Biomedical subjects

Jeremy A Guggenheim

Publications and source records attributed to Jeremy A Guggenheim.

15 recordsLinked to original sources

PubMed2026

Variance Polygenic Scores (vPGS) as a Tool for Studying Gene-Environment Interactions Associated With Refractive Error.

PURPOSE: Conventional polygenic scores predict an individual's phenotype based on their genetics. By contrast, variance polygenic scores (vPGS) quantify genetic predisposition to phenotypic variance. We tested the hypothesis that a vPGS for refractive error can identify individuals with increased susceptibility to environmental risk factors for myopia. METHODS: Six vPGS construction strategies were evaluated in UK Biobank participants: three variance heterogeneity genome-wide association study (vGWAS) methods and two reweighting schemes. vPGS performance was assessed using two metrics: (i) "Diff"-difference in phenotypic variance in vPGS decile ten versus one; (ii) Spearman correlation of phenotypic variance versus vPGS decile. The optimal vPGS was used to test for vPGS × time spent reading or vPGS × time spent outdoors interactions in children aged 15 years (ALSPAC cohort; n = 3471). RESULTS: Of the vGWAS methods, conditional quantile regression outperformed SCAMPI and Levene's Test. Of the re-weighting schemes, LDpred2 outperformed pruning and thresholding. In an independent sample of UK Biobank participants (n = 19,470), the top-performing vPGS successfully stratified individuals into groups with increasing variance in refractive error, even after adjusting for a conventional PGS (Diff: 2.55, 95% confidence interval [CI], 1.64-3.47; Spearman correlation = 0.87; 95% CI, 0.43-0.93). However, in ALSPAC participants, there was minimal support for vPGS interactions with time reading (P = 0.80) or time outdoors (P = 0.89). CONCLUSIONS: A novel vPGS successfully stratified individuals into groups with relatively high or low genetic susceptibility to refractive error variance. However, the vPGS could not identify individuals at enhanced risk from lifestyle risk factors for myopia.

Humans↗

PubMed2026

Nonuniform Association of Genetic Risk Scores for Intraocular Pressure.

IMPORTANCE: Elevated intraocular pressure (IOP) is a risk factor for primary open-angle glaucoma, and genetic risk scores hold promise as a tool for screening for ocular hypertension. However, genetic risk scores for IOP have a nonuniform association across the range of IOP, which reduces their accuracy. OBJECTIVE: To test the hypothesis that nonuniform behavior of genetic risk scores for IOP is associated with a specific type of genetic interaction. DESIGN, SETTING, AND PARTICIPANTS: Cross-sectional, post hoc genetic association studies were performed using linear and quantile regression in a sample of UK Biobank participants. Data were analyzed from January to September 2025. EXPOSURES: Ninety-eight genetic variants associated with IOP. MAIN OUTCOMES AND MEASURES: Tests were carried out for 98 genetic variants associated with IOP (P < 5.0 ×10-8) to examine (1) dominant or recessive genetic effects, (2) genotype × genotype interactions, (3) genotype × age interactions, and (4) genotype × sex interactions. RESULTS: A total of 98 235 participants (mean [SD] age, 58.1 [7.9] years; 52 168 female [53.1%]) were included in this analysis. More variants exhibited genotype × age interactions than expected by chance (14 of the 98 variants associated with IOP had at least nominal evidence of an interaction with age; P = 3.76 ×10-4). For 12 of these 14 variants, age increased rather than decreased the magnitude of the IOP vs genotype association. However, integrating age interactions into the genetic risk score construction process did not yield improved accuracy (incremental noninteraction model, R2 = 4.05; 95% CI, 3.82-4.31 and interaction model, R2 = 4.04; 95% CI, 3.80-4.27). There was little support for other types of genetic interaction. CONCLUSIONS AND RELEVANCE: In the current work, findings show minimal evidence that nonadditive allelic effects, genotype × genotype interactions, and genotype × sex interactions contributed to the nonuniform association of genetic variants with IOP across quantiles of IOP. Although a genetic risk score for IOP was more accurate in older vs younger individuals, efforts to account for genotype × age interactions in genetic risk score construction did not improve accuracy. These findings suggest other factors, such as gene-environment interactions, contribute to the nonuniform relationship of genetic variants with IOP.

Humans↗

PubMed2026

Genome-wide discovery reveals 30 loci for choroidal thickness and uncovers potential causal links with angle-closure glaucoma.

The choroid is critical for maintaining vision and implicated in several ocular diseases, being the sole source of nutrients and waste removal for the outer retina. Genetic discovery can help elucidate the pathways through which choroidal features influence disease risk. Our meta-analysis of genome-wide association studies (n= 78,682 participants) identified 30 genomic regions, including 20 novel loci, associated with choroidal thickness. Findings suggest inflammatory and vascular processes drive choroidal thickness, with overlapping mechanisms shared with refractive error. Genome-wide independently significant SNPs accounted for 18.7% of the genetic variance in choroidal thickness. Mendelian randomisation analyses showed a causal effect of age-related macular degeneration on choroidal thickness, and suggest a bidirectional causal effect between choroidal thickness and primary angle-closure glaucoma. These findings provide insight into the shared genetic architecture and biological pathways linking choroidal thickness and related diseases.

Canadian Longitudinal Study on Aging↗

PubMed2006

Correlations in refractive errors between siblings in the Singapore Cohort Study of Risk factors for Myopia.

BACKGROUND: The prevalence of myopia in parts of South East Asia has risen dramatically over the past 1-2 generations, suggesting that environmental factors may be particularly important determinants of refractive development in these populations. AIM: To assess the contribution of familial factors (shared genes and/or shared family environment) to refractive error and ocular component dimensions of school-aged children in Singapore. METHODS: Data were available for 315 children who had one or more siblings also participating in the Singapore Cohort Study of the Risk factors for Myopia (SCORM). Refractive error and ocular biometric parameters were measured under cycloplegia at baseline when children were 7-9 years, and at yearly follow-up sessions for the next 3 years, using consistent clinical procedures. The time children spent performing a variety of nearwork-related tasks was obtained from questionnaires. Familial influences were assessed by calculating between-sibling correlations. RESULTS: After adjusting for age and sex, the between-sibling correlation in refractive error was 0.447 (95% CI 0.314 to 0.564), suggesting that familial factors account for 63-100% of the variation in the cohort. The between-sibling correlation for 1-year change in refractive error was similarly high, at 0.420 (95% CI 0.282 to 0.543). All ocular component dimensions were correlated significantly between siblings, especially for corneal curvature and vitreous chamber depth--the major structural determinants of refraction. The amount of time siblings spent engaged in nearwork tasks (reading, watching TV, playing video games, computing) and in outdoor activities was also highly correlated between siblings (p<0.001). CONCLUSION: Shared genes and/or shared environment are important factors in the refractive development of children in Singapore. Because the time spent in nearwork tasks is highly correlated between siblings, epidemiological studies will benefit from precise, quantitative measures of refractive error in parents and more distant relatives in order to begin to dissociate genetic and environmental sources of variation.

Biometry↗

PubMed2006

Is active glucose transport present in bovine ciliary body epithelium?

Hyperglycemia is a major risk factor for diabetic cataract formation. Effective regulation of glucose transport by the ciliary body epithelium (CBE) is pivotal to normal glycemic control in the anterior eye, which in turn affects the glucose level of the crystalline lens. The present study aimed to characterize the glucose transport mechanisms across the bovine blood-aqueous barrier (BAB) represented by the CBE. With an Ussing-type chamber, the glucose transport kinetics were measured and characterized in the presence and absence of various glucose transporter inhibitors. The saturation characteristics of the CBE to glucose were estimated from an Eadie-Hofstee plot. The mRNA expression of glucose transporters in specific regions of the bovine CBE was assessed using RT-PCR. The trans-CBE glucose flux was found to be sensitive to the glucose transporter inhibitors cytochalasin B, phloretin, and phlorizin. The transport system had a kinetic constant of 5.3 mM and a maximum velocity of 349.5 nmol.h(-1).cm(-2). Gene expression for GLUT1, GLUT3, GLUT4, GLUT5, and SGLT2 was observed in both the pars plana and pars plicata regions of the bovine CBE. This study demonstrates that glucose transport across the bovine CBE is primarily passive in nature. However, the novel findings of 1) the presence of a phlorizin-sensitive glucose flux and 2) gene expression for SGLT2 mean that a potential role for active glucose transport cannot be ruled out. The elucidation of the exact function of SGLT2 in the bovine CBE may shed important light on the glucose transport and physiology of the BAB and inform future studies of glycemic control in relation to diabetic cataract formation.

Animals↗

PubMed2006

Proteases in eye development and disease.

The eye is one of the classical systems in developmental biology. Furthermore, diseases of the eye, many of which have a developmental basis, have devastating effects that often result in blindness. Proteases have diverse roles in ocular physiology and pathophysiology. Here, a broad overview is provided of the recent literature pertaining to the involvement of proteases in various aspects of eye development and disease: lens development (focusing on apoptosis and lens fiber cell denucleation and organelle loss) and cataract progression, cornea development and disease, retina development and degeneration, sclera development and myopia, and the trabecular meshwork and glaucoma. Proteases discussed include caspases, calpains, matrix metalloproteases (MMPs), a disintegrin and metalloproteinases (ADAMs) and ADAM with thrombospondin motifs (ADAMTS), the ubiquitin-proteasome pathway (UPP), tissue plasminogen activator (tPA), and secretases. It is clear that proteases have diverse and important roles in ocular development and disease, and represent, in many cases, useful therapeutic targets for treating ocular conditions, which would otherwise lead to visual impairment.

Animals↗

PubMed2006

A chick retinal proteome database and differential retinal protein expressions during early ocular development.

Proteomics approach as a research tool has gained popularity in a growing number of basic and clinical researches. However, proteomic research has yet to gain significant momentum in eye research. Hence, we decided to build a retinal proteome database using postnatal retinal tissue from chick, a commonly used animal model in eye research. Employing 2-D gels with the coverage of 3-10 pH gradients, we were able to resolve hundreds of proteins from young chick retinae. Among them, 155 high abundant proteins were identified by Peptide Mass Fingerprinting (PMF) after the Matrix-Assisted Laser Desorption Ionization-Time-of-Flight Mass Spectrometry (MALDI-TOF MS). These proteins were then classified according to their functions. Making use of the retinal database, we were able to identify several differentially expressed proteins that might be involved in early retinal development by comparing the 2-DE maps of chick retinal tissues (3, 10, and 20 days after hatching). With the current proteomics approach, we not only documented the most abundant soluble proteins in the chick retinal tissue, but also demonstrated the dynamic protein expression changes during early ocular development. This represents one of the first steps in building a complete protein database in chick retinae which is applicable to the study of eye diseases from a few selected protein candidates to the whole proteome. Proteomic technology may provide a high throughput platform for advancing eye research in the feasible future.

Animals↗

PubMed2005

Anisometropia is independently associated with both spherical and cylindrical ametropia.

PURPOSE: To explore the associations between anisometropia and spherical ametropia, astigmatism, age, and sex. METHOD: Associations between the prevalence and magnitude of anisometropia with age, sex, spherical power, and cylindrical power, were assessed in a group of 90,884 subjects attending optometry practices in the United Kingdom. Logistic regression models were used to assess the independent contribution of each explanatory variable. RESULTS: Logistic regression analyses that included all subjects or just those aged 20 to 40 years showed that spherical ametropia and astigmatism were independently associated with anisometropia (myopes, P < 1.0E-61; hyperopes, P < 1.0E-11). Anisometropia was relatively stable between the ages of 20 and 40 years, but then became more common with age, in myopes from the age of 40 years onward (P < 0.003) and in hyperopes from the age of 70 years onward (P < 1.0E-6). Sex was not associated with anisometropia to a clinically significant extent. CONCLUSIONS: This is the first study to show an independent association between anisometropia and both spherical ametropia and astigmatism. The results also suggest that the previously noted increased prevalence of anisometropia with age occurs later in hyperopes than in myopes, once other covariates have been controlled for. However, it could not be ruled out that this latter effect was due to clinical selection bias in our sample. The findings suggest that research projects involving the recruitment of highly ametropic subjects, such as those investigating the genetics of refractive error, may benefit by avoiding the use of stringent inclusion criteria for anisometropia, because otherwise a large proportion of the relevant population will be excluded.

Adolescent↗

PubMed2004

Chloride channel gene expression in the rabbit cornea.

PURPOSE: The maintenance of stromal hydration by the corneal endothelium relies on active transendothelial anion transport, with bicarbonate and chloride the major anions carrying the current. However, the ion transport pathways that operate to maintain stromal hydration have yet to be fully elucidated. METHODS: We used RT-PCR to identify the gene expression profile of members of the ClC family of chloride channels in freshly isolated samples of rabbit corneal endothelium, stroma, and epithelium. The expression of a separate group of genes was also examined to confirm the purity of the sample collection protocol. The expression of the ClC-2 and ClC-3 channel protein in the cornea was also evaluated by light and electron microscopic immunolabelling. RESULTS: The mRNA for ClC-2, ClC-3, ClC-5, ClC-6, and ClC-7 were expressed in both the corneal epithelium and endothelium, and in the stroma. The mRNA for the skeletal muscle specific channel ClC-1 and the kidney specific chloride channel ClC-Ka were not detectable. ClC-4 mRNA was not detected in any rabbit tissue examined. The expression pattern of the mRNAs for collagens V, VI, VII, and VIII demonstrated the absence of contamination in epithelial and endothelial samples. ClC-2 and ClC-3 immunolabelling confirmed the presence of these proteins in corneal endothelium, stroma, and epithelium. CONCLUSIONS: Together with cystic fibrosis transmembrane conductance regulator (CFTR) and calcium activated chloride channel-1 (CLCA1), these results bring the number of chloride channel genes known to be expressed in the corneal endothelium and epithelium to seven. These channels are likely to be important for the maintenance of corneal transparency.

Animals↗

PubMed2004

Astigmatic axis is related to the level of spherical ametropia.

PURPOSE: Against-the-rule (ATR) astigmatism has been shown to be a risk factor for subsequent myopia development. In this study, we evaluated the relationship between astigmatic axis and the level of spherical ametropia in both myopes and hypermetropes. METHODS: Astigmatic axes were analyzed in two distinct cohorts. First, 53 high myopes from families that were recruited for linkage analysis were compared with an age-matched control group derived from family members. Second, cross-sectional data were analyzed for 90,884 subjects attending 19 optometric practices in the north of England. Initially, the relationship between astigmatic axis and cylinder power and between axis and sphere power were analyzed in 21- to 40-year olds and 21- to 30-year olds, respectively, to control for the effects of age. Multivariate logistic regression analysis was then performed using data for all compound astigmats in the cohort to examine the effect of sphere power, cylinder power, age, and sex on the odds of subjects having either ATR or with-the-rule (WTR) astigmatism. RESULTS: In the genetic study cohort, there was an excess of WTR astigmats in the high myopes compared with controls, but this only reached significance for the right eye. In the much larger optometric practice sample, the association of WTR astigmatism with high myopia was highly significant. A parallel increase in WTR astigmatism was also found for high hypermetropes. In addition, the odds of having WTR astigmatism were increased if subjects were young or had a high cylinder power. ATR astigmatism occurred more often with increasing age and in subjects with lower spherical ametropia. Indeed, for 21- to 30-year-old subjects with low myopia (> or =-2.00 DS in the least minus meridian), ATR occurred more often than WTR astigmatism. CONCLUSION: Astigmatic axis was found to be related to the level of ametropia, with both a higher spherical component or higher cylinder power increasing the odds of astigmatism being WTR. Low ametropes, particularly myopes, were more likely to have axes ATR.

Adolescent↗

PubMed2004

The association between spherical and cylindrical component powers.

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Eyeglasses↗

PubMed2004

Family aggregation of high myopia: estimation of the sibling recurrence risk ratio.

PURPOSE: To estimate the sibling recurrence risk (KS) and the sibling recurrence risk ratio (lambda(S)) for high myopia in a cohort in the United Kingdom. METHOD: The recurrence risks for myopia and high myopia were estimated in the siblings of 296 randomly selected high myopes ascertained from an optometric practice population. A model using an age of onset of spectacle wear for myopia of 9.1 +/- 0.7 years or younger was developed as a surrogate for high myopia. The influence of parental myopia on the sibling recurrence risk for high myopia was also evaluated. RESULTS: KS was estimated (95% confidence limits) to be 10.0% (5.9, 14.8) and lambdaS to be 4.9 (2.8, 7.6). High myopes without myopic parents were surprisingly common ( approximately 40%) and were less likely to have highly myopic siblings (KS approximately 6%) than those with at least one myopic parent (KS approximately 14%). CONCLUSIONS: The sibling recurrence risk ratio reported herein (lambdaS approximately 4.9) implies that the high penetrance autosomal dominant loci for high myopia identified to date account for only a minority of cases of high myopia in the United Kingdom. Furthermore, high-penetrance autosomal dominant inheritance or even high-penetrance recessive inheritance, per se, cannot account for most cases of high myopia. Instead, it may be necessary to consider high myopia as a "complex disease" resulting from the influence of either alleles of reduced penetrance ("susceptibility genes"), environmental factors, or both.

Adolescent↗

PubMed2004

Linkage analysis of the genetic loci for high myopia on 18p, 12q, and 17q in 51 U.K. families.

PURPOSE: To determine the extent to which high myopia in a cohort of 51 U.K. families can be attributed to currently identified genetic loci. METHODS: The families comprised 245 subjects with phenotypic information and DNA available, of whom 170 were classified as affected. Subjects were genotyped for microsatellite markers spanning approximately 40cM regions on 18p (MYP2), 12q (MYP3) and 17q, together with markers flanking COL2A1, COL11A1, and FBN1. Two-point linkage analyses were performed using the same disease gene segregation model as was used in the original publications, followed by nonparametric and multipoint analyses using Genehunter (http://linkage.rockefeller.edu/soft/gh/ provided in the public domain by Rockefeller University, New York, NY), with additional maximization over the parameter alpha, the proportion of linked families. RESULTS: Evidence of linkage was found for the MYP3 locus on 12q (two-point Zmax = 2.54, P = 0.0003 and multipoint hLOD = 1.08 at alpha = 0.24, P = 0.023 for marker D12S332; nonparametric linkage [NPL] = 1.49, P = 0.07 for marker D12S1607). For the 17q locus there was weak evidence of excess allele sharing and linkage under a recessive model (NPL = 1.34, P = 0.09 for marker D17S956; two-point hLOD = 1.24 at alpha = 0.30 for marker D17S1795; multipoint hLOD = 1.24 at alpha = 0.17, P = 0.014 for marker at 77.68 cM, between markers D17S956 and D17S1853). No significant linkage was found to the MYP2 locus on 18p, or to the COL2A1, COL11A1, and FBN1 genes. CONCLUSIONS: These results suggest that the MYP3 locus on 12q could be responsible for high myopia in approximately 25% of the U.K. families showing apparent autosomal dominant transmission, but that the loci on 18p and 17q are less common causes. Thus, additional loci for high myopia are likely to be the cause of the majority of cases of high myopia in the United Kingdom.

Chromosome Mapping↗

PubMed2002

Similar genetic susceptibility to form-deprivation myopia in three strains of chicken.

Myopia development in humans depends on a complex interplay between genetic and environmental factors. Many of those who become myopic when exposed to a myopigenic environment are likely to do so because of a genetic susceptibility, whereas others somehow remain immune. In the most intensively studied model of environmentally induced myopia, form-deprivation myopia in the chick, there is convincing evidence of differential genetic susceptibility to myopia development, both within-strains and between-strains. To date, however, these have involved relatively small differential responses. The aim of this investigation was to examine genetic susceptibility to a highly uniform regimen of form-deprivation in three strains of chick (white leghorn, brown leghorn and broiler) expected to differ greatly in genetic background and in normal eye size, and to gauge the potential for mapping the quantitative trait loci (QTL) underlying this differential susceptibility. Despite striking differences in normal eye size, all three strains studied developed a similar degree of induced myopia. Whilst the degree of induced vitreous chamber elongation differed significantly between-strains, it was concluded that the high within-strain variation in the response to form-deprivation would prevent the effective application of QTL mapping approaches to identify genes conferring this susceptibility. In contrast, the strains used here would be ideal for use in mapping QTL controlling normal ocular component dimensions.

Analysis of Variance↗

PubMedDate not supplied

Postnatal refractive development in the Brown Norway rat: limitations of standard refractive and ocular component dimension measurement techniques.

PURPOSE: The genetic tractability of the rat and its larger eye size as compared to the mouse make it an attractive model for studies of ocular development and emmetropisation. This study aimed to provide normative data in the strain of rat being used for the rat genome sequencing project whilst also evaluating standard measurement techniques. METHODS: Ocular refraction (retinoscopy, Hartinger coincidence optometry) and ocular component dimensions (keratometry, A-scan ultrasonography, calliper measures, eye weight) were measured at intervals from eye-opening to adulthood. RESULTS: There was no convincing evidence of visually guided emmetropisation during normal development. Key measurement techniques such as high-resolution A-scan ultrasonography, which work effectively in several other animal species, were unusable or inaccurate in the rat. CONCLUSIONS: This study found no evidence of emmetropisation during normal development in rat. As in mice, technical difficulties prevent accurate measurement of ocular refraction and vitreous chamber depth and may complicate tests of emmetropisation to imposed blur.

Aging↗