Familial Risk Ratio of Sarcoidosis in African-American Sibs and Parents

Benjamin A. Rybicki1, Kandace L. Kirkey1, Marcie Major2, Mary J. Maliarik2, John Popovich, Jr.2, Gary A. Chase1 and Michael C. Iannuzzi2

1 Department of Biostatistics and Research Epidemiology, Henry Ford Health System, Detroit, MI.
2 Division of Pulmonary and Critical Care Medicine, Henry Ford Health System, Detroit, MI.


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
While sarcoidosis is thought to aggregate in families, little is known about the risk to relatives of sarcoidosis patients. To estimate the familial risk ratio ({lambda}) of sarcoidosis in sibs and parents of cases, the authors studied 179 African-American families ascertained through an index sarcoidosis case diagnosed at Henry Ford Hospital in Detroit, Michigan. Among those relatives enrolled between 1997 and 1999, 12 of 327 (3.7%) sibs and 11 of 161 (6.8%) parents reported a history of sarcoidosis. The {lambda} in this sample of relatives, estimated by computing an age, sex, and race standardized incidence ratio, was 2.24 (95% confidence interval: 1.16, 3.92) for sibs and 2.82 (95% confidence interval: 1.41, 5.05) for parents. For sibs and parents combined, {lambda} was 2.49 (95% confidence interval: 1.58, 3.73). Results stratified by proband characteristics indicated that {lambda} was greater for relatives of younger ({lambda} = 2.93, 95% confidence interval: 1.52, 5.12) and male ({lambda} = 3.98, 95% confidence interval: 1.99, 7.12) probands. A higher {lambda} was also found for male family members and sibs born later in the birth order. A Monte Carlo method was also used to estimate {lambda}, with similar results obtained. Overall, these results indicate that, in African Americans, sibs and parents of sarcoidosis cases have about a 2.5-fold increased risk for sarcoidosis and that heterogeneity in disease risk may exist among family members.

birth order; incidence; lung diseases; odds ratio; parents; Poisson distribution; sarcoidosis

Abbreviations: HFHS, Henry Ford Health System


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Sarcoidosis is a multisystem granulomatous disorder of unknown etiology. In the United States, African Americans are between four and 17 times more likely to develop sarcoidosis compared with Caucasians (1Go, 2Go). African Americans, in addition to being more frequently affected, are also more severely affected (3Go, 4Go). African Americans are more likely to be younger at diagnosis, have widespread extrathoracic disease, require treatment with corticosteroids, and die from sarcoidosis (5Go), whereas Caucasians generally have a shorter disease course and fewer complications (3Go, 4Go). While it is possible that African Americans have a greater exposure to environmental risk factors for sarcoidosis, racial variation in sarcoidosis incidence and severity may also be due to genetic differences.

Of the many possible risk factors for sarcoidosis, an inherited susceptibility is the most likely (6Go, 7Go). Families with two or more affected members are a relatively common occurrence (8GoGoGo–11Go), despite the low population incidence of sarcoidosis (2Go). In a previous study (9Go), we found that familial sarcoidosis (defined as having a first- or second-degree relative affected with sarcoidosis) is almost three times more common in African Americans (17 percent) than in Caucasians (6 percent). In this same population of African Americans, a significant heterogeneity of familial risk existed, even after controlling for race, suggesting that disease susceptibility may be determined by one or more major factors (e.g., genes) (11Go). To optimize a study designed to search for putative sarcoidosis susceptibility genes, it is important to know the potential effect of these genes on disease risk. In fact, while clustering of sarcoidosis in African-American families appears to be common, currently no quantitative measure of sarcoidosis familial aggregation in African Americans exists. Actual comparisons of disease occurrence in relatives of sarcoidosis cases compared with the general population are limited to two studies. Headings et al. (12Go) estimated that sarcoidosis heritability was between 60 and 70 percent based on a comparison of disease incidence in the general population and in 11 African-American families ascertained through a sarcoidosis proband. Buck and McKusick (13Go) found a 2 percent prevalence of disease in 125 relatives of first-degree sarcoidosis cases who were primarily African American, but no affected first-degree relatives of controls were discovered. Subsequently they reported no estimate of familial aggregation.

From a methodological standpoint, family studies are better equipped to elucidate the genetic and environmental risk factors in sarcoidosis compared with traditional case-control designs (14Go). In terms of measuring familial aggregation, family studies are specifically designed to measure disease occurrence and risk factors in relatives of index cases. The key factor that family studies lack to adequately quantify familial aggregation is a normal comparison group. Use of population estimates of disease risk as a baseline measure for quantifying familial aggregation from family data can be precarious, if the families studied are not drawn from the population used as a reference. In the present family study, the expected disease incidence was based on the observed sarcoidosis incidence in the same population from which the probands for the family study were sampled. The results show an increased risk of sarcoidosis in sibs and parents of index cases and that disease risk may segregate differentially depending upon both the characteristics of the index case and the relative at risk for disease.


    MATERIALS AND METHODS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Study population
To estimate the familial risk ratio of sarcoidosis in sibs and parents of cases, we used data from two separate sources: 1) a family study of sarcoidosis in African Americans and 2) our own published (2Go) study of sarcoidosis incidence from 1990 to 1994 in the same population from which sarcoidosis cases for the above-referenced family study were drawn.

The sarcoidosis family study was approved by the institutional review board at Henry Ford Hospital. Informed consent was obtained from probands and family members prior to participation. African-American sarcoidosis families were ascertained through cases diagnosed in the Henry Ford Health System (HFHS) between 1970 and 1999. Over 90 percent of the HFHS patient population live in the three-county metropolitan Detroit area. The HFHS comprises an 800-bed hospital and outpatient clinic located in the city of Detroit and 31 outpatient clinics throughout the metropolitan Detroit area. Probands were African-American patients with one or more visits to the HFHS who had a history of sarcoidosis characterized by a typical clinicoradiographic presentation (15Go) and negative special stains and cultures for acid fast bacilli and fungi. Diagnosis was confirmed by a tissue biopsy of noncaseating granulomas in 94 percent of the cases used in our data analysis (see reasons for exclusions below). The cases without histologic confirmation of disease had radiographic evidence of bilateral hilar adenopathy and satistified at least one of the three following criteria: 1) presence of erythema nodosum; 2) clinical observation for >=2 years with no other medical condition that could explain the radiographic abnormalities; 3) typical skin involvement (i.e., lupus pernio, annular lesions, macular papular lesions, nodules, plaques), uveitis, hepatosplenomegaly, or gallium scan with a thoracic lambda (lacrimal) or panda (parietal) pattern. Between February 1997 and October 1999, 653 African Americans with a history of sarcoidosis were sent a letter inviting them to enroll in the study. An interviewer subsequently telephoned each prospective proband and recruited him or her for study. Probands who agreed to participate and signed an informed consent were given an interviewer-administered questionnaire that included a family history of sarcoidosis in first-degree relatives. For each first-degree relative still alive, probands were asked to give the names and contact information of those who would be willing to participate.

Of the 653 probands recruited, 103 (15.7 percent) could not be contacted, 21 (3.2 percent) were found deceased, 15 (2.3 percent) had no eligible family members, and 11 (1.7 percent) were found ineligible because of misclassified race or diagnosis. This left 503 eligible subjects, of whom 402 (79.9 percent) agreed to participate. Upon recruitment of family members, 306 probands had one or more family members participate, resulting in a final family participation percentage of 60.8 percent (306 of 503). In the family histories reported by the initial 402 probands who agreed to participate, 760 eligible (alive and age 18 years or older) sibs and parents were identified. Of these 760 persons, 64.2 percent agreed to participate. Participation varied significantly by relative type (sibs = 60.9 percent vs. parents = 72.2 percent; p = 0.003), sex (males = 49.8 percent vs. females = 73.6 percent; p = 0.001), and sarcoidosis-affected status as reported by the proband (affected = 85.2 percent vs. unaffected = 63.4 percent; p = 0.021). Separate Breslow-Day tests of homogeneity showed no statistically significant differential in participation by proband-reported affected status and relative type (p = 0.141) or sex (p = 0.564).

Of the 306 probands who had one or more family members participate, 265 had at least one sib or parent participate (the others had children only participate). To minimize selection bias and make the analysis sample more comparable with the population used for reference incidence estimates (2Go), we excluded families in which the proband was not receiving his or her primary medical care in the HFHS at the time of diagnosis, resulting in a final sample of 179 probands. In these 179 families, 161 parents and 327 sibs were available for analysis. Table 1 shows the composition of the 179 families by number of sibs and parents.


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TABLE 1. Composition of enrolled families (n = 179) in a sarcoidosis family study of African Americans at Henry Ford Hospital, Detroit, Michigan, 1997–1999

 
Values for baseline sarcoidosis risk were derived from previously published incidence estimates from a study of members of the Health Alliance Plan health maintenance organization who received their health care in the HFHS (2Go). Health Alliance Plan patients who use the HFHS comprise about 50 percent of the total HFHS patient population and 5 percent of the greater metropolitan Detroit area population. Incidence estimates were based on 5 years of newly diagnosed sarcoidosis cases in this population between 1990 and 1994. Using the average annual sarcoidosis incidence in African Americans over the entire 5 years of this study, we calculated the cumulative incidence of sarcoidosis in each 10-year age epoch from 20 to 70 years. Since no incident cases before age 20 or after age 70 were detected (incident cases during these ages are extremely rare), the sarcoidosis risk before age 20 was set at zero, and after age 70, the sarcoidosis risk was considered to be unchanged. Table 2 shows the annual and cumulative incidence of sarcoidosis based on this study. The cumulative incidence of sarcoidosis in African Americans by age 70 was 2.1 percent in males and 2.7 percent in females.


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TABLE 2. Annual and cumulative lifetime sarcoidosis risk (per 100,000) by age and sex in African Americans in the Henry Ford Health System, Detroit, Michigan, 1997–1999*

 
Statistical methods
A comparison of the observed and expected frequency of sarcoidosis in the sib and parent sample was used to estimate a sarcoidosis familial risk ratio ({lambda}). Two different statistical methods were used to estimate {lambda}. First, an estimator based on the standardized incidence ratio was calculated by dividing the observed number of cases by the expected number based on the population estimates of age- and sex-specific cumulative sarcoidosis incidence. The variance of this estimator was computed by a standard Poisson distribution.

Because the occurrence of sarcoidosis is relatively rare and the study sample size was modest, particularly after stratification, {lambda} was also estimated using simulation. The actual test statistic was a matched-pairs odds ratio (i.e., number of pairs where sib or parent is affected and control is unaffected/number of pairs where sib or parent is unaffected and control is affected). The matched "controls" consisted of simulated samples of the family members with the same age/sex structure as the observed sample, but where disease status was assigned probabilistically on the basis of the age and sex cumulative sarcoidosis risk in the HFHS African-American population. An odds ratio using discordant pairs was calculated for each replicate. For each sample analyzed, the estimator for {lambda} was the median odds ratio of 10,000 replicates, and the 95 percent confidence interval was calculated based on the observed resampling distribution of odds ratios over the simulated sample.

Using each of the two methods described above, we calculated an estimate of {lambda} for the entire sib and parent sample, sibs and parents separately, and other substrata based on the characteristics of both the proband and the relatives in the study sample.


    RESULTS
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
Table 3 shows the age and sex distribution of the family sample used in this study. Probands had a mean age of 42.7 years at the time of study enrollment and were an average of approximtely 4.5 years past their initial date of diagnosis when enrolled. The proband sample was mostly female, as were the sib and parent samples. Of the sibs and parents who participated, 12 of 327 sibs (3.7 percent) and 11 of 161 parents (6.8 percent) self-reported a history of a physician-diagnosed sarcoidosis. Sibs were 2.2 years older than probands at the time of enrollment, but affected sibs were diagnosed at about the same mean age as were probands (37.8 vs. 38.1 years). Affected sibs were 1.8 years younger than unaffected sibs at the time of enrollment. Parents were an average of 21 years older than sibs, with affected parents almost 5 years younger than unaffected parents at the time of enrollment. However, the mean age at diagnosis of affected parents was about 2 years higher than that of probands and affected sibs.


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TABLE 3. Age and sex distribution of participants in a sarcoidosis family study of African Americans at Henry Ford Hospital, Detroit, Michigan, 1997–1999

 
Overall, compared with the expected sarcoidosis cumulative incidence, sibs of sarcoidosis probands were at a greater than twofold increased risk for sarcoidosis, whereas parents had close to a threefold increased risk (table 4). When the sib and parent samples were combined, the {lambda} was 2.49 or 2.56, depending on the method of estimation. When the sample was stratified according to the characteristics of the proband, certain patterns emerged (table 5). Relatives of male probands had {lambda} values two times higher than did relatives of female probands. Dividing the proband sample by the median age at diagnosis and computing the {lambda} for the relatives in each subset, we found a greater increased risk for sarcoidosis in the relatives of younger probands.


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TABLE 4. Estimates of the familial risk ratio ({lambda}) of sarcoidosis in sibs and parents in a sarcoidosis family study of African Americans in Henry Ford Hospital, Detroit, Michigan, 1997–1999

 

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TABLE 5. Estimates of the familial risk ratio ({lambda}) of sarcoidosis in sibs and parents stratified by proband characteristics in a sarcoidosis family study of African Americans at Henry Ford Hospital, Detroit, Michigan, 1997–1999

 
Next, the sarcoidosis risk in different subsets of relatives according to sex and birth order was examined. Male relatives had a {lambda} almost two times greater than did females (table 6). Between mothers and sisters, there was little difference in {lambda}, but for male relatives, the fathers had a sarcoidosis {lambda} almost two times higher than that for the brothers when the standardized incidence ratio was used to estimate {lambda}. Table 7 shows the differences in sarcoidosis risk among sibs according to their place in the sibship birth order. While sibs adjacent to the proband in the birth order had no increased risk for sarcoidosis, those one or more sibs removed from the proband had more than a 2.5-fold increased risk. A similar increased risk was observed for sibs born after the proband ({lambda} = 3.65 or 4.50) compared with those born before the proband ({lambda} = 1.07 or 1.00). With regard to the overall position in the birth order, an increased risk for sarcoidosis was found exclusively in sibs born fifth or later. The increased risk remained in an analysis restricted to sibships of size five or greater (data not shown). The elevated {lambda} in these later born sibs was based on only eight observed cases, and therefore further dissection of this putative birth order effect was not possible.


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TABLE 6. Estimates of the familial risk ratio ({lambda}) of sarcoidosis in enrolled sibs and parents stratified by relative characteristics in a sarcoidosis family study of African Americans at Henry Ford Hospital, Detroit, Michigan, 1997–1999

 

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TABLE 7. Estimates of the familial risk ratio ({lambda}) of sarcoidosis in sibs stratified by birth order in a sarcoidosis family study of African Americans at Henry Ford Hospital, Detroit, Michigan, 1997–1999

 

    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 
On the basis of the results of the present study, we conclude that sibs and parents of African-American sarcoidosis cases are at about a 2.5-fold increased risk for sarcoidosis compared with the African-American general population. By age 70, this increased familial risk would result in 2–3 additional cases of sarcoidosis for every 100 sibs and parents than would be expected on the basis of the sarcoidosis incidence in the general African-American population. The results of the present study confirm earlier reports that first-degree relatives of sarcoidosis patients are at an increased risk of disease (12Go, 13Go) but, unlike previous studies (9Go, 10Go, 16Go, 17Go), the present study quantified familial risk with respect to sarcoidosis risk in the general population. The familial risk ratio estimates in the present study provide a benchmark of familial aggregation in sarcoidosis that should facilitate both the planning of future linkage studies and the interpretation of their results (18Go, 19Go). The latter point is particularly relevant to the genetic dissection of complex diseases, such as sarcoidosis, where the significance of a susceptibility gene is judged by the relative magnitude of its locus-specific {lambda} with respect to the overall {lambda}.

While the sarcoidosis literature is replete with reports of sarcoidosis clustering in families (16Go, 20GoGoGoGoGoGo–26Go), few studies have systematically measured the risk for relatives of sarcoidosis patients. In the only case-control study to examine familial sarcoidosis, Buck and McKusick (13Go) found a 2 percent prevalence of disease in 125 first-degree relatives of sarcoidosis cases. Their sample comprised mainly African-American sarcoidosis cases (59 of 62) and, therefore, based on race, it was comparable to the family sample in the present study. However, only 65 first-degree relatives of the 62 matched controls participated, and none had a history of sarcoidosis, which precluded making an estimate of sarcoidosis familial aggregation with any degree of precision. Headings et al. (12Go) found eight (1.5 percent) affected members of 523 first-degree relatives of 80 African-American sarcoidosis cases. Among sibs, they found that 1.9 percent were affected, whereas the present study found that 3.3 percent were affected. Under the analytical assumption of a continuous disease liability (i.e., multifactorial inheritance), they estimated that sarcoidosis heritability was between 60 and 70 percent. The comparison group they used, however, African Americans in the 20- to 29-year-old age group from a New York City incidence study, was not the same population from which their cases were sampled nor did it encompass the full age range of family members studied. Interestingly, although the comparison group for this study was an age group where sarcoidosis incidence is high (2Go), the familial risk ratio in sibs was approximately 15, a value much larger than that reported in the present study.

The sample of sibs and parents in the present study was large enough to conduct stratified analyses that provide some further insight into the familial aggregation of sarcoidosis. The similar values of {lambda} for sibs and parents suggested that shared genes may be more important than shared environment and that sarcoidosis may be inherited in a dominant fashion. In addition, sibs closest to the proband in the birth order (and likely to share the most common environment) were at no increased risk for disease. Other evidence that shared environmental factors do not play a major role in sarcoidosis is the fact that only two of 198 spouses of probands (1 percent) were reported to have sarcoidosis (data not shown).

In terms of where a sib was in the birth order, sibs born after the proband and/or fifth or later in the birth order had an appreciably increased disease risk. This finding is difficult to interpret and likely needs to be explored further, since it is correlated with several factors including sibship size and advanced parental age. An increased disease risk that is associated with sibship size might suggest an infectious etiology, but sibship size was not correlated with disease risk for sibs born earlier in the birth order. The higher values of {lambda} for younger and male probands, as well as the higher {lambda} values for male relatives, are consistent with a polygenic threshold model involving an inherited liability that is greater when the proband has characteristics that would place him or her at lower risk for disease (27Go).

In the calculation of {lambda} for sibs and parents, a standardized incidence ratio was used with a variance estimate based on Poisson distribution. {lambda} was also estimated using an odds ratio and 95 percent confidence interval based on simulation of a set of pseudo family members with risk commensurate to the general population. In terms of the best parametric approach to estimate the variance of {lambda}, the Poisson distribution was utilized because of the low expected number of cases in the study population. While the Monte Carlo method likely overestimated the magnitude of risk since it used an odds ratio calculation, it should have provided a better variance estimate for {lambda}. In general, the variance estimates for the simulation method were greater than those estimated assuming a Poisson distribution, with the greatest discrepancies between the two methods observed in the smaller samples. Despite these differences, in terms of statistical significance, no results were different between the two methods at the alpha level of 0.05.

The results of the present study are relevant only for African Americans and probably should not be extrapolated to other ethnic groups. Caucasians are at a lower risk for sarcoidosis (1Go, 2Go) and, as a group, may have fewer or less penetrant genetic factors that play a role in disease susceptibility. The sample of sarcoidosis probands used in this analysis was restricted to those who used the Henry Ford Health System as their primary source of health care. This restriction was used to limit referral biases that could result in an unrepresentative sample, particularly with respect to familial cases. Only those first-degree relatives enrolled in the study were analyzed to increase the validity of affected status. A higher participation percentage in eligible parents, females, and family members reported affected by the proband would suggest that our family sample was not representative of all eligible family members. However, an analysis that included all family members reported by the proband had results that were not appreciably different from those reported (data not shown). Likewise, no statistically significant differences in family member participation by proband-reported affected status and relative type or sex were found. This would suggest that the familial risk ratios we estimated in subsets of the data defined by these parameters were not appreciably affected by volunteer bias. No screening of family members was done to detect undiagnosed sarcoidosis cases, but this also made the family member sample more comparable with the population sample to which it was compared.

In summary, African-American sibs and parents of sarcoidosis cases are at a 2.5- to 3-fold higher risk for disease compared with the general African-American population. The stratified analysis results suggest that any shared genetic factors are likely part of a multifactorial risk component. Studies are currently in progress to determine if these putative genetic risk factors can be detected by linkage or association analyses.


    ACKNOWLEDGMENTS
 
This work was supported by National Institutes of Health grant R01 HL54306.


    NOTES
 
Correspondence to Dr. Benjamin A. Rybicki, Department of Biostatistics and Research Epidemiology, Henry Ford Health System, 1 Ford Place, 3E, Detroit, MI 48202 (e-mail: brybick1{at}hfhs.org).


    REFERENCES
 TOP
 ABSTRACT
 INTRODUCTION
 MATERIALS AND METHODS
 RESULTS
 DISCUSSION
 REFERENCES
 

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Received for publication February 21, 2000. Accepted for publication June 5, 2000.