...the exact mechanisms through which these genes act to regulate ocular refraction are unknown, and current animal models may be inadequate to hypothesize mechanisms for later-onset myopia in ...humans. ...a clearer picture of myopia and refractive error genetics will require incorporating measures of environmental exposures into our statistical analyses in GWAS.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To estimate the prevalence and risk factors of dry eye disease (DED) in a female cohort in the UK.
Population-based cross-sectional association study of 3824 women from the TwinsUK cohort aged 20-87 ...years. A questionnaire was used to evaluate DED and several risk factors. Binary logistic regression, corrected for age, was used to examine the association between DED and risk factors.
9.6% of women had a DED diagnosis and concomitant use of artificial tears, and 20.8% experienced DED symptoms in the past 3 months. Risk factors that were significantly associated with DED were age, asthma, eczema, the presence of any allergy, cataract surgery, rheumatoid arthritis, osteoarthritis, migraine and stroke. The highest effect sizes were found with depression, pelvic pain, irritable bowel syndrome and chronic widespread pain syndrome (all p<0.0005). Subjects with DED symptoms scored significantly lower on self-perceived health, compared with controls (p=0.001).
DED is common and increases with age within this cohort of female twins. We confirmed established risk factors for the first time in a British population, and found important risk factors that might relate to an underlying aetiology involving chronic pain predisposition or somatisation.
This study investigated temporal trends in the epidemiology of primary myopia and associations with key environmental risk factors in a UK population. Data were collected at recruitment ...(non-cycloplegic autorefraction, year of birth, sex, ethnicity, highest educational attainment, reason and age of first wearing glasses and history of eye disease) from 107,442 UK Biobank study participants aged 40 to 69 years, born between 1939 and 1970. Myopia was defined as mean spherical equivalent (MSE) ≤-1 dioptre (D). Temporal changes in myopia frequency by birth cohort (5-year bands using date of birth) and associations with environmental factors were analysed, distinguishing both type (childhood-onset, <18 years versus adult-onset) and severity (three categories: low -1.00 to -2.99D, moderate -3.00 to -5.99D or high ≥-6.00D). Overall myopia frequency increased from 20.0% in the oldest cohort (births 1939-1944) to 29.2% in the youngest (1965-1970), reflecting a relatively higher increase in frequency of adult-onset and low myopia. Childhood-onset myopia peaked in participants born in 1950-54, adult-onset myopia peaked in the cohort born a decade later. The distribution of MSE only shifted for childhood-onset myopia (median: -3.8 IQR -2.4, -5.4 to -4.4 IQR -3.0, -6.2). The magnitude of the association between higher educational attainment (proxy for educational intensity) and myopia overall increased over time (adjusted Odds Ratio (OR) 2.7 2.5, 2.9 in the oldest versus 4.2 3.3, 5.2 in the youngest cohort), being substantially greater for childhood-onset myopia (OR 3.3 2.8, 4.0 to 8.0 4.2, 13). Without delineating childhood-onset from adult-onset myopia, important temporal trends would have been obscured. The differential impact of educational experience/intensity on both childhood-onset and high myopia, amplified over time, suggests a cohort effect in gene-environment interaction with potential for increasing myopia frequency if increasing childhood educational intensity is unchecked. However, historical plateauing of myopia frequency does suggest some potential for effective intervention.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Integrating epigenetic data with genome-wide association study (GWAS) results can reveal disease mechanisms. The genome sequence itself also shapes the epigenome, with CpG density and transcription ...factor binding sites (TFBSs) strongly encoding the DNA methylome. Therefore, genetic polymorphism impacts on the observed epigenome. Furthermore, large genetic variants alter epigenetic signal dosage. Here, we identify DNA methylation variability between GWAS-SNP risk and non-risk haplotypes. In three subsets comprising 3128 MeDIP-seq peripheral-blood DNA methylomes, we find 7173 consistent and functionally enriched Differentially Methylated Regions. 36.8% can be attributed to common non-SNP genetic variants. CpG-SNPs, as well as facilitative TFBS-motifs, are also enriched. Highlighting their functional potential, CpG-SNPs strongly associate with allele-specific DNase-I hypersensitivity sites. Our results demonstrate strong DNA methylation allelic differences driven by obligatory or facilitative genetic effects, with potential direct or regional disease-related repercussions. These allelic variations require disentangling from pure tissue-specific modifications, may influence array studies, and imply underestimated population variability in current reference epigenomes.
Keratoconus is a relatively frequent disease leading to severe visual impairment. Existing therapies are imperfect and clinical management may benefit from improved understanding of mechanisms ...leading to this disease. We aim to investigate the replication of 11 single nucleotide polymorphisms (SNPs) with keratoconus.
SNPs from loci previously found in association with keratoconus were genotyped in 165 keratoconus cases of Caucasian Czech origin (108 males and 57 females) and 193 population and gender-matched controls. They included rs1536482 (COL5A1), rs4839200 (KCND3), rs757219 and rs214884 (IMMP2L), rs1328083 and rs1328089 (DAOA), rs2721051 (FOXO1), rs4894535 (FNDC3B), rs4954218 (MAP3K19, RAB3GAP1), rs9938149 (ZNF469) and rs1324183 (MPDZ). A case-control association analysis was assessed using Fisher's exact tests.
The strongest association was found for rs1324183 (allelic test OR = 1.58; 95% CI, 1.10-2.24, p = 0.01). Statistically significant values were also obtained for rs2721051 (allelic test OR = 1.72; 95% CI, 1.07-2.77, p = 0.025) and rs4954218 (allelic test OR = 1.53; 95% CI, 1.01-2.34; p = 0.047) which showed an opposite effect direction compared to previously reported one.
Independent replication of association between two SNPs and keratoconus supports the association of these loci with the risks for the disease development, while the effect of rs4954218 warrants further investigation. Understanding the role of the genetic factors involved in keratoconus etiopathogenesis may facilitate development of novel therapies and an early detection.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
To report the methodology and findings of a large scale investigation of burden and distribution of refractive error, from a contemporary and ethnically diverse study of health and disease in adults, ...in the UK.
U K Biobank, a unique contemporary resource for the study of health and disease, recruited more than half a million people aged 40-69 years. A subsample of 107,452 subjects undertook an enhanced ophthalmic examination which provided autorefraction data (a measure of refractive error). Refractive error status was categorised using the mean spherical equivalent refraction measure. Information on socio-demographic factors (age, gender, ethnicity, educational qualifications and accommodation tenure) was reported at the time of recruitment by questionnaire and face-to-face interview.
Fifty four percent of participants aged 40-69 years had refractive error. Specifically 27% had myopia (4% high myopia), which was more common amongst younger people, those of higher socio-economic status, higher educational attainment, or of White or Chinese ethnicity. The frequency of hypermetropia increased with age (7% at 40-44 years increasing to 46% at 65-69 years), was higher in women and its severity was associated with ethnicity (moderate or high hypermetropia at least 30% less likely in non-White ethnic groups compared to White).
Refractive error is a significant public health issue for the UK and this study provides contemporary data on adults for planning services, health economic modelling and monitoring of secular trends. Further investigation of risk factors is necessary to inform strategies for prevention. There is scope to do this through the planned longitudinal extension of the UK Biobank study.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
Refractive errors, in particular myopia, are a leading cause of morbidity and disability worldwide. Genetic investigation can improve understanding of the molecular mechanisms that underlie abnormal ...eye development and impaired vision. We conducted a meta-analysis of genome-wide association studies (GWAS) that involved 542,934 European participants and identified 336 novel genetic loci associated with refractive error. Collectively, all associated genetic variants explain 18.4% of heritability and improve the accuracy of myopia prediction (area under the curve (AUC) = 0.75). Our results suggest that refractive error is genetically heterogeneous, driven by genes that participate in the development of every anatomical component of the eye. In addition, our analyses suggest that genetic factors controlling circadian rhythm and pigmentation are also involved in the development of myopia and refractive error. These results may enable the prediction of refractive error and the development of personalized myopia prevention strategies in the future.
To test the association between serum metabolites and dry eye disease (DED) using a hypothesis-free metabolomics approach.
Cross-sectional association study.
A total of 2819 subjects from the ...population-representative TwinsUK cohort in the United Kingdom, with a mean age of 57 years (range, 17–82 years).
We tested associations between 222 known serum metabolites and DED. All subjects underwent nontargeted metabolomic analysis of plasma samples using gas and liquid chromatography in combination with mass spectrometry (Metabolon Inc., Durham, NC). Dry eye disease was defined from the validated Short Questionnaire for Dry Eye Syndrome (SQDES) as a previous diagnosis of DED by a clinician or “often” or “constant” symptoms of dryness and irritation. Analyses were performed with linear mixed effect models that included age, BMI, and sex as covariates, corrected for multiple testing.
Primary outcome was DED as defined by the SQDES, and secondary outcomes were symptom score of DED and a clinical diagnosis of DED.
Prevalence of DED as defined by the SQDES was 15.5% (n = 436). A strong and metabolome-wide significant association with DED was found with decreased levels of the metabolites androsterone sulfate (P = 0.00030) and epiandrosterone sulfate (P = 0.00036). Three other metabolites involved in androgen metabolism, 4-androsten-3beta,17beta-diol disulfate 1 and 2, and dehydroepiandrosterone sulfate, were the next most strongly associated of the 222 metabolites, but did not reach metabolome-wide significance. Dryness and irritation symptoms, as opposed to a clinical diagnosis, were particularly strongly associated with decreased androgen steroid metabolites, with all reaching metabolome-wide significance (androsterone sulfate, P = 0.000000029; epiandrosterone sulfate, P = 0.0000040; 4-androsten-3beta,17beta-diol disulfate 1, P = 0.000016; 4-androsten-3beta,17beta-diol disulfate 2, P = 0.000064; and dehydroepiandrosterone sulfate, P = 0.00011). Of these 5 androgens, epiandrosterone sulfate (P = 0.0076) was most associated with 2-year incidence of clinician-diagnosed DED. In addition, we found decreased glycerophosphocholines to be associated with DED, although not at metabolome-wide significance.
This hypothesis-free metabolomic approach found decreased serum androgens to be highly associated with DED and adds important evidence to the growing body of research that links androgens to ocular surface disease and DED.
Cataract is the leading cause of blindness among the elderly worldwide and cataract surgery is one of the most common operations performed in the United States. As the genetic etiology of cataract ...formation remains unclear, we conducted a multiethnic genome-wide association meta-analysis, combining results from the GERA and UK Biobank cohorts, and tested for replication in the 23andMe research cohort. We report 54 genome-wide significant loci, 37 of which were novel. Sex-stratified analyses identified CASP7 as an additional novel locus specific to women. We show that genes within or near 80% of the cataract-associated loci are significantly expressed and/or enriched-expressed in the mouse lens across various spatiotemporal stages as per iSyTE analysis. Furthermore, iSyTE shows 32 candidate genes in the associated loci have altered gene expression in 9 different gene perturbation mouse models of lens defects/cataract, suggesting their relevance to lens biology. Our work provides further insight into the complex genetic architecture of cataract susceptibility.
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