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Comprehensive testing of positionally cloned asthma genes in two populations.

ABSTRACT: Replication of gene-disease associations has become a requirement in complex trait genetics.In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and 439 Hispanic children from the Central Valley of Costa Rica. We genotyped 98 linkage disequilibrium-tagging single-nucleotide polymorphisms (SNPs) in five genes: ADAM33, DPP10, GPR154 (HUGO name: NPSR1), HLA-G, and the PHF11 locus (includes genes SETDB2 and RCBTB1). SNPs were tested for association with asthma and two intermediate phenotypes: airway hyperresponsiveness and total serum immunoglobulin E levels.Despite differing ancestries, linkage disequilibrium patterns were similar in both cohorts. Of the five evaluated genes, SNP-level replication was found only for GPR154 (NPSR1). In this gene, three SNPs were associated with asthma in both cohorts, although the opposite alleles were associated in either study. Weak evidence for locus-level replication with asthma was found in the PHF11 locus, although there was no overlap in the associated SNP across the two cohorts. No consistent associations were observed for the three other genes.These results provide some further support for the role of genetic variation in GPR154 (NPSR1) and PHF11 in asthma susceptibility and also highlight the challenges of replicating genetic associations in complex traits such as asthma, even for genes identified by linkage analysis.

SUBMITTER: Hersh CP

PROVIDER: S-EPMC2048676 | biostudies-literature | 2007 Nov

REPOSITORIES: biostudies-literature

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Comprehensive testing of positionally cloned asthma genes in two populations.

Hersh Craig P CP Raby Benjamin A BA Soto-Quirós Manuel E ME Murphy Amy J AJ Avila Lydiana L Lasky-Su Jessica J Sylvia Jody S JS Klanderman Barbara J BJ Lange Christoph C Weiss Scott T ST Celedón Juan C JC

American journal of respiratory and critical care medicine 20070816 9

<h4>Rationale</h4>Replication of gene-disease associations has become a requirement in complex trait genetics.<h4>Objectives</h4>In studies of childhood asthma from two different ethnic groups, we attempted to replicate associations with five potential asthma susceptibility genes previously identified by positional cloning.<h4>Methods</h4>We analyzed two family-based samples ascertained through an asthmatic proband: 497 European-American children from the Childhood Asthma Management Program and ...[more]

PMID: 17702965

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Project description:BACKGROUND: The central nervous tissue contains diverse subtypes of neurons with characteristic morphological and physiological features and different neurotransmitter phenotypes. The generation of neurons with defined neurotransmitter phenotypes seems to be governed by factors differently expressed along the anterior-posterior and dorsal-ventral body axes. The mechanisms of the cell-type determination, however, are poorly understood. Selected neuronal phenotypes had been generated from embryonic stem (ES) cells, but similar results were not obtained on more restricted neural stem cells, presumably due to the lack of homogeneous neural stem cell populations as a starting material. RESULTS: In the presented work, the establishment of different neurotransmitter phenotypes was investigated in the course of in vitro induced neural differentiation of a one-cell derived neuroectodermal cell line, in conjunction with the activation of various region-specific genes. For comparison, similar studies were carried out on the R1 embryonic stem (ES) and P19 multipotent embryonic carcinoma (EC) cells. In response to a short treatment with all-trans retinoic acid, all cell lines gave rise to neurons and astrocytes. Non-induced neural stem cells and self-renewing cells persisting in differentiated cultures, expressed "stemness genes" along with early embryonic anterior-dorsal positional genes, but did not express the investigated CNS region-specific genes. In differentiating stem-like cell populations, on the other hand, different region-specific genes, those expressed in non-overlapping regions along the body axes were activated. The potential for diverse regional specifications was induced in parallel with the initiation of neural tissue-type differentiation. In accordance with the wide regional specification potential, neurons with different neurotransmitter phenotypes developed. Mechanisms inherent to one-cell derived neural stem cell populations were sufficient to establish glutamatergic and GABAergic neuronal phenotypes but failed to manifest cathecolaminergic neurons. CONCLUSION: The data indicate that genes involved in positional determination are activated along with pro-neuronal genes in conditions excluding any outside influences. Interactions among progenies of one cell derived neural stem cells are sufficient for the activation of diverse region specific genes and initiate different routes of neuronal specification.

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Comprehensive testing of positionally cloned asthma genes in two populations.

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Comprehensive testing of positionally cloned asthma genes in two populations.

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