Association of IL1RL1, IL18R1, and IL18RAP gene cluster polymorphisms with asthma and atopy

To the Editor: Several genome-wide screens, including our own, have shown strong linkage with asthma, lung function, and atopy on chromosome 2q.1Koppelman G.H. Stine O.C. Xu J. Howard T.D. Zheng S.L. Kauffman H.F. et al.Genome-wide search for atopy susceptibility genes in Dutch families with asthma.J Allergy Clin Immunol. 2002; 109: 498-506Abstract Full Text Full Text PDF PubMed Scopus (165) Google Scholar The IL-1 receptorlike-1 (IL1RL1) gene, also known as ST2, is a promising candidate gene for asthma and atopy. IL1RL1 is located on 2q12 and resides in a cluster of IL1 receptor genes (IL-1 receptor 2 [IL1R2], IL1R1, IL1RL2, IL1RL1, IL-18 receptor 1 [IL18R1], IL-18 receptor accessory protein [IL18RAP]).2Dale M. Nicklin M.J. Interleukin-1 receptor cluster: gene organization of IL1R2, IL1R1, IL1RL2 (IL-1Rrp2), IL1RL1 (T1/ST2), and IL18R1 (IL-1Rrp) on human chromosome 2q.Genomics. 1999; 57: 177-179Crossref PubMed Scopus (90) Google Scholar IL1RL1, a member of the Toll–IL-1 receptor superfamily, is a receptor located on mast cells, TH2 cells, regulatory T cells, and macrophages and is also present in serum in a soluble form. IL1RL1 binds IL-33 and exerts its role through Toll-like receptor pathways. Various forms of IL1RL1 can either stimulate or inhibit TH2 responses.3Brint E.K. Xu D. Liu H. Dunne A. McKenzie A.N. O'Neill L.A. et al.ST2 is an inhibitor of interleukin 1 receptor and Toll-like receptor 4 signaling and maintains endotoxin tolerance.Nat Immunol. 2004; 5: 373-379Crossref PubMed Scopus (433) Google Scholar, 4Mangan N.E. Dasvarma A. McKenzie A.N. Fallon P.G. T1/ST2 expression on Th2 cells negatively regulates allergic pulmonary inflammation.Eur J Immunol. 2007; 37: 1302-1312Crossref PubMed Scopus (55) Google Scholar, 5Schmitz J. Owyang A. Oldham E. Song Y. Murphy E. McClanahan T.K. et al.IL-33, an interleukin-1-like cytokine that signals via the IL-1 receptor-related protein ST2 and induces T helper type 2-associated cytokines.Immunity. 2005; 23: 479-490Abstract Full Text Full Text PDF PubMed Scopus (2798) Google Scholar, 6Hayakawa H. Hayakawa M. Kume A. Tominaga S. Soluble ST2 blocks interleukin-33 signaling in allergic airway inflammation.J Biol Chem. 2007; 282: 26369-26380Crossref PubMed Scopus (428) Google Scholar Interestingly, single nucleotide polymorphisms (SNPs) located in the IL1RL1 gene are associated with atopic dermatitis.7Shimizu M. Matsuda A. Yanagisawa K. Hirota T. Akahoshi M. Inomata N. et al.Functional SNPs in the distal promoter of the ST2 gene are associated with atopic dermatitis.Hum Mol Genet. 2005; 14: 2919-2927Crossref PubMed Scopus (153) Google Scholar The adjacently located family members IL18R1 and IL18RAP may also be important in the development of asthma and atopy. The gene products of both IL18R1 and IL18RAP form the α-chain and β-chain of the IL-18 receptor (IL-18R).8Torigoe K. Ushio S. Okura T. Kobayashi S. Taniai M. Kunikata T. et al.Purification and characterization of the human interleukin-18 receptor.J Biol Chem. 1997; 272: 25737-25742Crossref PubMed Scopus (433) Google Scholar IL18R is a key regulator of TH1 cells. Binding of IL-18 to IL-18R stimulates TH1 cytokine release, but also TH2-type cytokines, depending on its cytokine milieu.9Nakanishi K. Yoshimoto T. Tsutsui H. Okamura H. Interleukin-18 is a unique cytokine that stimulates both Th1 and Th2 responses depending on its cytokine milieu.Cytokine Growth Factor Rev. 2001; 12: 53-72Abstract Full Text Full Text PDF PubMed Scopus (557) Google Scholar A recent publication showed strong associations with SNPs located in IL18R1 and asthma and atopic phenotypes.10Zhu G. Whyte M.K. Vestbo J. Carlsen K. Carlsen K.H. Lenney W. et al.Interleukin 18 receptor 1 gene polymorphisms are associated with asthma.Eur J Hum Genet. 2008; (Apr 2 [epub ahead of print])Google Scholar Our aim was to investigate whether SNPs in the IL1RL1 gene are associated with asthma, atopy, and allergic rhinitis. Given the strong linkage disequilibrium (LD) in this region, we also investigated the adjacently located family members IL18R1 and IL18RAP. We analyzed 200 well-characterized Dutch asthma families (n = 1259) with an asthma proband and used 407 independent asthma trios and 226 rhinitis trios to replicate our results. Furthermore, we performed a combined analysis of asthma families and trios to increase power. The medical ethics committee of the University Medical Center Groningen approved all studies, and all participants signed written informed (parental) consent. Families were assessed as described previously.11Panhuysen C.I. Bleecker E.R. Koeter G.H. Meyers D.A. Postma D.S. Characterization of obstructive airway disease in family members of probands with asthma: an algorithm for the diagnosis of asthma.Am J Respir Crit Care Med. 1998; 157: 1734-1742Crossref PubMed Scopus (63) Google Scholar The trios were characterized using the standardized protocol similar to that used in the family study. Bronchial hyperresponsiveness (BHR) to histamine was measured as described previously.11Panhuysen C.I. Bleecker E.R. Koeter G.H. Meyers D.A. Postma D.S. Characterization of obstructive airway disease in family members of probands with asthma: an algorithm for the diagnosis of asthma.Am J Respir Crit Care Med. 1998; 157: 1734-1742Crossref PubMed Scopus (63) Google Scholar BHR was defined as a PC20 ≤32 mg/mL (30 seconds inhalation). Intracutaneous skin testing was performed with 16 (for the families) and 12 (for the trios) common aeroallergens. Asthma was defined by a previously published algorithm.11Panhuysen C.I. Bleecker E.R. Koeter G.H. Meyers D.A. Postma D.S. Characterization of obstructive airway disease in family members of probands with asthma: an algorithm for the diagnosis of asthma.Am J Respir Crit Care Med. 1998; 157: 1734-1742Crossref PubMed Scopus (63) Google Scholar Twenty-one SNPs located in IL1RL1, IL18R1, and IL18RAP were genotyped. SNPs were selected from the Celera database (http://www.celeradiscoverysystem.com; Celera, Alameda, Calif), and primers were ordered through assay by design service (Applied Biosystems, Foster City, Calif). SNP selection was based on minor allele frequency >10% and location. Whenever possible, the SNPs were located in coding regions with ≈5 kb distance between each other. Eleven selected SNPs are present in the HapMap database (release 22, April 2007),12The International HapMap Consortium. The International HapMap Project.Nature. 2003; 426: 789-796Crossref PubMed Scopus (4941) Google Scholar of which 7 were haplotype tagging SNPs capturing ≈75% of SNPs located in the IL1RL1, IL18R1, and IL18RAP gene cluster. PCR was performed by using an ABI Prism 9700 HT real-time thermal cycler (Applied Biosystems). In-house software was used to test for LD (D′ and r2) between the SNPs. Family-Based Association Tests (version 2.0.2) analyses were used for investigation of preferential transmission of alleles (www.biostat.harvard.edu).13Laird N.M. Horvath S. Xu X. Implementing a unified approach to family-based tests of association.Genet Epidemiol. 2000; 19: S36-S42Crossref PubMed Scopus (744) Google Scholar Sliding window analysis with 3 consecutive SNPs was used with Haplotype-Based Association Tests.12The International HapMap Consortium. The International HapMap Project.Nature. 2003; 426: 789-796Crossref PubMed Scopus (4941) Google Scholar Results were considered significant if P < .05. Family and trio characteristics are shown in this article's Table E1 in the Online Repository at www.jacionline.org. All SNPs were in Hardy-Weinberg equilibrium (P > .01). Minor allele frequencies within the asthma families, asthma trios, and rhinitis trios were similar (see this article's Table E2 in the Online Repository at www.jacionline.org). Genotyping of 2 of 21 SNPs failed because of design problems. Strong LD between the SNPs was present in all 3 populations (eg, asthma families; Fig 1). Asthma families: Eight of 19 SNPs located in the IL1RL1, IL18R1, and IL18RAP genes were strongly associated with BHR, severity of BHR, and total serum IgE (Table I and Table E3, Table E4, Table E6 in the Online Repository at www.jacionline.org). SNPs located in IL18R1 and IL18RAP were also associated with serum eosinophils (see this article's Table E7 in the Online Repository at www.jacionline.org). Haplotype analysis using sliding windows of 3 consecutive SNPs in all 3 genes showed even stronger associations (asthma, P = .003-.05; BHR, P = .005-.05; severity of BHR, P = .0003-.05; IgE, P = .03-.05; and serum eosinophils, P = .03-.05).Table IFamily-Based Association Test of IL1RL1, IL18R1, and IL18RAP with BHR, asthma, and total IgE in the separate and combined analysis of Dutch asthma families and asthma triosAsthma familiesAsthma triosAsthma families and trios combinedGeners No.Allele∗Allele 1, major allele; 2, minor allele.z (P values)z (P values)Informative familiesz (P values)BHRIL1RL1rs142010121.311 (.190)1.474 (.141)2111.927 (.054)rs192162212.067 (.039)1.432 (.152)2122.463 (.014)rs186124611.969 (.049)1.292 (.196)1752.314 (.021)IL1RL1 /IL18R1rs1299936421.660 (.097)1.777 (.076)1982.402 (.016)IL18R1rs155862712.291 (.022)0.526 (.599)1801.973 (.049)rs227029712.208 (.027)0.590 (.555)1851.975 (.048)rs103513021.496 (.142)1.273 (.203)1741.981 (.048)IL18RAPrs142010612.418 (.016)0.813 (.416)1842.277 (.023)Intergenicrs146879112.376 (.018)0.221 (.825)1881.816 (.069)HaplotypeIL1RL1rs1921622, rs1861246, rs102067531112.803 (.005)1.844 (.065)1923.311 (.0009)IL1RL1 /IL18R1rs10206753, rs12999364, rs14200991212.125 (.033)1.800 (.072)1792.770 (.006)Asthma†Asthma based on algorithm.AlleleIL1RL1rs192162211.508 (.132)1.451 (.147)1932.074 (.038)rs186124611.201 (.230)1.552 (.121)1631.952 (.050)IL1RL1 /IL18R1rs1299936421.702 (.089)1.622 (.105)1852.312 (.021)IL18R1rs103513021.547 (.122)1.205 (.228)1591.996 (.046)HaplotypeIL1RL1rs1921622, rs1861246, rs102067531113.020 (.003)1.766 (.077)1703.354 (.0008)IL18R1rs1420099, rs1558627, rs22702971112.749 (.006)1.694 (.090)1803.086 (.002)Total IgEAlleleIL1RL1rs10540962−0.971 (.331)1.998 (.046)1270.246 (.806)rs192162211.729 (.084)1.335 (.182)2762.207 (.027)rs186124612.069 (.039)1.070 (.285)2302.320 (.020)IL18R1rs155862712.554 (.011)0.229 (.819)2382.203 (.028)rs227029712.142 (.032)0.364 (.716)2391.930 (.054)IL18RAPrs142010612.659 (.008)0.554 (.579)2342.516 (.012)Intergenicrs146879112.118 (.034)0.257 (.797)2431.833 (.067)HaplotypeIL1RL1rs1921622, rs1861246, rs102067531111.988 (.046)1.888 (.059)2452.719 (.007)Significant SNP results and consistent haplotype results are shown. z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis.∗ Allele 1, major allele; 2, minor allele.† Asthma based on algorithm. Open table in a new tab Significant SNP results and consistent haplotype results are shown. z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Asthma trios: Significant associations were observed with total serum IgE, serum eosinophils, and skin test positivity and 2 SNPs located in the IL1RL1 and IL18R1 gene (Table I and Table E6, Table E7, Table E8). Haplotype analysis showed the associations to be present with SNPs located in the IL1RL1 and IL18R1 gene with total IgE (P = .03-.05), serum eosinophils (P = .04-.05), and skin test positivity (P = .02-.05). Three haplotype combinations, [rs1921622, rs1861246, and rs10206753], [rs10206753, rs12999364, and rs1420099], and [rs1420099, rs1558627, and rs2270297], strictly replicated results in the asthma families with similar (borderline) associations with BHR, asthma, and total IgE (Table I) and serum eosinophils (P = .03-.06). Asthma families and asthma trios combined: Combination of asthma families and trios resulted in similar or more significant results (Table I and Table E3, Table E4, Table E5, Table E6). Interestingly, significant associations between asthma and SNPs located in IL1RL1 and IL18R1 were found that were not present when analyzing the both cohorts separately (Tables I and E5). Also, haplotype analysis showed a more significant association with asthma (P = .0008-.05), BHR (P = .0009-.05), BHR severity (P = .0006-.05), total IgE (P = .007-.05), and serum eosinophils (P = .005-.05) in all 3 genes, compared with the analysis of both cohorts separately. Rhinitis trios: No significant associations were found with SNPs located in the IL1RL1 and IL18R1 gene and atopic phenotypes in the rhinitis trios (data not shown). This is the first study that provides suggestive evidence for associations of SNPs in the IL1RL1 gene and adjacently located family members IL18R1 and IL18RAP with asthma and atopy in 2 independent Dutch asthma populations, but not with rhinitis. This study thus shows the importance of analyzing SNPs in adjacently located genes because it is not decisive whether the associations are caused by the IL1RL1, IL18R1, and/or IL18RAP gene as a result of strong LD in the region. Tabled 1Clinical characteristics of Dutch families from probands with asthmaProbandsSpousesChildrenGrandchildrenNo. (% female)200 (38)201∗One proband married twice; both spouses participated in the study. (62)556 (54)194 (51)Age (y), median (range)52.5 (37.8-75.3)51.5 (33.1-76.5)24.5 (6.8-53.4)12.7 (4.6-41.8)Asthma (%)9110.631.439.6BHR (%)10025.645.359.8Total IgE (IU/mL), geometric mean (range)92.9 (1.0-2880)26.2 (0.5-1940)63.5 (0.5-3360)63.8 (0.5-3710)Positive skin tests (%)82.831.053.332.8Blood eosinophils 10E7, mean (range)15.8 (0-126.5)9.4 (0-63.8)15.8 (0-294.8)20.5 (0-177)Clinical characteristics of probands of asthma and rhinitis triosAsthma probandsRhinitis probandsNo. (% female)407 (63.1)226 (56.2)Age (y), median (range)34.3 (18.1-64.7)32.5 (18-46.7)Asthma (%)86.915.3BHR (%)9133Total IgE (IU/mL), geometric mean (range)108.5 (0.5-12400)115.7 (5-6915)Positive skin tests (%)82.995.5Blood eosinophils 10E7, mean (range)16.5 (1.0-94)16.3 (1.0-78)∗ One proband married twice; both spouses participated in the study. Open table in a new tab Tabled 1SNPs selected for IL1RL1, IL18R1 and IL18RAP in Dutch asthma family study, asthma trios and rhinitis triosMinor allele frequencyGeneRs no.FunctionAllele∗Major allele first.Asthma familiesAsthma triosRhinitis triosIL1RL1rs1041973MissenseC/A0.150.180.19IL1RL1rs873022IntronG/T0.330.290.29IL1RL1rs1420101Intron/silentG/A0.380.350.36IL1RL1rs129053′UTR/intronG/A0.320.290.29IL1RL1rs1054096IntronT/C0.080.090.11IL1RL1rs1921622IntronA/G0.460.460.46IL1RL1rs1861246IntronC/T0.220.240.23IL1RL1rs10206753MissenseT/C0.380.390.38IL1RL1 /IL18R1rs129993643′UTR/promoterC/T0.360.380.39IL18R1rs1420099IntronC/G0.380.380.38IL18R1rs1558627IntronA/G0.220.250.23IL18R1rs2270297IntronC/T0.230.25NGIL18R1rs1035130MissenseA/G0.330.290.29IL18R1rs1420096IntronC/T0.470.46NGIL18R1rs37321273′UTRG/C0.130.13NGIL18RAPrs1420106PromoterG/A0.220.25NGIL18RAPrs887971IntronT/C0.320.33NGIL18RAPrs2058659IntronG/A0.480.45NGIntergenicrs1468791IntergenicG/A0.220.25NGNG, Not genotyped; UTR, untranslated region.∗ Major allele first. Open table in a new tab NG, Not genotyped; UTR, untranslated region. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with BHR in the separate and combined analysis of Dutch asthma families and asthma triosBHRFamiliesTriosAsthma families and trios combinedGeneRs no.Allelez (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197310.028 (.978)0.266 (.790)1540.212 (.831)rs87302221.204 (.229)0.587 (.557)1971.297 (.194)rs142010121.311 (.190)1.474 (.141)2111.927 (.054)rs1290521.513 (.130)0.899 (.368)1901.741 (.082)rs105409620.186 (.852)1.395 (.163)911.016 (.310)rs192162212.067 (.039)1.432 (.152)2122.463 (.014)rs186124611.969 (.049)1.292 (.196)1752.314 (.021)rs1020675310.337 (.736)1.237 (.216)2141.044 (.297)IL1RL1 /IL18R1rs1299936421.660 (.097)1.777 (.076)1982.402 (.016)IL18R1rs142009910.335 (.738)1.504 (.133)2141.210 (.226)rs155862712.291 (.022)0.526 (.599)1801.973 (.049)rs227029712.208 (.027)0.590 (.555)1851.975 (.048)rs103513021.496 (.142)1.273 (.203)1741.981 (.048)rs14200961−0.302 (.763)0.469 (.639)2270.072 (.942)rs37321271−0.043 (.966)0.749 (.454)1260.596 (.551)IL18RAPrs142010612.418 (.016)0.813 (.416)1842.277 (.023)rs88797120.795 (.427)0.840 (.401)2051.157 (.247)rs20586591−0.217 (.828)0.668 (.504)2330.281 (.777)Intergenicrs146879112.376 (.018)0.221 (.825)1881.816 (.069)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with BHR severity in the separate and combined analysis of Dutch asthma families and asthma triosBHR severityFamiliesTriosAsthma families and trios combinedGeneRs no.Allelez (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197320.703 (.482)−0.184 (.854)1600.446 (.656)rs87302221.637 (.101)0.106 (.916)1981.413 (.158)rs142010122.145 (.032)−0.028 (.978)2131.79 (.073)rs1290521.742 (.082)0.228 (.819)1921.578 (.114)rs105409621.693 (.090)0.032 (.974)1011.512 (.131)rs192162212.637 (.008)−0.246 (.806)2141.979 (.048)rs186124612.235 (.025)1.113 (.266)1762.420 (.016)rs1020675311.045 (.296)0.241 (.810)2081.032 (.301)IL1RL1 /IL18R1rs1299936423.150 (.002)0.142 (.887)2032.640 (.008)IL18R1rs142009911.004 (.315)−0.106 (.916)2100.827 (.409)rs155862712.631 (.009)−0.199 (.841)1801.881 (.060)rs227029712.442 (.015)0.083 (.934)1831.925 (.054)rs103513021.836 (.066)0.376 (.707)1761.747 (.081)rs142009620.272 (.785)−0.149 (.881)2210.152 (.880)rs373212720.926 (.355)0.227 (.821)1270.851 (.395)IL18RAPrs142010612.633 (.008)−0.006 (.995)1812.000 (.045)rs88797121.494 (.135)−0.334 (.739)2041.010 (.312)rs205865920.196 (.844)−0.028 (.978)2260.151 (.880)Intergenicrs146879112.673 (.008)−0.224 (.823)1841.887 (.059)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with asthma in the separate and combined analysis of Dutch asthma families and asthma triosAsthma∗Asthma based on algorithm.15FamiliesTriosAsthma families and trios combinedGeneRs no.Allelez (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197320.020 (.984)0.092 (.926)1390.083 (.934)rs87302221.382 (.167)0.300 (.764)1781.201 (.230)rs142010121.816 (.069)1.155 (.248)1962.063 (.039)rs1290521.460 (.144)0.688 (.491)1711.540 (.124)rs105409620.000 (1.000)1.612 (.107)791.212 (.225)rs192162211.508 (.132)1.451 (.147)1932.074 (.038)rs186124611.201 (.230)1.552 (.121)1631.952 (.050)rs1020675311.397 (.162)0.827 (.408)1901.575 (.115)IL1RL1 /IL18R1rs1299936421.702 (.089)1.622 (.105)1852.312 (.021)IL18R1rs142009911.479 (.139)1.109 (.268)1901.823 (.068)rs155862711.387 (.166)0.846 (.397)1641.527 (.127)rs227029711.309 (.191)0.905 (.366)1711.536 (.125)rs103513021.547 (.122)1.205 (.228)1591.996 (.046)rs142009610.381 (.703)0.000 (1.000)2010.266 (.790)rs373212711.175 (.240)0.385 (.700)1221.019 (.308)IL18RAPrs142010611.427 (.154)1.134 (.257)1701.796 (.073)rs88797121.592 (.111)0.641 (.521)1851.556 (.120)rs205865910.892 (.372)0.206 (.837)2030.762 (.446)Intergenicrs146879111.180 (.238)0.526 (.599)1731.169 (.243)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis.∗ Asthma based on algorithm.15 Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with total IgE in the separate and combined analysis of Dutch asthma families and asthma triosTotal IgEFamiliesTriosAsthma families and trios combinedGeneRs no.Allelez (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197320.343 (.732)0.513 (.879)1970.364 (.716)rs87302220.872 (.383)0.396 (.692)2650.952 (.341)rs142010120.840 (.401)1.385 (.166)2761.469 (.142)rs1290521.091 (.275)0.891 (.373)2551.406 (.160)rs10540962−0.971 (.331)1.998 (.046)1270.246 (.806)rs192162211.729 (.084)1.335 (.182)2762.207 (.027)rs186124612.069 (.039)1.070 (.285)2302.320 (.020)rs102067531−0.124 (.901)1.351 (.179)2740.638 (.524)IL1RL1 /IL18R1rs1299936420.100 (.920)1.800 (.072)2661.212 (.226)IL18R1rs14200991−0.181 (.856)1.743 (.081)2740.824 (.410)rs155862712.554 (.011)0.229 (.819)2382.203 (.028)rs227029712.142 (.032)0.364 (.716)2391.930 (.054)rs103513020.582 (.561)1.131 (.258)2401.109 (.267)rs142009621.062 (.288)−0.441 (.659)2890.598 (.550)rs373212710.432 (.666)0.760 (.447)1580.872 (.383)IL18RAPrs142010612.659 (.008)0.554 (.579)2342.516 (.012)rs8879712−0.018 (.986)0.583 (.560)2740.324 (.746)rs205865920.568 (.570)−0.675 (.499)2960.057 (.954)Intergenicrs146879112.118 (.034)0.257 (.797)2431.833 (.067)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with serum eosinophils in the separate and combined analysis of Dutch asthma families and asthma triosSerum eosinophilsFamiliesTriosAsthma families and trios combinedGeneRs no.Allelez (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197320.010 (.992)0.298 (.766)1900.183 (.855)rs87302220.720 (.471)0.461 (.645)2540.853 (.394)rs142010120.784 (.433)1.379 (.168)2671.369 (.171)rs1290520.904 (.366)0.834 (.404)2491.203 (.229)rs10540962−0.330 (.742)1.791 (.073)1250.566 (.572)rs192162211.512 (.130)1.438 (.150)2682.040 (.041)rs186124611.861 (.063)1.538 (.124)2272.374 (.018)rs1020675310.012 (.990)1.226 (.220)2660.657 (.511)IL1RL1 /IL18R1rs1299936420.147 (.883)2.012 (.044)2571.281 (.200)IL18R1rs14200991−0.074 (.941)1.705 (.088)2650.844 (.399)rs155862712.411 (.016)0.640 (.522)2352.323 (.020)rs227029712.086 (.037)0.773 (.440)2342.127 (.033)rs103513020.444 (.657)0.979 (.328)2330.886 (.376)rs142009621.007 (.314)−0.155 (.877)2790.754 (.451)rs373212710.661 (.509)0.318 (.750)1520.717 (.473)IL18RAPrs142010612.879 (.004)1.081 (.280)2302.968 (.003)rs8879712−0.105 (.916)0.891 (.373)2650.397 (.691)rs205865920.841 (.400)−0.343 (.731)2860.513 (.608)Intergenicrs146879112.123 (.034)0.684 (.494)2392.093 (.036)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis. Tabled 1Family-Based Association Test of IL1RL1, IL18R1, and IL18RAP with positive skin test result in the separate and combined analysis of Dutch asthma families and asthma triosPositive skin test resultFamiliesTriosAsthma families and trios combinedGeneRs no.Allele∗Allele 1, major allele; 2, minor allele.z (P values)z (P values)Informative familiesz (P values)IL1RL1rs104197320.573 (.567)−0.191 (.849)1370.249 (.080)rs87302210.307 (.759)−0.234 (.815)1920.096 (.932)rs14201012−0.176 (.860)1.199 (.230)2020.584 (.560)rs1290520.063 (.950)0.318 (.750)1840.244 (.807)rs10540962−0.863 (.388)2.151 (.031)880.796 (.426)rs192162210.000 (1.000)1.474 (.141)2050.968 (.333)rs186124611.020 (.308)0.811 (.417)1691.273 (.203)rs102067531−0.338 (.735)1.631 (.103)2030.751 (.452)IL1RL1 /IL18R1rs129993642−1.121 (.262)1.818 (.069)1970.321 (.748)IL18R1rs14200991−0.283 (.777)1.613 (.107)2050.798 (.424)rs155862711.256 (.209)0.160 (.873)1801.030 (.303)rs227029710.787 (.431)0.157 (.875)1820.676 (.499)rs10351302−0.512 (.609)0.828 (.408)1720.102 (.919)rs142009621.211 (.226)−0.489 (.625)2170.578 (.563)rs37321271−0.388 (.698)1.294 (.196)1200.699 (.485)IL18RAPrs142010611.693 (.090)0.552 (.581)1741.626 (.104)rs88797110.660 (.509)−0.455 (.649)1940.211 (.833)rs205865920.668 (.504)−0.626 (.532)2180.077 (.939)Intergenicrs146879111.065 (.287)−0.078 (.938)1830.724 (.469)z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis.∗ Allele 1, major allele; 2, minor allele. Open table in a new tab z Scores and (uncorrected) P values are shown for the asthma families and asthma trios. Numbers of informative families, z scores, and P values are shown for the combined analysis.