Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy

Hoffjan, Sabine; Ostrovnaja, Irina; Nicolae, Dan L.; Newman, Dina L.; Nicolae, Raluca; Gangnon, Ronald E.; Steiner, Lori; Walker, Karen; Reynolds, Rebecca; Greene, Deborah; Mirel, Daniel B.; Gern, James E.; Lemanske, Robert F.; Ober, Carole

doi:10.1016/j.jaci.2003.10.044

Cited by 93 publications

(64 citation statements)

References 45 publications

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“…Interestingly, there are now many examples of established associations with different functional variants within the same gene or with opposite alleles at the same SNP in different populations (1). For example, IgE levels are associated with IL13-1112CϾT in some populations (33,34) and with IL13-2044GϾA (12,33,35) or IL13-1512AϾC (36) in others. Protection from allergy and/or asthma is associated with both the T (9) and the C (37) allele of CD14-159.…”

Section: Discussionmentioning

confidence: 99%

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

Cameron

Webster

Strempel

et al. 2006

The Journal of Immunology

111

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IL-13 is a central mediator of allergic inflammation. The single nucleotide polymorphism IL13-1112C>T (rs1800925) is associated with allergic phenotypes in ethnically distinct populations, but the underlying mechanism(s) remain unknown. Using in vivo, in vitro, and in silico analysis, we show that the IL13-1112T allele enhanced IL13 promoter activity in primary human and murine CD4+ Th2 lymphocytes. Increased expression of IL13-1112T in Th2 cells was associated with the creation of a Yin-Yang 1 binding site that overlapped a STAT motif involved in negative regulation of IL13 expression and attenuated STAT6-mediated transcriptional repression. Because IL-13 secretion was increased in IL13-1112TT homozygotes, we propose that increased expression of IL13-1112T in vivo may underlie its association with susceptibility to allergic inflammation. Interestingly, IL13-1112T had opposite transcriptional effects in nonpolarized CD4+ T cells, paralleled by distinct patterns of DNA-protein interactions at the IL13 promoter. Our findings suggest the nuclear milieu dictates the functional outcome of genetic variation.

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Section: Discussionmentioning

confidence: 99%

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

Cameron

Webster

Strempel

et al. 2006

The Journal of Immunology

111

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“…18 Genotyping Genotyping was performed with two linear array panels developed by Roche Molecular Systems, Inc (Alameda, CA, USA). Genotyping accuracy by this assay is estimated at 499% (S. Cheng et al, personal communication).…”

Section: Methodsmentioning

confidence: 99%

Are common disease susceptibility alleles the same in outbred and founder populations?

et al. 2004

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Founder populations have been the subjects of complex disease studies because of their decreased genetic heterogeneity, increased linkage disequilibrium and more homogeneous environmental exposures. However, it is possible that disease alleles identified in founder populations may not contribute significantly to susceptibility in outbred populations. In this study we examine the Hutterites, a founder population of European descent, for 103 polymorphisms in 66 genes that are candidates for cardiovascular or inflammatory diseases. We compare the frequencies of alleles at these loci in the Hutterites to their frequencies in outbred European-American populations and test for associations with cardiovascular disease-associated phenotypes in the Hutterites. We show that alleles at these loci are found at similar frequencies in the Hutterites and in outbred populations. In addition, we report associations between 39 alleles or haplotypes and cardiovascular disease phenotypes (Po0.05), with five loci remaining significant after adjusting for multiple comparisons. These data indicate that this founder population is informative and offers considerable advantages for genetic studies of common complex diseases.

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“…Although some epidemiologic studies found significant associations between C-509T and asthma occurrence in adults (5,7,8), data on childhood asthma are limited and are inconsistent (9)(10)(11)(12). This promoter variant has been associated with wheeze during the first year of life due to respiratory syncytial virus infection (9) and with asthma in Mexican American children (10), but others have failed to find significant associations with asthma in children (11,12). The inconsistency in the results could be due in part to differences in environmental exposures or to confounding by racial admixture.…”

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confidence: 99%

Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma

Salam

Gauderman

McConnell

et al. 2007

Am J Respir Crit Care Med

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Rationale: Transforming growth factor (TGF)-b1 is involved in airway inflammation and remodeling, two key processes in asthma pathogenesis. Tobacco smoke and traffic emissions induce airway inflammation and modulate TGF-b1 gene expression. We hypothesized that the effects of functional TGF-b1 variants on asthma occurrence vary by these exposures. Objectives: We tested these hypotheses among 3,023 children who participated in the Children's Health Study. Methods: Tagging single-nucleotide polymorphisms rs4803457 C.T and C-509T (a functional promoter polymorphism) accounted for 94% of the haplotype diversity of the upstream region. Exposure to maternal smoking in utero was based on smoking by biological mother during pregnancy. Residential distance from nearest freeway was calculated based on residential address at study entry. Measurements and Main Results: Children with the 2509TT genotype had a 1.8-fold increased risk of early persistent asthma (95% confidence interval [CI], 1.11-2.95). This association varied marginally significantly by in utero exposure to maternal smoking. Compared with children with the 2509CC/CT genotype with no in utero exposure to maternal smoking, those with the 2509TT genotype with such exposure had a 3.4-fold increased risk of early persistent asthma (95% CI, 1.46-7.80; interaction, P 5 0.11). The association between TGF-b1 C-509T and lifetime asthma varied by residential proximity to freeways (interaction P 5 0.02). Children with the 2509TT genotype living within 500 m of a freeway had over three-fold increased lifetime asthma risk (95% CI, 1.29-7.44) compared with children with CC/CT genotype living . 1500 m from a freeway. Conclusions: Children with the TGF-b1 2509TT genotype are at increased risk of asthma when they are exposed to maternal smoking in utero or to traffic-related emissions.

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Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy

Cited by 93 publications

References 45 publications

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

Are common disease susceptibility alleles the same in outbred and founder populations?

Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma

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Genetic variation in immunoregulatory pathways and atopic phenotypes in infancy

Cited by 93 publications

References 45 publications

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C&gt;T, a Polymorphism Associated with Allergic Inflammation

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C&gt;T, a Polymorphism Associated with Allergic Inflammation

Are common disease susceptibility alleles the same in outbred and founder populations?

Transforming Growth Factor-β1 C-509T Polymorphism, Oxidant Stress, and Early-Onset Childhood Asthma

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Product

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Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation

Th2 Cell-Selective Enhancement of HumanIL13Transcription byIL13-1112C>T, a Polymorphism Associated with Allergic Inflammation