Familial Aggregation of Age-related Maculopathy

Familial Aggregation of Age-related Maculopathy mMmummmmmmmmmmmMmmmmamtmi

JOHANNA M. SEDDON, MD, UMED A. AJANI, MBBS, AND BRAXTON D. MITCHELL, PHD

• PURPOSE: To determine whether age-related maculopathy aggregates in families by evaluating whether its prevalence is higher among relatives of case subjects with age-related maculopathy com­ pared with relatives of control subjects without age-related maculopathy. • METHODS: Individuals with (n = 119) and without (n = 72) age-related maculopathy were identified. First-degree relatives of case and con­ trol probands (parents, siblings, or offspring) 40 years of age or older were asked whether they had ever been diagnosed with macular degeneration. Medical records of 177 case and 146 control relatives confirmed the presence or absence of age-related maculopathy. • RESULTS: The prevalence of medical-record confirmed age-related maculopathy was signifi­ cantly higher among first-degree relatives of case probands (23.7%) compared with first-degree rel­ atives of control probands (11.6%) with an ageand sex-adjusted odds ratio (OR), 2.4; 95% confi­ dence interval (CI), 1.2 to 4.7; P = .013. Rela­ tives of 78 case probands with exudative disease had a significantly higher prevalence of maculopa­ thy (26.9%) compared with relatives of the 72 unaffected control probands (11.6%) (adjusted

Accepted for publication Oct 8, 1996. From the Epidemiology Unit and Department of Ophthalmology, Massachusetts Eye and Ear Infirmary, Harvard Medical School (Drs Seddon and Ajani), and the Department of Epidemiology, Harvard School of Public Health (Dr Seddon), Boston, Massachusetts; and the Department of Genetics, Southwest Foundation for Biomedical Research, San Antonio, Texas (Dr Mitchell). Reprint requests to Johanna M. Seddon, MD, Epidemiology Unit, Massachusetts Eye and Ear Infirmary, 243 Charles St, Boston, MA 02114; fax: (617) 573-3570; e-mail:[email protected]

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OR, 3.1; 95% CI, 1.5 to 6.7; P = .003), whereas the prevalence of age-related maculopathy among relatives of 41 probands with dry maculopathy (19.2%) was slightly but not significantly higher (adjusted OR, 1.5; 95% CI, 0.6 to 3.7; P = .36). • CONCLUSIONS: The prevalence of age-related maculopathy among first-degree relatives of sub­ jects with age-related maculopathy, particularly with exudative disease, is greater than among first-degree relatives of subjects without this dis­ ease. Results suggest that macular degeneration has a familial component and that genetic or shared environmental factors, or both, contribute to its development.

A

GE-RELATED MACULOPATHY IS THE MOST COM-

mon cause of severe visual impairment among persons over age 50 years in the United States and other developed countries. Dry age-related macu­ lopathy is more common and consists of drusen and retinal pigment epithelial abnormalities and atrophy, whereas exudative age-related maculopathy with reti­ nal pigment epithelial detachment or choroidal neovascularization is less common but is associated with a greater likelihood of visual loss.1 In some classification systems, the diagnosis of age-related macular degener­ ation is confined to advanced forms of age-related maculopathy, with geographic atrophy or exudative disease,1 although other forms of age-related maculo­ pathy can also be vision threatening. As the number of older people in our population increases, the associated social and economic consequences of agerelated maculopathy-related visual impairment and blindness are destined to increase unless successful means of prevention or treatment can be found. In spite of the enormous public health impact, age-

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related maculopathy remains a poorly understood disease. Except for curtailing cigarette smoking,2 no means have been firmly established to modify the risk of developing this disease because other etiologic factors have not been fully elucidated. Specifically, the relative roles of environmental and genetic factors in its pathogenesis are unclear. It has been speculated that age-related maculopa­ thy or a susceptibility toward developing it may be at least partially inherited.3'7 In addition, some forms of retinal degeneration that are inherited,8'14 although for the most part different from age-related maculopa­ thy, may have phenotypic similarities with the agerelated form of macular degeneration. We have de­ scribed the heterogeneity of signs of age-related maculopathy in eight families15 and have demonstrat­ ed no linkage between age-related maculopathy and one candidate gene, TIMP3.12,16 Few studies, however, have quantified the transmission of age-related macu­ lopathy through families. One common approach for assessing familial aggre­ gation is to compare the proportion of cases and controls who report having a history of the disease. However, a family history of the disease is a function of the number of relatives, the background risk of disease, the age distribution of relatives, and the correlation in risk among relatives.17 Such studies may overestimate the extent of familial aggregation as a result of recall bias. An alternative approach, as described by Khoury and Flanders,17 is to reconstruct cohorts of relatives, then compare disease risks among relatives of case subjects with those among relatives of control subjects. We therefore conducted a retrospec­ tive study to evaluate the extent of familial aggrega­ tion of age-related maculopathy by comparing its prevalence among first-degree relatives of persons with and without age-related maculopathy.

SUBJECTS AND METHODS A TOTAL OF 119 UNRELATED INDIVIDUALS WITH AGE-

related maculopathy, aged 50 years and older, were identified from the ophthalmology outpatient clinics at the Massachusetts Eye and Ear Infirmary, Boston, Massachusetts. The diagnosis of age-related maculo­ pathy among these individuals, whom we refer to as

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"case probands," was based on the presence of dry age-related maculopathy (large or extensive macular drusen, retinal pigment epithelial abnormalities, and geographic atrophy) or exudative disease (retinal pigment epithelial detachment or choroidal neovascularization confirmed by fluorescein angiography). Among probands with age-related maculopathy, 41 (34.5%) had dry disease and 78 (65.5%) had the exudative form. The case probands were identified from a consecu­ tive series of all patients with age-related macular degeneration who were seen between April 1989 and December 1990. Only those individuals 50 years of age or older with age-related maculopathy who had at least one living first-degree relative (parent, sibling, or child) 40 years of age or older were eligible to participate. Case probands were invited to participate in the study based only on their age and the availability of an age-eligible relative, not on any knowledge of a relative's disease status. All patients with age-related maculopathy were asked to partici­ pate regardless of the presence or absence of eye disease in the family. The 119 eligible case probands represent a 74% sample of all patients with age-related maculopathy older than age 50 (n = 160) diagnosed in the clinic during this time. A total of 72 individuals older than age 50 without age-related maculopathy (control probands) who were seen in the same ophthalmology outpatient clinics as the case probands and during the same period were identified as control probands. The control probands had one of the following diagnoses: conjunctivitis, blepharitis, vitreous floaters, or posterior vitreous detachment. These eye problems are not known to share common risk factors with age-related maculopa­ thy. All underwent a dilated retinal examination during which the absence of age-related maculopathy was confirmed. Because all case probands were white, only whites were included as control probands. Simi­ lar to eligibility for case probands, eligibility for control probands required availability of at least one living first-degree relative aged 40 years or older. Identification of control probands was made without knowledge of the history of eye disease in the family. The mean age (±SD) was 73.2 years (±7.5 years) for eligible case probands and 66.9 years (±5.9 years) for eligible control probands (P = .0001). Thirty-

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Table 1. Number of Case and Control Relatives for Whom Questionnaires and Medical Records Were Obtained Relatives of 119 Case Probands

Relatives of 72 Control Probands

No. With

No. With

Permission

Parents Siblings Offspring Total

Permission From Proband

No. Returning

Medical

No. With

From Proband

No. Returning

Medical

No. Living

to Contact

Questionnaire

Record

No. Living

to Contact

Questionnaire

Record

13 248 132 393

5 163 122 290/393 (74%)

5 131 104 240/290 (83%)

3 98 76 177/240 (74%)

13 222 61 296

7 174 55 236/296 (80%)

6 145 47 198/236 (84%)

4 112 30 146/198 (74%)

seven percent of the case probands were men, com­ pared with 46% of control probands (P = .2). Case probands had an average of 3.8 total siblings and 2.1 living siblings, compared with 4.3 total siblings and 3.1 living siblings for the control probands. Permission was requested from eligible case and control probands to contact their parents, siblings, and children aged 40 years or older for the purpose of determining if any of these relatives had ever been told by an ophthalmologist that they had age-related maculopathy or any other eye disease. The 119 case probands had 393 living relatives aged 40 years and older compared with 296 living relatives for the 72 control probands (Table 1). Permission was granted from probands to contact 74% (290/393) of the case relatives and 80% (236/296) of the control relatives. A questionnaire was sent to these family members to obtain information about prior diagnosis of eye dis­ eases, including age-related maculopathy. Among relatives for whom permission to contact was granted by the proband, questionnaires were returned from 83% (240/290) of case relatives and 84% (198/236) of control relatives. Because of our concern that relatives of case probands might be more aware of age-related maculo­ pathy than would relatives of control probands and might therefore misclassify their eye problems as age-related maculopathy, we verified self-reported age-related maculopathy by obtaining medical rec­ ords. The ophthalmologist's report was obtained for 177 of the 240 participating case relatives (74%) and for 146 of the 198 participating control relatives (74%). Records were reviewed without knowledge of

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the case-control status of the proband. The study was approved by the Institutional Review Committee, and appropriate consents were obtained from all partici­ pating individuals. Age-related maculopathy was considered to be present when there was an indication of age-related maculopathy documented in the medical records. Specific signs of dry and exudative age-related macu­ lopathy were also noted in all but one relative. The prevalence of age-related maculopathy was compared among relatives of case and control probands. Com­ parisons were initially stratified by age group and age-adjusted odds ratios (ORs), and 95% confidence intervals (CIs)18 were computed to determine whether relatedness to a proband was associated with the presence of age-related maculopathy in the relative. Multiple logistic regression analysis was used to adjust simultaneously for the effects of age (as a continuous variable) and sex.

RESULTS THE MEAN AGE OF THE 240 CASE RELATIVES WHO RE-

turned questionnaires was 61.4 years (±13 years) compared to 60.6 years (±12.1 years) for the 198 control relatives who returned questionnaires. Fortytwo percent of the case relatives and 43% of the control relatives were men. The prevalence of selfreported age-related maculopathy was 8.8% (21/240) among relatives of case probands and 2.0% (4/198) among relatives of control probands. Among relatives of both case and control probands, women were more likely to report a history of age-related maculopathy

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Table 2. Comparison of Self-reported ARM With Medical Records Among Relatives of Cases and Controls Self-reported ARM (no.) Medical Hecord ARM

Yes No No Record Total

Relatives of Case Probands

Relatives of Control Probands

Yes

No

Don't Know

Total

Yes

No

Don't Know

Total

19 1 1 21

17 122 44 183

6 12 18 36

42 135 63 240

3 1 0 4

13 111 50 174

1 17 2 20

17 129 52 198

ARM = age-related maculopathy.

Table 3. Prevalence of ARM Among First-degree Relatives of Case and Control Probands According to Age* Relatives of Control Probands

Relatives of Case Probands Age of Relative (yrs)

40-54 55-64 65-74 ==75 Total

Total No.

No. (%) With ARM

Total No.

No. (%) With ARM

Odds Ratio

62 50 32 33 177

3 (4.8) 8(16.0) 10(31.3) 21 (63.6) 42 (23.7)

44 47 42 13 146

0(0) 6(12.8) 5(11.9) 6 (46.2) 17(11.6)

1.3 3.4 2.0 2.4

CO

ARM = age-related maculopathy. 'Overall, age- and sex-adjusted odds ratio == 2.4 (95% confidence interval,1.2 to 4.7); P = .013.

than were men (13.3% vs 5.9% in case relatives; 4.0% vs 1.0% in control relatives). Table 2 displays the frequency of self-reported age-related maculopathy and the diagnosis of agerelated maculopathy as recorded in the ophthalmolo­ gist's report for those individuals for whom both endpoints were available. The diagnosis of selfreported age-related maculopathy was verified by the ophthalmologist's report in 19 of 20 case relatives (95%) and in three of four control relatives (75%). Among individuals reporting that they had never been told they had age-related maculopathy, the absence of age-related maculopathy was confirmed in 122 of 139 case relatives (87.8%) and in 111 of 124 control relatives (89.5%). The prevalence of age-related maculopathy in par­ ents, siblings, and offspring of case probands was 33.3% (1/3), 36% (35/98), and 8% (6/76), respec­ tively, compared with 50% (2/4), 13% (15/112), and

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0% (0/30) for parents, siblings, and offspring of control relatives. Table 3 shows the prevalence of medical recorddocumented age-related maculopathy in all firstdegree relatives combined according to age group. The prevalence of age-related maculopathy was high­ er among relatives of case probands than among relatives of control probands in each age category. After adjustment for age and sex, the overall preva­ lence of age-related maculopathy was significantly higher in case relatives compared with control rela­ tives (adjusted OR, 2.4; 95% CI, 1.2 to 4.7; P = .013). These results were essentially unchanged when relatives younger than 55 years were excluded from the analyses (OR, 2.1; 95% CI, 1.03 to 4.1; P = .04). As shown in Table 3, age-specific odds ratios appeared highest for relatives 65 years of age or older, although there were too few cases in the younger age groups from which to draw firm conclusions.

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Table 4. Prevalence of ARM Among Relatives of Exudative ARM, Dry ARM, and Control Probands and Associated Odds Ratios* Relatives of Case Probands

Age (yrs)

40-54 55-64 65-74 S:75

Total

Relatives

Relatives of Case Probands With Dry ARM

With Exudative ARM

of Control Probands

Total No

No. (%) With ARM

Total No.

No. (%) With ARM

Total No

No. (%) With ARM

36 31 18 19 104

2 (5.5) 6(19.3) 7 (38.9) 13(68.4) 28 (26.9)

26 19 14 14 73

1 (3.8) 2(10.5) 3(21.4) 8(57.1) 14(19.2)

44 47 42 13 146

0(0) 6 (12.8) 5(11.9) 6 (46.2) 17(11.6)

ARM = age-related maculopathy. *Age- and sex-adjusted odds ratios (95% confidence interval); exudative ARM vs control, 3.1 (1.5 to 6.7), P ■■.003; dry ARM vs control, 1.5 (0.6 to 3.7), P = .36.

The severity of clinical findings was compared among the 42 case relatives and the 17 control relatives who had age-related maculopathy based on the ophthalmologist's report. There were no signifi­ cant differences in the proportions of case and control relatives who had drusen, geographic atrophy, retinal pigment epithelial abnormalities, or retinal pigment epithelial detachment, although seven (16.3%) case relatives had choroidal neovascularization compared with none of the control relatives. The mean number of signs of age-related maculopathy was similar between affected relatives of case probands and affected relatives of control probands (1.9 vs 1.7). Using information from the medical records, we considered more stringent criteria for age-related maculopathy and reanalyzed our data. Individuals with only drusen or only retinal pigment epithelial changes were considered to be unaffected for these analyses. With these criteria, 20/177 (11.3%) of the case relatives and 9/146 (6.2%) of the control rela­ tives were affected. The prevalence of "more ad­ vanced" age-related maculopathy among case rela­ tives was higher than that among control relatives (age and sex adjusted OR, 2.1; 95% CI, 0.9 to 5.2; P = .098), although this difference was not statistical­ ly significant. To determine whether familial aggregation of agerelated maculopathy was associated with type of age-related maculopathy in the proband (exudative vs dry), we compared the prevalence of any form of age-related maculopathy among relatives of the 78

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exudative age-related maculopathy probands, relatives of the 41 dry age-related maculopathy probands, and relatives of the 72 control probands. These results are shown in Table 4. Overall, 26.9% (28/104) of the relatives of exudative age-related maculopathy probands were affected compared with 19.2% (14/73) of relatives of dry age-related maculopathy probands. Relatives of exudative age-related maculopathy probands were significantly more likely to have medical record-confirmed age-related maculopathy than were relatives of control probands after adjusting for age and sex (OR, 3.1; 95% CI, 1.5 to 6.7; P = .003). Relatives of dry age-related maculopathy probands were slightly more likely to have medical recordconfirmed age-related maculopathy than were rela­ tives of control probands, although this difference was not statistically significant (age- and sex-adjusted OR, 1.5; 95% CI, 0.6 to 3.7; P = .36). Thus, the risk of age-related maculopathy appeared highest among rel­ atives of probands with exudative age-related macu­ lopathy compared with relatives of control probands.

DISCUSSION OUR RESULTS SUGGEST THAT AGE-RELATED MACULOPA-

thy aggregates in families. Relatives of case subjects with age-related maculopathy were significantly more likely to have age-related maculopathy than were relatives of control subjects, with an age- and sexadjusted odds ratio of 2.4. The reasons for this familial

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aggregation are unknown but could include a shared genetic susceptibility to age-related maculopathy among family members or exposure to similar envi­ ronmental risk factors that are associated with this disease. Environmental factors associated with agerelated macular degeneration that are shared more often among siblings than among unrelated individu­ als include dietary intake19 and smoking habits.2 Gene-environmental interactions may also play a role; that is, it is possible that some persons may be genetically predisposed to develop age-related macu­ lopathy and that these susceptible individuals will manifest signs of this disease only when they are exposed during their lifetimes to certain environmen­ tal or biologic influences. Unlike some previous investigators, we obtained information directly from all of the participating relatives of probands, whether they reported agerelated maculopathy or not. We also evaluated cohorts of relatives of case and control probands for the presence or absence of disease, and the relationship to either a case or a control proband was the "exposure" variable.20 This approach represents a strength over study designs in which comparisons are conducted between the proportion of case and con­ trol subjects reporting a family history of age-related macular degeneration. This latter design is sensitive to recall bias because case subjects may be more aware of disease in their relatives than are control subjects. Although our methods and analyses differ, our results are consistent with inferences from previous studies.4'7 Heiba and associates6 reported significant correlations of signs of age-related maculopathy among siblings. A positive family history was a risk factor for age-related macular degeneration in a case-control study.4 Re­ ports of high concordance rates in monozygotic twins have also been noted,5,7 although these observations based on small volunteer samples are subject to certain biases and require a comparison group and confirmation with larger studies. A n interesting hypothesis suggested by our data is that age-related maculopathy may be a heterogeneous condition (with various forms having different caus­ es), as indicated by the finding that familial aggrega­ tion was more strongly associated with exudative than with dry age-related maculopathy. Different phenotypes, for example, geographic atrophy or exudative

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disease, may have different genetic and environmen­ tal causes, and there may also be different relative contributions of genetic and environmental factors to the origin of these subtypes. In addition, the full expression of the disease may be influenced by multiple genes or environmental factors, or both. For example, only a small proportion of individuals with dry age-related maculopathy eventually develop the more visually disabling exudative form of the disease, and factors associated with the transition to exudative age-related maculopathy are largely unknown. One may speculate that the possible greater degree of familial aggregation among relatives of exudative age-related maculopathy probands reflects genetic risk factors or shared environmental risk factors, or both, that play a role in this transition. The evaluation of familial aggregation of late-onset diseases such as age-related maculopathy poses several challenges. Many individuals in the family are young and have not yet reached the age of risk, and many of the older family members have died. Therefore, several generations with informative individuals are rarely available for genetic studies. In our report, the living case and control relatives on whom analyses were based had similar age distributions. For example, 35% of case relatives and 30% of control relatives in this study were aged 40 to 54 years. The correspond­ ing numbers for the two age groups 55 to 64 years and 65 years and older were 28% and 32%, and 37% and 38%, respectively. The participation rates between case and control relatives were nearly identical among those whom the proband granted us permission to contact. In addi­ tion, although some family members did not have medical records available, the rate of missing informa­ tion did not differ between case and control families. It is unlikely that participation by ophthalmologists was related to knowledge of the individual's status as a relative of a case or a control proband. However, if affected case relatives were more likely to participate than affected control relatives, this would lead to an overestimation of the prevalence of disease among case relatives (or an underestimation of prevalence of disease among control relatives) and, consequently, an overestimation of the OR. A strength of our study is the confirmation of self-reported diagnosis of age-related maculopathy by

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medical record review as well as the confirmation of negative reports. Nonetheless, it is possible that affected case relatives were more likely to seek medical care or more likely to have been diagnosed by their physicians as having age-related maculopathy than were control relatives. Also, the decision of probands to participate may have been influenced in part by their family history of disease, although this is unlike­ ly because of the recruitment strategy and attempt to enroll all eligible subjects regardless of family history. Information derived from medical records is not standardized, and physicians may have different thresholds for diagnosing age-related maculopathy. For these reasons, we also recorded specific signs of age-related maculopathy from the records to analyze whether different definitions of age-related maculopa­ thy would alter the results. The potential for these biases could have been more conclusively evaluated had it been possible to obtain standardized ocular photographs for all relatives. However, even when we used more stringent criteria for the diagnosis of age-related maculopathy, so that relatives with mini­ mal age-related maculopathy (drusen only or retinal pigment epithelial changes only) were excluded, or when we evaluated exudative disease separately, there was still an age- and sex-adjusted estimated risk that was two to three times higher for medical recordconfirmed age-related maculopathy among relatives of case probands compared with relatives of control probands. These and other data raise the question whether elderly first-degree relatives of patients with agerelated maculopathy should have periodic evaluations. Although it is premature at this point to recommend general screening measures, there is growing evidence that relatives of at least some patients with age-related maculopathy may benefit from such a policy. Al­ though the therapeutic benefit of detecting the dry form of age-related maculopathy at an early stage has not been quantified, early detection of the exudative type of age-related maculopathy can be helpful. Therefore, given the evidence to date, it is reasonable to suggest that first-degree relatives of patients with the exudative form of age-related maculopathy, partic­ ularly those over age 65 years, be examined for evidence of age-related maculopathy. Periodic eye examinations are already recommended for persons in

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this age group, so a family history of advanced age-related maculopathy should serve as yet another reason to undergo such an evaluation. In summary, results of our study suggest that age-related maculopathy aggregates in families. The familial nature of this disease may be caused by either genetic factors or environmental influences, or it may involve both mechanisms, that is, genetic susceptibili­ ty to environmental or biologic factors or geneenvironment interaction. A collaborative approach that combines the disciplines of genetics and epide­ miology is needed to determine the relative contribu­ tion of each of these potential mechanisms to the origin of this important, complex disease.

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15. De La Paz MA, Pericak-Vance MA, Haines JL, Seddon JM. Phenotypic heterogeneity in families with age-related macular degeneration. ARVO abstracts. Invest Ophthalmol Vis Sci 1996;37(3,suppl):S112. 16. Seddon JM, Pericak-Vance M, Haines J, Rimmler J, De La Paz MA. Genetic linkage analysis of the T1MP3 locus in age-related macular degeneration. ARVO abstracts. Invest Ophthalmol Vis Sci 1996;37(3,suppl):S992. 17. Khoury MJ, Flanders WD. Bias in using family history as a risk factor in case-control studies of disease. Epidemiology 1995;6:511-519.

18. Mantel N, Haenszel W. Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst 1959;22:719-748. 19. Seddon JM, Ajani UA, Sperduto RD, et al. Dietary carotenoids, vitamins A, C, and E, and advanced age-related macular degeneration. JAMA 1994;272:1413-1420. 20. Khoury M, Beaty TH. Applications of the case-control method in genetic epidemiology. Epidemiol Rev 1994;16: 134-150.

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