Lessons Learned From GWAS of Asthma

Kim, Kyung Won; Ober, Carole

doi:10.4168/aair.2019.11.2.170

Cited by 86 publications

(100 citation statements)

References 92 publications

(110 reference statements)

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“…Genome-wide association studies (GWAS) have confirmed the contribution of genetic factors to risk of asthma with over 140 susceptibility loci having been identified over the last decade [5][6][7][8][9][10][11][12][13][14][15][16][17][18][19][20][21][22][23][24] . However, the risk alleles, most of which are common in the population, still only explain a small fraction of the overall heritability for asthma 25,26 . This observation implies either the existence of additional variants with smaller effect sizes, rare susceptibility alleles, and/or interactions between genes and environmental factors.…”

Section: Introductionmentioning

confidence: 99%

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

Han

Jia

Jahani

et al. 2019

Preprint

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We carried out a genome-wide association study (GWAS) for asthma in UK Biobank, followed by a meta-analysis with results from the Trans-National Asthma Genetic Consortium (TAGC). 66 novel genomic regions were identified, bringing the number of known asthma susceptibility loci to 211. Significant gene-sex interactions were also observed where susceptibility alleles, either individually or as a function of polygenic risk scores, increased asthma risk to a greater extent in men than women. Bioinformatics analyses demonstrated that asthma-associated variants were enriched for colocalizing to regions of open chromatic in immune cells and identified candidate causal genes at 52 of the novel loci, including CD52. An anti-CD52 (α-CD52) antibody mimicked the immune cell-depleting effects of an FDA-approved human α-CD52 antibody and reduced allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma, provide evidence that the immune system plays a prominent role in its pathogenesis, and suggest that CD52 represents a potentially novel therapeutic target for treating asthma.

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Section: Introductionmentioning

confidence: 99%

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

Han

Jia

Jahani

et al. 2019

Preprint

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“…Consistent with this notion, estimates for the heritability of asthma have ranged between 35% and 95% 3 , although those based on twin studies have been lower 4 . Genome-wide association studies (GWAS) have confirmed the contribution of genetic factors to risk of asthma, with over 140 susceptibility loci having been identified thus far [5][6][7][8][9][10][11][12][13] . However, the risk alleles, most of which are common in the population, still only explain a small fraction of the overall heritability for asthma [5][6][7] .…”

mentioning

confidence: 99%

“…Genome-wide association studies (GWAS) have confirmed the contribution of genetic factors to risk of asthma, with over 140 susceptibility loci having been identified thus far [5][6][7][8][9][10][11][12][13] . However, the risk alleles, most of which are common in the population, still only explain a small fraction of the overall heritability for asthma [5][6][7] . This observation could be due to the use of a qualitative outcome in most genetic studies, which does not depict the spectrum of asthma heterogeneity, or the existence of additional variants with smaller effect sizes, rare susceptibility alleles, and/or interactions between genes and environmental factors.…”

mentioning

confidence: 99%

Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

et al. 2020

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Asthma is a chronic and genetically complex respiratory disease that affects over 300 million people worldwide. Here, we report a genome-wide analysis for asthma using data from the UK Biobank and the Trans-National Asthma Genetic Consortium. We identify 66 previously unknown asthma loci and demonstrate that the susceptibility alleles in these regions are, either individually or as a function of cumulative genetic burden, associated with risk to a greater extent in men than women. Bioinformatics analyses prioritize candidate causal genes at 52 loci, including CD52, and demonstrate that asthma-associated variants are enriched in regions of open chromatin in immune cells. Lastly, we show that a murine anti-CD52 antibody mimics the immune cell-depleting effects of a clinically used human anti-CD52 antibody and reduces allergen-induced airway hyperreactivity in mice. These results further elucidate the genetic architecture of asthma and provide important insight into the immunological and sex-specific relevance of asthma-associated risk variants.

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“…Besides this prominent locus, SNPs in 1q31-32 (IL-10), 2q12 (IL-1RL1/IL-18R1), 5q22 (thymic stromal lymphopoietin (TSLP)), 5q31.1 (interferon regulatory factor 1 (IRF1)), 6q21 (human leukocyte antigens (HLA)-DR), and 9p24 (IL-33) have been identified as asthma susceptibility loci [49]. Their immunological role involves primarily the regulation of Th1/Th2 immunity (IL10, IL-1RL1, IL-18R1, TSLP, IL33, IRF1) and antigen presentation (HLA-DR).…”

Section: Role Of Geneticsmentioning

confidence: 99%

Role of early life immune regulation in asthma development

2019

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Development of childhood asthma is complex with a strong interaction of genetic, epigenetic, and environmental factors. Ultimately, it is critical how the immune system of a child responds to these influences and whether effective strategies for a balanced and healthy immune maturation can be assured. Pregnancy and early childhood are particularly susceptible for exogenous influences due to the developing nature of a child's immune system. While endogenous influences such as family history and the genetic background are immutable, epigenetic regulations can be modulated by both heredity and environmental exposures. Prenatal influences such as a mother's nutrition, smoking, or infections influence the complex interplay of innate and adaptive immune regulation as well as peri-and postnatal influences including mode of delivery. Early in life, induction and continuous training of healthy maturation include balanced innate immunity (e.g., via innate lymphoid cells) and an equilibrium of T-cell subpopulations (e.g., via regulatory T cells) to counterregulate potential pro-inflammatory or exuberant immune reactions. Later in childhood, rather compensatory immune mechanisms are required to modulate deviant regulation of a child's already primed immune trajectory. The specific effects of exogenous and endogenous influences on a child's maturing immune system are summarized in this review, and its importance and potential intervention for early prevention and treatment strategies are delineated.

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Lessons Learned From GWAS of Asthma

Cited by 86 publications

References 92 publications

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

Large-scale Genetic Analysis Identifies 66 Novel Loci for Asthma

Genome-wide analysis highlights contribution of immune system pathways to the genetic architecture of asthma

Role of early life immune regulation in asthma development

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