A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

Xu, Xin; Fang, Zhang; Zhang, Yuanyuan; Chen, Changzhong; Guang, Wenwei; Jin, Yaqing; Yang, Jianghua; Lewitzky, Steve; Aelony, Avram; Parker, Alex; Meyer, Joanne M.; Weiss, Scott T.; Xu, Xiping

doi:10.1086/324650

Cited by 88 publications

(59 citation statements)

References 24 publications

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“…This is in agreement with other phenotypic studies, which have shown that FEV1 does not systematically strongly correlate with disease symptoms [2,17]. Moreover, none of the published genome-wide screens conducted for lung function in asthmatic families reported linkage to the 2p23 region, detected here for the asthma severity score [18][19][20]. Taken together, these results indicate that FEV1 (% pred) is more likely to be controlled by specific genetic determinants.…”

Section: Phenotype Definition and Linkage Analysis Outcomessupporting

confidence: 92%

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

Siroux¹,

Dizier²,

Lemainque³

et al. 2007

Eur Respir J

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There is ongoing debate as to how asthma should be defined in order to forward understanding of the underlying mechanisms. The aim of the present study was to build quantitative scores of asthma and asthma severity and to assess whether refinement of disease phenotypes can facilitate the identification of chromosomal regions harbouring susceptibility genes.A genome-wide linkage scan was conducted in 110 families with at least two asthmatic siblings (n5508) from the French Epidemiological study on the Genetics and Environment of Asthma, bronchial hyperresponsiveness and atopy (EGEA). The phenotypes studied were an asthma severity score (assessed among asthmatics by combining clinical data and treatment), forced expiratory volume in one second (FEV1) and an asthma score (including both asthmatics and nonasthmatics and representing the whole disease spectrum).This analysis showed genome-wide suggestive evidence of linkage of the asthma score to 18p11, a novel region undetected in a previous screen of dichotomous asthma. There was potential linkage of 2p23 to asthma severity score and of three regions (1p36, 2q36 and 6q14) to FEV1. Moreover, FEV1 appeared to have no genetic determinant in common with asthma severity and asthma scores.Asthma and asthma severity quantitative scores revealed new regions of linkage and thus provide support for considering these phenotypes in future genetic studies.

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Section: Phenotype Definition and Linkage Analysis Outcomessupporting

confidence: 92%

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

Siroux¹,

Dizier²,

Lemainque³

et al. 2007

Eur Respir J

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“…A genome-wide study of the French population failed to detect a linkage to asthma but detected linkage to eosinophilia around the 130 cM region (Dizier et al 2000). There was no evidence of linkage to asthma-related phenotypes of chromosome 12 markers in the Chinese population, which is ethnically close to the Japanese population (Xu et al 2001b). In combination, the results of our and previous studies suggest that several genes located in 12q24-q33 are likely to be responsible for susceptibility to asthma.…”

Section: Discussioncontrasting

confidence: 53%

“…On the other hand, many studies have shown negative linkage for total IgE. These include studies of the Australian population by Daniels et al (1996), the Germans by Heinzmann et al (2000a), the Germans and Swedish by Wjst et al (1999), the Hutterites by Ober et al (2000), the Chinese by Xu et al (2001b), the French by Dizier et al (2000), the Finnish by Leitinen et al (2001), the Italians by Malerba et al (2000), and the Danish by Haagerup et al (2002). This inconstancy suggests that the relative importance of chromosome 12 loci in controlling total IgE varies from population to population.…”

Section: Discussionmentioning

confidence: 99%

“…Asthma is an etiologically complex disease and develops by the interaction of multiple genes and environmental factors. Genome-wide linkage studies have identified a number of autosomal regions providing evidence of linkage to asthma, atopy, eosinophilia, and/or other associated phenotypes (CSGA 1997;Daniels et al 1996;Dizier et al 2000;Haagerup et al 2002;Hakonarson et al 2002;Laitinen et al 2001;Ober et al 2000;Wjst et al 1999;Xu et al 2001a;Xu et al 2000;Xu et al 2001b;Yokouchi et al 2000). Some of these studies (CSGA 1997;Dizier et al 2000;Haagerup et al 2002;Wjst et al 1999;Xu et al 2001a;Xu et al 2000;Yokouchi et al 2000) and those focused on a single chromosome (Barnes et al 1999;Barnes et al 1996;Kruglyak et al 1996;Malerba et al 2000;Nickel et al 1997;Wilkinson et al 1998;Raby et al 2003) suggested linkage of chromosome 12q regions to asthma or related phenotypes in diverse populations.…”

Section: Introductionmentioning

confidence: 99%

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Linkage and association of childhood asthma with the chromosome 12 genes

et al. 2004

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Several studies have shown linkage of chromosome region 12q13-24 to bronchial asthma and related phenotypes in ethnically diverse populations. In the Japanese population, a genome-wide study failed to show strong evidence of linkage of this region. Chromosome 12 genes that showed association with the disease in at least one report include: the signal transducer and activator of transcription 6 gene (STAT6), the nitrogen oxide synthetase 1 gene (NOS1), the interferon c gene (IFNG), and the activation-induced cytidine deaminase gene (AICDA). To evaluate the linkage between chromosome 12 and childhood asthma in the Japanese population, we performed sib-pair linkage analysis on childhood asthma families using 18 microsatellite markers on chromosome 12. To investigate association between chromosome 12 candidate genes and asthma, distributions of alleles and genotypes of repeat polymorphisms of STAT6, NOS1, and IFNG were compared between controls and patients. Single nucleotide polymorphism of AICDA was also investigated. Chromosome region 12q24.23-q24.33 showed suggestive linkage to asthma. The NOS1 intron 2 GT repeat and STAT6 exon 1 GT repeat were associated with asthma. Neither the IFNG intron 1 CA repeat nor 465C/T of AICDA showed any association with asthma. Our results suggest that NOS1 and STAT6 are asthmasusceptibility genes and that chromosome region 12q24.23-q24.33 contains other susceptibility gene(s).

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“…In a second-stage analysis among a subset of the CSGA AfricanAmerican families, strong evidence for linkage has been observed at 11q21 (80). Follow-up fine-mapping studies have narrowed the critical linkage region to one containing several interesting candidates, including CD44, EHF, ELF5, and GSTP1 (81,82).…”

Section: Update On Genetic Studies Of Asthma In Populations Of Africamentioning

confidence: 99%

African Americans with Asthma: Genetic Insights

Barnes

Grant²,

Hansel³

et al. 2007

Proceedings of the American Thoracic Society

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It has been well established that genetic factors strongly affect susceptibility to asthma and its associated traits. It is less clear to what extent genetic variation contributes to the ethnic disparities observed for asthma morbidity and mortality. Individuals of African descent with asthma have more severe asthma, higher IgE levels, a higher degree of steroid dependency, and more severe clinical symptoms than individuals of European descent with asthma but relatively few studies have focused on this particularly vulnerable ethnic group. Similar underrepresentation exists for other minorities, including Hispanics. In this review, a summary of linkage and association studies in populations of African descent is presented, and the role of linkage disequilibrium in the dissection of a complex trait such as asthma is discussed. Consideration for the impact of population stratification in recently admixed populations (i.e., European, African) is essential in genetic association studies focusing on African ancestry groups. With the most recent update on the International HapMap Project, efficient selection of haplotype tagging single nucleotide polymorphisms (htSNPs) for African Americans has accelerated and efficiency of htSNPs chosen from one population to represent other continental groups (e.g., African) has been demonstrated. Cutting-edge approaches, such as genomewide association studies, admixture mapping, and phylogenetic analyses, offer new opportunities for dissecting the genetic basis for asthma in populations of African descent.

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A Genomewide Search for Quantitative-Trait Loci Underlying Asthma

Cited by 88 publications

References 24 publications

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

Scores of asthma and asthma severity reveal new regions of linkage in EGEA study families

Linkage and association of childhood asthma with the chromosome 12 genes

African Americans with Asthma: Genetic Insights

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