disomy and indicated that the chromosome was transmitted without recombination from mother to child. These results corroborate the findings of a previous study and support the hypothesis that inherited mosaicism is due to transmission of an unstable chromosome either prone to ring opening or to ring re-formation.

8.
J Lipid Res ; 2018 Nov 09.
Artigo em Inglês | MEDLINE | ID: mdl-30413653

RESUMO

Lipoprotein(a) concentrations are among the strongest genetic risk factors for cardiovascular disease and present pronounced inter-ethnic and inter-individual differences. About 90% of lipoprotein(a) variance is controlled by the LPA gene, which contains a 5.6 kb large copy number variation (KIV-2 repeat) that generates >40 protein isoforms. Variants within the KIV-2 region are not called in common sequencing projects, leaving up to 70% of the LPA coding region currently unaddressed. To allow a complete assessment of the variability in LPA, we developed a sequencing strategy for this region and report here the first map of genetic variation in the KIV-2 region, a comprehensively evaluated ultra-deep sequencing protocol and an easy-to-use variant analysis pipeline (https://github.com/genepi/lpa-pipeline). We sequenced 123 Central-European individuals and additionally reanalyzed public data of 2,504 individuals from 26 populations. We found dozens of loss-of-function and splice site mutations, as well as >100, partially even common, missense variants. Some coding variants were frequent in one population, but absent in others. This provides novel candidates to explain the large ethnic and individual differences in Lp(a) concentrations. Importantly, our approach and pipeline are applicable also to other similar copy number variable regions, allowing accessing regions, which are not captured by common genome sequencing.

9.
Arterioscler Thromb Vasc Biol ; 38(5): 1230-1241, 2018 May.
Artigo em Inglês | MEDLINE | ID: mdl-29567679

RESUMO

OBJECTIVE: Lp(a) (lipoprotein(a)) concentrations are widely genetically determined by the LPA isoforms and show 5-fold interpopulation differences. Two- to 3-fold differences have been reported even within Europe. Finns represent a distinctive population isolate within Europe and have been repeatedly reported to present lower Lp(a) concentrations than Central Europeans. The significance of this finding was unclear for a long time because of the difficult comparability of Lp(a) assays. Recently, a large standardized study in >50 000 individuals from 7 European populations confirmed this observation but could not provide insights into the causes. APPROACH AND RESULTS: We investigated Lp(a) concentrations, LPA isoforms, and genotypes of established genetic variants affecting Lp(a) concentrations (LPA variants, APOE isoforms, and PCSK9 R46L) in the Finnish YFS (Cardiovascular Risk in Young Finns Study) population (n=2281) and 3 Non-Finnish Central European populations (n=10 003). We observed ≈50% lower Lp(a) concentrations in Finns. The isoform distribution was shifted toward longer isoforms, and the percentage of low-molecular-weight isoform carriers was reduced. Most interestingly, however, Lp(a) was reduced in each single-isoform group. In contrast to the known inverse relationship between LPA isoforms and Lp(a) concentrations, especially very short isoforms presented unexpectedly low Lp(a) concentrations in Finns. The investigated genetic variants, as well as age, sex, and renal function, explained 71.8% of the observed population differences. CONCLUSIONS: The population differences in Lp(a) concentrations between Finnish and Central European populations originate not only from a different LPA isoform distribution but suggest the existence of novel functional variation in the small-isoform range.

10.
Diabetes Care ; 40(10): 1386-1393, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28877915

RESUMO

OBJECTIVE: The human vitamin E-binding glycoprotein afamin is primarily expressed in the liver and has been associated with prevalent and incident metabolic syndrome. These data were in line with observations in transgenic mice. We thus investigated whether afamin concentrations are associated with prediabetes, type 2 diabetes, and insulin resistance (IR). RESEARCH DESIGN AND METHODS: Individual-level baseline (n = 20,136) and follow-up data (n = 14,017) of eight prospective cohort studies were investigated. Study-level data were combined using random-effects meta-analyses. Main outcomes were prevalent and incident type 2 diabetes, prediabetes, and IR. Discrimination and reclassification of participants was analyzed for incident type 2 diabetes. RESULTS: Mean afamin concentrations between studies ranged from 61 to 73 mg/L. The eight studies included 1,398 prevalent and 585 incident cases of type 2 diabetes. Each increase of afamin by 10 mg/L was associated with prevalent type 2 diabetes (odds ratio [OR] 1.19 [95% CI 1.12-1.26], P = 5.96 × 10-8). Afamin was positively associated with IR assessed by HOMA-IR (ß 0.110 [95% CI 0.089-0.132], P = 1.37 × 10-23). Most importantly, afamin measured at baseline was an independent predictor for 585 incident cases of type 2 diabetes (OR 1.30 [95% CI 1.23-1.38], P = 3.53 × 10-19) and showed a significant and valuable gain in risk classification accuracy when added to this extended adjustment model. CONCLUSIONS: This pooled analysis in >20,000 individuals showed that afamin is strongly associated with IR, prevalence, and incidence of type 2 diabetes independent of major metabolic risk factors or parameters. Afamin might be a promising novel marker for the identification of individuals at high risk for the development of type 2 diabetes.


Assuntos
Proteínas de Transporte/sangue , Diabetes Mellitus Tipo 2/epidemiologia , Glicoproteínas/sangue , Síndrome Metabólica/epidemiologia , Estado Pré-Diabético/epidemiologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/sangue , Índice de Massa Corporal , Colesterol/sangue , Diabetes Mellitus Tipo 2/sangue , Feminino , Seguimentos , Hemoglobina A Glicada/metabolismo , Humanos , Incidência , Resistência à Insulina , Masculino , Síndrome Metabólica/sangue , Pessoa de Meia-Idade , Estado Pré-Diabético/sangue , Prevalência , Estudos Prospectivos , Fatores de Risco , Albumina Sérica Humana , Triglicerídeos/sangue
11.
Atherosclerosis ; 264: 58-66, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28772107

RESUMO

BACKGROUND AND AIMS: Hypercholesterolemia confers susceptibility to cardiovascular disease (CVD). Both serum total cholesterol (TC) and LDL-cholesterol (LDL-C) exhibit a strong genetic component (heritability estimates 0.41-0.50). However, a large part of this heritability cannot be explained by the variants identified in recent extensive genome-wide association studies (GWAS) on lipids. Our aim was to find genetic causes leading to high LDL-C levels and ultimately CVD in a large Austrian family presenting with what appears to be autosomal dominant inheritance for familial hypercholesterolemia (FH). METHODS: We utilized linkage analysis followed by whole-exome sequencing and genetic risk score analysis using an Austrian multi-generational family with various dyslipidemias, including elevated TC and LDL-C, and one family branch with elevated lipoprotein (a) (Lp(a)). RESULTS: We did not find evidence for genome-wide significant linkage for LDL-C or apparent causative variants in the known FH genes rather, we discovered a particular family-specific combination of nine GWAS LDL-C SNPs (p = 0.02 by permutation), and putative less severe familial hypercholesterolemia mutations in the LDLR and APOB genes in a subset of the affected family members. Separately, high Lp(a) levels observed in one branch of the family were explained primarily by the LPA locus, including short (<23) Kringle IV repeats and rs3798220. CONCLUSIONS: Taken together, some forms of FH may be explained by family-specific combinations of LDL-C GWAS SNPs.


Assuntos
Colesterol/sangue , Hiperlipoproteinemia Tipo II/genética , Mutação , Polimorfismo de Nucleotídeo Único , Apolipoproteína B-100/genética , Áustria , Biomarcadores/sangue , Análise Mutacional de DNA , Feminino , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Hereditariedade , Humanos , Hiperlipoproteinemia Tipo II/sangue , Hiperlipoproteinemia Tipo II/diagnóstico , Lipoproteína(a)/sangue , Lipoproteína(a)/genética , Masculino , Pessoa de Meia-Idade , Linhagem , Fenótipo , Receptores de LDL/genética , Fatores de Risco , Sequenciamento Completo do Exoma
12.
Sci Rep ; 7(1): 8734, 2017 Aug 18.
Artigo em Inglês | MEDLINE | ID: mdl-28821713

RESUMO

Apolipoprotein A-IV (apoA-IV) has been observed to be associated with lipids, kidney function, adiposity- and diabetes-related parameters. To assess the causal relationship of apoA-IV with these phenotypes, we conducted bidirectional Mendelian randomization (MR) analyses using publicly available summary-level datasets from GWAS consortia on apoA-IV concentrations (n = 13,813), kidney function (estimated glomerular filtration rate (eGFR), n = 133,413), lipid traits (HDL cholesterol, LDL cholesterol, triglycerides, n = 188,577), adiposity-related traits (body-mass-index (n = 322,206), waist-hip-ratio (n = 210,088)) and fasting glucose (n = 133,010). Main analyses consisted in inverse-variance weighted and multivariable MR, whereas MR-Egger regression and weighted median estimation were used as sensitivity analyses. We found that eGFR is likely to be causal on apoA-IV concentrations (53 SNPs; causal effect estimate per 1-SD increase in eGFR = -0.39; 95% CI = [-0.54, -0.24]; p-value = 2.4e-07). Triglyceride concentrations were also causally associated with apoA-IV concentrations (40 SNPs; causal effect estimate per 1-SD increase in triglycerides = -0.06; 95% CI = [-0.08, -0.04]; p-value = 4.8e-07), independently of HDL-C and LDL-C concentrations (causal effect estimate from multivariable MR = -0.06; 95% CI = [-0.10, -0.02]; p-value = 0.0014). Evaluating the inverse direction of causality revealed a possible causal association of apoA-IV on HDL-cholesterol (2 SNPs; causal effect estimate per one percent increase in apoA-IV = -0.40; 95% CI = [-0.60, -0.21]; p-value = 5.5e-05).

13.
J Clin Endocrinol Metab ; 102(8): 2974-2984, 2017 08 01.
Artigo em Inglês | MEDLINE | ID: mdl-28591793

RESUMO

Context: An increase of bile acids (BAs), fibroblast growth factor 19 (FGF19), and glucagon-like peptide 1 (GLP-1) has been implicated in metabolic improvements after Roux-en-Y gastric bypass and vertical sleeve gastrectomy. However, data are still conflicting regarding their role after laparoscopic adjustable gastric banding (LAGB). Objective: To assess the fasting BA, FGF19, and GLP-1 concentrations in plasma before and after LAGB and to test for correlations with immunometabolic parameters. Furthermore, hepatic farnesoid X receptor (FXR) expression and regulation of FXR-dependent genes were analyzed. Design and Setting: Observational study at the University Hospital Innsbruck. Patients: Twenty obese patients. Interventions: Fasting plasma samples were taken before, 3, 6, and 12 months after LAGB. Liver biopsies were obtained at surgery and after 6 months postoperatively. Main Outcome Measures: BA profiles, GLP-1 and FGF19 levels, hepatic FXR expression and regulation of FXR target genes were determined. Results: Total, conjugated, and secondary BAs transiently increased 3 months after LAGB (P < 0.01). Only one BA, glycolithocholic acid sulfate, remained significantly elevated throughout the whole follow-up period (P < 0.05). GLP-1 had increased transiently 3 months after surgery (P < 0.01), whereas FGF19 levels increased continuously (P < 0.05). Insulin, homeostasis model assessment index, C-reactive protein, FGF19, and GLP-1 correlated positively with different BAs. No differences were seen in hepatic FXR expression and FXR-regulated genes. Conclusions: Our study results, not only identified LAGB-induced changes in BAs and BA-induced hormones, but also revealed associations between changes in BA profile with GLP-1 and FGF19.


Assuntos
Ácidos e Sais Biliares/sangue , Fatores de Crescimento de Fibroblastos/sangue , Peptídeo 1 Semelhante ao Glucagon/sangue , Fígado/metabolismo , Obesidade Mórbida/sangue , Receptores Citoplasmáticos e Nucleares/metabolismo , Adulto , Cirurgia Bariátrica , Proteína C-Reativa/metabolismo , Feminino , Regulação da Expressão Gênica , Ácido Glicocólico/análogos & derivados , Ácido Glicocólico/sangue , Humanos , Imuno-Histoquímica , Insulina/sangue , Resistência à Insulina , Laparoscopia , Masculino , Obesidade Mórbida/cirurgia , Reação em Cadeia da Polimerase em Tempo Real
14.
J Lipid Res ; 58(9): 1834-1844, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28512139

RESUMO

High lipoprotein (a) [Lp(a)] concentrations are an independent risk factor for cardiovascular outcomes. Concentrations are strongly influenced by apo(a) kringle IV repeat isoforms. We aimed to identify genetic loci associated with Lp(a) concentrations using data from five genome-wide association studies (n = 13,781). We identified 48 independent SNPs in the LPA and 1 SNP in the APOE gene region to be significantly associated with Lp(a) concentrations. We also adjusted for apo(a) isoforms to identify loci affecting Lp(a) levels independently from them, which resulted in 31 SNPs (30 in the LPA, 1 in the APOE gene region). Seven SNPs showed a genome-wide significant association with coronary artery disease (CAD) risk. A rare SNP (rs186696265; MAF ∼1%) showed the highest effect on Lp(a) and was also associated with increased risk of CAD (odds ratio = 1.73, P = 3.35 × 10-30). Median Lp(a) values increased from 2.1 to 91.1 mg/dl with increasing number of Lp(a)-increasing alleles. We found the APOE2-determining allele of rs7412 to be significantly associated with Lp(a) concentrations (P = 3.47 × 10-10). Each APOE2 allele decreased Lp(a) by 3.34 mg/dl corresponding to ∼15% of the population's mean values. Performing a gene-based test of association, including suspected Lp(a) receptors and regulators, resulted in one significant association of the TLR2 gene with Lp(a) (P = 3.4 × 10-4). In summary, we identified a large number of independent SNPs in the LPA gene region, as well as the APOE2 allele, to be significantly associated with Lp(a) concentrations.


Assuntos
Apolipoproteínas A/metabolismo , Estudo de Associação Genômica Ampla/métodos , Lipoproteína(a)/genética , Lipoproteína(a)/metabolismo , Animais , Apolipoproteínas A/genética , Humanos , Polimorfismo de Nucleotídeo Único , Isoformas de Proteínas/metabolismo , Caracteres Sexuais
15.
Eur Heart J ; 38(23): 1823-1831, 2017 Jun 14.
Artigo em Inglês | MEDLINE | ID: mdl-28444229

RESUMO

Aims: Lp(a) concentrations represent a major cardiovascular risk factor and are almost entirely controlled by one single locus (LPA). However, many genetic factors in LPA governing the enormous variance of Lp(a) levels are still unknown. Since up to 70% of the LPA coding sequence are located in a difficult to access hypervariable copy number variation named KIV-2, we hypothesized that it may contain novel functional variants with pronounced effects on Lp(a) concentrations. We performed a large scale mutation analysis in the KIV-2 using an extreme phenotype approach. Methods and Results: We compiled an discovery set of 123 samples showing discordance between LPA isoform phenotype and Lp(a) concentrations and controls. Using ultra-deep sequencing, we identified a splice site variant (G4925A) in preferential association with the smaller LPA isoforms. Follow-up in a European general population (n = 2892) revealed an exceptionally high carrier frequency of 22.1% in the general population. The variant explains 20.6% of the Lp(a) variance in carriers of low molecular weight (LMW) apo(a) isoforms (P = 5.75e-38) and reduces Lp(a) concentrations by 31.3 mg/dL. Accordingly the odds ratio for cardiovascular disease was reduced from 1.39 [95% confidence interval (CI): 1.17-1.66, P = 1.89e-04] for wildtype LMW individuals to 1.19 [95%CI: 0.92; 1.56, P = 0.19] in LMW individuals who were additionally positive for G4925A. Functional studies point towards a reduction of splicing efficiency by this novel variant. Conclusion: A highly frequent but until now undetected variant in the LPA KIV-2 region is strongly associated with reduced Lp(a) concentrations and reduced cardiovascular risk in LMW individuals.


Assuntos
Doenças Cardiovasculares/genética , Kringles/genética , Lipoproteína(a)/genética , Adulto , Idoso , Variações do Número de Cópias de DNA/genética , Feminino , Genótipo , Humanos , Desequilíbrio de Ligação/genética , Lipoproteína(a)/metabolismo , Masculino , Pessoa de Meia-Idade , Fenótipo , Polimorfismo de Nucleotídeo Único/genética , Isoformas de Proteínas/genética , Isoformas de Proteínas/metabolismo , Fatores de Risco
16.
Sci Rep ; 8: 45833, 2017 04 03.
Artigo em Inglês | MEDLINE | ID: mdl-28367968

RESUMO

Patients with intermittent claudication carry a high risk for cardiovascular complications. The TransAtlantic Inter-Society Consensus (TASC) Group estimated a five-year overall mortality of 30% for these patients, the majority dying from cardiovascular causes. We investigated whether this evaluation is still applicable in nowadays patients. We therefore prospectively followed 255 male patients with intermittent claudication from the CAVASIC Study during 7 years for overall mortality, vascular morbidity and mortality and local PAD outcomes. Overall mortality reached 16.1% (n = 41). Most patients died from cancer (n = 20). Half of patients (n = 22; 8.6%) died within the first five years. Incident cardiovascular events were observed among 70 patients (27.5%), 54 (21.2%) during the first five years. Vascular mortality was low with 5.1% (n = 13) for the entire and 3.1% for the first five years of follow-up. Prevalent coronary artery disease did not increase the risk to die from all or vascular causes. PAD symptoms remained stable or improved in the majority of patients (67%). In summary, compared to TASC, the proportion of cardiovascular events did not markedly decrease over the last two decades. Vascular mortality, however, was low among our population. This indicates that nowadays patients more often survive cardiovascular events and a major number dies from cancer.

17.
Arterioscler Thromb Vasc Biol ; 36(11): 2252-2258, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-27687604

RESUMO

OBJECTIVE: A recent observational study with almost 2 million men reported an association between low high-density lipoprotein (HDL) cholesterol and worse kidney function. The causality of this association would be strongly supported if genetic variants associated with HDL cholesterol were also associated with kidney function. APPROACH AND RESULTS: We used 68 genetic variants (single-nucleotide polymorphisms [SNPs]) associated with HDL cholesterol in genome-wide association studies including >188 000 subjects and tested their association with estimated glomerular filtration rate (eGFR) using summary statistics from another genome-wide association studies meta-analysis of kidney function including ≤133 413 subjects. Fourteen of the 68 SNPs (21%) had a P value <0.05 compared with the 5% expected by chance (Binomial test P=5.8×10-6). After Bonferroni correction, 6 SNPs were still significantly associated with eGFR. The genetic variants with the strongest associations with HDL cholesterol concentrations were not the same as those with the strongest association with kidney function and vice versa. An evaluation of pleiotropy indicated that the effects of the HDL-associated SNPs on eGFR were not mediated by HDL cholesterol. In addition, we performed a Mendelian randomization analysis. This analysis revealed a positive but nonsignificant causal effect of HDL cholesterol-increasing variants on eGFR. CONCLUSIONS: In summary, our findings indicate that HDL cholesterol does not causally influence eGFR and propose pleiotropic effects on eGFR for some HDL cholesterol-associated SNPs. This may cause the observed association by mechanisms other than the mere HDL cholesterol concentration.


Assuntos
HDL-Colesterol/sangue , Dislipidemias/genética , Taxa de Filtração Glomerular/genética , Nefropatias/genética , Rim/fisiopatologia , Polimorfismo de Nucleotídeo Único , Biomarcadores/sangue , Bases de Dados Genéticas , Dislipidemias/sangue , Dislipidemias/diagnóstico , Dislipidemias/epidemiologia , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Nefropatias/diagnóstico , Nefropatias/epidemiologia , Nefropatias/fisiopatologia , Análise da Randomização Mendeliana , Fenótipo , Medição de Risco , Fatores de Risco
18.
Hum Mol Genet ; 25(16): 3635-3646, 2016 08 15.
Artigo em Inglês | MEDLINE | ID: mdl-27412012

RESUMO

Apolipoprotein A-IV (apoA-IV) is a major component of HDL and chylomicron particles and is involved in reverse cholesterol transport. It is an early marker of impaired renal function. We aimed to identify genetic loci associated with apoA-IV concentrations and to investigate relationships with known susceptibility loci for kidney function and lipids. A genome-wide association meta-analysis on apoA-IV concentrations was conducted in five population-based cohorts (n = 13,813) followed by two additional replication studies (n = 2,267) including approximately 10 M SNPs. Three independent SNPs from two genomic regions were significantly associated with apoA-IV concentrations: rs1729407 near APOA4 (P = 6.77 × 10 - 44), rs5104 in APOA4 (P = 1.79 × 10-24) and rs4241819 in KLKB1 (P = 5.6 × 10-14). Additionally, a look-up of the replicated SNPs in downloadable GWAS meta-analysis results was performed on kidney function (defined by eGFR), HDL-cholesterol and triglycerides. From these three SNPs mentioned above, only rs1729407 showed an association with HDL-cholesterol (P = 7.1 × 10 - 07). Moreover, weighted SNP-scores were built involving known susceptibility loci for the aforementioned traits (53, 70 and 38 SNPs, respectively) and were associated with apoA-IV concentrations. This analysis revealed a significant and an inverse association for kidney function with apoA-IV concentrations (P = 5.5 × 10-05). Furthermore, an increase of triglyceride-increasing alleles was found to decrease apoA-IV concentrations (P = 0.0078). In summary, we identified two independent SNPs located in or next the APOA4 gene and one SNP in KLKB1 The association of KLKB1 with apoA-IV suggests an involvement of apoA-IV in renal metabolism and/or an interaction within HDL particles. Analyses of SNP-scores indicate potential causal effects of kidney function and by lesser extent triglycerides on apoA-IV concentrations.


Assuntos
Apolipoproteínas A/genética , Estudo de Associação Genômica Ampla , Polimorfismo de Nucleotídeo Único/genética , Alelos , Apolipoproteínas A/sangue , HDL-Colesterol/sangue , HDL-Colesterol/genética , Feminino , Humanos , Rim/metabolismo , Lipídeos/sangue , Lipídeos/genética , Masculino , Triglicerídeos/sangue , Triglicerídeos/genética
19.
Sci Rep ; 6: 25398, 2016 05 03.
Artigo em Inglês | MEDLINE | ID: mdl-27138987

RESUMO

Measurement of telomere length is widely used in epidemiologic studies. Insufficient standardization of the measurements processes has, however, complicated the comparison of results between studies. We aimed to investigate whether DNA extraction methods have an influence on measured values of relative telomere length (RTL) and whether this has consequences for epidemiological studies. We performed four experiments with RTL measurement in quadruplicate by qPCR using DNA extracted with different methods: 1) a standardized validation experiment including three extraction methods (magnetic-particle-method EZ1, salting-out-method INV, phenol-chloroform-isoamyl-alcohol PCI) each in the same 20 samples demonstrated pronounced differences in RTL with lowest values with EZ1 followed by INV and PCI-isolated DNA; 2) a comparison of 307 samples from an epidemiological study showing EZ1-measurements 40% lower than INV-measurements; 3) a matching-approach of two similar non-diseased control groups including 143 pairs of subjects revealed significantly shorter RTL in EZ1 than INV-extracted DNA (0.844 ± 0.157 vs. 1.357 ± 0.242); 4) an association analysis of RTL with prevalent cardiovascular disease detected a stronger association with INV than with EZ1-extracted DNA. In summary, DNA extraction methods have a pronounced influence on the measured RTL-values. This might result in spurious or lost associations in epidemiological studies under certain circumstances.


Assuntos
DNA/genética , DNA/isolamento & purificação , Homeostase do Telômero/genética , Telômero/genética , Adulto , DNA/química , Impressões Digitais de DNA/métodos , Estudos Epidemiológicos , Feminino , Humanos , Masculino , Telômero/química
20.
Wien Med Wochenschr ; 166(3-4): 88-94, 2016 Mar.
Artigo em Alemão | MEDLINE | ID: mdl-26795628

RESUMO

The introduction of genome-wide association studies resulted in a tremendous increase in the number of genes associated with obesity and related phenotypes (BMI, waist and waist-hip-ratio). Despite this enormous gain in knowledge the search for genes is only started since only a small fraction of the heritability of these phenotypes is explained yet: each single gene of the 97 hitherto known BMI-associated genes and 49 waist-hip-ratio-associated genes explains only a tiny fraction of the variance of these phenotypes. Sex-specific differences are mainly known for waist-hip-ratio and Ì´40% of the genes showed only an effect in women but no or a markedly smaller effect in men. The functional characterization of the identified genes will take a lot of time. It is unclear whether and how fast the findings will result in therapeutic consequences. It is of utmost importance that we understand the involved mechanisms before new therapeutic strategies can be developed.


Assuntos
Estudo de Associação Genômica Ampla , Obesidade/genética , Índice de Massa Corporal , Feminino , Predisposição Genética para Doença , Humanos , Masculino , Obesidade/terapia , Fenótipo , Caracteres Sexuais , Relação Cintura-Quadril
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