Sequence variations in the myocilin (MYOC) gene account for approximately 2% to 4% of glaucoma cases. One particular MYOC mutation, Gln368Stop (dbSNP accession number: rs74315329), is the most common ...genetic mutation causing glaucoma by increasing intraocular pressure (IOP). The objective of this study was to evaluate the effect of this MYOC mutation on IOP using data from large-scale European population panels (directly sequenced and imputation based).
Cross-sectional, cohort study.
For this study, the penetrance of the variant rs74315329 was estimated in 2 population-based cohorts, the TwinsUK (N = 6092) and the Rotterdam Study (RS) (N =11 189).
Carriers of the risk allele for rs74315329 were identified using whole-genome sequencing and imputation data (based on 1000 Genomes Project and Haplotype Reference Consortium panels). The penetrance of this variant was evaluated using IOP measurements and data on visual field testing/a diagnosis of glaucoma (if available).
The penetrance of the variant rs74315329 was estimated from the percentage of the carriers of the risk allele of the variant who had high IOP (ocular hypertension) or glaucoma.
In our study, the observed penetrance of the variant rs74315329 in relation to increased IOP was 12.5% and 19.4% in the TwinsUK and the RS, respectively. Thus, our study suggests a much lower penetrance for rs74315329 for ocular hypertension (and thus glaucoma), in comparison with that reported previously.
The significance of this finding is that higher numbers of healthy individuals in the population are expected to be carriers of this mutation, which in turn reduces the utility of identifying carriers of this mutation as a screening tool for glaucoma.
Background Hyponatremia is one of the most common adverse reactions to thiazide diuretics. In the present study, we analyzed differences in thiazide-associated hyponatremia between men and women and ...between different categories of age, body mass index (BMI), daily thiazide dose, and estimated glomerular filtration rate. Study Design Population-based cohort study. Setting & Participants 13,325 individuals 45 years and older living in a suburb of Rotterdam, as part of the Rotterdam Study. Predictor Exposure to thiazide diuretics. Outcomes The association between thiazide exposure and hyponatremia (defined as sodium level ≤135 mmol/L; mild hyponatremia, 130-≤135 mmol/L; moderate, >125-<130 mmol/L; and severe, ≤125 mmol/L) was studied in a period covering more than 10 years using Cox proportional hazard regression analyses. Results 718 participants used thiazides at baseline, and 2,738 participants started on thiazide therapy during follow-up. 522 participants developed hyponatremia, of whom 32.4% were exposed to thiazide diuretics at the time of hyponatremia. Thiazide exposure was associated with an almost 5 times higher risk of hyponatremia than no exposure (HR, 4.95; 95% CI, 4.12-5.96). The risk of mild hyponatremia was more than 4.5 times higher in thiazide-exposed individuals; risks of moderate and severe hyponatremia were both 8 times higher in individuals exposed to thiazides. Age and BMI (but not sex P = 0.8 or estimated glomerular filtration rate P = 0.2) significantly modified this risk of thiazide-associated hyponatremia ( P < 0.05). Limitations Some cases of severe hyponatremia may have been missed if patients were admitted to the hospital without assessment of serum sodium in the general practitioner's laboratory. Nonproportionality of hazards in the first period was explained as possible “depletion of susceptibles” in this closed cohort. Conclusions Thiazide use is associated with a substantially increased risk of hyponatremia. Age and BMI significantly influenced the thiazide-associated risk of hyponatremia.
Secretory Phospholipase A2 -IIA and Cardiovascular Disease Holmes, Michael V., MSc; Simon, Tabassome, MD, PhD; Exeter, Holly J., PhD ...
Journal of the American College of Cardiology,
11/2013, Letnik:
62, Številka:
21
Journal Article
Recenzirano
Odprti dostop
Objectives This study sought to investigate the role of secretory phospholipase A2 (sPLA2 )-IIA in cardiovascular disease. Background Higher circulating levels of sPLA2 -IIA mass or sPLA2 enzyme ...activity have been associated with increased risk of cardiovascular events. However, it is not clear if this association is causal. A recent phase III clinical trial of an sPLA2 inhibitor (varespladib) was stopped prematurely for lack of efficacy. Methods We conducted a Mendelian randomization meta-analysis of 19 general population studies (8,021 incident, 7,513 prevalent major vascular events MVE in 74,683 individuals) and 10 acute coronary syndrome (ACS) cohorts (2,520 recurrent MVE in 18,355 individuals) using rs11573156, a variant in PLA2G2A encoding the sPLA2 -IIA isoenzyme, as an instrumental variable. Results PLA2G2A rs11573156 C allele associated with lower circulating sPLA2 -IIA mass (38% to 44%) and sPLA2 enzyme activity (3% to 23%) per C allele. The odds ratio (OR) for MVE per rs11573156 C allele was 1.02 (95% confidence interval CI: 0.98 to 1.06) in general populations and 0.96 (95% CI: 0.90 to 1.03) in ACS cohorts. In the general population studies, the OR derived from the genetic instrumental variable analysis for MVE for a 1-log unit lower sPLA2 -IIA mass was 1.04 (95% CI: 0.96 to 1.13), and differed from the non-genetic observational estimate (OR: 0.69; 95% CI: 0.61 to 0.79). In the ACS cohorts, both the genetic instrumental variable and observational ORs showed a null association with MVE. Instrumental variable analysis failed to show associations between sPLA2 enzyme activity and MVE. Conclusions Reducing sPLA2 -IIA mass is unlikely to be a useful therapeutic goal for preventing cardiovascular events.
Abstract Mutations in TMEM230 have recently been associated to Parkinson’s disease (PD). To further understand the role of this gene in the Caucasian population, we interrogated our large repository ...of next generation sequencing data from unrelated PD cases and controls, as well as multiplex families with autosomal dominant PD. We identified 2 heterozygous missense variants in two unrelated PD cases and not in our control database (p.Y106H and p.I162V), and a heterozygous missense variant in two PD cases from the same family (p.A163T). However, data presented herein is not sufficient to support the role of any of these variants in PD pathology. A series of unified sequence kernel association tests (SKAT-O) also failed to show a cumulative effect of rare variation in this gene on the risk of PD in the general Caucasian population. Further evaluation of genetic data from different populations is needed to understand the genetic role of TMEM230 in PD etiology.
To investigate whether the 2 subtypes of advanced age-related macular degeneration (AMD), choroidal neovascularization (CNV), and geographic atrophy (GA) segregate separately in families and to ...identify which genetic variants are associated with these 2 subtypes.
Sibling correlation study and genome-wide association study (GWAS).
For the sibling correlation study, 209 sibling pairs with advanced AMD were included. For the GWAS, 2594 participants with advanced AMD subtypes and 4134 controls were included. Replication cohorts included 5383 advanced AMD participants and 15 240 controls.
Participants had the AMD grade assigned based on fundus photography, examination, or both. To determine heritability of advanced AMD subtypes, a sibling correlation study was performed. For the GWAS, genome-wide genotyping was conducted and 6 036 699 single nucleotide polymorphisms (SNPs) were imputed. Then, the SNPs were analyzed with a generalized linear model controlling for genotyping platform and genetic ancestry. The most significant associations were evaluated in independent cohorts.
Concordance of advanced AMD subtypes in sibling pairs and associations between SNPs with GA and CNV advanced AMD subtypes.
The difference between the observed and expected proportion of siblings concordant for the same subtype of advanced AMD was different to a statistically significant degree (P = 4.2 × 10(-5)), meaning that in siblings of probands with CNV or GA, the same advanced subtype is more likely to develop. In the analysis comparing participants with CNV to those with GA, a statistically significant association was observed at the ARMS2/HTRA1 locus (rs10490924; odds ratio OR, 1.47; P = 4.3 × 10(-9)), which was confirmed in the replication samples (OR, 1.38; P = 7.4 × 10(-14) for combined discovery and replication analysis).
Whether CNV versus GA develops in a patient with AMD is determined in part by genetic variation. In this large GWAS meta-analysis and replication analysis, the ARMS2/HTRA1 locus confers increased risk for both advanced AMD subtypes, but imparts greater risk for CNV than for GA. This locus explains a small proportion of the excess sibling correlation for advanced AMD subtype. Other loci were detected with suggestive associations that differ for advanced AMD subtypes and deserve follow-up in additional studies.
Abstract Objectives To study the relationship between 25-hydroxy (OH) vitamin D serum levels and osteoarthritis (OA) of the knee, hip, and hand in a meta-analysis, with updated and expanded results ...of our previous study. Methods Pubmed was searched from February 1975 to December 2014 for articles assessing the relationship between vitamin D levels and OA. In our meta-analysis, 6 cross-sectional and 6 longitudinal studies were included. The number of subjects in these studies ranged from 99 to 1248 subjects. The latter 1248 subjects (58% women) were drawn from the Rotterdam Study, a prospective population-based cohort study of the elderly. At baseline, 25(OH) vitamin D serum levels were measured and prevalent OA of knees, hips and hands was scored by the Kellgren–Lawrence grading system. After a mean follow-up time was 8.4 years, incidence and progression of OA were assessed. Results No clear association between vitamin serum levels and prevalent, incident or progressive knee, hip or hand OA was observed. The quality of most studies was low, and the results were conflicting. Meta-analysis of 3 cross-sectional studies on vitamin D levels and knee joint space narrowing (JSN) showed an increased risk of prevalent JSN with decreasing vitamin D levels (OR = 1.52, 95% CI: 1.15–2.01). The association observed in the meta-analysis of 3 studies on low vitamin D levels and incident and progressive knee OA was not significant (OR = 1.37, 95% CI: 0.97–1.92); however, when considering solely progressive knee OA, the risk was significantly increased (OR = 2.40, 95% CI: 1.22–4.72). Conclusions Epidemiological studies do not provide evidence of an independent association between 25(OH) vitamin D serum levels with hip or hand OA. When analyzing subgroups of knee OA, significant associations of low vitamin D levels with prevalent knee JSN and with progressive knee OA were observed. Overall, the results of this study do not support the advice to supplement vitamin D to prevent the onset or worsening of osteoarthritis, except perhaps for progressive knee OA.
Background The fraction of exhaled nitric oxide (F eno ) value is a biomarker of eosinophilic airway inflammation and is associated with childhood asthma. Identification of common genetic variants ...associated with childhood F eno values might help to define biological mechanisms related to specific asthma phenotypes. Objective We sought to identify the genetic variants associated with childhood F eno values and their relation with asthma. Methods F eno values were measured in children age 5 to 15 years. In 14 genome-wide association studies (N = 8,858), we examined the associations of approximately 2.5 million single nucleotide polymorphisms (SNPs) with F eno values. Subsequently, we assessed whether significant SNPs were expression quantitative trait loci in genome-wide expression data sets of lymphoblastoid cell lines (n = 1,830) and were related to asthma in a previously published genome-wide association data set (cases, n = 10,365; control subjects: n = 16,110). Results We identified 3 SNPs associated with F eno values: rs3751972 in LYR motif containing 9 ( LYRM9 ; P = 1.97 × 10−10 ) and rs944722 in inducible nitric oxide synthase 2 ( NOS2 ; P = 1.28 × 10−9 ), both of which are located at 17q11.2-q12, and rs8069176 near gasdermin B ( GSDMB ; P = 1.88 × 10−8 ) at 17q12-q21. We found a cis expression quantitative trait locus for the transcript soluble galactoside-binding lectin 9 (LGALS9) that is in linkage disequilibrium with rs944722. rs8069176 was associated with GSDMB and ORM1-like 3 (ORMDL3) expression. rs8069176 at 17q12-q21, but not rs3751972 and rs944722 at 17q11.2-q12, were associated with physician-diagnosed asthma. Conclusion This study identified 3 variants associated with F eno values, explaining 0.95% of the variance. Identification of functional SNPs and haplotypes in these regions might provide novel insight into the regulation of F eno values. This study highlights that both shared and distinct genetic factors affect F eno values and childhood asthma.
To explore the association between polymorphisms in the complement component 3 (C3) gene and age-related macular degeneration (AMD), and to investigate the modifying effect of complement factor H ...(CFH) Y402H, LOC387715 A69S and smoking.
Pooled data from the prospective, population-based Rotterdam Study (enrolment between 1990 and 1993, and 3 follow-up examinations between September 1, 1993, and December 31, 2004) and an independent case-control study from the Netherlands.
The Rotterdam Study comprised a total of 6418 persons aged >or=55 years who had gradable fundus photographs. The case-control study consisted of 357 unrelated AMD patients and 173 control individuals aged >or=55 years.
The variants R102G and P314L of the C3 gene, CFH Y402H and LOC387715 A69S, were genotyped in all study participants. Information on cigarette smoking was obtained by interview at baseline.
Early and late stages of prevalent and incident AMD, graded according to the international classification and grading system for AMD.
We found a population frequency of 0.217 for R102G and 0.211 for P314L in the Rotterdam Study. Both alleles significantly increased the risk of early AMD and all subtypes of late AMD, and this risk seemed to be independent of CFH Y402H, LOC387715 A69S, and smoking. Detailed analysis showed that the haplotype carrying both alleles had the highest frequency difference between cases and controls (P=0.006). We estimated a total population-attributable risk of 14.6%. A meta-analysis of all currently available data yielded a pooled odds ratio (OR) of 1.61 (95% confidence interval CI, 1.46-1.78) for the R102G allele, and an OR of 1.50 (95% CI, 1.31-1.71) for the P314L allele.
Our study showed a significant association between variants in the C3 gene and AMD and further highlights the crucial role of the complement pathway in the etiology of AMD.
Genome-wide association studies have revealed new insights into the genetic determinants of open-angle glaucoma (OAG). This study was performed to determine to what extent variants within established ...genes (MYOC, OPTN, and WDR36) and newly identified common genetic variants (ATOH7, CDKN2B, and SIX1) contribute to the risk of OAG.
Population-based setting, family-based setting, and a case-control study.
The Rotterdam Study I cohort (N = 5312; mean age±standard deviation SD, 68.0±8.4 years). Findings were replicated in the Genetic Research in Isolated Populations combined with the Erasmus Rucphen Family study (N = 1750; mean age±SD, 48.3±15.2 years), and a cohort from Southampton (N = 702; mean age±SD, 72.5±10.7 years).
After identifying common variants associated with OAG within the established genes, the risk of OAG was analyzed using logistic regression. Discriminative accuracy was assessed by comparing the area under the receiver operator characteristic curve (AUC) for models, including the number of risk alleles, intraocular pressure, age, and gender, with the AUC for the same model but without the risk alleles.
Odds ratios and AUCs of individual and combined risk alleles.
No consistent significant associations for the established genes (MYOC, OPTN, and WDR36) with OAG were found. However, when comparing the load of risk variants between cases and controls, 2 of 3 studies showed a significant increased risk of OAG for participants carrying more risk alleles of the 3 established genes. When combining all 6 genes, participants carrying a high number of risk alleles (highest tertile) had a 2.29-fold to 3.19-fold increase in risk of OAG compared with those carrying only a few risk alleles. The addition of the newly identified genes to IOP, age, and gender resulted in a higher AUC compared with the AUC without the newly identified genes (P = 0.027).
A significant contribution to the risk of OAG was found for the new common variants identified by recent genome-wide association studies, but not for variants within the established genes. Participants carrying a high number of risk alleles had an approximately 3-fold increase in the risk of OAG compared with those with a low number of risk alleles.
The author(s) have no proprietary or commercial interest in any materials discussed in this article.
First, the association between serum 25-hydroxyvitamin D (25OHD) and cognitive performance was examined. Second, we assessed whether there was evidence for an interplay between 25(OH)D and glucose ...homeostasis in the association with cognitive performance.
Associations were studied using cross-sectional data of 776 (3 domains) up to 2722 (1 domain) Dutch community-dwelling older adults, aged 65 years or older.
Serum 25(OH)D, plasma glucose, and insulin concentrations were obtained. Cognitive performance was assessed with an extensive cognitive test battery. Prevalence ratios (PRs) were calculated to quantify the association between 25(OH)D and cognition; poor performance was defined as the worst 10% of the distribution of the cognitive scores.
The overall median MMSE score was 29 (IQR 28-30). Higher serum 25(OH)D was associated with better attention and working memory, PR 0.50 (95% CI 0.29-0.84) for the third serum 25(OH)D tertile, indicating a 50% lower probability of being a poor performer than participants in the lowest tertile. Beneficial trends were shown for 25(OH)D with executive function and episodic memory. Serum 25(OH)D was not associated with plasma glucose or insulin. Plasma insulin only modified the association between serum 25(OH)D and executive function (P for interaction: .001), suggesting that the improvement in executive function with high 25(OH)D concentrations is stronger in participants with high plasma insulin concentrations compared with those with low plasma insulin concentrations.
Higher 25(OH)D concentrations significantly associated with better attention and working memory performance. This study does not demonstrate an interplay between serum 25(OH)D and glucose homeostasis in the association with cognitive performance.
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