Pseudoexfoliation and Co-Morbidities

Principal Investigator: Barbara  Wirostko
Keywords: Glaucoma , Exfoliation syndrome , Family study Department: Ophthalmology
IRB Number: 00081512 Co Investigator: Alan Crandall
Specialty: Ophthalmology, Ophthalmology
Sub Specialties: Glaucoma, Comprehensive Ophthalmology
Recruitment Status: Recruiting

Contact Information

Barbara  Wirostko

Brief Summary

This study will examine epidemiologic, genetic and clinically associated risk factors associated with Pseudoexfoliative syndrome (XFS) and glaucoma (XFG) and other related disorders in the University of Utah health care system, in an effort to better characterize the phenotype and genotype of this disease associated with elastin and fibrilin repair. In recent years, several studies have shown a possible association with retinal degeneration, vascular, cardiac and other organ elastin degenerative diseases in patients with XFS and pseudoexfoliative glaucoma (XFG) (1-5). Initially we will focus on the relationship between XFS and XFG with Pelvic Organ Prolapse (POP) based on the possible genetic association with LOXL1, however we plan to look into other possible related disorders in the future. Through identification of a patient population diagnosed with either XFS, XFG and or POP and related family members both with the disease and no disease, utilizing the unique and extensive resources afforded through the state of Utah and the University of Utah, this pilot study will allow us to interview patients, perform standard eye exams and collect blood and other discarded tissue samples for genetic studies.  This study provides the foundation for future studies aimed at greater understanding of the genetics, related comorbidities and pathophysiology of XFS/XFG in affected individuals and family members by enabling a phenotype and genotype analysis.

Objectives include:

1. To identify individuals with XFS, XFG and/or POP in the University of Utah Healthcare system (UUHC) as well as family members who may have the clinical phenotype. The team will clinically characterize the phenotype of participating individuals and interested living family members seen in the UUHC system through investigator referral, self-referral and/or active recruitment. These individuals will be examined for the desired ocualr phenotype and also be asked to donate a blood sample and potentially lens capsule tissue (if undergoing cataract extraction) for genetic testing.

2. Through a Material Transfer Agreement, blood samples will be shared along with a de-identified subject identifier with Dr. Tin Aung and colleagues at the Genome Institute of Singapore for genetic analysis. Lens capsule tissue will also be shared when a patient with XFS/XFG and/or POP undergoes a cataract surgery and the tissue is readily accessible.

3.  De-identified clinical exam data, medical histories, and self-reported family histories will be shared with Duke University under an established collaboration with Dr. Rand Allingham, Professor of Ophthalmology and Director of Glaucoma Services at Duke University, and external co-investigator on this project. He is a premier glaucoma researcher who has pursued both basic science and clinical research in the subspecialty of glaucoma. His major research interest is the study of genetic eye disorders, primarily the inherited glaucomas such as Pseudoexfoliation.

4. To expand study participation beyond investigator and self-referral, individuals identified with XFS/XFG using ICD-9 diagnosis codes in the University of Utah (UUHC) enterprise data warehouse (EDW) records linked to the Utah Population Database (UPDB) will be actively recruited by the study PI and clinical staff. This will be true for individuals with POP as well. We will also use the UPDB and UUHC EDW linkage to the UPDB to determine the demographics, systemic and ocular comorbidities, medications prescribed, and modifiable risk factors (e.g. smoking and BMI), associated with XFS/XFG and or POP and compare these factors with age and gender-matched controls who do not have an XFS/XFG or POP diagnosis in UPDB. We will retrospectively examine the epidemiology of XFS/XFG and POP in the UUHC system of hospitals and clinics using the UPDB, and compare summary results to other national and global studies.

5. Using family relationships in the UPDB, the investigators affiliated with Pedigree and Population Resource (PPR)will examine familial relative risks of an XFS/XFG diagnosis in probands with XFS/XFG compared to controls also from the UPDB to establish evidence of familiality of this ocular disorder or associated comorbidities like POP.  If familiality is established, we will search for clustering of XFS/XFG in pedigrees using the familial standardized incidence ratio (FSIR), using kinship analysis tools (KAT) developed by PPR for UPDB kinship analyses. We can then rank these pedigrees in terms of risk for disease development as well as genotypically characterize pedigrees of XFS/XFG patients. We can then ascertain and compare LOXL1 genotypes in these families, as well as look for other genotypes in these families that are discovered through the collaboration with Duke and the Genome Institute of Singapore.

6.  To describe the epidemiology of XFS/XFG and associated comorbidities (including pelvic floor disorders (prolapse and hernias), cardiovascular conditions such as atrial fibrillation (Afib), chronic obstructive pulmonary disease (COPD), cancers implicated in the lysyl oxidase (LOX) and lysyl oxidase-like (LOXL) pathway, and other diseases characterized by collagen elastic abnormalities in Utah using statewide medical data from Utah Department of Health (UDOH) inpatient and ambulatory facility records, Utah Cancer Registry (UCR), and Center for Medicare & Medicaid (CMS) claims data in UPDB, supplemented by outpatient clinic diagnoses from the UUHSC EDW.

7.  Atrial fibrillation has been found to be associated with Sleep apnea as well as glaucoma (XFG).  We are looking for the specific associations of sleep apnea to XFG.

8.  Birdshot uveitis is a rare form of bilateral posterior uveitis affecting the eye. It causes severe, progressive inflammation of both the choroid and retina and symptoms include blurred vision, photopsia, and loss of color vision. Birdshot lesions are located in the deep choroidal stroma and are associated with the choroidal veins (Minos et al., 2016). As vascular involvement and dysfunction are general features in XFS (Hollo, 2018), we hypothesize there may be a relationship between these ocular disorders and other vascular-related comorbidities.

Inclusion Criteria

All eligible subjects will be > 18 years old at the time of diagnosis of pseudoexfoliative syndrome (XFS) or, pseudoexfoliative glaucoma (XFG), and/or a possibly related collagen elastic condition such as pelvic organ prolapse (POP), atrial fibrillation (Afib), chronic obstructive pulmonary disease (COPD), aortic aneurysm or hernia; or, the patient has a family member or members that have been diagnosed with XFS/XFG; or, the patient has XFS/XFG and is scheduled to have glaucoma surgery, cataract surgery, and or clear lens extraction surgery. Additionally, individuals identified through historic UUHSC EDW records by an ICD-9-CM code diagnosis of XFS/XFG and/or related collagen elastic conditions (see above) for recruitment by the study PI and clinical staff will have their diagnoses verified by chart review prior to contact.

Pseudoexfoliative syndrome (XFS) and or glaucoma (XFG) subjects will be included if they have an established diagnosis of pseudoexfoliation material in their anterior segment made by an ophthalmologist. This diagnosis will be based on dilated slit lamp exam by one of the listed PIs, co PIs and or a referring ophthalmologist. The criteria to determine if a subject can be included in the XFS/XFG group will include: the presence of pseudoexfoliation material on the lens capsule or near the pupil; transillumination defects near the pupil; increased pigmentation or pseudoexfoliation material at the angle, or both; an intraocular pressure of more than 21 mmHg without treatment; typical glaucomatous optic nerve changes; and glaucomatous visual field defects.

Individuals with an established diagnosis of Pelvic Organ Prolapse (POP) will also be included in the study. This diagnosis may be made clinically by an Obstetrics and Gynecological physician and/or be included in their charts as part of a historic medical record.

Individuals with an established diagnosis of Atrial Fibrillation (Afib) will also be included in the study. This diagnosis may be made clinically by a cardiologist and/or be included in their charts as part of a historic medical record.

Individuals with an established diagnosis of sleep apnea will also be included in the study. This diagnosis may be made clinically and/or be included in their charts as part of a historic medical record.

Family members of the affected individual identified through ‘family expansion’ (relatives referred by the affected patient) will then be contacted and offered an eye exam at no cost to them, to evaluate them for the presence of XFS material. If diagnosed with XFS/XFG, these individuals will be asked if they would want to be included in this study; a medical and surgical history obtained as well as blood and or lens capsule tissue (if undergoing cataract surgery) for genetic analysis, and they will be referred to an ophthalmologist and or glaucoma specialist of their choice.

Additionally, we will identify an estimated 500,000 individuals in UPDB with XFS/XFG or associated comorbidities from historic UDOH diagnosis data in UPDB, CMS data linked to UPDB through a CMS data reuse agreement, or UUHSC EDW data linked to UPDB to comprehensively describe the epidemiology and familial clustering of exfoliative disorders.  See UPDB data access table in the Study Procedures section for  further details.

To identify familial relationships between study subjects, we may touch on ~3 million family history records in UPDB.

Adults seen at the Lions Club Eye Hospital in Salama, Guatemala for ophthalmology services provided by the Moran Eye Center Outreach Team will be invited to participate in the research.  

Exclusion Criteria

Exclusion criteria will include any subject for whom the PI feels an underlying systemic disease and or condition may compromise the ability to get reliable data. Study participants will be required to be competent in their ability to complete the informed consent.