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Wise et al.

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the candidate genes reported in the literature have not been well-replicated across studies and populations. 427,504 This could be due to inadequate statistical power related to small sample sizes, inconsistent phenotype definition, or lack of true disease association. Additionally, rare variant studies focusing on candidate genes have not been particularly successful. 494 The candidate gene approach is particularly necessary for hypothesis-driven analyses and functional genetic analyses, for example in populations with specific environmental exposures or with mixed ethnic backgrounds. methylation) other than changes in the underlying DNA sequence, have been proposed to constitute a link between genetic and environmental factors. Recent studies show that DNA methylation in children is very strongly influenced by well-known risk factors for allergic diseases such as maternal smoking during pregnancy 505 and air pollution exposure. 506 Currently, however, it is not known if these methylation changes are causally related to the development of AR and asthma, or if these “biomarkers” are solely markers of exposure. Several studies have convincingly linked methylation profiles to AR 507-509 and IgE-related outcomes, 510,511 but large-scale studies have yet to be completed. In summary, a family history of AR remains a risk factor for disease development, and strong associations have been identified with genes involved in T-cell activation (eg, LRRC32 ) and innate immunity (eg, TLRs ). Shared genetic mechanisms for AR and other allergy-related diseases have been very clearly identified in recent large-scale studies. There is, however, a need to functionally characterize variants in these candidate genes to understand mechanisms underlying the pathogenesis of AR. With increasing evidence for the role of epigenetics in AR, future research should also focus on investigating epigenetic mechanisms, thereby providing a functional explanation for the link between environmental exposures, genetic variants, and disease development. • Aggregate Grade of Evidence: C (Level 2a: 5 GWASs. Candidate gene studies not assessed regarding grade of evidence). Gene-environment interactions and epigenetic effects— Epigenetic mechanisms, defined as changes in phenotype or gene expression caused by mechanisms (eg, AR is characterized by a loss of immunological and clinical tolerance toward a specific allergen. This involves production of sIgE which initiates allergic inflammation following allergen exposure. Therefore, sIgE is a hallmark of allergy and its production defines sensitization. Sensitization is a complex phenomenon, regulated by genetic and environmental factors, requiring a primitive exposure to a specific allergen. If a subject is never exposed to an allergen, sensitization to that allergen cannot occur. On the other hand, it is fundamental to distinguish between sensitization and allergy. Allergy, which involves the development of symptoms after the sensitizing exposure, is different from mere sensitization. Without sensitization allergy cannot exist, but not vice versa. In this section, the in utero and early childhood exposure to inhalant allergens, including mites, pollens, animal dander, and fungal allergens, will be evaluated as risk factor the development of AR.

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VI.B. Inhalant allergens (in utero and early childhood exposure)

Int Forum Allergy Rhinol . Author manuscript; available in PMC 2020 June 10.