Using 930 individuals connected in a single pedigree from an isolated population, participants of the Erasmus Rucphen Family (ERF) study, we investigated the heritability of carotid-femoral pulse ...wave velocity (PWV), carotid intima media thickness (IMT), and carotid plaque score.
PWV was measured between the carotid and femoral arteries as an indicator of aortic stiffness. Common carotid IMT and plaque score, quantifying alterations in arterial wall structure, were measured by ultrasonography.
All 3 traits were significantly associated with classic cardiovascular risk factors. Age- and gender-adjusted heritability estimates were 0.36 for PWV, 0.41 for carotid IMT, and 0.28 for plaque score. After adjustment for appropriate risk factors, the heritabilities were 0.26, 0.35, and 0.21 for PWV, IMT, and plaque score, respectively. All heritability estimates were statistically significant (P<0.001). Taking into account different proportions of variance associated with covariates for each trait, genetic factors explained &12% of the total variability for each of the phenotypes.
To our knowledge, this is the first report on the heritability of PWV. The heritability estimates of IMT and plaque score were similar to those in previous reports. We conclude that genetic factors significantly contribute to arterial structure and function in this isolated population, presenting the opportunity to locate susceptibility genes related to cardiovascular disorders.
Abstract
Background
In sub-Saharan Africa, the material and human capacity to diagnose patients reporting with fever to healthcare providers is largely insufficient. Febrile patients are typically ...treated presumptively with antimalarials and/or antibiotics. Such over-prescription can lead to drug resistance and involves unnecessary costs to the health system. International funding for malaria is currently not sufficient to control malaria. Transition to domestic funding is challenged by UHC efforts and recent COVID-19 outbreak. Herewith we present a digital approach to improve efficiencies in diagnosis and treatment of malaria in endemic Kisumu, Kenya: Connected Diagnostics. The objective of this study is to evaluate the feasibility, user experience and clinical performance of this approach in Kisumu.
Methods
Our intervention was performed Oct 2017–Dec 2018 across five private providers in Kisumu. Patients were enrolled on M-TIBA platform, diagnostic test results digitized, and only positive patients were digitally entitled to malaria treatment. Data on socio-demographics, healthcare transactions and medical outcomes were analysed using standard descriptive quantitative statistics. Provider perspectives were gathered by 19 semi-structured interviews.
Results
In total 11,689 febrile patients were digitally tested through five private providers. Malaria positivity ranged from 7.4 to 30.2% between providers, significantly more amongst the poor (
p
< 0.05). Prescription of antimalarials was substantially aberrant from National Guidelines, with 28% over-prescription (4.6–63.3% per provider) and prescription of branded versus generic antimalarials differing amongst facilities and correlating with the socioeconomic status of clients. Challenges were encountered transitioning from microscopy to RDT.
Conclusion
We provide full proof-of-concept of innovative Connected Diagnostics to use digitized malaria diagnostics to earmark digital entitlements for correct malaria treatment of patients. This approach has large cost-saving and quality improvement potential.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Light-to-moderate alcohol consumption reduces the risk of coronary heart disease and stroke. Because vascular disease is associated with cognitive impairment and dementia, we hypothesised that ...alcohol consumption might also affect the risk of dementia.
We examined the relation between alcohol consumption and risk of dementia in individuals taking part in the Rotterdam Study—a prospective population-based study of 7983 individuals aged 55 years and older. We studied all participants who did not have dementia at baseline (1990–93) and who had complete data on alcohol consumption (n=5395). Through follow-up examinations in 1993–94 and 1997–99 and an extensive monitoring system, we obtained nearly complete follow-up (99·7%) until the end of 1999. We used proportional hazards regression analysis, adjusted for age, sex, systolic blood pressure, education, smoking, and body-mass index, to compare the risk of developing dementia between individuals who regularly consumed alcohol and individuals who did not consume alcohol.
The average follow-up was 6·0 years. During this period, 197 individuals developed dementia (146 Alzheimer's disease, 29 vascular dementia, 22 other dementia). The median alcohol consumption was 0·29 drinks per day. Light-to-moderate drinking (one to three drinks per day) was significantly associated with a lower risk of any dementia (hazard ratio 0·58 95% CI 0·38–0·90) and vascular dementia (hazard ratio 0·29 0·09–0·93). We found no evidence that the relation between alcohol and dementia varied by type of alcoholic beverage.
These findings suggest that light-to-moderate alcohol consumption is associated with a reduced risk of dementia in individuals aged 55 years or older. The effect seems to be unchanged by the source of alcohol.
Variation in serum bilirubin is associated with altered cardiovascular disease risk and drug metabolism. We aimed to identify genetic contributors to variability in serum bilirubin levels by ...combining results from three genome-wide association studies (Framingham heart study, n = 3424; Rotterdam study, n = 3847; Age, Gene, Environment and Susceptibility-Reykjavik, n = 2193). Meta-analysis showed strong replication for a genetic influence on serum bilirubin levels of the UGT1A1 locus (P < 5 × 10−324) and a 12p12.2 locus. The peak signal in the 12p12.2 region was a non-synonymous SNP in SLCO1B1 (rs4149056, P = 6.7 × 10−13), which gives rise to a valine to alanine amino acid change leading to reduced activity for a hepatic transporter with known affinity for bilirubin. There were also suggestive associations with several other loci. The top variants in UGT1A1 and SLCO1B1 explain ∼18.0 and ∼1.0% of the variation in total serum bilirubin levels, respectively. In a conditional analysis adjusted for individual genotypes for the top UGT1A1 variant, the top SLCO1B1 variant remained highly significant (P = 7.3 × 10−13), but no other variants achieved genome-wide significance. In one of the largest genetic studies of bilirubin to date (n = 9464), we confirm the substantial genetic influence of UGT1A1 variants, consistent with past linkage and association studies, and additionally provide strong evidence of a role for allelic variation in SLCO1B1. Given the involvement of bilirubin in a number of physiological and disease processes, and the roles for UGT1A1 and SLCO1B1 in drug metabolism, these genetic findings have potential clinical importance. In analyses for association with gallbladder disease or gallstones, top bilirubin SNPs in UGT1A1 and SLCO1B1 were not associated.
The Rotterdam Study is a prospective cohort study ongoing since 1990 in the city of Rotterdam in The Netherlands. The study targets cardiovascular, endocrine, hepatic, neurological, ophthalmic, ...psychiatric and respiratory diseases. As of 2008, 14,926 subjects aged 45 years or over comprise the Rotterdam Study cohort. The findings of the Rotterdam Study have been presented in close to a 1,000 research articles and reports (see www.epib.nl/rotterdamstudy). This article gives the rationale of the study and its design. It also presents a summary of the major findings and an update of the objectives and methods.
Humans sleep approximately a third of their lifetime. The observation that individuals with either long or short sleep duration show associations with metabolic syndrome and psychiatric disorders ...suggests that the length of sleep is adaptive. Although sleep duration can be influenced by photoperiod (season) and phase of entrainment (chronotype), human familial sleep disorders indicate that there is a strong genetic modulation of sleep. Therefore, we conducted high-density genome-wide association studies for sleep duration in seven European populations (N=4251). We identified an intronic variant (rs11046205; P=3.99 × 10(-8)) in the ABCC9 gene that explains asymptotically =5% of the variation in sleep duration. An influence of season and chronotype on sleep duration was solely observed in the replication sample (N=5949). Meta-analysis of the associations found in a subgroup of the replication sample, chosen for season of entry and chronotype, together with the discovery results showed genome-wide significance. RNA interference knockdown experiments of the conserved ABCC9 homologue in Drosophila neurons renders flies sleepless during the first 3h of the night. ABCC9 encodes an ATP-sensitive potassium channel subunit (SUR2), serving as a sensor of intracellular energy metabolism.
Primary open-angle glaucoma (POAG) is a blinding disease. Two important risk factors for this disease are a positive family history and elevated intraocular pressure (IOP), which is also highly ...heritable. Genes found to date associated with IOP and POAG are ABCA1, CAV1/CAV2, GAS7 and TMCO1. However, these genes explain only a small part of the heritability of IOP and POAG. We performed a genome-wide association study of IOP in the population-based Rotterdam Study I and Rotterdam Study II using single nucleotide polymorphisms (SNPs) imputed to 1000 Genomes. In this discovery cohort (n = 8105), we identified a new locus associated with IOP. The most significantly associated SNP was rs58073046 (β = 0.44, P-value = 1.87 × 10(-8), minor allele frequency = 0.12), within the gene ARHGEF12. Independent replication in five population-based studies (n = 7471) resulted in an effect size in the same direction that was significantly associated (β = 0.16, P-value = 0.04). The SNP was also significantly associated with POAG in two independent case-control studies n = 1225 cases and n = 4117 controls; odds ratio (OR) = 1.53, P-value = 1.99 × 10(-8), especially with high-tension glaucoma (OR = 1.66, P-value = 2.81 × 10(-9); for normal-tension glaucoma OR = 1.29, P-value = 4.23 × 10(-2)). ARHGEF12 plays an important role in the RhoA/RhoA kinase pathway, which has been implicated in IOP regulation. Furthermore, it binds to ABCA1 and links the ABCA1, CAV1/CAV2 and GAS7 pathway to Mendelian POAG genes (MYOC, OPTN, WDR36). In conclusion, this study identified a novel association between IOP and ARHGEF12.
Summary Background Hyperuricaemia, a highly heritable trait, is a key risk factor for gout. We aimed to identify novel genes associated with serum uric acid concentration and gout. Methods ...Genome-wide association studies were done for serum uric acid in 7699 participants in the Framingham cohort and in 4148 participants in the Rotterdam cohort. Genome-wide significant single nucleotide polymorphisms (SNPs) were replicated in white (n=11 024) and black (n=3843) individuals who took part in the study of Atherosclerosis Risk in Communities (ARIC). The SNPs that reached genome-wide significant association with uric acid in either the Framingham cohort (p<5·0×10−8 ) or the Rotterdam cohort (p<1·0×10−7 ) were evaluated with gout. The results obtained in white participants were combined using meta-analysis. Findings Three loci in the Framingham cohort and two in the Rotterdam cohort showed genome-wide association with uric acid. Top SNPs in each locus were: missense rs16890979 in SLC2A9 (p=7·0×10−168 and 2·9×10−18 for white and black participants, respectively); missense rs2231142 in ABCG2 (p=2·5×10−60 and 9·8×10−4 ), and rs1165205 in SLC17A3 (p=3·3×10−26 and 0·33). All SNPs were direction-consistent with gout in white participants: rs16890979 (OR 0·59 per T allele, 95% CI 0·52–0·68, p=7·0×10−14 ), rs2231142 (1·74, 1·51–1·99, p=3·3×10−15 ), and rs1165205 (0·85, 0·77–0·94, p=0·002). In black participants of the ARIC study, rs2231142 was direction-consistent with gout (1·71, 1·06–2·77, p=0·028). An additive genetic risk score of high-risk alleles at the three loci showed graded associations with uric acid (272–351 μmol/L in the Framingham cohort, 269–386 μmol/L in the Rotterdam cohort, and 303–426 μmol/L in white participants of the ARIC study) and gout (frequency 2–13% in the Framingham cohort, 2–8% in the Rotterdam cohort, and 1–18% in white participants in the ARIC study). Interpretation We identified three genetic loci associated with uric acid concentration and gout. A score based on genes with a putative role in renal urate handling showed a substantial risk for gout. Funding Netherlands Organisation for Scientific Research (NWO); the National Heart, Lung, and Blood Institute.
To analyze the diagnostic sensitivity and specificity of various brain-derived proteins (14-3-3, Tau, neuron specific enolase NSE, and S100b) in the CSF of patients with Creutzfeldt-Jakob disease ...(CJD) and to analyze biologic factors that modify these parameters.
CSF was tested for 14-3-3, Tau, NSE, and S100b in 1,859 patients with sporadic, genetic, iatrogenic, and variant CJD, and in 1,117 controls.
The highest sensitivity was achieved for 14-3-3 and Tau in sporadic CJD (85% and 86%), and a combined determination of 14-3-3 and Tau, S100b, or NSE increased the sensitivity to over 93%. A multivariate analysis showed that the sensitivity of all tests was highest in patients with the shortest disease duration, age at onset >40 years, and homozygosity at codon 129 of the prion protein gene. In a group of patients with repeated lumbar punctures, a second test also increased the diagnostic sensitivity.
The detection of elevated levels of brain-derived proteins in the CSF in patients with suspected Creutzfeldt-Jakob disease is a valuable diagnostic test. A second lumbar puncture may be of value in patients with atypical clinical course in whom the first test was negative.
Abstract Cathepsin D ( CTSD ) is a gene involved in amyloid precursor protein processing and is considered a candidate for Alzheimer's disease (AD). The aim of the current study was to examine if ...variation in CTSD increases the risk of AD. We performed a candidate-gene analysis in a population-based cohort study ( N = 7983), and estimated the effect of CTSD on the risk of AD. Additionally, a large meta-analysis was performed incorporating our data and previously published data. The T-allele of CTSD rs17571 was associated with an increased risk of AD ( p -value 0.007) in the Rotterdam Study. This association was predominantly found in APOE ε4 noncarriers. A meta-analysis of previously published data showed a significantly increased risk of AD in carriers of the T-allele of rs17571 (OR 1.22, 95% CI 1.03–1.44), irrespective of APOE ε4 carrier status. This study adds to the evidence that CTSD increases the risk of AD, although the effect size is moderate.
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