Family concordance of IgE, atopy, and disease

Transcription

1 Family concordance of IgE, atopy, and disease Michael D. Lebowitz, Ph.D., Robert Barbee, M.D., and Benjamin Burrows, M.D. Tucson, Ari~ Family concordance of lge was determined in 344 nuclear families that were studied in, community population of white families in the Tucson area. Total circulating IgE, qfter controlling for age, sex, smoking status, and skin test reactivity demonstrated a signi6cam family concordance with the use of multifactional analysis of variance. This relationship wa~ strongest among siblings, was significant as well between parents and children, and was not present between spouses. Skin test reactivio' demonstrated independent family concordam'c ~ irh the same statistical methods. Reported diagnoses of asthma, wheeze, and allergic-rhiniti.~ histories demonstrated a strong concordance of prevalence rates in families as well. (.! 4t.L~R~,Y CL/N IMMUNOL 73: , 1984.) The familial predisposition for asthma and allergies has been known for some time. x-6 Furthermore several investigators ~-;' have been able to show that genetic analysis of asthma and of allergic rhinitis demonstrated independence of the two. Bazaral et al, 7 was able to show that circulating IgE levels were highly concordant in twins. Since then several studies have shown concordance of IgE in pedigrees a-~2 and in families. 1.~ The type of genetic transmission has not been resolved.,4-~r Age and sex have been demonstrated to have an effect on both skin test reactivity and IgE levels. 10. ~8-z2 These studies have shown significant seasonal variance of IgE as well. In addition smoking has been reported to have a significant impact on circulating IgE levels When the familial concordance From the University of Arizona College of Medicine, Division of Respiratory Sciences, Westend Research Laboratories, Tucson, Ariz. Supported by a Specialized Center of Research grant HL from the National Heart, Lung, and Blood Institute and Environmental Protection Agency grant R Received for publication Sept. 27, Accepted for publication Aug. 17, Rqxint requests: Michael D. Lebowitz, Ph.D., University of Arizona College of Medicine, Division of Respiratory Sciences, Tucson, AZ The resetrch described in this article has been funded wholly or in part by the Unitcxi States Environmental Protection Agency through contract or grant (R805318) to M. D. Lebowitz, Ph.D.; it has not been subjected to the Agency's required peer and policy review and therefore does not necessarily reflect the views of the Agency. No official endorsement should be infened. of lge and/or skin test reactivity is examined, it is necessary to take these colinear and confounding factors into account. Although the method of analysis is quite important, it is more critical in the determination of the type of genetic transmission involved.j3. 26-~,~ This article attempts to analyze the family concordance of IgE and of skin test reactivity. Because the two are related and because each is related to other factors, especially age and sex, ~s' t9 these factors will also be examined and adjusted for colinearity. The major objective is to see if there is family concordance of either factor that is independent of one another after controlling for these various confounding and covariables. METHODS There were 344 nuclear families studied, which included both parents and one or more of their natural children. They were part of a representative community-population sample of non-mexican, white Americans who were enrolled in the Tucson Epidemiologic Study of Airways Obstructive Diseases. The study design and subject-selection methods have been published previously. :~-a~ Briefly, a representative stratified, geographic-cluster sample of households (n = 1655) was enrolled for study in 1972 with block census statistics to stratify on the basis of social status and age of head of household. The 344 nuclear families contained 44% of all the individuals (1359, see Table I). The data that was used in this paper are from the first survey in which more than 90% of those family members age 6 yr and more had blood that was drawn for IgE analysis, and more than 95% of those family members age 3 yr or older were skin tested. The number of subjects in each analysis represents those 259

2 260 Lebowitz et al. J. ALLERGY CLIN. IMMUNOL. FEBRUARY 1984 TABLE I. Physician-diagnosed past or present asthma in 344 nuclear families No One Both parents with asthma parent with asthma parents with asthma Number of families (N) % of families with I* (29) 10.6%* (18) 26.5% (3) 100.0% asthmatic children (N) % of oldest children with (15) 5.5% (13) 19.1% (I) 33.3% asthma Number of children I 1 (N) % of children with asthma (35) 6.5%* (24) 19.7% (7) 63.6% (N) = number. *Rates of asthma significantly higher with one or more asthmatic parent (p < 0.005). TABLE II. Relationship of LOG IgE of child to LOG IgE of parent y=a+bx* Parent Child R P a b N Father Son > Father Daughter < Mother Son < I Mother Daughter 0,128 < N = number of parent-child pairs. *y is child's log ige, x is parent's log IgE; in regression a is intercept, b is slope, R is correlation coefficient. family members with values for the variables that were used in that analysis (i.e., complete data). All subjects completed standard National Heart, Lung, and Blood Institute questionnaires. Symptoms of "wheezing," "attacks of shortness of breath with wheeze," "allergic rhinitis," and physician diagnoses (physician-confirmed asthma) were derived from the questionnaire,:s~ and these symptoms represented subjects' responses. Prick skin tests were performed with Pepys' methods. Antigens (Hollister Stier Laboratories, Leandro, Calif.) included: house dust (1:10), Dematiaceae mold mix (1:100), Bermuda grass (1:20), local tree mix (1:20), local weed mix (1:20), and a control (50% glycerine). The results of the tests were read 20 rain after application by trained nurses. 18 Bermuda grass produced the most reactions, and those subjects with multiple reactions almost uniformly included Bermuda grass, tree mix, or weed mix among them. Is In the geographic area that was studied, it was found that skin test reactions were neither seasonal nor diurnal dependent. ~ The skin test index that was used in the analysis is an index of positivity, which was derived as previously reported. ~ Total circulating lge was determined with the paper radioimmunosorbent test, and Bermuda grass-specific IgE was determined with the radioallergosorbent test method as described previously. 19 Seasonal adjustment of lge was unnecessary in these analyses as all family members had blood drawn and analyzed at the same time. lge levels were log transformed to obtain normal distributions and reduce the marked variability in IgE; values of less than 0.1 [U were described at values of 0.05 IU before transformation. Initial analyses examined parent/oldest child pairs, sibling pairs, and spouse pairs; dependence of data that is present when multiple children and parents in the same family are examined was minimized in these analyses by examining the oldest child of a given sex. After the method of Donner and Koval,:~2 the estimation of intraclass correlations in the analysis of the complete family data set used the method of analysis of variance. Multifactorial analysis of variance allowed for removal of the effects of interactions, effects of covariables, and effects of other explanatory (main) variables when the effects of individual explanatory (main) variables were evaluated. All analyses were performed by using the SPSS package on the DEC-10/Cyber 175 at the University Computer Facility. RESULTS There was a significant family concordance of reported physician-confirmed asthma in families (Table I). Reported physician-confirmed asthma in children was directly related to the number of parents who had reported physician-confirmed asthma. There was an increase in the proportion of one or more asthmatic children, the proportion of oldest children with asthma, and the proportion of all children with asthma. These relationships persisted after controlling for "allergic" rhinitis by observing, separately,

3 NIJMBER 2 TABLE III. Analysis of variance of log IgE in children in nuclear families, controiting i:<:~ a! smoking, and skin test reactivity (276 children and their parents! Log IgE Skin tests Age and 2-way Total Source* smoking Father Mother Father Mother interaction explained Resir~ua{ Total SS ,949 4, () t !2, q~ 53,715 df F 0.641t , i 1.7~ p O12 O *SS = sums of squares (~[xi - ~,]~); df = degrees of freedom; F = F ratio for statistical test: p =p va~ue ~ F r;~i ~ TABLE IV. Children's log IgE by parent's log IgE, all ages, smoking, allergy, and skin test index Covariates Log IgE Skin test (age, Total Total Source* smoking) Father Mother Father Mother Interactions explained residual Total Age < 10 yr SS ,346 J 9A~i~, df F p ,921 0, Age 10+ yr SS , ,;;'6:2 t ~3,278 df ~99 F ,315 3, , p Note: Child's allergy skin test index significantly related to their Log IgE in both age groups. *SS = sums of squares (Z~[xi - ~]o); df = degrees of freedom; F = F ratio for statistical test; p = p value of F ratio families with and without allergic rhinitis. In addition there was a significant association of self-reported "allergic" rhinitis in nuclear families when the symptoms were analyzed in the same manner as asthma. This was independent of which parent had current "allergic" rhinitis. Prevalence rates for current rhinitis in the oldest children were 54% if either parent had rhinitis, and the rate was 25% if neither parent had rhinitis (p < When the presence or absence of skin test reactivity (atopy) in the parents was examined, the association between parental and childhood rhinitis still persisted in nonreactors. This relationship may be due to a bias of perception, which has been reported previously2 a For this reason "allergic" rhinitis as a reported symptom was not evaluated further. Initial paired analyses of the oldest child's log IgE compared to the parents' log IgE were statistically significant for most parent/child pairs, as shown in Table II. This analysis revealed marked variation in the parent/child IgE relationship; father/son-ige association was very poor, whereas mother/son-ige association was excellent. Father/daughter- and mother/ daughter-ige associations fell in between. Analysis of variance, with age as a covariant, adjusted for the relationships between skin test reactivity and log lge; the results were most significant for sibling pairs. There was no relationship between spouses in any of these analyses. Analysis of variance of log lge in nuclear families. controlling for age, indicated a statistically significant relationship with each parent's log lge contributing significantly as explanatory variables 1main effects) to the children's log IgE. After controlling for age and smoking, the relationship of children's log lge to parent's log IgE was of even greater significance. About 50% of fathers and 38% of mothers were present smokers. For both parents there were interactions that were observed between the parent's log lge and their smoking status as well, which have been reported previously. 24 These interactions were removed from the other relationships examined. Removing the effect of smoking also removed the effect of sex so that it was not considered as a covariate in further analyses Further analysis of variance of log lge in nuclear families was controlled for skin test reactivity as well as age and smoking of the parents. The purpose wa~:

4 262 Lebowitz et al. J. ALLERGY CLIN. IMMUNOL, FEBRUARY 1984 TABLE V. Children's allergy skin test index by parents' allergy skin tests index and IgE Allergy Log IgE skin tests Covariate 2-Way Total Source* (ages) Father Mother Father Mother interactions explained Residual Total SS t df F p *ss = sums of squares (Xl[xi - ~]2); df = degrees of freedom; F = F ratio for statistical test; p = p value of F ratio. ~-Significant interactions: Father's log IgE and skin test index; mother's log lge and skin test index. to remove effects of the strong relationship between skin test reactivity and IgE in individuals ~9 and to remove any effects of family concordance of skin test reactivity. The analysis demonstrated highly significant contributions of parent's log IgE, especially mother's log IgE, to children's log IgE as seen in Table III, Skin test reactivity in the children because it is so highly correlated with their own IgE was not included in the analysis. The same analysis that was restricted to children less than or equal to age 10 yr and children more than age 10 yr demonstrated that the relationship was significant only for the older children as seen in Table IV. Allergy skin test reactions of the children became the dependent variable in an analysis of variance with parent's log IgE and skin tests as the explanatory variables with age as a covariate. As revealed in Table V, the results were significant (p < 0.001), which indicated family concordance of skin test reactivity. The father's skin test-reactivity status positivity related most strongly to the children's skin test reactivity, and the mother's log IgE related strongly to the children's skin test positivity (see discussion above). The children's log IgE related best to their skin test reactivity when that variable was included in the analysis (p < 0.001). Since the most prevalent aeroallergen in this community ~8 was Bermuda grass, then the effect of the children's log Bermuda-specific IgE is the most statistically significant factor if the Bermuda- skin test reactivity is examined. Thus in both cases the age covariate and the children's log lge-skin test reactivity relationship was highly significant. DISCUSSION This study of randomly selected nuclear families was aided by the ability to objectively ascertain IgE and skin test reactivity rather than relying on reported illness. In addition the use of major covariables and environmentally related variables such as age, sex, and smoking and the ability to evaluate the interaction of the IgE levels and the skin test reactivity allowed some clarification of the independent relationship of the two. Despite general variability in individual responsiveness to specific allergens, familial concordance was observed for specific-bermuda grass IgE and for a skin test index (in which Bermuda grass is the most common reactor followed by local tree and weed mixes). This indicates communality of responses in families. Although other investigators have found differences in skin test reactivity by season in other areas, we did not find such seasonal variability. This is probably related to the characteristics of the region that was studied, such as a pollen calendar that has fewer seasonal perturbations than are seen elsewhere. The pollen that are related to the most common skin test (Bermuda grass, trees, and weeds) occur throughout large parts of the year. Reactions to these three antigens were highly coverated. 18 Thus that form of variability did not affect our results. Finally, seasonal adjustments of IgE have not changed any of the findings in regard to IgE. Wheeze apart from colds and attacks of wheezing dyspnea have been demonstrated to be distinct from diagnosed asthma, 24 although all asthmatic individuals have attacks of wheezing dyspnea. These two symptoms were also concordant in families with a higher proportion of children with asthma or wheeze in families with asthma or wheeze. These relationships were not as strong as those relationships of asthma per se. However, even asthma, which is highly correlated with both skin test reactivity and IgE levels, can not be predicted only by these objective tests, and familial asthma is not fully explained by these tests either. There was a marked variation in the relationships of child IgE to parents' IgE, which varied by sex. The findings that the mother/son relationship was best, whereas father/son relationship was worse may be caused by some underlying genetic reason, which

5 VOLUME 73 IgE atop,,,, ar,,d disease $'!~ NUMBER 2 would be speculative at present. The daughter/parent relationships, which were better, might fit into the same speculations. The correlation of IgE and skin test reactivity '~ produced some marked variability in the findings (Tables IV and V) that is more a statistical problem than meaningful. That is, because of their interaction, one may be significant whereas the other is not in some of the more complicated analyses, Age is another factor in this interaction, ~, 24 which cannot be controlled completely. Nevertheless, the strongest relationship that was observed is between parents' log lge and their children's log IgE (Table III). It was not possible to determine the specific forms of genetic inherence in the manner of Ran et al. ~:~ or Elston and Stewart. '~; The analysis demonstrated that differences between the sexes in IgE levels of adults were due to differences in smoking. Furthermore the interaction between smoking and IgE was important to remove in evaluating familial concordance. The analysis also demonstrated that there either is a major influence of environmental factors in childhood, which lead to a concordance of IgE that is greater in older children, and/or a factor of penetrance that is associated with polygenic factors as inferred by Rao~ '4 Sibbald, ~ and Leigh and Marley, :~4 Since we were not examining reactivity to specific aeroallergens as they were related to specific IgE, we were not able to examine specific immunoresponses. This is because we are more interested in the relationship of IgE and skin test reactivity in general and how they relate to asthma and allergic rhinitis. Furthermore, as an association of human leukocyte antigen with asthma has not been demonstrated, :~5 we did not evaluate human leukocyte antigen. The theory that there may be limits to the number of lge clones, which then go through a stage of recognition and increase, ='2 would be an attractive hypothesis to explain our findings. It was noted that the atopically inclined family members appear to have several genetic controis and a complex set of environmental influences. This would nicely fit our theories and data. There certainly appears to be at least one antigenic nonspecific control subject that is a non-human leukocyte antigen dependent regulator of IgE. The next logical step is to determine if log IgE levels in families or skin test-reactivity associations in families can predict which children are going to develop asthma and/or allergic rhinitis and what might be the relationship between the two findings. We wish to acknowledge the statistical and programming contributions of David Armet, M.S., Catherine Holberg, M.S,. and Martha Ctine, M.S. We also wish to acknowl- edge the lge determinations and ~he c,)mmen~s by Marilyn Halonen, Ph,D REFERENCES 1. Schwarz M: Heredity in bronchiai asthma Acta Allergol 51 suppl)2: Sibbald B, Turner-Warwick M: Factors influencing the prevalence of asthma among first degree relatives of extrinsic and intrinsic asthmatics. Thorax 34:332, t Sibhald B. Horn MEC, Brain EA, Gregg I: Genetic factors in childhood asthma. Thorax 35: Sibbald B. Horn MEC, Gregg I: A family study of the genetic basis of asthma and wheezy bronchitis. Arch Dis Childhood 55:354, Sibbald B: A family study approach to the gerretic basis of asthma. Ph.D. Thesis, University of Londor,~, Edfors-Lubs ML: Allergy in 7000 twin pairx. Acta Allergol 26:249, Bazaral M, Orgel HA, Hamburger RN: Genetics of tge and allergy: serum lge levels in twins J AI.I t~c;,t Clan [MMUNOL 54:288, Marsh DG, Bias WB, Ishizaka K: Genetic control of basal serum immunoglohulin E level and its eflect on specific reaginc sensitivity. Proc Natl Acad Sci LISA 77:3588, Gerrard JW, Ran DC, Morton NE: A gene~ic study ot immunoglobulin E. Am J Hum Genet 30:46~ Blumenthal MN, Namboodiri KK. Mendel? N, Gleich G, Yunis E. Elston RC: study of genetic transmission of serum [ge levels. J ALLERC, Y CLIN IMMUNO~. 63: Meyers DA. Marsh DG: Report on a National Institute of Allergy and Infectious Disease-sponsored workshop on the genetics of total immunoglobulin E levels in humans, J A t ~_.er(~v CLIN IMMUNOL 67:167, Meyers DA, Marsh DG, Hasstedt SJ, King MC, Bias WB, Skolnick M: Total IgE levels in Mormon and Amish families. J ALLERGY CLIN [MMUNOL 67(suppl):55, 198:t 13. Ran DC, Lalouel JM, Morton NE, Gerrard JW lmmunoglobulin E revisited. Am.1 Hum Genet 32:620~ t Ran DC: Genetics of serum immunogtobutin E levels in man. Presented at the lmmunogenetics Workshop ~n Omaha, Neb. September, 198 l 15. Smith JM, Knowles LA: Epidemiology of asthma and allergic rhinitis. 11. In a university-centered community Am Rev Respir Dis 92:31, Anderson HR, Bailey PA, Bland JM: The effl~c! of birth month on asthma, eczema, hayfever, respiratory symptoms lung function and hospital admissions for asthma ln~ J Epidemiol 10:45, Soothill JF, Stokes CR, Turner MW, Norman AP, Taylor B: Predisposing factors and the development of reaginic allergy in infancy. Clin Allergy 6:305, Barbee R. Lebowitz MD. Burrows B, Thompson H: Immediate skin-test reactivity in a general population sample. Ann Intern Med 84:129, Barbee RA, Halonen M, Lebowitz MD, Burroves [q: The distribution of lge in a community population sample; correlations with age, sex, and allergen skin test reactivity. J A~- LERGY ClAN IMMUNOI. 68:106, Gerrard JW, Brook D: Serum IgE levels in lbrty t2~rni~ies tbl lowed for 2-3 years. Ann Allergy 38:396, Meyers DA, Marsh DG: Report on a NIAID sponsored workshop on the genetics of total lge levels in humans ~ AI ~ Er~(;'~ CLtN lr~mc, No~ 67:167. t981

6 264 Lebowitz et a}. J. ALLERGY CLIN. IMMUNOL. FEBRUARY Marsh DG, Meyers DA, Bias WB: The epidemiology and genetics of atopic allergy. N Engl J Med 305:1551, Gerrard JW, Heiner DC, Ko CG, Mink J, Meyers A, Dosman JA: Immunoglobulin levels in smokers and nonsmokers. Ann Allergy 44:261, Burrows B, Halonen M, Barbee RA, Lebowitz MD: The relationship of serum immunoglobulin E to cigarette smoking. Am Rev Respir Dis 124:523, Warren CPW, Holford-Strevens V, Wong C, Manfreda J: The relationship between smoking and total immunoglobulin E levels. J ALLERGY CLIN IMMUNOL 69:370, Elston RC, Stewart J: A general model for the genetic analysis of pedigree data. Hum Hered 21:523, Morton NE, MacLean CJ: Analysis of family resemblance. III. Complex segregation of quantitative traits. Am J Hum Genet 26:489, Ott J: Maximum likelihood estimation by counting methods under polygenic and mixed models in human pedigrees, Am J Hum Genet 31:161, Lalouel JM, Morton NE: Segregation analysis with pointers. Hum Hered (in press) 30. Lebowitz MD, Knudson RJ, Burrows B: The Tucson epidemiology study of chronic obstructive lung disease. I. Methodology and prevalence of disease. Am J Epidemiol 102:137, Lebowitz MD, Burrows B: The Tucson epidemiology study of chronic lung disease. II. The effects of in-migration on prevalence rates of disease. Am J Epidemiol 102:153, Donner A, Koval J J: The estimation of intraclass correlation in the analysis of family data. Biometrics 36:19, Freidhoff LR, Meyers DA, Bias WB, Chase GA, Hussain R, Marsh 13(3: A genetic-epidemiological study of human immune responsiveness to allergens in an industrial population: I. Epidemiology of reported allergy and skin-test positivity. Am J Med Genet 9:323, Leigh D, Marley E: Bronchial asthma. Oxford, 1967, Pergammon Press, Inc 35. Turton LWG, Morris L, Buckingham JA, Lawler SD, Turner-Warwick M: Histocompatibility antigens in asthma-- population and family studies. Thorax 34:670, 1979