Human Molecular Genetics, 2002, Vol. 11, No. 13 1539-1548
© 2002 Oxford University Press
Susceptibility loci for atopic dermatitis on chromosomes 3, 13, 15, 17 and 18 in a Swedish population
1Department of Molecular Medicine and 2Department of Dermatology and Venereology, Karolinska Institutet at Karolinska Hospital, SE-171 76 Stockholm, Sweden
Received February 22, 2002; Accepted April 15, 2002
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ABSTRACT |
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Atopic dermatitis is a hereditary, pruritic, inflammatory and chronic skin disease that typically presents in early childhood and may continue or recur later. The etiology of atopic dermatitis is unknown, but several lines of evidence indicate that it is a multifactorial disorder caused by the combined influence of genetic and environmental factors, even though the relative contributions of genes and environment are not known. To identify important loci that contribute to the development of atopic dermatitis, we conducted a genome-wide linkage analysis with 367 microsatellite markers, using a non-parametric affected relative-pair method in 109 pedigrees. Three qualitative phenotypes and one semi-quantitative phenotype were studied. For the phenotype atopic dermatitis, linkage to chromosome region 3p24–22 was found. For another phenotype, atopic dermatitis combined with raised allergen-specific IgE levels, a suggestive linkage was found to chromosome region 18q21. For the semi-quantitative phenotype severity score of atopic dermatitis, suggestive linkage was found to chromosome regions 3q14, 13q14, 15q14–15 and 17q21. Identifying chromosome regions linked to susceptibility genes for atopic dermatitis provides a platform from which the search for atopic dermatitis genes can proceed.
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INTRODUCTION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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Atopic dermatitis (AD) is a hereditary, pruritic, inflammatory and chronic skin disease that typically presents in early childhood and may continue or recur later. A marked increase has occurred in its prevalence during the past decades in urbanized societies (1–3). In Sweden, the prevalence of AD in schoolchildren has more than doubled between 1979 and 1991 (4), and is now one of the highest in the world, at approximately 15% (5). The etiology of AD is unknown, but several lines of evidence indicate that it is a multifactorial disorder caused by the combined influence of genetic and environmental factors, even though the relative contributions of genes and environment are not known (6,7). Twin studies support the role of a strong genetic contribution with a concordance rate of 0.86 in monozygotic twins and 0.21 in dizygotic twins (3). When both parents have AD, children have a risk of up to 75% of developing the disease (8). AD is often associated with other clinical atopic manifestations, such as asthma, allergic rhinoconjunctivitis and elevated total and/or allergen-specific serum IgE levels (9,10).
One way to reveal the etiology of a multifactorial disease with an inherited component is to locate genes contributing to the disease. Several genetic studies of asthma and atopy have been published, but few of AD. Some studies [e.g. (11–14)] have focused on chromosome regions with candidate genes in AD, and two genome-wide linkage analyses of AD were reported recently (15,16). Lee et al. (15) found a major susceptibility locus in AD to chromosome region 3q21. This was not confirmed by Cookson et al. (16), who instead found linkage to chromosome regions 1q21, 17q25 and 20p. None of these four loci matches the previously identified atopy or asthma loci, but, interestingly, the same regions have been linked to psoriasis (16).
To identify important loci that contribute to the development of AD, we conducted a genome-wide linkage analysis with 367 microsatellite markers, using a non-parametric affected relative-pair method. We used 109 pedigrees forming 197 affected full-sib pairs and 9 affected half-sib pairs – in total 470 individuals. Five pedigrees included affected sib pairs in more than one generation.
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RESULTS |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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In the multipoint linkage analysis, evidence in favor of linkage (P<0.01) for at least one phenotype were found to chromosomes 1, 3, 4, 5, 6, 7, 10, 13, 15, 17, 18, 21 and X (Figs 1 and 2).
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Atopic dermatitis
In the analysis of the AD phenotype, 109 pedigrees were included (Table 1). The highest multipoint LOD score for the qualitative traits in this genome-wide linkage analysis was obtained close to marker D3S1768 on chromosome region 3p24–22 (LOD=2.18, P<0.001) to AD (Fig. 1). This marker also showed evidence of linkage in single-point analysis (P<0.005, Table 2). Weaker evidence in favor of linkage in multipoint analysis was seen to three additional chromosome regions; 5p13 (LOD=1.47, P<0.005), 6q16 (LOD=1.39, P<0.01) and 10p13–12 (LOD=1.42, P<0.01). In single-point analysis, the chromosome regions 6q16 and 10p11 also show evidence of linkage (P<0.005) (Table 2), but not the region on 5p13. An additional marker in chromosome region 10p13–11 (D10S1412) showed evidence of linkage in the single-point analysis (P<0.005) (Table 2).
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0.005 for at least one of the phenotypes and flanking markers
Atopic dermatitis combined with elevated allergen-specific IgE levels
In the analysis of the sp-IgE+ phenotype, 62 pedigrees were included (Table 1). In chromosome region 18q21, evidence in favor of linkage in the multipoint analysis was obtained close to marker D18S851 to sp-IgE+ (LOD=2.16, P<0.001) (Fig. 1). The highest single-point LOD score was observed to the same marker (LOD=2.20, P<7.4x10-4) (Table 2). In addition, two flanking markers (D18S858 and D18S64) showed weaker evidence of linkage (P<0.005 and P<0.05 respectively) in the single-point analysis (Table 2). Weaker evidence in favor of linkage in the multipoint analysis was also seen to three additional chromosome regions: 4q24–26 (LOD=1.56, P<0.005), 6p (LOD=1.51, P<0.005) and 1p32 (LOD=1.36, P<0.01) (Fig. 1). In the single-point analysis, chromosome regions 1p32 and 11q13 also showed evidence of linkage (P<0.005) (Table 2).
Extreme atopic dermatitis
In the analysis of the extreme AD phenotype, 32 pedigrees were included (Table 1). The most prominent multipoint linkage, using the extreme AD phenotype, was in a region on chromosome 18p close to marker D18S542 (LOD=1.88, P<0.005) (Fig. 1). In the single-point analysis, evidence of linkage was seen to chromosome region 18q21 (D18S858; LOD=1.67, and P<0.005) (Table 2). Weaker evidence of linkage in the multipoint analysis was observed on chromosome regions 21q21 (LOD=1.69, P<0.005) and 7p14 (LOD=1.48, P<0.005) (Fig. 1). In the single-point analysis, linkage was shown to chromosome region Xp11 close to marker DXS6800 (MLS=2.64, P<0.005).
Severity score of atopic dermatitis
In the analysis of the semiquantitative phenotype severity score of AD, 109 pedigrees were included (Table 1). For this phenotype, evidence in favor of linkage was found to four regions (Fig. 2); one on chromosome 13q14 close to the marker D13S325 (Z-score=3.21, P<7.4x10-4), one on chromosome 15q14–15 close to the marker D15S118 (Z-score=3.07, P<7.4x10-4), one on chromosome 17q21 close to marker D1751290 (Z-score=3.08, P<7.4x10-4) and one on chromosome 3q14 close to the marker D3S2459 (Z-score=2.55, P<7.4x10-4).
Significance levels
The definition of suggestive linkage is a LOD score that by chance would be observed once per genome-wide linkage analysis (17). In order to evaluate our findings, we performed computer simulations. In 921 of the 5000 computer simulations for the qualitative phenotype AD, at least one peak reaching the suggestive level (LOD>2.20) was obtained. Two peaks next to each other were counted as one if the separation was less than 20 cM. This is less than expected (P<10-5).
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DISCUSSION |
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TOPABSTRACTINTRODUCTIONRESULTSDISCUSSIONMATERIALS AND METHODSREFERENCES |
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We report a genome-wide linkage analysis with 367 microsatellite markers in 109 pedigrees forming 197 full-sib pairs and 9 half-sib pairs affected with AD.
When interpreting the results from genome-wide linkage analysis, opinion differs regarding the thresholds for linkage. Lander and Kruglyak (18) give P<7.4x10-4 as the threshold for suggestive linkage and P<2.2x10-5 for significant linkage when allele-sharing methods in human sib pairs are used. According to these criteria, suggestive linkage means statistical evidence of one random occurrence in a genome-wide linkage analysis, while significant linkage is 0.05 random occurrences in a genome-wide linkage analysis (18). We identified five loci fulfilling the criteria for suggestive linkage (chromosome 3, 13, 15, 17 and 18) and another locus on chromosome 3 almost reaching this level. However, these authors' criteria are intended for studying one phenotype, which was not the case in our study. Furthermore, the phenotypes that we studied are not independent, since approximately 70% of the siblings had increased total and/or allergen-specific serum IgE levels. The IgE levels were also included as one component in the severity scoring of AD. We performed simulations to evaluate the results from the genome-wide linkage analysis and to obtain more precise significance levels in our material. The simulation was done for the qualitative phenotype AD. In the simulation, 921 of the 5000 simulations had at least one peak reaching the level for suggestive linkage (LOD=2.20). This is much less than the expected 5000 peaks, indicating that the threshold for suggestive linkage according to Lander and Kruglyak (18) is too conservative for this study. On the other hand, we have not corrected for studying more than one phenotype.
The region on 3p24–22 that linked to AD in our study has earlier been identified as a susceptibility locus for asthma in a founder population of European origin (19,20). The other region on 3q14, which linked to the severity score of AD in our material, is located just centromeric of the locus on 3q21. This has been identified as a major susceptibility locus for AD in the recent genome-wide linkage analysis (15). In this region, CD80/CD86 are interesting candidate genes, since they are involved in co-stimulatory signals in T-cell activation (21).
The susceptibility region identified on chromosome 13q14 for severity score of AD has already been linked to atopy in published genome-wide linkage analyses for asthma (22,23). An earlier study of AD has shown linkage and association to 13q12–14 in a Swedish and a German population (24). An interesting candidate gene in this region is the gene for the high-mobility-group protein-1 (HMG-1). This is important in gene regulation and stimulation of pro-inflammatory cytokine synthesis in human monocytes (25). Another candidate gene in region 13q12 is that for the Wiskott–Aldrich protein family member 3, WASF3 (26). This is because patients with Wiskott–Aldrich syndrome show eczema very similar to AD. However, the most well-known gene for the Wiskott–Aldrich syndrome is located on Xp11 and has recently been investigated as a candidate gene for AD (27). We found weak linkage (MLS=1.68, P<0.05) in the region to the phenotype severity score of AD, but not to any other phenotype investigated at that point. However, when defining the new qualitative phenotype, extreme AD, in the genome-wide linkage analysis, we found stronger evidence for linkage to the WAS region on Xp11 (MLS=2.64, P<0.005).
We also obtained suggestive linkage for the phenotype sp-IgE+ to a region on chromosome 18q21 (Fig. 2, Table 2). The same region has indicated evidence in favor of linkage to asthma-related phenotypes in a Finnish founder population (28).
The region on chromosome 15q14–15 has not previously been identified as a susceptibility locus for AD. This region reached the level of suggestive linkage to the semiquantitative phenotype severity score of AD, but not to any of the other phenotypes.
The region on chromosome 17q21 that showed evidence in favor of linkage to the severity score of atopic dermatitis has earlier been linked to asthma (19). Furthermore, this is centromeric of the locus, 17q25, that has been linked to AD by Cookson et al. (16) and to psoriasis (PSORS2) (29–31). The linkage to chromosome region 1q21 was close to another psoriasis susceptibility locus (PSORS4), where a cluster of genes regulating epidermal differentiation is located (32). This locus was identified in the genome-wide linkage analysis for AD together with 17q25 and 20p (16). Interestingly, the chromosome region 20p has also been linked to psoriasis (16,33). For the AD phenotype, the region on chromosome 20p could be excluded at 
s
2 in our material. Furthermore, the identified major susceptibility locus for AD on 3q21 (15) also corresponds closely with an already-identified psoriasis locus (34). Even if AD and psoriasis differs clinically, some of the susceptibility genes might be shared in these two inflammatory skin disorders.
The regions where we had weaker positive findings; 1p32, 4q24–26, 5p13, 6q16, 7p14, 10p13–11 and 21q21, have all been linked to asthma-related phenotypes by several groups (19,22,23,28,35–40). Comparison with studies showing linkage to asthma is interesting, since asthma and AD are related phenotypes and 74% of our patients reported asthma and/or allergic rhinoconjunctivitis. The linkage finding in chromosome region 5p13 is outside the previously described interleukin cluster region, and the locus on chromosome 6q16 is separated from the major histocompatibility complex (MHC).
Both genome-wide linkage analysis and candidate gene studies for AD have revealed partly conflicting results. That might be a consequence of genetic heterogeneity in datasets within or between studies, differences in the diagnostic criteria, false negatives according to excessive distances between markers or too small sample sizes, false positives, environmental factors, misdiagnosis, and incomplete penetrance. The latter two problems were minimized in this study, since all participating siblings were examined by the same dermatologist and only the affected siblings and their parents were analyzed. Our findings, in combination with earlier results, suggest that atopic diseases, including AD, are a heterogeneous group of disorders, although it is possible that several susceptibility genes are shared by some of the phenotypes studied. The heterogeneity in the linkage results for atopic diseases, as well as the small number of affected sib-pairs in our sub groups, also illustrates the needs for large sample sizes for replication of findings.
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MATERIALS AND METHODS |
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Recruitment of families
Families were recruited during 1995–1997. Patient registries were used from the Departments of Dermatology, Karolinska Hospital and Danderyd Hospital, Stockholm, Sweden. 5000 patients diagnosed with AD were identified and contacted by letter. Families with at least two affected siblings above 4 years of age were included. All participating patients gave their informed consent, and for children below 18 years of age consent was also obtained from their parents. The parents were included when possible regardless of their atopic status. The siblings in the present study form part of a larger collection of patient material obtained in Sweden as previously described (41). Pedigrees are available on request. The study was approved by the Karolinska Hospital Ethics Committee.
Clinical examination
All siblings were evaluated by the same dermatologist (M.B.), applying the UK Working Party's Diagnostic Criteria (42–44) and the criteria of Hanifin and Rajka (45). Siblings fulfilling the UK Working Party's Diagnostic Criteria were considered as affected and were included. The distribution of any eczema was recorded. All affected siblings participated in a standardized interview covering different aspects of AD and other atopic manifestations. The parents were not examined, but answered a questionnaire based on the UK Working Party's Diagnostic Criteria for AD. An arbitrary score for the severity of AD among the siblings was obtained according to the classification in Table 3.
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Quantification of IgE antibodies
IgE was measured at the Department of Clinical Immunology, Karolinska Hospital. The following were measured in all affected siblings: (i) the total serum IgE concentration using the Pharmacia CAP System, IgE FEIA (Pharmacia & Upjohn Diagnostics AB, Uppsala, Sweden). The cutoff was 2 kU/l; (ii) IgE antibodies to Phadiatop, a mixture of inhalant allergens (Pharmacia CAP System Phadiatop FEIA). The Phadiatop was reported as either positive or negative; (iii) IgE antibodies to a mixture of relevant food allergens (fx5) (Pharmacia CAP System RAST FEIA). The RAST mixture was divided into six classes, where a concentration below 0.35 kU/l represents a negative result (class 0). In the linkage analysis, we considered increased allergen-specific serum IgE antibodies (sp-IgE+) to either Phadiatop or food allergens as affected for the sp-IgE+ phenotype.
Phenotype categorization
We studied four phenotypes in the affected siblings. In one, AD was diagnosed according to the UK Working Party Diagnostic Criteria (AD). In another, AD was combined with elevated allergen-specific serum IgE levels (sp-IgE+). A third consisted of patients with a more severe phenotype (extreme AD). The group was defined as having an early age of onset (at 2 years or younger), combined with a severity score of 3 or more. Finally, we followed one semiquantitative trait, the severity score of AD. When studying a semiquantitative phenotype, siblings who share more alleles identical by descent should be more similar in phenotype than those sharing fewer alleles at a locus influencing the phenotype. The numbers of affected sib-pairs in each group and their clinical characteristics are listed in Table 1.
Genotyping
Genomic DNA was extracted from peripheral venous blood using standard protocols. The PCR investigations of the polymorphic microsatellite markers were carried out as single reactions in 96-well plates, using standard protocols. The PCR products were pooled prior to gel electrophoresis. PCR conditions are available on request. All the forward primers were fluorescence-labeled and the PCR products were size-fractionated on an ABI377 (Applied Biosystems). The resulting genotype data were analyzed with Genescan 2.1 and Genotyper 2.0 software (Applied Biosystems). Allele numbers were assigned for each marker, their sizes being standardized for each marker using a control DNA with known alleles on each 96-well plate. This DNA was also run on each gel. Genotypes were determined for a total of 351 autosomal and 16 X-chromosome markers. The basis for the microsatellite markers was the Weber 6 screening set (46). In sparsely covered regions, new markers were added from the Genome DataBase (http://gdbwww.gdb.org/) and the Marshfield Medical Research Foundation (http://research.marshfieldclinic.org/genetics/). Mean heterozygosity for the autosomal markers was 0.82 and that for the X chromosome was 0.71. The mean average intermarker distance was 10.3 cM.
Statistical analysis
As the mode of inheritance is unclear, non-parametric affected relative-pair-based methods were used to detect linkage. Linkage analyses for the qualitative traits were performed in the Allegro software (47) and corresponding P-values were interpreted according to Lander and Kruglyak (18), as summarized by Nyholt (48). Equal weights were assigned to each family in a linear model.
Linkage analysis for the semiquantitative trait was performed in Genehunter 2.0 (49), using the non-parametric command, and the corresponding P-values were interpreted according to Lander and Kruglyak (18), as summarized by Nyholt (48). Linkage analysis for the X chromosome was performed using MAPMAKER/SIBS (17) as suggested by Nyholt (48). Allele frequencies were estimated from all genotyped individuals using the zGenStat 1.126 program (Henric Zazzi, unpublished). The map distances used were based on the Marshfield map (http://research.marshfieldclinic.org/genetics/) in order to avoid underestimation of marker distances in regions linked to the phenotypes studied. Crimap was used for checking the orders of the markers, and this order agreed with published maps (50). Exclusion mapping was performed for four different locus-specific s levels, 1.2, 1.5, 2.0 and 3.0 using Genehunter 2.0 for the three qualitative phenotypes (49). A LOD score of less than -2.0 was considered as significant evidence of exclusion for a region.
All genotyped markers were checked for Mendelian incompatibilities using PedCheck 1.0 (51) or zGenStat 1.126. Either incompatibilities were resolved unambiguously, or individuals and/or pedigrees were excluded from linkage analyses. To identify markers with allele dropout or other problems, the expected number of homozygotes was calculated based on the estimated allele frequencies and compared with the observed numbers of homozygotes. For this the Pearson 
2-test as implemented in the zGenStat 1.126 software was used. Any marker showing significant deviation from expected homozygosity frequency (P<0.001) was reanalyzed. Family structures were verified using the Siberror program (52), based on genotype data of markers spaced at 30 cM. We identified one previously unidentified monozygotic twin pair, which was excluded from further analysis.
We performed 5000 computer simulations of genotypes in Allegro (47) in order to evaluate the results from the genome-wide linkage analysis and to more precisely obtain the significance levels in our material. In the simulations, we used the same family structures, the same observed allele frequencies and the same mean success rates for the autosomal markers as in the genome-wide linkage analysis. Genotypes were only generated for individuals that actually were genotyped in the genome-wide linkage analysis. The simulation was carried out for the AD phenotype using 109 families. Multipoint linkage analysis was performed using a linear model and equal weights for all families.
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ACKNOWLEDGEMENTS |
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We thank Marie Norberg, Berit Rydlander and Sivonne Arvidsson for skilful technical support. We express our gratitude to all the family members who were a part of this study, whose cooperation was essential for the success of this study. This work was supported by grants from the Swedish Asthma and Allergy Association, the Swedish Foundation for Health Care Science and Allergy Research, Swedish Strategic Funds (SSF) and the Edward Welander-Finsen Foundation. I.K. was supported by an AMF Jubilee Fund stipend.
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FOOTNOTES |
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* To whom correspondence should be addressed at: Department of Molecular Medicine, CMM 02, Karolinska Hospital, SE-171 76 Stockholm, Sweden. Fax: +46 8 51773620; Email: magnus.nordenskjold{at}cmm.ki.se
Present address: H. Luthman, Department of Endocrinology, Wallenberg Laboratory, University Hospital MAS, SE-205 02 Malmö, Sweden.
The authors wish it to be known that, in their opinion, the first two authors should be regarded as joint First Authors.
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REFERENCES |
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1 Taylor, B., Wadsworth, J., Wadsworth, M. and Peckham, C. (1984) Changes in the reported prevalence of childhood eczema since the 1939–45 war. Lancet, ii, 1257–1255.
2 Schultz Larsen, F., Holm, N.V. and Henningsen, K. (1986) Atopic dermatitis: A genetic-epidemiologic study in a population-based twin sample. J. Am. Acad. Dermatol., 15, 487–494.[Web of Science][Medline]
3 Schultz Larsen, F. (1993) Atopic dermatitis: a genetic-epidemiologic study in a population-based twin sample. J. Am. Acad. Dermatol., 28, 719–723.[Web of Science][Medline]
4 Åberg, N., Hesselmar, B., Åberg, B. and Eriksson, B. (1995) Increase of asthma, allergic rhinitis and eczema in Swedish schoolchildren between 1979 and 1991. Clin. Exp. Allergy, 25, 815–819.[Web of Science][Medline]
5 ISAAC (1998) Worldwide variation in prevalence of symptoms of asthma, allergic rhinoconjunctivitis, and atopic eczema: ISAAC. The International Study of Asthma and Allergies in Childhood (ISAAC) Steering Committee. Lancet, 351, 1225–1232.[Web of Science][Medline]
6 Coleman, R., Trembath, R.C. and Harper, J.I. (1993) Chromosome 11q13 and atopy underlying atopic eczema. Lancet, 341, 1121–1122.[Web of Science][Medline]
7 Panhuysen, C.I., Meyers, D.A., Postma, D.S. and Bleecker, E.R. (1995) The genetics of asthma and atopy. Allergy, 50, 863–869.[Web of Science][Medline]
8 Schultz Larsen, F. (1991) Genetic aspects of atopic eczema. In Ruzicka, T., Ring, J. and Przybilla, B. (eds), Handbook of Atopic Eczema. Springer-Verlag, Berlin–Heidelberg, pp. 15–26.
9 Rajka, G. (1989) The atopic antibody. In Essential Aspects of Atopic Dermatitis. Springer-Verlag, Berlin–Heidelberg, pp. 111–120.
10 Rajka, G. (1989) Associated conditions. In Essential Aspects of Atopic Dermatitis. Springer-Verlag, Berlin–Heidelberg, pp. 35–37.
11 Mao, X.Q., Shirakawa, T., Yoshikawa, T., Yoshikawa, K., Kawai, M., Sasaki, S., Enomoto, T., Hashimoto, T., Furuyama, J., Hopkin, J.M. et al. (1996) Association between genetic variants of mast-cell chymase and eczema. Lancet, 348, 581–583.[Web of Science][Medline]
12 Folster-Holst, R., Moises, H.W., Yang, L., Fritsch, W., Weissenbach, J. and Christophers, E. (1998) Linkage between atopy and the IgE high-affinity receptor gene at 11q13 in atopic dermatitis families. Hum. Genet., 102, 236–239.[Web of Science][Medline]
13 Cox, H.E., Moffatt, M.F., Faux, J.A., Walley, A.J., Coleman, R., Trembath, R.C., Cookson, W. and Harper, J.I. (1998) Association of atopic dermatitis to the beta subunit of the high affinity immunoglobulin E receptor. Br. J. Dermatol., 138, 182–187.[Web of Science][Medline]
14 Söderhäll, C., Bradley, M., Kockum, I., Wahlgren, C.F., Luthman, H. and Nordenskjöld, M. (2001) Linkage and association to candidate regions in Swedish atopic dermatitis families. Hum. Genet., 109, 129–135.[Web of Science][Medline]
15 Lee, Y.A., Wahn, U., Kehrt, R., Tarani, L., Businco, L., Gustafsson, D., Andersson, F., Oranje, A.P., Wolkertstorfer, A., v Berg, A. et al. (2000) A major susceptibility locus for atopic dermatitis maps to chromosome 3q21. Nat. Genet., 26, 470–473.[Web of Science][Medline]
16 Cookson, W.O., Ubhi, B., Lawrence, R., Abecasis, G.R., Walley, A.J., Cox, H.E., Coleman, R., Leaves, N.I., Trembath, R.C., Moffatt, M.F. et al. (2001) Genetic linkage of childhood atopic dermatitis to psoriasis susceptibility loci. Nat. Genet., 27, 372–373.[Web of Science][Medline]
17 Kruglyak, L. and Lander, E.S. (1995) Complete multipoint sib-pair analysis of qualitative and quantitative traits. Am. J. Hum. Genet., 57, 439–454.[Web of Science][Medline]
18 Lander, E. and Kruglyak, L. (1995) Genetic dissection of complex traits: guidelines for interpreting and reporting linkage results. Nat. Genet., 11, 241–247.[Web of Science][Medline]
19
Ober, C., Cox, N.J., Abney, M., Di Rienzo, A., Lander, E.S., Changyaleket, B., Gidley, H., Kurtz, B., Lee, J., Nance, M. et al. (1998) Genome-wide search for asthma susceptibility loci in a founder population. The Collaborative Study on the Genetics of Asthma. Hum. Mol. Genet., 7, 1393–1398.
20 Ober, C., Tsalenko, A., Parry, R. and Cox, N.J. (2000) A second-generation genomewide screen for asthma-susceptibility alleles in a founder population. Am. J. Hum. Genet., 67, 1154–1162.[Web of Science][Medline]
21 Sansom, D.M. (2000) CD28, CTLA-4 and their ligands: Who does what and to whom? Immunology, 101, 169–177.[Web of Science][Medline]
22 Daniels, S.E., Bhattacharrya, S., James, A., Leaves, N.I., Young, A., Hill, M.R., Faux, J.A., Ryan, G.F., le Souef, P.N., Lathrop, G.M. et al. (1996) A genome-wide search for quantitative trait loci underlying asthma. Nature, 383, 247–250.[Medline]
23 CSGA (1997) A genome-wide search for asthma susceptibility loci in ethnically diverse populations. The Collaborative Study on the Genetics of Asthma (CSGA). Nat. Genet., 15, 389–392.[Web of Science][Medline]
24 Beyer, K., Nickel, R., Freidhoff, L., Bjorksten, B., Huang, S.K., Barnes, K.C., MacDonald, S., Forster, J., Zepp, F., Wahn, V. et al. (2000) Association and linkage of atopic dermatitis with chromosome 13q12–14 and 5q31–33 markers. J. Invest. Dermatol., 115, 906–908.[Web of Science][Medline]
25
Andersson, U., Wang, H., Palmblad, K., Aveberger, A.C., Bloom, O., Erlandsson-Harris, H., Janson, A., Kokkola, R., Zhang, M., Yang, H. et al. (2000) High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J. Exp. Med., 192, 565–570.
26 Suetsugu, S., Miki, H. and Takenawa, T. (1999) Identification of two human WAVE/SCAR homologues as general actin regulatory molecules which associate with the Arp2/3 complex. Biochem. Biophys. Res. Commun., 260, 296–302.[Web of Science][Medline]
27 Bradley, M., Söderhäll, C., Wahlgren, C.-F., Luthman, H., Nordenskjöld, M. and Kockum, I. (2001) The Wiskott–Aldrich syndrome gene as a candidate gene for atopic dermatitis. Acta Derm. Venereol. (Stockh.), 81, 340–342.
28 Laitinen, T., Daly, M.J., Rioux, J.D., Kauppi, P., Laprise, C., Petays, T., Green, T., Cargill, M., Haahtela, T., Lander, E.S. et al. (2001) A susceptibility locus for asthma-related traits on chromosome 7 revealed by genome-wide scan in a founder population. Nat. Genet., 28, 87–91.[Web of Science][Medline]
29
Tomfohrde, J., Silverman, A., Barnes, R., Fernandez-Vina, M.A., Young, M., Lory, D., Morris, L., Wuepper, K.D., Stastny, P., Menter, A. et al. (1994) Gene for familial psoriasis susceptibility mapped to the distal end of human chromosome 17q. Science, 264, 1141–1145.
30
Nair, R.P., Henseler, T., Jenisch, S., Stuart, P., Bichakjian, C.K., Lenk, W., Westphal, E., Guo, S.W., Christophers, E., Voorhees, J.J. et al. (1997) Evidence for two psoriasis susceptibility loci (HLA and 17q) and two novel candidate regions (16q and 20p) by genome-wide scan. Hum. Mol. Genet., 6, 1349–1356.
31 Enlund, F., Samuelsson, L., Enerback, C., Inerot, A., Wahlstrom, J., Yhr, M., Torinsson, A., Martinsson, T. and Swanbeck, G. (1999) Analysis of three suggested psoriasis susceptibility loci in a large Swedish set of families: confirmation of linkage to chromosome 6p (HLA region), and to 17q, but not to 4q. Hum. Hered., 49, 2–8.[Web of Science][Medline]
32 Capon, F., Semprini, S., Chimenti, S., Fabrizi, G., Zambruno, G., Murgia, S., Carcassi, C., Fazio, M., Mingarelli, R., Dallapiccola, B. et al. (2001) Fine mapping of the PSORS4 psoriasis susceptibility region on chromosome 1q21. J. Invest. Dermatol., 116, 728–730.[Web of Science][Medline]
33
Trembath, R.C., Clough, R.L., Rosbotham, J.L., Jones, A.B., Camp, R.D., Frodsham, A., Browne, J., Barber, R., Terwilliger, J., Lathrop, G.M. et al. (1997) Identification of a major susceptibility locus on chromosome 6p and evidence for further disease loci revealed by a two stage genome-wide search in psoriasis. Hum. Mol. Genet., 6, 813–820.
34 Enlund, F., Samuelsson, L., Enerback, C., Inerot, A., Wahlstrom, J., Yhr, M., Torinsson, A., Riley, J., Swanbeck, G. and Martinsson, T. (1999) Psoriasis susceptibility locus in chromosome region 3q21 identified in patients from southwest Sweden. Eur. J. Hum. Genet., 7, 783–790.[Web of Science][Medline]
35 Hizawa, N., Freidhoff, L.R., Chiu, Y.F., Ehrlich, E., Luehr, C.A., Anderson, J.L., Duffy, D.L., Dunston, G.M., Weber, J.L., Huang, S.K. et al. (1998) Genetic regulation of Dermatophagoides pteronyssinus-specific IgE responsiveness: a genome-wide multipoint linkage analysis in families recruited through 2 asthmatic sibs. Collaborative Study on the Genetics of Asthma (CSGA). J. Allergy Clin. Immunol., 102, 436–442.[Web of Science][Medline]
36
Kawashima, T., Noguchi, E., Arinami, T., Yamakawa-Kobayashi, K., Nakagawa, H., Otsuka, F. and Hamaguchi, H. (1998) Linkage and association of an interleukin 4 gene polymorphism with atopic dermatitis in Japanese families. J. Med. Genet., 35, 502–504.
37 Wjst, M., Fischer, G., Immervoll, T., Jung, M., Saar, K., Rueschendorf, F., Reis, A., Ulbrecht, M., Gomolka, M., Weiss, E.H. et al. (1999) A genome-wide search for linkage to asthma. German Asthma Genetics Group. Genomics, 58, 1–8.[Web of Science][Medline]
38 Strauch, K., Fimmers, R., Kurz, T., Deichmann, K.A., Wienker, T.F. and Baur, M.P. (2000) Parametric and nonparametric multipoint linkage analysis with imprinting and two-locus-trait models: application to mite sensitization. Am. J. Hum. Genet., 66, 1945–1957.[Web of Science][Medline]
39 Kurz, T., Strauch, K., Heinzmann, A., Braun, S., Jung, M., Ruschendorf, F., Moffatt, M.F., Cookson, W.O., Inacio, F., Ruffilli, A. et al. (2000) A European study on the genetics of mite sensitization. J. Allergy Clin. Immunol., 106, 925–932.[Web of Science][Medline]
40 Xu, J., Meyers, D.A., Ober, C., Blumenthal, M.N., Mellen, B., Barnes, K.C., King, R.A., Lester, L.A., Howard, T.D., Solway, J. et al. (2001) Genomewide screen and identification of gene–gene interactions for asthma-susceptibility loci in three U.S. populations: collaborative study on the genetics of asthma. Am. J. Hum. Genet., 68, 1437–1446.[Web of Science][Medline]
41 Bradley, M., Kockum, I., Söderhäll, C., Van Hage-Hamsten, M., Luthman, H., Nordenskjöld, M. and Wahlgren, C.F. (2000) Characterization by phenotype of families with atopic dermatitis. Acta Derm. Venereol. (Stockh.), 80, 106–110.
42 Williams, H.C., Burney, P.G., Hay, R.J., Archer, C.B., Shipley, M.J., Hunter, J.J., Bingham, E.A., Finlay, A.Y., Pembroke, A.C., Graham-Brown, R.A. et al. (1994) The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. I. Derivation of a minimum set of discriminators for atopic dermatitis. Br. J. Dermatol., 131, 383–396.[Web of Science][Medline]
43 Williams, H.C., Burney, P.G., Strachan, D. and Hay, R.J. (1994) The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. II. Observer variation of clinical diagnosis and signs of atopic dermatitis. Br. J. Dermatol., 131, 397–405.[Web of Science][Medline]
44 Williams, H.C., Burney, P.G., Pembroke, A.C. and Hay, R.J. (1994) The U.K. Working Party's Diagnostic Criteria for Atopic Dermatitis. III. Independent hospital validation. Br. J. Dermatol., 131, 406–416.[Web of Science][Medline]
45 Hanifin, J.M. and Rajka, G. (1980) Diagnostic features of atopic dermatitis. Acta Derm. Venereol. (Stockh.), 92(Suppl.), 44–47.
46
Sheffield, V.C., Weber, J.L., Buetow, K.H., Murray, J.C., Even, D.A., Wiles, K., Gastier, J.M., Pulido, J.C., Yandava, C., Sunden, S.L. et al. (1995) A collection of tri- and tetranucleotide repeat markers used to generate high quality, high resolution human genome-wide linkage maps. Hum. Mol. Genet., 4, 1837–1844.
47 Gudbjartsson, D.F., Jonasson, K., Frigge, M.L. and Kong, A. (2000) Allegro, a new computer program for multipoint linkage analysis. Nat. Genet., 25, 12–13.[Web of Science][Medline]
48 Nyholt, D.R. (2000) All LODs are not created equal. Am. J. Hum. Genet., 67, 282–288.[Web of Science][Medline]
49 Kruglyak, L., Daly, M.J., Reeve-Daly, M.P. and Lander, E.S. (1996) Parametric and nonparametric linkage analysis: a unified multipoint approach. Am. J. Hum. Genet., 58, 1347–1363.[Web of Science][Medline]
50 Hauser, E.R., Boehnke, M., Guo, S.W. and Risch, N. (1996) Affected-sib-pair interval mapping and exclusion for complex genetic traits: sampling considerations. Genet. Epidemiol., 13, 117–137.[Web of Science][Medline]
51 O'Connell JR, W.D. (1998) PedCheck: a program for identification of genotype incompatibilities in linkage analysis. Am. J. Hum. Genet., 63, 259–266.[Web of Science][Medline]
52 Ehm, M. and Wagner, M. (1998) A test statistic to detect errors in sib-pair relationships. Am. J. Hum. Genet., 62, 181–188.[Web of Science][Medline]
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