Risk for Exfoliation Syndrome in Women With Pelvic Organ Prolapse : A Utah Project on Exfoliation Syndrome (UPEXS) Study | Genetics and Genomics | JAMA Ophthalmology | JAMA Network
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Figure.  Pelvic Organ Prolapse and Risk of Exfoliation Syndrome in Female Utah Medicare Beneficiaries
Pelvic Organ Prolapse and Risk of Exfoliation Syndrome in Female Utah Medicare Beneficiaries

Overall results and stratified by age last enrolled (substudy A) are shown. Adjusted for age last enrolled, number of years enrolled, parity, and race/ethnicity. The y-axis is shown on a log10 scale; all P < .001. The horizontal lines represent the position of the value of the hazard ratio on the x-axis and y-axis coordinates. Vertical lines represent the 95% CIs, with ends representing the values of the upper and lower limits. OR indicates odds ratio.

Table 1.  Definition of Pelvic Organ Prolapsea
Definition of Pelvic Organ Prolapsea
Table 2.  Characteristics of Female Medicare Beneficiaries in Substudy Aa
Characteristics of Female Medicare Beneficiaries in Substudy Aa
Table 3.  Characteristics of UUHC Patients in Substudy Ba
Characteristics of UUHC Patients in Substudy Ba
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Original Investigation
November 2016

Risk for Exfoliation Syndrome in Women With Pelvic Organ Prolapse : A Utah Project on Exfoliation Syndrome (UPEXS) Study

Author Affiliations
  • 1Department of Ophthalmology and Visual Sciences, John A. Moran Eye Center, University of Utah School of Medicine, Salt Lake City
  • 2Sharon Eccles Steele Center for Translational Medicine, University of Utah School of Medicine, Salt Lake City
  • 3Department of Internal Medicine, University of Utah School of Medicine, Salt Lake City
  • 4Einhorn Clinical Research Center, New York Eye and Ear Infirmary of Mount Sinai, New York
  • 5Huntsman Cancer Institute, Department of Family and Consumer Studies and Population Science, University of Utah, Salt Lake City
  • 6Department of Ophthalmology, Duke University, Durham, North Carolina
JAMA Ophthalmol. 2016;134(11):1255-1262. doi:10.1001/jamaophthalmol.2016.3411
Key Points

Question  What is the relationship of exfoliation syndrome with pelvic organ prolapse in the Utah Population Database, part of the Utah Project on Exfoliation Syndrome?

Findings  Pelvic organ prolapse was associated with a 1.56-fold increased risk of exfoliation syndrome in 132 772 female Medicare beneficiaries in Utah from 1992 to 2009 using a cross-sectional analysis. A 48% increased incident risk of exfoliation syndrome in younger women, aged 30 to 65 years at baseline, who had a pelvic organ prolapse diagnosis compared with control individuals was observed.

Meaning  The diagnosis of exfoliation syndrome was more frequent in women with pelvic organ prolapse in the Utah Population Database.

Abstract

Importance  Exfoliation syndrome, an inherited systemic disorder of elastin and extracellular matrix (ECM), is associated with the LOXL1 gene locus. Pelvic organ prolapse is a common connective tissue disorder that affects women. The presence of an association between exfoliation syndrome (exfoliation of the lens capsule) and pelvic organ prolapse was investigated as part of the Utah Project on Exfoliation Syndrome (UPEXS).

Objective  To examine the association between exfoliation syndrome and pelvic organ prolapse using the Utah Population Database, a comprehensive resource linked to medical records.

Design, Setting, and Participants  A 2-pronged approach was used. In substudy A, a cross-sectional analysis was performed to determine the association between pelvic organ prolapse and exfoliation syndrome in women enrolled in Medicare in Utah from calendar year 1992 to 2009 (n = 132 772). In substudy B, the risk of incident exfoliation syndrome from January 1, 1995, to December 31, 2014, was estimated in a cohort of women aged 30 to 65 years at baseline with a diagnosis of pelvic organ prolapse (n = 5130) compared with birth year–matched women serving as controls who did not have pelvic organ prolapse (n = 15 338).

Main Outcomes and Measures  Exfoliation syndrome outcome was defined by International Classification of Diseases, Ninth Revision, diagnosis codes for exfoliation syndrome or exfoliation glaucoma (366.11 or 365.52, respectively). In substudy A, odds ratios (ORs) from unconditional logistic regression models were used to estimate the exfoliation syndrome risk in women with pelvic organ prolapse compared with those without pelvic organ prolapse. In substudy B, hazard ratios (HRs) from Cox proportional hazards models were used to estimate incident exfoliation syndrome risk in patients with pelvic organ prolapse (without exfoliation syndrome history) compared with unaffected controls. Models were adjusted for age, years enrolled, parity, and race/ethnicity.

Results  Of the 132 772 women enrolled in Utah Medicare from 1992 to 2009, the mean [SD] age at the last enrollment was 82.2 [7.7] years. Pelvic organ prolapse was associated with a 1.56-fold increased risk of exfoliation syndrome in Medicare beneficiaries (OR, 1.56; 95% CI, 1.42-1.72) in substudy A. We observed a 48% increased incident risk of exfoliation syndrome in women aged 30 to 65 years at baseline who had a pelvic organ prolapse diagnosis compared with controls during 20 years of follow-up (HR, 1.48; 95% CI, 1.14-1.91).

Conclusions and Relevance  The diagnosis of exfoliation syndrome was more frequent in women with pelvic organ prolapse in the Utah Population Database, a robust population-based resource, thus supporting an association of exfoliation syndrome with a nonocular systemic condition. Systemic conditions with altered ECM metabolism, such as pelvic organ prolapse, may share common biological pathways with exfoliation syndrome. LOXL1 dysregulation, thought to occur in exfoliation syndrome, may be a contributing factor.

Introduction

Exfoliation syndrome is a complex, inherited systemic disorder clinically recognized by the deposition of extracellular matrix (ECM) on structures within the anterior segment of the eye. Exfoliation syndrome often leads to exfoliation glaucoma, the most common recognizable cause of open-angle glaucoma worldwide.1 Exfoliation syndrome occurs primarily in older individuals and may be more prevalent in women, although this may reflect differences in life expectancy.2,3

Exfoliation syndrome has a strong genetic association with the lysyl oxidase-like 1 (LOXL1: OMIM 153456) locus that was first reported in Scandinavians and subsequently replicated in other populations.4-11 Given the systemic nature of exfoliation syndrome, characteristic fibrillary deposits are found in multiple organ systems, including heart, brain, lung, skin, and eye.12-14 Patients with exfoliation syndrome reportedly have an increased risk of developing a variety of systemic disorders; these include cardiovascular and cerebrovascular disease, hearing loss, and other disorders that share abnormalities in the repair and maintenance of elastin ECM.15-22

Pelvic organ prolapse is the descent of abdominal organs in women, including the bladder, uterus, small and large intestines, and vaginal cuff, which lead to urogenital symptoms.23 Risk factors for pelvic organ prolapse include vaginal birth, parity, increased body mass index, family history, and increasing age.24 Pelvic organ prolapse is a major health issue for women. Prevalence estimates of symptomatic pelvic organ prolapse range between 3% and 11%, and 11% to 19% of women will require pelvic organ prolapse surgical repair during their lifetime.25-28 Pelvic organ prolapse is believed to be associated with defects produced by muscle and connective tissue injury in conjunction with abnormalities in pathways for ECM tissue repair.29-31

A possible association between LOLX1 and pelvic organ prolapse in humans was based on evidence29-32 derived from the LOXL1 knockout mouse, which exhibits postpartum uterine prolapse. Studies33,34 have reported altered messenger RNA (mRNA) expression of the elastin-forming gene, LOXL1, in vaginal tissue biopsies from women with pelvic organ prolapse. Exfoliation material from the eyes of patients with exfoliation syndrome stain positively for the LOXL1 protein and its elastin substrate tropoelastin as well as fibulin 5 and fibrillin 1.14,35

Because both exfoliation syndrome and pelvic organ prolapse are characterized by changes in elastin-containing ECM tissue, we hypothesized that women with pelvic organ prolapse are more likely to develop exfoliation syndrome during their lifetime. As part of the Utah Project on Exfoliation Syndrome (UPEXS), we conducted a large, population-based investigation in 2 phases: (1) an analytical cross-sectional study to investigate the association between pelvic organ prolapse and exfoliation syndrome analysis (substudy A) and (2) a retrospective cohort analysis of incident risk (substudy B) to examine the association between a diagnosis history of pelvic organ prolapse and exfoliation syndrome using the Utah Population Database (UPDB).

Methods
Study Participants

In substudy A of this UPEXS study, which used a cross-sectional design, women older than 65 years enrolled in Medicare parts A and B in Utah between 1992 and 2009 for 3 or more consecutive years were surveyed, and those who linked to a person-record in the UPDB were included. In substudy B, we identified a female population within the University of Utah Health Care (UUHC), a large Utah health care system, who received any eye-related service from 1995 (when electronic medical records became available) through 2014 and who were aged 30 to 65 years on January 1, 1995 (baseline). The study was approved, with waiver of informed consent, by the University of Utah Institutional Review Board and the Resource for Genetic and Epidemiologic Research. All data were deidentified.

Case and Comparison Groups

In substudy A, participants were women with a diagnosis history of pelvic organ prolapse in the Medicare claims record (1992-2009), based on 1 or more occurrences of an International Classification of Diseases, Ninth Revision (ICD-9), or Current Procedural Technology (CPT) code listed in Table 1. These women were compared with Medicare enrollees with no pelvic organ prolapse diagnosis or procedural history to determine the association of pelvic organ prolapse and an outcome of exfoliation syndrome, defined below. In substudy B, case patients with a pelvic organ prolapse diagnosis (first occurrence in the medical record of any code listed in Table 1) and no prior exfoliation syndrome history were compared with 3:1 age-matched female control individuals randomly selected from the same UUHC source population with no pelvic organ prolapse diagnosis or procedural history. Both case and control cohorts were followed forward in historical records from 1995 to 2014 to determine exfoliation syndrome risk.

Outcomes

In substudies A and B, women with an ICD-9 code of 365.52 (exfoliation glaucoma [exfoliation syndrome]) and/or 366.11 (exfoliation of the lens capsule) in the diagnostic record defined an outcome of an exfoliation syndrome diagnosis. In substudy A, exfoliation syndrome was designated as the dependent variable (outcome) because the distribution of age at an index diagnosis of exfoliation syndrome was older than that of an index diagnosis of pelvic organ prolapse in Medicare enrollees (Table 2). Because exfoliation syndrome is typically first diagnosed in individuals older than 68 years and rarely before 60 years, and whereas the mean age of surgery for pelvic organ prolapse is 55 years,2,36 the patient population in substudy B was restricted to women aged 30 to 65 years at baseline in whom the incidence of exfoliation syndrome could be reasonably determined over 20 years of follow-up.

Statistical Analysis

In substudy A, cross-sectional analysis of Utah Medicare claims, an unconditional logistic regression model was used to calculate an odds ratio (OR) and 95% CI to estimate the risk of exfoliation syndrome in women with pelvic organ prolapse compared with women without pelvic organ prolapse. Adjustment for covariates included age during the most recent year of enrollment (age last enrolled), number of years enrolled, parity (categorized as 1-2 children, ≥3 children, and no children/unknown based on Utah birth certificates linked to individuals in the UPDB), and race/ethnicity (categorized as non-Hispanic white, Hispanic and white, nonwhite, or unavailable). Because data on ethnicity were sparse in substudy A, non-Hispanic white individuals and those reporting Hispanic ethnicity were combined. Age-stratified models (age last enrolled of 66-75, 76-85, and ≥86 years) were also examined. A likelihood ratio test was used to assess an interaction of age as a continuous variable and pelvic organ prolapse status compared with a reduced model with no interaction term.

In the substudy B analysis, patients aged 30 to 65 years at baseline (January 1, 1995) with no exfoliation syndrome history before an index diagnosis of pelvic organ prolapse during follow-up were designated as the exposed (case) cohort. Patients with pelvic organ prolapse diagnosed before age 30 years were excluded (n = 121) since a subsequent exfoliation syndrome diagnosis was highly unlikely. Random female controls were identified from the UUHC population and individually matched 3:1 to cases on birth year. Controls were required to have as many years of follow-up in Utah (from UPDB records) and no exfoliation syndrome history before the index pelvic organ prolapse diagnosis date of their respective matched case. The exposure period for controls and their respective matched case was time from an index date of pelvic organ prolapse until December 31, 2014, or date of the last follow-up (if before the study end), at which time observations were right-censored. The estimated risk of an exfoliation syndrome diagnosis in cases compared with controls was determined from the hazard ratio (HR) and 95% CI using a Cox proportional hazards model with covariate adjustment for parity and race/ethnicity. In addition, the model in substudy B included adjustment for body mass index (BMI [calculated as weight in kilograms divided by height in meters squared]) within 5 years of pelvic organ prolapse diagnosis (or for controls, the date of diagnosis of their respective case) and number of patient visits because these data were available. Analogous to conditional logistic regression, separate hazard functions were incorporated for each group (an exposed case and 3 associated controls) to account for case-control matching. Because exfoliation syndrome is typically a later-onset disorder, a competing-risks framework was incorporated to include death as a competing risk.37 Analyses were conducted using SAS, version 9.4 (SAS Institute Inc).

Results
Substudy A

Clinical and demographic characteristics of 132 772 women enrolled in Utah Medicare from 1992 to 2009 are shown in Table 2. Proportions of women were as follows: 11 820 (8.9%) with pelvic organ prolapse but not exfoliation syndrome, 2606 (2%) with exfoliation syndrome but not pelvic organ prolapse, 520 (0.4%) with both pelvic organ prolapse and exfoliation syndrome, and the remaining 117 826 (88.7%) with neither diagnosis. The median age last enrolled was 82 years overall (mean [SD] age, 82.2 [7.7] years). Age last enrolled was higher in women with an exfoliation syndrome diagnosis and both a negative or positive history of pelvic organ prolapse diagnosis (85 and 84 years, respectively). Overall, the median number of years enrolled was 11 (mean [SD], 11 [4.6] years]). Women with both an exfoliation syndrome and pelvic organ prolapse history had the highest median enrollment compared with groups with no exfoliation syndrome history (Table 2). A greater proportion of women with pelvic organ prolapse had 3 or more children compared with women with no pelvic organ prolapse diagnosis, as would be expected (45.7% vs 38.5%; P < .001) based on parity as a risk factor. Among women with a diagnosis of exfoliation syndrome but not pelvic organ prolapse, 43.1% had 3 or more children. Consistent with the Medicare-age population in Utah, participants were primarily white.38 Women who had a pelvic organ prolapse diagnosis (regardless of exfoliation syndrome status) were more likely to be alive on December 31, 2009, than were women with no diagnosis history of pelvic organ prolapse or exfoliation syndrome. Women with pelvic organ prolapse and either a negative or positive exfoliation syndrome diagnosis history were more likely to have survived (49.6% and 61.3%, respectively; P < .001) compared with women with only exfoliation syndrome (45.1%) or neither diagnosis (39.4%).

In substudy A, we observed a 1.56-fold increased risk of an exfoliation syndrome diagnosis in female Utah Medicare beneficiaries who had a history of pelvic organ prolapse compared with women with no pelvic organ prolapse diagnosis after adjusting for age, number of years enrolled, and parity (HR, 1.56; 95% CI, 1.42-1.72; P < .001). When stratified by maximum age attained, women between ages 66 and 75 years during the most recent year enrolled who had pelvic organ prolapse exhibited a 2.15-fold risk of exfoliation syndrome (Figure). Conversely, women older than 85 years with pelvic organ prolapse had a 1.31-fold increased risk of exfoliation syndrome compared with women with no diagnosis of pelvic organ prolapse. The 95% CIs between these age groups overlapped slightly (HR, 2.15; 95% CI, 1.49-3.09; vs HR, 1.31; 95% CI, 1.13-1.52). Because a trend was suggested of increasing exfoliation syndrome risk in women with decreasing age of pelvic organ prolapse onset compared with women without pelvic organ prolapse from these age-stratified results (Figure), we tested an interaction of age last enrolled as a continuous variable and pelvic organ prolapse status (P < .001 for interaction based on a log-likelihood test of a model including an interaction term compared with a reduced model with no interaction).

Substudy B

Characteristics of 5130 women aged 30 to 65 years on January 1, 1995, who had clinical records in the UUHC between 1995 and 2014 and corresponding 3:1 age-matched UUHC controls are reported in Table 3. Both the exposed cases (women with pelvic organ prolapse) and unexposed controls (no pelvic organ prolapse history) had similar lengths of follow-up (mean [SD], 8.9 [5] vs 8.5 [5] years) and a similar number of eye-related patient visits (7.1 [10.6] vs 7.2 [10.7] years). Controls had a higher proportion of unreported race/ethnicity than did cases and were more likely to be nonwhite (620 [4] vs 112 [2.2]; P < .001) although both cohorts were generally non-Hispanic white persons. Cases were more likely to have given birth to 3 or more children in Utah, consistent with reported pelvic organ prolapse risk factors (48.9% vs 33.6%, respectively; P < .001). Regarding BMI, women with a pelvic organ prolapse diagnosis had a somewhat higher proportion of overweight women (BMI, 25.0-29.9) than controls. However, a slightly greater proportion of controls were obese (BMI, 30 to ≥40). The median age of a woman with a pelvic organ prolapse diagnosis was 55 years (mean [SD], 55.3 [12.1] years). In 211 controls and 85 cases with a subsequent exfoliation syndrome diagnosis during the follow-up period, the distribution of age at exfoliation syndrome diagnosis and years from exposure to an exfoliation syndrome diagnosis did not substantively differ between cases and controls (Table 3).

The John A. Moran Eye Center/UUHC data include 272 316 patients who underwent 1 or more eye-related services from 1995 to 2014. In women who were younger than 65 years at baseline (substudy B), patients who had a pelvic organ prolapse diagnosis during the 20-year study period exhibited a nearly 50% increased risk of incident exfoliation syndrome compared with age-matched control patients with no pelvic organ prolapse diagnosis (HR, 1.48; 95% CI, 1.14-1.91; P = .004) after adjusting for potential confounders, number of children born in Utah, BMI, number of eye-related patient visits, and race/ethnicity. This finding is confirmatory of the increased exfoliation syndrome risk found in women with pelvic organ prolapse in substudy A.

Discussion

We hypothesized that exfoliation syndrome, a systemic elastinopathy, would be more common in patients with pelvic organ prolapse than in those without pelvic organ prolapse.29-35 This UPEXS study was designed in 2 parts. In substudy A, we found that a history of pelvic organ prolapse in Utah Medicare beneficiaries was associated with an approximate 60% increased risk of an exfoliation syndrome diagnosis. In women aged 66 to 75 years during the last year enrolled, we observed a 2.15-fold increased risk of exfoliation syndrome in those who had a diagnosis of pelvic organ prolapse compared with women with no pelvic organ prolapse. The level of risk for exfoliation syndrome was noted to decrease in this group of older women. The presence of pelvic organ prolapse appeared to influence the age of presentation of exfoliation syndrome in this population, which further supports their association. To assess longitudinal and potentially predictive data, substudy B retrospectively examined the risk of incident exfoliation syndrome among a large cohort of patients with a diagnosis of pelvic organ prolapse (and no history of exfoliation syndrome) compared with an unaffected control group over a 20-year follow-up period. The cohort findings suggest that women with pelvic organ prolapse have an almost 40% increased risk of a subsequent exfoliation syndrome diagnosis later in life. These findings confirm hypothesized biological plausibility.

The role of LOXL1 in pelvic organ prolapse is unclear and may vary depending on the menopausal state of the patient. Mouse models and clinical vaginal biopsy studies11,30,33-35,39,40 suggest that altered expression of LOXL1 and collagens involved with ECM maintenance may contribute to the development of pelvic organ prolapse. Kobak et al41 reported a reduction in mRNA expression of LOX, a relative of LOXL1, in patients with severe pelvic organ prolapse, whereas Kow et al34 found upregulated LOXL1 mRNA expression in biopsy samples from women with severe pelvic organ prolapse. Zhao and Zhou,42 unlike Kow et al,34 found the opposite in postmenopausal women with advanced POP—a decrease in mRNA expression of LOXL1 in the uterosacral ligaments—which may differ based on tissue sampling.

Although the diagnosis of exfoliation syndrome is based on its ocular manifestations, it is a systemic and genetically influenced disorder associated with the presence of LOXL1 risk alleles. Similarly, pelvic organ prolapse is a disorder of pelvic floor connective tissue in women, has a familial pattern of inheritance, and perhaps is influenced by LOXL1.43

As part of this UPEXS study, we identified an association between exfoliation syndrome and pelvic organ prolapse using the robust UPDB in conjunction with Centers for Medicare & Medicaid claims data. This method can be applied to other elastin disorders to determine risk, time to event, and the likelihood of such elastin/collagen ECM comorbidities being associated with exfoliation syndrome. Phenotypes across this Utah data set can be easily identified from ICD-9 or CPT codes and clinically validated. Through identification of shared risk factors, systemic diseases, and genetic familial linkage pedigrees using an established, statewide research database in Utah, such modulators may be identified.43,44

Epidemiologic studies45-47 of individuals with exfoliation syndrome suggest a variety of systemic comorbidities, such as abdominal aortic aneurysm, cardiovascular disease, and cerebrovascular disease. These studies were conducted based on the hypothesis that connective tissue containing elastin, regulated and repaired by enzymes such as LOXL1, may be associated with exfoliation syndrome. These data have helped to inform our understanding of the implications of exfoliation syndrome and its role in systemic disorders.47,48 Such associations of comorbidities with exfoliation syndrome have clinical implications that can help with management of patient care.

Study Strengths

To our knowledge, this is the first population-based investigation of an association of pelvic organ prolapse and exfoliation syndrome. The UPDB is a unique resource (to our knowledge, it is the only database of its kind in the United States and one of few in the world) that enables high-quality, health-related research from a compilation of statewide medical information, decades of state vital records, and census data on 8 million individuals residing in Utah. The UPDB also contains a vast Utah genealogy of large pedigrees that represent most families in the state linked to medical and vital records to identify familial clustering of disease.48 Given that exfoliation syndrome is usually diagnosed after age 60 years, Medicare claims data in UPDB represent most women in Utah at risk for exfoliation syndrome. Furthermore, medical information in UPDB links to examinations within a large health care system that offers comprehensive eye services throughout the state: the UUHC John A. Moran Eye Center.

This investigation, using the UPDB, has identified that having pelvic organ prolapse is a risk factor for a future diagnosis of exfoliation syndrome. These data suggest that pelvic organ prolapse may be considered an indicator of probable subsequent development of exfoliation syndrome later in life, and consideration should be given to routinely performing eye examinations on women with pelvic organ prolapse.

Study Limitations

Diagnostic coding using ICD-9 can be inaccurate. To address this issue, we randomly selected 540 medical records on 1901 patients with a diagnosis of exfoliation syndrome from 1996 to 2012 using ICD-9. Exfoliation syndrome diagnosis accuracy was confirmed in more than 90% of medical records.47 We recognize that the true number of patients with exfoliation syndrome may be higher given that the syndrome may not be identified early in clinical examination. Because the mean age of women at the time of surgery for pelvic organ prolapse is 55 years, we acknowledge that those who had a diagnosis and related surgical repair before enrollment could be misclassified if they no longer have claims for these conditions in their Medicare record.36 However, studies have shown that, although most women present with pelvic organ prolapse during middle age, surgery is rare before age 30 years.23 Our study population is primarily non-Hispanic and white and may not be generalizable to nonwhite populations. We acknowledge that there may be a detection bias for exfoliation syndrome if patients with pelvic organ prolapse underwent eye examinations at a greater frequency than women with no pelvic organ prolapse diagnosis. In 11 775 Medicare beneficiaries with John A. Moran Eye Center patient records electronically available beginning in 1996, women with no pelvic organ prolapse diagnosis had a similar number of visits for eye care services compared with women with pelvic organ prolapse: a mean (SD) of 9.4 (12.8) and 10.4 (12.9) visits with a median of 5 and 6 visits, respectively. We adjusted our model in substudy B for the number of eye-related patient visits to address detection bias in John A. Moran Eye Center/UUHC patients with pelvic organ prolapse and control patients.

Conclusions

The diagnosis of exfoliation syndrome, a complex inherited systemic disorder, was more frequent in women with pelvic organ prolapse in the UPDB. This study used a robust, population-based resource to support an association of exfoliation syndrome with a nonocular systemic ECM condition. Systemic conditions with altered ECM metabolism, such as pelvic organ prolapse, may share common biological pathways with exfoliation syndrome. We hypothesize that LOXL1 dysregulation, mediated by variants in the LOXL1 antisense gene, a proposed mechanism of disease in exfoliation syndrome, may be a common contributing factor.9 Determining common biological pathways may help to improve our understanding of shared processes in such diseases.

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Article Information

Corresponding Author: Barbara M. Wirostko, MD, John A. Moran Eye Center, University of Utah School of Medicine, 65 Mario Capecchi Dr, Salt Lake City, UT 84132 (barbara.wirostko@hsc.utah.edu).

Accepted for Publication: July 28, 2016.

Published Online: September 15, 2016. doi:10.1001/jamaophthalmol.2016.3411

Author Contributions: Drs Wirostko and Curtin had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Study concept and design: Wirostko, Curtin, Ritch, Thomas, Allen-Brady, Hageman, Allingham.

Acquisition, analysis, or interpretation of data: Wirostko, Curtin, Thomas, Smith, Allingham.

Drafting of the manuscript: Wirostko, Curtin, Thomas, Allen-Brady, Hageman, Allingham.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Wirostko, Curtin, Allingham.

Obtaining funding: Wirostko, Hageman.

Administrative, technical, or material support: Wirostko, Curtin, Ritch, Thomas, Hageman.

Study supervision: Wirostko, Smith, Allingham.

Conflict of Interest Disclosures: All authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This study was supported in part by an unrestricted grant from Research to Prevent Blindness, Inc; by the Sharon Eccles Steele Center for Translational Medicine (Dr Hageman) and University of Utah Department of Ophthalmology and Visual Sciences; by grant RO1 HD061821 from the Eunice Kennedy Shriver National Institute of Child Health and Human Development; by partial support for data collection through grant P30 CA2014 from the Huntsman Cancer Foundation, University of Utah, and Huntsman Cancer Institute Cancer Center Support; and from the University of Utah’s Program in Personalized Health and Center for Clinical and Translational Science.

Role of the Funder/Sponsor: The funding organizations had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication.

Additional Information: Research reuse of Utah Medicare claims data (originally obtained by Dr Smith) was authorized by the Centers for Medicare & Medicaid in Data Use Agreement 25883.

Additional Contributions: Heidi Hanson, PhD, and Diana Lane Reed, MS (University of Utah), assisted with extracting diagnosis data from Medicare beneficiary claims in the Utah Population Data Base. Steven M. Christiansen, MD (University of Utah [now with The University of Iowa]), assisted in medical record review validation of exfoliation syndrome diagnosis codes. There was no financial compensation.

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