A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

Basehore, Monica J.; Howard, Timothy D.; Lange, Leslie A.; Moore, Wendy C.; Hawkins, Gregory A.; Marshik, Patricia; Harkins, Michelle; Meyers, Deborah A.; Bleecker, Eugene R.

doi:10.1016/j.jaci.2004.05.035

Cited by 107 publications

(84 citation statements)

References 46 publications

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“…Although, the results of these linkage mappings varied across studies and across racial and ethnic groups, regions 5q and 13q are two of the few most frequently reproduced regions in these studies Ober et al 1998;Ober et al 2000;Wiltshire et al 1998;Xu et al 2000). It is interesting to note that these regions contain the asthma candidate genes IL4, IL13, and TGFβ, which have been studied extensively (Bartram and Speer 2004;Basehore et al 2004;Battle 2007;CamorettiMercado and Solway 2005;Howard et al 2002;Li et al 2007;Marsh et al 1994). In addition, these regions contain several new potential asthma candidate genes including IL3, IL5, IL9, SMAD5, IRF1, FBN2 and SMAD9 that warrant further investigation.…”

Section: Discussionmentioning

confidence: 96%

Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region

Choudhry

Taub

Mei³

et al. 2008

Hum Genet

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While the number of success stories for mapping genes associated with complex diseases using genome-wide association approaches is growing, there is still much work to be done in developing methods for such studies when the samples are collected from a population which may not be homogeneous. Here we report the first genome-wide association study to identify genes associated with asthma in an admixed population. We genotyped 96 Puerto Rican moderate to severe asthma cases and 88 controls as well as 109 samples representing Puerto Rico's founding populations using the Affymetrix GeneChip Human Mapping 100K array sets. The data from samples representing Puerto Rico's founding populations was used to identify ancestry informative markers for admixture mapping analyses. In addition, a genome-wide association analysis using logistic regression was performed on the data. Although neither admixture mapping nor regression analysis gave any significant association with asthma after correction for multiple testing, an overlap analysis using the top scoring SNPs from different methods suggested chromosomal regions 5q23.3 and 13q13.3 as potential regions harboring genes for asthma in Puerto Ricans. The validation analysis of these two regions in 284 Puerto Rican asthma trios gave significant association for the 5q23.3 region. Our results provide strong evidence that the previously linked 5q23 region is associated with asthma in Puerto Ricans. The detection of causative variants in this region will require fine mapping and functional validation. †Correspondence and reprint requests: Shweta Choudhry, Ph.D., M.Sc.,

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Section: Discussionmentioning

confidence: 96%

Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region

Choudhry

Taub

Mei³

et al. 2008

Hum Genet

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“…Furthermore, three U.S. case-control populations were recruited from three ethnically diverse US populations (African-American [n 5 522], Hispanic [n 5 246], and white [n 5 665]) as part of the Collaborative Study on the Genetics of Asthma (20,21). BHR measurements to methacholine or reversibility to albuterol were performed in the cases (Table E2) (21).…”

Section: Study Populationsmentioning

confidence: 99%

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Koppelman¹,

Meyers²,

Howard³

et al. 2009

Am J Respir Crit Care Med

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127

140

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Rationale: Asthma is a chronic inflammatory airway disease that affects more than 300 million individuals worldwide. Asthma is caused by interaction of genetic and environmental factors. Bronchial hyperresponsiveness (BHR) is a hallmark of asthma and results from increased sensitivity of the airways to physical or chemical stimulants. BHR and asthma are linked to chromosome 5q31-q33. Objectives: To identify a gene for BHR on chromosome 5q31-q33. Methods: In 200 Dutch families with asthma, linkage analysis and fine mapping were performed, and the Protocadherin 1 gene (PCDH1) was identified. PCDH1 was resequenced in 96 subjects from ethnically diverse populations to identify novel sequence variants. Subsequent replication studies were undertaken in seven populations from The Netherlands, the United Kingdom, and the United States, including two general population samples, two family samples, and three case-control samples. PCDH1 mRNA and protein expression was investigated using polymerase chain reaction, Western blotting, and immunohistochemistry. Measurements and Main Results: In seven out of eight populations (n 5 6,168) from The Netherlands, United Kingdom, and United States, PCHD1 gene variants were significantly associated with BHR (P values, 0.005-0.05) This association was present in both families with asthma and general populations. PCDH1 mRNA and protein were expressed in airway epithelial cells and in macrophages. Conclusions: PCDH1 is a novel gene for BHR in adults and children. The identification of PCDH1 as a BHR susceptibility gene may suggest that a structural defect in the integrity of the airway epithelium, the first line of defense against inhaled substances, contributes to the development of BHR.

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“…The -589T allele of the IL-4 gene [18], which has been associated with raised serum IgE concentrations [19], had an allele frequency of 0.544 in African-Americans (whose origins lie mostly in tropical West Africa) compared with 0.183 in European-Americans [20].…”

Section: Are Pro-th2 Alleles More Frequent In Populations With Prolonmentioning

confidence: 99%

Evolution and respiratory genetics

Souëf¹,

Candelaria²,

Goldblatt³

2006

European Respiratory Journal

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Evolution is a plausible explanation for between-population differences in particular allele frequencies if: the genes involved have related functions; the heterogeneous alleles involved have similar functional consequences; the involved genes are not linked chromosomally; and the patterns observed would result in a biologically plausible, survival-enhancing geneenvironment interaction. However, possible evolutionary effects have to be differentiated from founder effects and random genetic drift.The current authors have noted the existence of a consistent pattern of allelic frequencies in genes related to T-helper 2 (Th2) immune responses in humans of different ancestral backgrounds, residing in climatically similar regions. Th2 responses are thought to have evolved in mammals to resist infection by parasites, particularly helminths. Modern man arose in tropical Africa where helminths thrived. Relatively recently, humans migrated to cooler or drier climates where most helminths struggled to reproduce. The genetic tendency to strong Th2 responses may have become a health liability, the reduction in risk from parasites being counterbalanced by an increased inherited propensity to atopic or allergic diseases.The pattern noted by the present authors includes specific alleles of interleukin-4 and its receptor, interleukin-13, interleukin-10, the b chain of the high-affinity receptor for immunoglobulin E, the b 1 -adrenergic receptor, and the alpha chain of tumour necrosis factor. These population-specific polymorphism profiles are likely to be relevant in current disease patterns. The high incidence of asthma in migrants from tropical locations to affluent temperate countries is likely to be related to these patterns. Of even more concern is the possibility that increasing westernisation among the ,2 billion people living in the tropics will produce rapidly increasing levels of asthma, as these populations have a high genetic predisposition to allergic disease.

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A comprehensive evaluation of IL4 variants in ethnically diverse populations: association of total serum IgE levels and asthma in white subjects

Cited by 107 publications

References 46 publications

Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region

Genome-wide screen for asthma in Puerto Ricans: evidence for association with 5q23 region

Identification of PCDH1 as a Novel Susceptibility Gene for Bronchial Hyperresponsiveness

Evolution and respiratory genetics

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