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1.  Genome-wide association study and meta-analysis of intraocular pressure 
Human genetics  2013;133(1):41-57.
Elevated intraocular pressure (IOP) is a major risk factor for glaucoma and is influenced by genetic and environmental factors. Recent genome-wide association studies (GWAS) reported associations with IOP at TMCO1 and GAS7, and with primary open-angle glaucoma (POAG) at CDKN2B-AS1, CAV1/CAV2, and SIX1/SIX6. To identify novel genetic variants and replicate the published findings, we performed GWAS and meta-analysis of IOP in >6,000 subjects of European ancestry collected in three datasets: the NEI Glaucoma Human genetics collaBORation, GLAUcoma Genes and ENvironment study, and a subset of the Age-related Macular Degeneration-Michigan, Mayo, AREDS and Pennsylvania study. While no signal achieved genome-wide significance in individual datasets, a meta-analysis identified significant associations with IOP at TMCO1 (rs7518099-G, p = 8.0 × 10−8). Focused analyses of five loci previously reported for IOP and/or POAG, i.e., TMCO1, CDKN2B-AS1, GAS7, CAV1/CAV2, and SIX1/SIX6, revealed associations with IOP that were largely consistent across our three datasets, and replicated the previously reported associations in both effect size and direction. These results confirm the involvement of common variants in multiple genomic regions in regulating IOP and/or glaucoma risk.
PMCID: PMC3982323  PMID: 24002674
2.  Risk of Endophthalmitis and Other Long-Term Complications of Trabeculectomy in the Collaborative Initial Glaucoma Treatment Study (CIGTS) 
American journal of ophthalmology  2012;155(4):674-680.e1.
To report the risk of endophthalmitis and other long-term complications in patients randomized to trabeculectomy in the Collaborative Initial Glaucoma Treatment Study (CIGTS).
A longitudinal cohort study using data collected from a multicenter, randomized clinical trial.
Long-term post-operative complications in the 300 patients randomized to trabeculectomy in CIGTS were tabulated. Kaplan-Meier analyses were used to estimate the time-related probability of blebitis, hypotony, and endophthalmitis.
285 patients were included in the final trabeculectomy cohort after accounting for assignment refusal and other early events. Patients were followed for an average of 7.2 years. 163 patients (57%) received 5-fluorouracil (5-FU) intraoperatively. Of the 247 patients with at least 5 years of follow-up, 50 required further treatment for glaucoma. Cataract extraction was performed in 57 patients (20%). Forty patients (14%) required bleb revision at least once. Bleb-related complications included bleb leak (N = 15), blebitis (N = 8), and hypotony (N = 4). Three patients were noted to have endophthalmitis, although the diagnosis in two patients was presumptive. The occurrences of blebitis, hypotony, or endophthalmitis were not significantly associated with 5-FU use. The Kaplan-Meier calculated risks of blebitis and hypotony at 5 years were both 1.5%, while the risk of endophthalmitis was 1.1%.
The potential efficacy of trabeculectomy must be weighed against the long-term risk of complications, especially endophthalmitis, when selecting treatments for patients with open-angle glaucoma. We report a low 5-year risk of endophthalmitis (1.1%) and other bleb-related complications in the trabeculectomy cohort of the CIGTS.
PMCID: PMC3608803  PMID: 23246272
3.  The NEIGHBOR Consortium Primary Open Angle Glaucoma Genome-wide Association Study: Rationale, Study design and Clinical variables 
Journal of glaucoma  2013;22(7):517-525.
Primary open-angle glaucoma (POAG) is a common disease with complex inheritance. The identification of genes predisposing to POAG is an important step toward the development of novel gene-based methods of diagnosis and treatment. Genome-wide association studies (GWAS) have successfully identified genes contributing to complex traits such as POAG however, such studies frequently require very large sample sizes, and thus, collaborations and consortia have been of critical importance for the GWAS approach. In this report we describe the formation of the NEIGHBOR consortium, the harmonized case control definitions used for a POAG GWAS, the clinical features of the cases and controls and the rationale for the GWAS study design.
PMCID: PMC3485429  PMID: 22828004
4.  CDKN2B-AS1 Genotype – Glaucoma Feature Correlations in Primary Open-Angle Glaucoma Patients from the United States 
American journal of ophthalmology  2012;155(2):342-353.e5.
To assess the association between single nucleotide polymorphisms (SNPs) of the gene region containing cyclin dependent kinase inhibitor 2B antisense noncoding RNA (CDKN2B-AS1) and glaucoma features among primary open-angle glaucoma (POAG) patients.
Retrospective observational case series.
We studied associations between ten CDKN2B-AS1 SNPs and glaucoma features among 976 POAG cases from the Glaucoma Genes and Environment (GLAUGEN) study and 1971 cases from the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium. For each patient, we chose the feature from the eye with the higher value. We created cohort-specific multivariable models for glaucoma features and then meta-analyzed the results.
For nine of the ten protective CDKN2B-AS1 SNPs with minor alleles associated with reduced disease risk (e.g., the G allele at rs2157719), POAG patients carrying these minor alleles had smaller cup-disc ratio (0.05 units smaller per G allele at diagnosis; 95% CI: −0.08, −0.03; p=6.23E-05) despite having higher intraocular pressure (IOP) (0.70 mm Hg higher per G allele at DNA collection; 95% CI: 0.40, 1.00; P=5.45E-06). For the one adverse rs3217992 SNP with minor allele A associated with increased disease risk, POAG patients with A alleles had larger cup-disc ratio (0.05 units larger per A allele at diagnosis; 95% CI: 0.02, 0.07; P=4.74E-04) despite having lower IOP (−0.57 mm Hg per A allele at DNA collection; 95% CI: −0.84, −0.29; P=6.55E-05).
Alleles of CDKN2B-AS1 SNPs, which influence risk of developing POAG, also modulate optic nerve degeneration among POAG patients, underscoring the role of CDKN2B-AS1 in POAG.
PMCID: PMC3544983  PMID: 23111177
5.  Visual Field Progression in the Collaborative Initial Glaucoma Treatment Study: The Impact of Treatment and other Baseline Factors 
Ophthalmology  2008;116(2):200-207.
To evaluate factors associated with visual field (VF) progression, using all available follow-up through nine years after treatment initiation, in the Collaborative Initial Glaucoma Treatment Study (CIGTS).
Longitudinal follow-up of participants enrolled in a randomized clinical trial.
607 newly diagnosed glaucoma patients.
In a randomized clinical trial, 607 subjects with newly diagnosed open-angle glaucoma were initially treated with either medication or trabeculectomy. After treatment initiation and early follow-up, subjects were evaluated clinically at 6-month intervals. Study participants in both arms of the CIGTS were treated aggressively in an effort to reduce intraocular pressure (IOP) to a level at or below a predetermined, eye-specific target pressure. VF progression was analyzed using repeated measures models.
Main outcome measures
VF progression, measured by Humphrey 24-2 full threshold testing and assessed by the change in the mean deviation (MD), and an indicator of substantial worsening of the VF (MD decrease of ≥3 dB from baseline), assessed at each follow-up visit.
Follow-up indicates minimal change from baseline in each initial treatment group’s average MD. However, at the eight year follow-up examination, substantial worsening (≥3 dB) of MD from baseline was found in 21.3% and 25.5% of the initial surgery and initial medicine groups, respectively. The effect of initial treatment on subsequent VF loss was modified by time (P<0.0001), baseline MD (P=0.03), and diabetes (P=0.01). Initial surgery led to less VF progression than initial medicine in subjects with advanced VF loss at baseline, whereas subjects with diabetes had more VF loss over time if treated initially with surgery.
The CIGTS intervention protocol led to a lowering of IOP that persisted over time in both treatment groups. Progression in VF loss was seen in a subset increasing to over 20% of the subjects. Our findings regarding initial surgery being beneficial for subjects who present at diagnosis with more advanced VF loss, but detrimental for patients with diabetes, are noteworthy and warrant independent confirmation.
PMCID: PMC3316491  PMID: 19019444
6.  Racial Disparities in the Use of Ancillary Testing to Evaluate Individuals with Open-Angle Glaucoma 
Archives of ophthalmology  2012;130(12):1579-1588.
To determine whether racial disparities exist in the use of ancillary testing to evaluate individuals with open-angle glaucoma (OAG).
We identified all enrollees aged ≥40 in a large U.S. managed-care network with retinal or optic nerve conditions that could warrant the use of ancillary testing. Among persons with OAG or glaucoma suspects, we performed repeated measures multivariable logistic regression to determine the odds and probabilities each year of undergoing visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) for black, white, Latino, and Asian-American males and females and compared the groups.
Among the 797,879 eligible enrollees, 149,018 individuals had OAG. The odds of undergoing VF testing decreased for all groups from 2001–2009, decreasing most (63% and 57%) for Latinos and Latinas, respectively (adjusted odds ratio (OR)=0.37, 95% confidence interval (CI)=0.31–0.43 and OR=0.43, CI=0.37–0.50) and least (36%) for Asian males (OR=0.64, CI 0.51–0.80). By comparison, the odds of undergoing OOI increased for all groups from 2001–2009, increasing most (173%) for black males and females (OR=2.73, CI=2.34–3.18 for males and OR=2.73, CI=2.40–3.09 for females) and least (77%) for Latinas (OR=1.77, CI=1.49–2.09).
Latinos and Latinas had considerably reduced odds of undergoing VF testing and OOI compared with other groups over the decade. Although increases in glaucoma testing have been noted in recent years among Latinos and Latinas for some types of ancillary tests, efforts should be made to better understand and overcome some of the persistent barriers to monitoring for glaucoma in this group.
PMCID: PMC3635134  PMID: 23229700
7.  Trends in Utilization of Ancillary Glaucoma Tests for Patients with Open-Angle Glaucoma from 2001 to 2009 
Ophthalmology  2012;119(4):748-758.
To assess trends in the use of ancillary diagnostic tests in the evaluation of patients with open-angle glaucoma (OAG) and glaucoma suspects over the past decade.
Retrospective longitudinal cohort analysis.
169,917 individuals with OAG and 395,721 with suspected glaucoma age ≥40 enrolled in a national United States managed care network between 2001–2009.
Claims data were analyzed to assess trends in visual field (VF) testing, fundus photography (FP), and other ocular imaging (OOI) testing for patients with OAG or suspected glaucoma in 2001–2009. Repeated measures logistic regression was performed to identify differences in the odds of undergoing these procedures in 2001, 2005, and 2009 and whether differences exist for patients under the exclusive care of optometrists versus ophthalmologists.
Main Outcome Measures
Odds and annual probabilities of undergoing VF testing, FP, and OOI for OAG from 2001–2009.
For patients with OAG, the odds of undergoing VF testing decreased by 36% from 2001 to 2005, 12% from 2005 to 2009, and 44% from 2001 to 2009. By comparison, the odds of having OOI increased by 100% from 2001 to 2005, 24% from 2005 to 2009, and 147% from 2001 to 2009. Probabilities of undergoing FP were relatively low (13–25%) for both provider types and remained fairly steady over the decade. For patients cared for exclusively by optometrists, the probability of VF testing decreased from 66% in 2001 to 44% in 2009. Among those seen exclusively by ophthalmologists, the probability of VF testing decreased from 65% in 2001 to 51% in 2009. The probability of undergoing OOI increased from 26% in 2001 to 47% in 2009 for patients of optometrists and from 30% in 2001 to 46% in 2009 for patients of ophthalmologists. By 2008, patients with OAG receiving care exclusively by optometrists had a higher probability of undergoing OOI than VF testing.
During 2001–2009 OOI rose dramatically whereas VF testing declined considerably. Since OOI has not been shown to be as effective at detecting OAG or disease progression compared to VF testing, increased reliance upon OOI technology, in lieu of VF testing, may be detrimental to patient care.
PMCID: PMC3319788  PMID: 22218146
8.  Estrogen pathway polymorphisms in relation to primary open angle glaucoma: An analysis accounting for gender from the United States 
Molecular Vision  2013;19:1471-1481.
Circulating estrogen levels are relevant in glaucoma phenotypic traits. We assessed the association between an estrogen metabolism single nucleotide polymorphism (SNP) panel in relation to primary open angle glaucoma (POAG), accounting for gender.
We included 3,108 POAG cases and 3,430 controls of both genders from the Glaucoma Genes and Environment (GLAUGEN) study and the National Eye Institute Glaucoma Human Genetics Collaboration (NEIGHBOR) consortium genotyped on the Illumina 660W-Quad platform. We assessed the relation between the SNP panels representative of estrogen metabolism and POAG using pathway- and gene-based approaches with the Pathway Analysis by Randomization Incorporating Structure (PARIS) software. PARIS executes a permutation algorithm to assess statistical significance relative to the pathways and genes of comparable genetic architecture. These analyses were performed using the meta-analyzed results from the GLAUGEN and NEIGHBOR data sets. We evaluated POAG overall as well as two subtypes of POAG defined as intraocular pressure (IOP) ≥22 mmHg (high-pressure glaucoma [HPG]) or IOP <22 mmHg (normal pressure glaucoma [NPG]) at diagnosis. We conducted these analyses for each gender separately and then jointly in men and women.
Among women, the estrogen SNP pathway was associated with POAG overall (permuted p=0.006) and HPG (permuted p<0.001) but not NPG (permuted p=0.09). Interestingly, there was no relation between the estrogen SNP pathway and POAG when men were considered alone (permuted p>0.99). Among women, gene-based analyses revealed that the catechol-O-methyltransferase gene showed strong associations with HTG (permuted gene p≤0.001) and NPG (permuted gene p=0.01).
The estrogen SNP pathway was associated with POAG among women.
PMCID: PMC3712669  PMID: 23869166
9.  Clinical Characteristics of Newly Diagnosed Primary, Pigmentary, and Pseudoexfoliative Open-Angle Glaucoma in the Collaborative Initial Glaucoma Treatment Study 
The British journal of ophthalmology  2012;96(9):1180-1184.
Three types of open-angle glaucoma (OAG) – primary, pigmentary, and pseudoexfoliative – are frequently encountered. The aim of this study was to compare demographic, ocular, and systemic medical information collected on people with these three OAG types at diagnosis, and determine if the OAG type affected prognosis.
Information on 607 participants of the Collaborative Initial Glaucoma Treatment Study was accessed. Descriptive statistics characterized their demographic, ocular, and medical status at diagnosis. Comparisons were made using analysis of variance (ANOVA), and chi-square or Fisher exact tests. Multinomial, mixed, and logistic regression analyses were also performed.
Relative to people with primary OAG, those with pigmentary OAG were younger, more likely to be white, less likely to have a family history of glaucoma, and were more myopic. Those with pseudoexfoliative OAG were older, more likely to be white, more likely to be female, less likely to have bilateral disease, and presented with higher IOP and better VA. The type of glaucoma was not associated with intraocular pressure or visual field progression during follow-up.
Characteristics of newly-diagnosed enrollees differed by the type of OAG. While some of these differences relate to the pathogenesis of OAG type, other differences are noteworthy for further evaluation within population-based samples of subjects with newly-diagnosed OAG.
PMCID: PMC3480313  PMID: 22773091
Glaucoma; Epidemiology
10.  Common Variants at 9p21 and 8q22 Are Associated with Increased Susceptibility to Optic Nerve Degeneration in Glaucoma 
PLoS Genetics  2012;8(4):e1002654.
Optic nerve degeneration caused by glaucoma is a leading cause of blindness worldwide. Patients affected by the normal-pressure form of glaucoma are more likely to harbor risk alleles for glaucoma-related optic nerve disease. We have performed a meta-analysis of two independent genome-wide association studies for primary open angle glaucoma (POAG) followed by a normal-pressure glaucoma (NPG, defined by intraocular pressure (IOP) less than 22 mmHg) subgroup analysis. The single-nucleotide polymorphisms that showed the most significant associations were tested for association with a second form of glaucoma, exfoliation-syndrome glaucoma. The overall meta-analysis of the GLAUGEN and NEIGHBOR dataset results (3,146 cases and 3,487 controls) identified significant associations between two loci and POAG: the CDKN2BAS region on 9p21 (rs2157719 [G], OR = 0.69 [95%CI 0.63–0.75], p = 1.86×10−18), and the SIX1/SIX6 region on chromosome 14q23 (rs10483727 [A], OR = 1.32 [95%CI 1.21–1.43], p = 3.87×10−11). In sub-group analysis two loci were significantly associated with NPG: 9p21 containing the CDKN2BAS gene (rs2157719 [G], OR = 0.58 [95% CI 0.50–0.67], p = 1.17×10−12) and a probable regulatory region on 8q22 (rs284489 [G], OR = 0.62 [95% CI 0.53–0.72], p = 8.88×10−10). Both NPG loci were also nominally associated with a second type of glaucoma, exfoliation syndrome glaucoma (rs2157719 [G], OR = 0.59 [95% CI 0.41–0.87], p = 0.004 and rs284489 [G], OR = 0.76 [95% CI 0.54–1.06], p = 0.021), suggesting that these loci might contribute more generally to optic nerve degeneration in glaucoma. Because both loci influence transforming growth factor beta (TGF-beta) signaling, we performed a genomic pathway analysis that showed an association between the TGF-beta pathway and NPG (permuted p = 0.009). These results suggest that neuro-protective therapies targeting TGF-beta signaling could be effective for multiple forms of glaucoma.
Author Summary
Loss of vision from glaucoma, a common cause of blindness worldwide, is due to irreversible damage to the optic nerve. Current therapies cannot prevent glaucoma-related optic nerve disease and very little is known about the underlying responsible molecular events. Glaucoma patients affected by the “normal-pressure” subtype of glaucoma (NPG) have increased susceptibility to optic nerve degeneration. Although NPG has a high heritability, common predisposing genetic variants have not been identified. Therefore, we performed a meta-analysis of two independent genome-wide association studies for a common form of glaucoma, primary open angle glaucoma (POAG), followed by NPG subgroup analysis. We found that SNPs in the CDKN2BAS gene region on 9p21 and a highly conserved region with a probable regulatory function on 8q22 were associated with NPG and with optic nerve disease in a second type of glaucoma, exfoliation glaucoma. Both genomic regions are predicted to influence TGF-beta activity, and using whole-genome data we showed that the TGF-beta signaling pathway overall is associated with NPG. These results reveal new insights into the molecular pathogenesis of optic nerve disease in glaucoma and are an important step toward the development of preventative and protective therapies.
PMCID: PMC3343074  PMID: 22570617
11.  GALC Deletions Increase the Risk of Primary Open-Angle Glaucoma: The Role of Mendelian Variants in Complex Disease 
PLoS ONE  2011;6(11):e27134.
DNA copy number variants (CNVs) have been reported in many human diseases including autism and schizophrenia. Primary Open Angle Glaucoma (POAG) is a complex adult-onset disorder characterized by progressive optic neuropathy and vision loss. Previous studies have identified rare CNVs in POAG; however, their low frequencies prevented formal association testing. We present here the association between POAG risk and a heterozygous deletion in the galactosylceramidase gene (GALC). This CNV was initially identified in a dataset containing 71 Caucasian POAG cases and 478 ethnically matched controls obtained from dbGAP (study accession phs000126.v1.p1.) (p = 0.017, fisher's exact test). It was validated with array comparative genomic hybridization (arrayCGH) and realtime PCR, and replicated in an independent POAG dataset containing 959 cases and 1852 controls (p = 0.021, OR (odds ratio) = 3.5, 95% CI −1.1–12.0). Evidence for association was strengthened when the discovery and replication datasets were combined (p = 0.002; OR = 5.0, 95% CI 1.6–16.4). Several deletions with different endpoints were identified by array CGH of POAG patients. Homozygous deletions that eliminate GALC enzymatic activity cause Krabbe disease, a recessive Mendelian disorder of childhood displaying bilateral optic neuropathy and vision loss. Our findings suggest that heterozygous deletions that reduce GALC activity are a novel mechanism increasing risk of POAG. This is the first report of a statistically-significant association of a CNV with POAG risk, contributing to a growing body of evidence that CNVs play an important role in complex, inherited disorders. Our findings suggest an attractive biomarker and potential therapeutic target for patients with this form of POAG.
PMCID: PMC3208571  PMID: 22073273
12.  Five-year follow-up optic disc findings of the Collaborative Initial Glaucoma Treatment Study 
American journal of ophthalmology  2009;147(4):717-724.e1.
To determine the effect of intraocular pressure (IOP) lowering on the optic disc in patients of the Collaborative Initial Glaucoma Treatment Study (CIGTS) after five years.
Randomized clinical trial
The baseline and five-year stereoscopic optic disc photographs of 348 eyes (patients) randomized to medical or surgical treatment of open-angle glaucoma were assessed by two independent readers for change in a masked side-by-side comparison, and confirmed by an independent committee.
303 (87.1%) eyes showed no change, 22 (6.3%) showed enlargement of the cup along any meridian (progression), and 23 (6.6%) showed a reduction in the cup along any meridian (reversal of cupping). Incidence of optic disc progression was higher (p=0.007) in the medicine group, 18/185 (10%) than in the surgical group 4/163 (3%); and the incidence of reversal of cupping was higher (p<0.001) in the surgical group, 21/163 (13%), than the medicine group, 2/185 (1%), (P<0.001). Visual field worsening (mean deviation) was significantly associated with progression of optic disc cupping (P<0.001). Reversal of cupping was also associated with lower postoperative IOP (P<0.001). Reversal of cupping was not associated with improvement of either visual acuity or central visual fields.
Surgery prevents or delays glaucomatous progression as measured by optic disc criteria in patients with early open-angle glaucoma. Reversal of cupping occurs more frequently in the surgical group than in the medical treatment group. Reversal is associated with lower IOP, but is not associated with improved visual function.
PMCID: PMC2714658  PMID: 19152871
13.  Factors Associated with Intraocular Pressure Prior to and during Nine Years of Treatment in the Collaborative Initial Glaucoma Treatment Study 
Ophthalmology  2007;115(6):927-933.
To evaluate, both at initial glaucoma diagnosis and during treatment, the role of demographic and clinical factors on intraocular pressure (IOP).
Cohort study of patients enrolled in a randomized clinical trial.
607 patients with newly diagnosed, open-angle glaucoma (OAG) were enrolled at 14 U.S. centers.
After randomization to initial surgery or medications, patients were followed at six-month intervals. IOP was measured by Goldmann applanation tonometry. Predictive factors for IOP at baseline and during follow-up were analyzed using linear mixed models.
Main Outcome Measure
IOP at baseline and during follow-up.
The mean baseline IOP was 27.5 mmHg (standard deviation, 5.6 mmHg). Predictive factors for higher baseline IOP included younger age (0.7 mmHg per 10 years), male sex (2.4 mmHg higher than females), pseudoexfoliative glaucoma (5.4 mmHg higher than primary OAG), and pupillary defect (2.2 mmHg higher than those without a defect). During nine years of follow-up, both surgery and medications dramatically reduced IOP from baseline levels, but the extent of IOP reduction was consistently greater in the surgery group. Over follow-up years 2–9, mean IOP was 15.0 vs. 17.2 mmHg for surgery vs. medicine, respectively. Predictive associations with higher IOP during follow-up included higher baseline IOP (P<0.0001), worse baseline visual field (mean deviation; P<0.0001), and lower level of education (P=0.0019). Treatment effect was modified by smoking status: non-smokers treated surgically had lower IOP than smokers treated surgically (14.6 vs. 16.7 mmHg, respectively; P=0.0013). Clinical center effects were significant (P<0.0001) in both the baseline and follow-up models.
In this large cohort of newly diagnosed glaucoma patients, predictors of pre-treatment IOP and IOP measurements over nine years of follow-up were identified. Our findings lend credence to the postulate that sociodemographic, economic, compliance, or other environmental influences play a role in IOP control during treatment.
PMCID: PMC2758572  PMID: 17964655
14.  CME, Physicians, and Pavlov: Can We Change What Happens When Industry Rings the Bell? 
To show how physicians’ conditioned response to “keeping up” has helped industry’s opportunistic funding of continuing medical education (CME) and to propose ways to counter the conditioned response to the benefit of patients and the public.
Review of the literature and commentary on it.
The pharmaceutical and device industries (hereafter referred to as industry) have a long history of bribing physicians to prescribe and use their products. Increasing pressure from Congress and the public has been brought to bear on industry gifting. This pressure, coinciding with increasing financial problems for the providers of CME, provided industry with reason and opportunity to expand its role in the financing of CME. Industry’s incentive to make its CME funding appear to be an arm’s-length transaction has spawned medical education service supplier (MESS) companies. Industry makes “unrestricted grants” to the MESS, and the MESS puts on the CME program. Helped by these CME programs, industry is able to subtly “buy” physicians one at a time, so that under the cover of “education” they and their academic institutions and medical organizations lose sight of being CME pawns in industry’s sole objective: profit.
Despite a vast literature showing how physician integrity is easy prey to industry, the medical profession continues to allow industry to have a detrimental influence on the practice of medicine and on physician respectability. It will take resolute action to change the medical profession’s conditioned response to industry’s CME bell and its negative effect on patients and the public.
PMCID: PMC2646445  PMID: 19277219
15.  Variation in optineurin (OPTN) allele frequencies between and within populations 
Molecular Vision  2007;13:151-163.
To evaluate the extent to which mutations in the optineurin (OPTN) glaucoma gene play a role in glaucoma in different populations.
Case-controlled study of OPTN sequence variants in individuals with or without glaucoma in populations of different ancestral origins and evaluate previous OPTN reports. We analyzed 314 subjects with African, Asian, Caucasian and Hispanic ancestries included 229 cases of primary open-angle glaucoma, 51 cases of juvenile-onset open-angle glaucoma, 33 cases of normal tension glaucoma, and 371 controls. Polymerase chain reaction-amplified OPTN coding exons were resequenced and case frequencies were compared to frequencies in controls matched for ancestry.
The E50K sequence variant was identified in one individual from Chile with normal tension glaucoma, and the 691_692insAG variant was found in one Ashkenazi Jewish individual from Russia. The R545Q variant was found in two Asian individuals with primary open-angle glaucoma; one of Filipino ancestry and one of Korean ancestry. In addition to presenting OPTN allele frequencies for Caucasian and Asian populations that have been the subject of previous reports, we also present information for populations of Hispanic and black African ancestries.
Our study contributes additional evidence to support the previously reported association of the OPTN E50K mutation with glaucoma. After finding an additional 691_692insAG OPTN variant, we can still only conclude that this variant is rare. Combined analysis of our data with data from more than a dozen other studies indicates no association of R545Q with glaucoma in most populations. Those same studies disagree in their conclusions regarding the role of M98K in glaucoma. Our analysis of the combined data provides statistically significant evidence of association of M98K with normal tension glaucoma in Asian populations, but not in Caucasian populations; however, the validity of this conclusion is questionable because of large differences in allele frequencies between and within populations. It is currently not possible to tell how much of the underlying cause of the allele frequency difference is attributable to demographic, technical, or ascertainment differences among the studies.
PMCID: PMC2533035  PMID: 17293779
16.  Investigation of founder effects for the Thr377Met Myocilin mutation in glaucoma families from differing ethnic backgrounds 
Molecular Vision  2007;13:487-492.
The aim of this study was to determine if there is a common founder for the Thr377Met myocilin mutation in primary open angle glaucoma (POAG) families with various ethnic backgrounds.
Genomic DNA of 24 POAG-affected individuals from nine pedigrees with the Thr377Met mutation and 104 unaffected family members was genotyped with six microsatellite markers and four single nucleotide polymorphisms. The families were from Greece, India, Finland, the USA, and Australia. To assess the degree of linkage disequilibrium across MYOC in the general population we also investigated data generated from the HapMap consortium.
Three distinct haplotypes associated with the Thr377Met myocilin mutation were identified. The families from the USA and Greece, as well as the three Australian families originating from Greece and the former Yugoslavian Republic of Macedonia had one common haplotype. Interestingly, however, HapMap data suggest that linkage disequilibrium across MYOC was not strong.
The Thr377Met myocilin mutation has arisen at least three separate times. Evidence for genetic founder effects in this prevalent age-related, yet heterogeneous, disease has important implications for future gene identification strategies.
PMCID: PMC2649311  PMID: 17417609

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