The Heritability and Sibling Risk of Angle Closure in Asians

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1 The Heritability and Sibling Risk of Angle Closure in Asians Nishani Amerasinghe, MRCOphth, 1,2 Jian Zhang, MSc, 3 Anbupalam Thalamuthu, PhD, 4 Mingguang He, MD, MPH, 3 Eranga N. Vithana, PhD, 1,5 Ananth Viswanathan, MD, 6 Tien Y. Wong, MD, PhD, 1,5 Paul J. Foster, PhD, FRCS(Ed), 6 Tin Aung, PhD, FRCS(Ed) 1,5 Purpose: To describe the heritability and sibling risk for angle closure. Design: Prospective clinical study. Participants: Probands with primary angle closure (PAC) and primary angle-closure glaucoma (PACG) and their first-degree relatives. Methods: One hundred probands with PAC and PACG and their first-degree relatives were examined prospectively. All subjects underwent an ophthalmic evaluation that included slit-lamp examination, optic disc evaluation, and gonioscopy. An angle was classified as narrow if the posterior (usually pigmented) trabecular meshwork could be seen for less than 180 of the angle circumference. The heritability of narrow angles was calculated by threshold models. The sibling recurrence and relative risk of having narrow angles compared with the general population was calculated using estimation of sibling genetic risk parameters, corrected for single ascertainment bias. Main Outcome Measures: Heritability and sibling risk for narrow angles. Results: One hundred probands (consisting of 76 subjects with PACG and 24 with PAC) were examined together with 327 first-degree relatives. There were 76 female probands and 24 male probands. Of the first-degree relatives, 146 were male and 181 were female. Of the 327 first-degree relatives, 105 (32.1%) had narrow angles. The heritability of narrow angles was 58.8% overall, with the genetic variance being 2.30 and the phenotypic variance being Of the 515 sibling pairs examined, 171 (33.1%) pairs had both siblings unaffected, 113 (21.9%) pairs had both siblings affected, 231 (45.0%) pairs had 1 sibling affected. The sibling recurrence risk for having narrow angles was 49% (95% confidence interval, 41.6% 56.8%), whereas the sibling relative risk for narrow angles was 7.57 (95% confidence interval, ). Conclusions: A high heritability of narrow angles of almost 60% was found. Siblings of Chinese patients with PAC or PACG have almost a 50% probability of having narrow angles and are more than 7 times more likely to have narrow angles than the general population. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Ophthalmology 2011;118: by the American Academy of Ophthalmology. Glaucoma is known to have a significant genetic basis. For primary open-angle glaucoma (POAG), population-based studies in white populations have reported a higher risk of glaucoma in siblings of patients with this condition. 1 The Rotterdam study found that the prevalence of POAG in first-degree relatives was 10.4% in siblings and 1.1% in the offspring of patients. 2 The Baltimore Eye Survey also found a higher risk of POAG in siblings (9.9%; odds ratio, 3.69), in parents (5.6%; odds ratio, 2.17), and in children (1.2%; odds ratio, 1.12) of probands as compared with the general population. 3 The Nottingham Family Glaucoma Screening Study found a prevalence for POAG in siblings to be 11.8%, and the Barbados Family Study found it to be 19.8%. 4,5 These reported risks have resulted in calls for the targeted screening of high-risk first-degree relatives of POAG patients. The Nottingham Family Glaucoma Screening Study published a study on longitudinal glaucoma screening for siblings of patients with POAG. 1 This found an increasing prevalence and incidence of POAG in siblings with age, and a lifetime risk estimate of approximately 20% by age 70 years. The authors concluded that an effective and repeated screening program should be considered for this high-risk group. 1 The prevalence of primary angle-closure glaucoma (PACG) is high in East Asians. 6 9 A positive family history has also been described as a predisposing risk factor for PACG, and first-degree relatives of subjects with PACG have a3to5times greater risk of the disorder developing compared with the general population. 10,12 14 Studies by Alsbirk 13 and Lowe 12 into the ocular biometry of first-degree relatives of patients with PACG suggest that biometric characteristics such as anterior chamber depth (ACD) also are heritable. However, although these studies suggest a familial risk of angle by the American Academy of Ophthalmology ISSN /11/$ see front matter Published by Elsevier Inc. doi: /j.ophtha

2 Amerasinghe et al Heritability and Sibling Risk of Narrow Angles closure, the heritability and sibling risk of PACG largely are unknown. This study examined a group of probands with angle closure consisting of PACG and primary angle closure (PAC) and their first-degree relatives to determine the heritability, sibling recurrence risk, and sibling relative risk of narrow angles, an important precursor to the development of PAC and PACG. Patients and Methods The study followed the principles of the declaration of Helsinki and ethics approval was obtained from the Institutional Review Board of the Singapore Eye Research Institute. Written informed consent for this research was obtained from all participants. Consecutive subjects newly diagnosed with PACG or PAC (defined below) seen at a Singapore Hospital were recruited as probands in the study. Those with a known family history of PAC or PACG were excluded. All first-degree relatives of these probands who were older than 30 years then were invited to participate in the study. The aim was to recruit at least 3 first-degree relatives (assumption of average size of 0.5 parent, 1 spouse, 1.5 siblings, and 1 child) for each proband. At a study clinic, participants underwent a standardized examination procedure. 15 A questionnaire was administered first regarding subjects demographics, history of ocular symptoms, past ophthalmic history, family history, and medical history. Subjects then underwent a slit-lamp examination and intraocular pressure (IOP) measurement by Goldmann applanation tonometry (Haag-Streit, Bern, Switzerland) by a single trained ophthalmologist (NA). The optic disc was examined at magnification of 10 with a 78-diopter lens. Gonioscopy was carried out in the dark with a Goldmann 2-mirror gonioscopy contact lens at magnification 16, with the eye in the primary position. A narrow 1-mm vertical beam of light was used to observe the superior and inferior angles, and this then was set to a horizontal slit beam to examine the temporal and nasal angles. Care was taken to avoid light falling on the pupil and inadvertent indentation during the examination. The angle in each quadrant was graded using the Scheie grading system (grade 1, visible ciliary body; grade 2, visible scleral spur; grade 3, visible anterior trabecular meshwork; grade 4, angle structures not visible) according to the anatomic structures observed during gonioscopy. 16 A Sussman 4-mirror gonioscopy lens (Ocular Instruments, Inc., Bellevue, WA) was used to determine if angle-closure was the result of apposition or peripheral anterior synechiae. If the examiner believed that the subject had narrow angles, glaucomatous optic disc changes, or both, the subject underwent automated perimetry (Swedish interactive threshold algorithm Fast 24-2, Humphrey Visual Field Analyzer II; Carl Zeiss Meditec, Dublin, CA) performed with near refractive correction. All subjects also underwent autorefraction, partial coherence interferometry (IOLMaster; Carl Zeiss Meditec, Dublin, CA) for measurement of axial length and ACD, and optic disc photography (Canon CR-DGi; Canon, Tokyo, Japan). Diagnostic Definitions For the purposes of this study, the main outcome criterion (for first-degree relatives) was the presence of narrow angles diagnosed with gonioscopy. This was defined as an eye in which the posterior trabecular meshwork was not seen for at least 180 on nonindentation gonioscopy, with IOP of 21 mmhg or less, healthy optic nerves, and normal visual fields. An individual was classified as having narrow angles (also termed PAC suspect) if at least 1 eye had narrow angles. The PAC eyes, in addition to narrow angles, had peripheral anterior synechiae, raised IOP (defined as an IOP of more than 21 mmhg), or both, but without glaucomatous optic neuropathy. Peripheral anterior synechiae was defined as abnormal adhesions of the iris to the angle that were present to the level of the anterior trabecular meshwork or higher and were deemed to be present if apposition between the peripheral iris and angle structures could not be broken with indentation gonioscopy. Primary angle-closure glaucoma was defined as eyes with PAC and glaucomatous optic neuropathy (defined as vertical cup-to-disc ratio of 0.8 or more, cup-to-disc asymmetry of more than 0.2, focal notching, or a combination thereof) with compatible visual field loss on static automated perimetry (Swedish interactive threshold algorithm Standard algorithm with a 24-2 test pattern; Humphrey Visual Field Analyzer II). This was defined as glaucoma hemifield test results outside normal limits with an abnormal pattern standard deviation, with P 0.05 occurring in the normal population and fulfilling the test reliability criteria (fixation losses of more than 20%, false positives of more than 33%, false negatives of more than 33%, or a combination thereof). 17 Some probands with PAC or PACG had a previous episode of acute PAC. Data Analysis and Genetic Modelling The full explanation of the data analysis and genetic modelling can be obtained in Appendix 1 (available at In brief, estimation of heritability was conducted with threshold models, 18 an approach commonly used for binary and ordered categorical traits. The trait for narrow angles was considered as a binary trait. Estimation of the distribution of the unknown parameters uses a technique of numerical integration referred to as Gibbs sampling. 19 A complete description of the Gibbs sampling process and its theoretical justification has been described by Sorensen et al 20 and in Van Tassell and Van Vleck, 19 published by the authors of the public domain software threshold Version of MTGSAM Programs. Sibling recurrence risk (i.e., the probability of the sibling of an affected individual also being affected) was calculated using Olson and Cordell s 21 formula for estimation of sibling genetic risk parameters corrected for single ascertainment bias. The sibling relative risk was calculated by dividing the sibling recurrence risk by the population prevalence of narrow angles, which was estimated as 6% in a Singaporean Chinese population. 22 Results One hundred probands and 327 first-degree relatives from 100 families were included in the analysis. Most study subjects (94%) were of Chinese ethnicity, the remaining being Malay and Indian. There were 76 female probands and 24 male probands; of these, 76 had PACG (including 23 with a previous acute angle closure attack) and 24 had PAC (including 11 with a previous acute angle closure attack). Of the first-degree relatives, 146 (44.6%) were male and 181 (55.4%) were female. The demographic characteristics of the study subjects are summarized in Table 1. Of the 327 first-degree relatives, 105 (32.1%) had narrow angles. Thirty-three of these first-degree relatives with narrow angles had PAC and 9 had PACG. Table 2 shows the heritability data, including mean variance, standard deviations, and 95% con- 481

3 Table 1. Demographic and Biometric Characteristics of Angle-Closure Probands and Their First-Degree Relatives Demographic and Clinical Characteristics Ophthalmology Volume 118, Number 3, March 2011 Relationship to Proband Self (Proband; n 100) Child (n 168) Parent (n 10)* Sibling (n 149) Gender Male Female Age (yrs) 65.7 (9.9) 43.6 (8.5) 80.5 (5.5) 57.9 (9.6) Anterior chamber depth (mm) Right eye 2.76 (0.50) 3.02 (0.34) 2.80 (0.39) 2.81 (0.34) Left eye 2.81 (0.54) 3.04 (0.35) 2.86 (0.51) 2.80 (0.32) Axial length (mm) Right eye (0.93) (1.57) (0.43) (1.21) Left eye (0.91) (1.41) (0.76) (1.28) Means and standard deviations in parentheses are given for continuous measurements. *Ten parents underwent a clinical examination; however, 1 parent was unable to provide anterior chamber, axial length, and lens thickness measurements. fidence intervals for the presence of narrow angles. The estimated genetic variance was 2.30 and the phenotypic variance was The heritability of narrow angles, calculated as the ratio of additive genetic variance (V A ) and total phenotypic variance (V P )[h 2 V A /V P ], was (95% CI, ), or 58.8%. The environmental influence on narrow angles was the standard common (permanent) environmental variance and was calculated as the ratio of environmental variance (V C ) to total phenotypic variance (V P ), which was 0.157, or 15.7%. The residual variance reflects the random environmental and measure error variance on narrow angles and was calculated by the ratio of residual variance (V E )to total phenotypic variance (V P ). Standard residual V E /V P, and therefore was 0.263, or 26.3%. Gender, age, and axial length had fixed effects on narrow angles. The results showed that narrow angles are more likely to occur in older people, in females, and in eyes with shorter axial length. Sibling Risk Analysis Five hundred fifteen sibling pairs, including the 100 probands, were included in the sibling risk analysis. Of these, 171 pairs (33.2%) had all siblings unaffected, 113 pairs (21.9%) had 2 siblings affected, and 231 (44.9%) pairs had 1 sibling affected. The sibling recurrence risk for having narrow angles was 49.2% (95% confidence interval, 41.6% 56.8%), whereas the sibling relative risk for narrow angles was 7.57 (95% confidence interval, ). Discussion Previous studies that have investigated the heritability of glaucoma have focused on POAG, mostly in white populations. To the best of the authors knowledge, this is the first study to explore specifically the heritability and sibling risk of narrow angles in a population of first-degree relatives of patients with PAC and PACG. This study demonstrated a high heritability for narrow angles (almost 60%), even after adjustment for axial length and age, suggesting that the presence of narrow angles is largely attributable to genetic effects. The sibling recurrence risk for narrow angles (i.e., the probability of the sibling of an affected individual also being affected) was nearly 50%, whereas the sibling relative risk (calculated by dividing the sibling recurrence risk by the population prevalence of narrow angles) was These data imply that first-degree relatives of patients with PAC or PACG, in particular siblings, are at high risk of having narrow angles. The study findings have significant potential implications. First, the high heritability and sibling risk for narrow angles means that patients with PAC or PACG should be encouraged to ask their first-degree relatives to be examined for narrow angles. The authors advocate that such family members undergo ophthalmic examination and gonioscopy Table 2. Calculation of the Heritability of Narrow Angles Mean Standard Deviation 95% Confidence Interval Genetic variance ( 2 A) Common environmental variance ( 2 C) Unique environment variance ( 2 E) Phenotypic variance ( 2 P) Heritability (h 2, 2 A/ 2 P) C/ 2 P E/ 2 P Contribution of age Contribution of axial length to Contribution of gender (female vs. male)

4 Amerasinghe et al Heritability and Sibling Risk of Narrow Angles at appropriate times, such as at the age of 40 years and every 5 to 10 years thereafter. There may even be cause to implement targeted screening of first-degree relatives of patients with PAC or PACG, as has been recommended with POAG patients. 1 Because the study population was small, it is difficult to suggest screening based on these findings alone, and further studies are required to evaluate the role of screening family members. Also, further research is required to determine the best tools for clinical screening of high-risk family individuals as well as the most efficacious timing and method of intervention. This is particularly important because blindness and significant visual morbidity from PACG potentially is preventable by prophylactic laser iridotomy. Several studies (both in twins and nuclear families) have examined the heritability of factors associated with POAG. Heritability estimates for IOP have been reported to range from 0.29 to 0.50, and those for cup-to-disc ratio have been reported to range from 0.48 to 0.80, leading authors to believe that POAG is strongly determined by additive genetic effects These results support a quantitative trait linkage analysis approach to discover new genes for POAG. With the high heritability of narrow angles found in this study, the important role of genetic factors in the cause of PAC and PACG also can be seen. A recent twin study from China found that the heritability of angle width measured by anterior segment optical coherence tomography was 60.7%. 27 This value closely matched the value obtained in the current study for heritability of narrow angles (58.8%). Studies have shown that biometric traits that determine angle width also are highly heritable. For example, the Guangzhou Twin Eye Study found that the heritability of ACD was 90%. 28 Similar high heritability for ACD has been reported in white populations. 29,30 All these studies have been carried out in twins, and genetic influences probably differ in a population of first-degree relatives. Interestingly, Tu et al 31 studied the heritability of shallow anterior chambers in Chinese families with PACG and found a high heritability of 92.6%. The sibling risk of narrow angles has not been calculated before; however, Tu et al 31 examined the sibling relative risk of shallow anterior chambers and found this to be The twin studies mentioned above were carried out in healthy children with no cases of angle closure in these samples 27,28,30 ; therefore, they may not be truly representative of an actual PAC and PACG population. The heritability calculated in twin studies also is likely to be cohort specific. However, environmental influences may compromise the likelihood of identifying the underlying genes influencing these traits, because discordant environmental factors may override the contribution of genes. One of the strengths of this study was low sampling bias because probands were newly diagnosed cases of PAC or PACG without a known family history of glaucoma. However, there could have been some ascertainment bias when examining family members, because it was known that these were relatives of subjects with angle closure. Another limitation of this study was the relatively modest sample size; a larger sample would have increased power of the study. The study population was mainly Chinese, and it is not known if the results can be applied to other racial groups. Another limitation was that probands with PAC and PACG were recruited, but the heritability and sibling risk for narrow angles was calculated. Because of the limited sample size, similar figures for PAC or PACG could not be calculated. The study evaluated gonioscopic angle closure only and did not evaluate angle width, or the effect of lens thickness or cataract. Finally, it should be noted that in the study model, age, gender, and axial length were treated as fixed effects; therefore, the mean of axial length (the same for the effect of age and gender) was adjusted for in the estimation of heritability. This study did not intend to calculate the shared genetic effects between axial length and narrow angles. However, heritability estimates for axial length have been shown to be high, between 40% and 94%. 28,29,32 Because axial length is a major determinant of angle closure, its high heritability may contribute to the high heritability of narrow angles. Further work to calculate the heritability estimation of axial length in this study population will be performed. In summary, a high heritability of narrow angles of almost 60% was found. The sibling recurrence risk for having narrow angles was 49%, and the sibling relative risk was 7.6. These findings are consistent with an important role of genetic factors in the cause of narrow angles. The worldwide estimate of the number of people with PACG is 15; 744; 965 in 2010, rising to 21000; 657 in It is estimated that 86% (18; 069; 006) will be from China, India, and South East Asia and that 25% (5; 250;164) of all PACG subjects worldwide will be bilaterally blind as a result of the disease by Therefore, there is a need to consider targeted screening to prevent this substantial visual morbidity. The results suggest that a targeted screening strategy among family members of patients, particularly siblings, with PAC or PACG may be useful to identify patients at risk. Further research is warranted to address this issue. References 1. Sung VC, Koppens JM, Vernon SA, et al. 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The number of people with glaucoma worldwide in 2010 and Br J Ophthalmol 2006; 90: Footnotes and Financial Disclosures Originally received: February 11, Final revision: June 14, Accepted: June 28, Available online: October 29, Manuscript no Singapore National Eye Centre, Singapore and Singapore Eye Research Institute, Singapore, Republic of Singapore. 2 Southampton Eye Unit, Southampton University Hospitals NHS, Trust, Southamption, UK. 3 State Key Laboratory of Ophthalmology, Zhong Shan Ophthalmic Centre, Sun Yat-Sen University, Guangzhou, China. 4 Genome Institute of Singapore, Singapore, Republic of Singapore. 5 Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Republic of Singapore. 6 National Institute for Health Research Biomedical Research Centre, Moorfields Eye Hospital and University College London Institute of Ophthalmology, London, United Kingdom. Financial Disclosure(s): The author(s) have no proprietary or commercial interest in any materials discussed in this article. Supported by grants from the National Medical Research Council, Singapore, Republic of Singapore, and the Singapore National Eye Centre, Singapore, Republic of Singapore. Dr. Foster is a consultant for Allergan and Pfizer and a Lecturer for Heidelberg Engineering GmbH; Dr. Viswanathan is a consultant for Allergan and a Lecturer for Pfizer, MSD, and Alcon. Dr Viswanathan and Foster acknowledge (a proportion of their) financial support from the Department of Health through the award made by the National Institute for Health Research to Moorfields Eye Hospital NHS 484

6 Amerasinghe et al Heritability and Sibling Risk of Narrow Angles Foundation Trust and UCL Institute of Ophthalmology for a Specialist Biomedical Research Centre for Ophthalmology. The views expressed in this publication are those of the authors and not necessarily those of the Department of Health. Correspondence: Tin Aung, MD, PhD, Singapore National Eye Center, 11 Third Hospital Avenue, Singapore, , Republic of Singapore. tin11@ pacific.net.sg. 485