Inheritance of open‐angle glaucoma in the Barbados family study

The majority of genetic studies on open‐angle glaucoma (OAG) have been conducted in primarily white populations, with investigations of inheritance patterns largely based on self‐reported information. The Barbados Family Study of Open‐Angle Glaucoma (BFSG) is the first study to investigate the transmission pattern(s) for OAG in a predominantly black population, based on standardized examinations. Each BFSG participant received a comprehensive examination including anthropometric and other measurements, best‐corrected visual acuity, perimetry, tonometry, lens gradings, fundus photography, venipuncture, an extensive interview including ocular, medical and family history information and a comprehensive ophthalmologic evaluation. Conservative criteria were used to define glaucoma status, including the presence of both visual field defects and optic disc damage. The study included 207 OAG‐affected probands (median age: 68 years) and 1,056 of their relatives (median age: 47 years). Among the relatives examined 10% (n = 106) had OAG and 13% (n = 141) had probable OAG. Segregation analyses were performed to determine the mode of inheritance for glaucoma in these families. The results indicate that transmission of OAG or probable OAG is most likely due to a major codominant gene. Both age and gender are shown to be significant factors as well; with an increase in risk being associated with each year of age over 54 years and an increase in risk for all ages and genotypes observed in males. These analyses do not, however, preclude the possible existence of an environmental component or other genetic determinants in OAG. Further evidence for the existence of a major gene may be obtained by additional follow‐up of the relatively young cohort of relatives, as well as ongoing linkage analyses. © 2001 Wiley‐Liss, Inc.     

Evidence of a major gene effect for angiotensinogen among Nigerians

To dissect the genetic pathway of hypertension, we measured angiotensinogen in 685 members of 186 families recruited from a rural community in southwest Nigeria. Commingling and segregation analyses were carried out. A mixture of two and/or three distributions fits the data significantly better than a single distribution in commingling analysis, suggesting a major gene effect. Segregation analysis confirmed that a recessive major gene model for low values of angiotensinogen provides the best fit to the data and about 13% of the variance was due to the recessive gene segregation.     

Family resemblance for fasting blood glucose: the Jerusalem Lipid Research Clinic

Familial aggregation of fasting plasma glucose was studied in a sample of families examined at the Jerusalem Lipid Research Clinic. We first examined homogeneity of familial correlations across major origin groups in the Israeli sample. Correlations were generally homogeneous across origin groups, except for mother-son pairs. The pooled familial correlations were relatively low for unadjusted blood glucose values, and somewhat higher upon adjustment for sex, age, ethnicity, education, seasonality, body mass, cigarette smoking, alcohol consumption and dietary intake. Genetic and cultural determinants of blood glucose were estimated utilizing a path model with 10 parameters to be estimated from a total of 16 correlations. Under a reduced model genetic heritability (h2) was estimated to be 0.18 +/- 0.08 and cultural heritability (c2) was 0.10 +/- 0.02. However, within this population the additive variation could be explained by a cultural model of inheritance without introducing genetic parameters, and most of the variance is due to "random" unmeasured environmental factors. Commingling analysis was also performed, and our findings imply that there is no evidence for admixture in the distribution of fasting blood glucose in this Israeli population sample.     

3D simulation of the aqueous flow in the human eye

Glaucoma results in an increase in the resistance of the aqueous humor outflow, which in turn leads to an increase of the intraocular pressure (IOP). Several treatments are proposed to reduce and stabilize the IOP that include medications, filtering surgery and glaucoma drainage devices (GDD). So far computational fluid dynamics (CFD) modeling of the eye drainage system has not yet been well studied. Therefore our goal was to provide a 3D CFD model of the eye based on the anatomy of a real human eye. Such a tool would serve for future evaluation of new glaucoma surgical techniques involving, for example, GDD. The model was based on stacks of microphotographs from human eye slides from which digital processing of the images of the eye structure and 3D reconstruction of the model were performed. Simulations of the distribution of pressure and flow velocity in the model of a healthy eye gave results comparable to physiology references. Mimicking glaucoma conditions led to an increase of the IOP from normal range, which went down to lower values after a filtering procedure. Further refinements in the boundary conditions for the filtering procedure shall improve the accuracy of this innovative tool for modeling glaucoma surgery.     

Glaucoma is an autoimmune disease

Glaucoma is characterized by retinal ganglion cell (RGC) neurodegeneration. Elevated intraocular pressure (IOP) is a major risk factor however, mechanisms independent of IOP play a role in RGC pathology. Both antibodies and CD4 T–cells as well as microbiota take part in the pathogenesis of both glaucoma and rheumatoid arteritis (RA).Heat shock proteins (HSPs) which originate in bacteria cross-react with RCG epitopes and were involved in rat model of retinal injury. Enhanced expression of HSPs in the retina was associated with glaucoma-like neuropathology and previous studies have also suggested a pathogenic role for HSPs in RA. In view of these data we suggest that glaucoma should be included in the spectrum of autoimmune diseases and that proven medications for RA should be adopted as an innovative IOP –independent therapeutic strategy for glaucoma.     

Commingling and segregation analysis of reading performance in families of normal reading probands

This paper reports the results of commingling and genetic segregation analyses performed on a quantitative reading phenotype in 125 families ascertained through normal, nondisabled readers. Commingling analysis using SKUMIX suggested that the reading phenotype best fit a skewed, single distribution model. Complex segregation using POINTER was then performed on the power adjusted data. While there were some analytical ambiguities and complexities, the segregation analysis indicated that there was familial transmission of the phenotype and that a significant percentage of the variance in this phenotype could be attributed to a major gene with dominance. Because the estimated frequency of the putative dominant allele is 35, 57% of the population would carry at least one copy of this allele. This common allele, with low penetrance, accounted for 54% of the phenotypic variance in reading scores. These findings are considered in the context of our earlier report of major gene influence on a qualitative dyslexic phenotype in a sample of 133 dyslexic proband families that were originally matched to the present sample of control families (Penningtonet al., 1991). The applicability of a classic single gene, multifactorial-polygenic, and oligogenic or QTL models for reading ability/disability is discussed.     

Genetic heterogeneity of primary open angle glaucoma and ocular hypertension: linkage to GLC1A associated with an increased risk of severe glaucomatous optic neuropathy.

The GLC1A locus for autosomal dominant juvenile and middle age onset primary open angle glaucoma (OAG) has been mapped to chromosome 1q21-q31. OAG, however, is a heterogeneous disease. We tested linkage of OAG and ocular hypertension (OHT), a major risk factor for OAG, to GLC1A in eight French families with multiple cases of juvenile and middle age onset OAG. There was strong evidence of genetic heterogeneity, four families being linked to GLC1A and two or three others being unlinked, depending on whether the complete OAG phenotype was analysed alone or jointly with OHT. Peak intraocular pressure (IOP) did not differ significantly between the two groups of families, while linkage to GLC1A conferred a highly increased risk of developing OAG and of having severe glaucomatous optic neuropathy. Testing linkage of familial OAG to GLC1A may therefore have prognostic value too.     

Stress reactivity of intraocular pressure after relaxation training in open-angle glaucoma patients

The present study was based on the hypothesis that stress may contribute to increased intraocular pressure (IOP) in open-angle glaucoma patients. It is investigated whether IOP reactivity to a mental stressor test (MST) can be influenced by relaxation training. Twenty three patients with open-angle glaucoma were randomly assigned either to a training group (TG) or to a waiting-list control group (CG). Prior to as well as after the completion of the training all patients were exposed to the MST. IOP and heart rate as well as self-ratings of psychological strain were assessed three times: (1) at baseline, (2) after exposition to the stressor, and (3) after a 10-min relaxation phase. Results provide evidence that the MST is a valid procedure to induce psychophysiological activation and that elevated IOP levels in open-angle glaucoma patients might be provoked by stressing situations. However, participation in the relaxation training did not influence IOP stress reactivity.     

Suggestive evidence of genetic association of −572G > C polymorphism with primary open angle glaucoma in a North Indian Punjabi population

BackgroundIL6 is an important candidate gene implicated in the pathogenesis of glaucoma. The present study assessed the genetic association of −174G > C and −572G > C polymorphisms in the IL6 promoter region with primary open angle glaucoma (POAG) and primary angle closure glaucoma (PACG) in a north Indian Punjabi cohort.Methods910 subjects (313 POAG, 148 PACG cases and 449 controls) were recruited. Genotyping was done by TaqMan assays. Genetic association was tested under different genetic models using Plink. Diplotype and linkage disequilibrium (LD) analysis was done through Haploview. Association of clinical parameters with the genotypes was assessed by one-way ANOVA. Adjustment for potential confounding variables was done by binary logistic regression. IL6 levels were measured in POAG patients and controls.Results572G > C variant showed marginal difference in genotype frequency between pooled cases and POAG subgroup with respect to controls (p = 0.042; OR = 1.33; and p = 0.041; OR = 1.37). The GC genotype conferred 1.37-fold protection under codominant model in POAG cases (p = 0.034, OR = 1.37, 95% CI = 1.02–1.85; p_corr = 0.025, OR = 1.45, 95% CI = 1.04–2.02). The mean value for IOP was elevated among cases having ‘CC’ genotype at the −572G > C locus (p = 0.037).Lower levels of IL6 were detected in POAG patients in plasma samples (p = 0.0001).ConclusionThe study reports suggestive evidence for −572G > C variant in IL6 in affecting genetic susceptibility to POAG in the targeted North Indian Punjabi cohort. A correlation of IL6 levels in aqueous humor (AH) and systemic circulation in POAG was observed, the functional and diagnostic relevance of which may be further investigated.     

The Genetic Structure of Human Populations Studied Through Short Insertion-Deletion Polymorphisms

In a landmark study Rosenberg et al. (2002) analyzed human genome diversity with 377 microsatellites in the HGDP‐CEPH Genome Diversity Panel and reported that the populations were structured into five geographical regions: America, Sub‐Saharan Africa, East Asia, Oceania and a cluster composed of Europe, the Middle East and Central Asia. They also observed that the within‐population component accounted for 93–95%, and that the among‐regions portion was only 3.6%, of the total genetic variance. We have also studied the HGDP‐CEPH Diversity Panel (1064 individuals from 52 populations) with a set of 40 biallelic slow‐evolving short insertion‐deletion polymorphisms (indels). We confirmed the partition of worldwide diversity into five genetic clusters that correspond to major geographic regions. Using the indels we have also disclosed an among‐regions component of genetic variance considerably larger (12.1%) than had been estimated using microsatellites. Our study demonstrates that a set of 40 well‐chosen biallelic markers is sufficient for the characterization of human population structure at the global level.     

Discovery and Functional Assessment of Gene Variants in the Vascular Endothelial Growth Factor Pathway

Angiogenesis is a host‐mediated mechanism in disease pathophysiology. The vascular endothelial growth factor (VEGF) pathway is a major determinant of angiogenesis, and a comprehensive annotation of the functional variation in this pathway is essential to understand the genetic basis of angiogenesis‐related diseases. We assessed the allelic heterogeneity of gene expression, population specificity of cis expression quantitative trait loci (eQTLs), and eQTL function in luciferase assays in CEU and Yoruba people of Ibadan, Nigeria (YRI) HapMap lymphoblastoid cell lines in 23 resequenced genes. Among 356 cis‐eQTLs, 155 and 174 were unique to CEU and YRI, respectively, and 27 were shared between CEU and YRI. Two cis‐eQTLs provided mechanistic evidence for two genome‐wide association study findings. Five eQTLs were tested for function in luciferase assays and the effect of two KRAS variants was concordant with the eQTL effect. Two eQTLs found in each of PRKCE, PIK3C2A, and MAP2K6 could predict 44%, 37%, and 45% of the variance in gene expression, respectively. This is the first analysis focusing on the pattern of functional genetic variation of the VEGF pathway genes in CEU and YRI populations and providing mechanistic evidence for genetic association studies of diseases for which angiogenesis plays a pathophysiologic role.     

Multiple‐threshold models for genetic influences on age of onset for Alzheimer disease: Findings in Swedish twins

Twin studies of dementia have typically used relatively simple 2 × 2 contingency tables with one threshold to estimate the relative importance of genetic variance for liability to disease. These designs are inadequate for addressing issues of age at onset, censoring of data, and distinguishing shared environmental effects from age effects. Meyer and Breitner [ 1998 : Am J Med Genet 81:92–97] applied a multiple‐threshold model to the NAS‐NRC Twin Panel (average age of onset, 63.5 years) and report that additive genetic effects and shared environmental effects account for 37% and 35% of the variation, respectively, in age of onset for Alzheimer disease. We apply a modified version of their model to the Study of Dementia in Swedish Twins (average age of onset, 75 years) and find that genetic effects account for 57%–78% of the variance, whereas shared environmental effects are of no importance. Heritability is lower when thresholds are freely estimated rather than fixed to the population prevalences. We interpret the findings to suggest that models with free thresholds confound influences on longevity with influences for the disease. Multiple‐threshold models, however, do not confound age effects with shared environmental influences. © 2001 Wiley‐Liss, Inc.     

T-cell-based vaccination for morphological and functional neuroprotection in a rat model of chronically elevated intraocular pressure

Acute or chronic glaucoma is often associated with an increase in intraocular pressure (IOP). In many patients, however, therapeutic pressure reduction does not halt disease progression. Neuroprotection has been proposed as a complementary therapeutic approach. We previously demonstrated effective T-cell-based neuroprotection in experimental animals vaccinated with the synthetic copolymer glatiramer acetate (copolymer-1, Cop-1), a weak agonist of self-antigens. This study was undertaken to test different routes and modes of vaccination with Cop-1 as treatment modalities for protection against retinal ganglion cell (RGC) death caused by chronic elevation of IOP in rats, and to determine whether anatomical neuroprotection is accompanied by functional neuroprotection. In a chronic model of unilaterally high IOP, Cop-1 vaccination, with or without an adjuvant, protected rats against IOP-induced loss of RGCs by eliciting a systemic T-cell-mediated response capable of cross-reacting with self-antigens residing in the eye. In rats deprived of T cells, Cop-1 (unlike treatment with ₂-adrenoreceptor agonists) was not protective of RGCs, substantiating the contention that its beneficial effect is not conferred directly but is T-cell-mediated. Pattern electroretinography provided evidence of functional protection. Thus, vaccination with adjuvant-free Cop-1 can protect RGCs from the consequences of elevated IOP in rats. This protection is manifested both morphologically and functionally. These findings can be readily implemented for the development of a therapeutic vaccination to arrest the progression of glaucoma.     

Detecting natural selection in high-altitude human populations

High-altitude natives have distinctive biological characteristics that appear to offset the stress of hypoxia. Evolutionary theory reasons that they reflect genetic adaptations resulting from natural selection on traits with heritable variation. Furthermore, high-altitude natives of the Andean and Tibetan Plateaus differ from one another, perhaps resulting from different evolutionary histories. Three approaches have developed a case for the possibility of population genetic differences: comparing means of classical physiological traits measured in samples of natives and migrants between altitudes, estimating genetic variance using statistical genetics techniques, and comparing features of species with different evolutionary histories. Tibetans have an inferred autosomal dominant major gene for high oxygen saturation that is associated with higher offspring survival, a strong indicator of ongoing natural selection. New approaches use candidate gene and genomic analyses. Conclusive evidence about population genetic differences and associations with phenotypes remains to be discovered.     

A sequence change (Arg158Gln) in the leucine zipper-like motif region of the MYOC/TIGR protein

The myocilin/trabecular meshwork-inducible glucocorticoid response (MYOC/TIGR) gene was identified as a gene that caused open angle glaucoma (OAG). Single-strand conformation polymorphism analysis and subsequent sequence analysis were performed for the MYOC/TIGR gene in 120 unrelated Japanese OAG patients with increased intraocular pressure (IOP), 116 unrelated OAG patients without increased IOP, and 106 unrelated control subjects without glaucoma. An Arg158Gln sequence change in the leucine zipper-like motif (LZM) region in the myosin-homology domain was found in 2 OAG patients with or without increased IOP, and in a 56-year-old control subject without glaucoma. This is the first report of missense sequence change in the LZM region of the MYOC/TIGR protein in subjects showing various phenotypes, including a control subject. These findings suggest that Arg158Gln in the LZM region is probably a rare nondisease-causing polymorphism, despite its important role in this region, because it was found in a control subject, although Arg158Gln was previously reported as a probable disease-causing mutation. Received: September 11, 2000 / Accepted: November 17, 2000     

Complement mediated apoptosis leads to the loss of retinal ganglion cells in animal model of glaucoma

This study investigated the role of complement in the protection of retinal ganglion cells (RGCs) in chronic ocular hypertension model of glaucoma. Intraocular pressure (IOP) was elevated in the right eye of Lewis rats by laser photocoagulation (two treatments, 7days apart) of episcleral and limbal veins. Left eye did not receive laser treatment and served as control. Animals were injected with cobra venom factor every fifth day starting day 7 after first laser, to deplete the complement system. Animals were sacrificed at 6-week post-laser. Levels of C3 split products and membrane attack complex (MAC) were elevated in the retina of eyes with increased IOP and complement depletion reduced the loss of Brn3a(+) RGCs accompanied by decreased expression of GFAP and reduced MAC deposition. In complement depleted rats with increased IOP, reduced TUNEL(+) cells in ganglion cell layer, and decreased levels of active caspase-8 and active caspase-9 was observed compared to PBS treated complement sufficient rats with increased IOP. Interestingly, complement depletion also resulted in reduction of calcium influx and levels of BAD in the retinal cells of the eyes with increased IOP. Together, our results provide evidence that complement mediated apoptosis plays a pivotal role in the loss of RGCs in chronic ocular hypertension model of glaucoma.     

Variance components analysis of forced expiration in families

Familial aggregation of forced expiration (as measured by forced expiratory volume in 1 sec (FEV1) and the ratio of this to total forced vital capacity (FEV1/FVC) was analyzed in 439 adult members of 108 families ascertained through control patients who had participated in a genetic and epidemiologic study of chronic obstructive pulmonary disease. Residual values for both FEV1 and FEV1/FVC obtained from regression on age, sex, race, and cigarette smoking (and height for FEV1) were used in a variance components analysis to assess the relative importance of genetic and nongenetic factors influencing familial aggregation of pulmonary function among adults. For both residual FEV1 and residual FEV1/FVC, the "best" model among a series of genetic and nongenetic models was a simple additive genetic model. A modified score test, which is robust to the assumption of multivariate normality, was used to test the significance of these estimated components. Under the most parsimonious model, additive genetic variation accounted for 28% of the variation in residual FEV1 in 108 families and 24% of the variation in residual FEV1/FVC. After outlying individuals were identified by examining goodness-of-fit statistics, the simple genetic model still gave the best fit to these data. There was little indication of non-normality in FEV1 in these families; however, FEV1/FVC did show evidence of non-normality when examining goodness-of-fit statistics. This genetic component contributing to the distribution of forced expiration may be a factor in the familial aggregation of certain respiratory diseases.     

Designing assisted living technologies ‘in the wild’: preliminary experiences with cultural probe methodology

Background

Primary open-angle glaucoma (POAG) is one of the leading causes of blindness in the United States and worldwide. While lowering intraocular pressure (IOP) has been proven to be effective in delaying or preventing the onset of POAG in many large-scale prospective studies, one of the recent hot topics in glaucoma research is the effect of IOP fluctuation (IOP lability) on the risk of developing POAG in treated and untreated subjects.

Method

In this paper, we analyzed data from the Ocular Hypertension Treatment Study (OHTS) and the European Glaucoma Prevention Study (EGPS) for subjects who had at least 2 IOP measurements after randomization prior to POAG diagnosis. We assessed the interrelationships among the baseline covariates, the changes of post-randomization IOP over time, and the risk of developing POAG, using a latent class analysis (LCA) which allows us to identify distinct patterns (latent classes) of IOP trajectories.

Result

The IOP change in OHTS was best described by 6 latent classes differentiated primarily by the mean IOP levels during follow-up. Subjects with high post-randomization mean IOP level and/or large variability were more likely to develop POAG. Five baseline factors were found to be significantly predictive of the IOP classification in OHTS: treatment assignment, baseline IOP, gender, race, and history of hypertension. In separate analyses of EGPS, LCA identified different patterns of IOP change from those in OHTS, but confirmed that subjects with high mean level and large variability were at high risk to develop POAG.

Conclusion

LCA provides a useful tool to assess the impact of post-randomization IOP level and fluctuation on the risk of developing POAG in patients with ocular hypertension. The incorporation of post-randomization IOP can improve the overall predictive ability of the original model that included only baseline risk factors.

     

Genetic influences on spatial ability: Transmission in an extended kindred

Transmission of six spatial tests, Card Rotations, Cube Comparisons, Group Embedded Figures, Hidden Patterns, Mental Rotations, and portable Rod and Frame, is examined among 73 members in four generations of an extended kindred. Nonadditive genetic variance is substantial for one of the six tests, Card Rotations. Whether this nonadditive genetic variance is due to a major autosomal gene is equivocal based on results from segregation and linkage analysis. There is no evidence for genetic variance for Mental Rotations or Hidden Patterns, in contrast to previous findings suggesting major gene involvement (Ashtonet al., 1979). If spatial ability is due, in part, to an autosomal major gene, the gene has variable expression (reflected in different tests) or genetic heterogeneity is pronounced.This work was supported by National Institutes of Health Grant HD-05615.