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Wise et al.

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VI. Risk factors for allergic rhinitis VI.A. Genetics

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AR is well-known to run in families, and 1 of the strongest risk factors is the presence of disease in first-degree family members. 483 Studies of twins support the genetic underpinnings of AR with a higher concordance rates for AR in monozygotic twins compared to dizygotic twins. 484,485 The estimated heritability of AR has been suggested to be as high as 70% to 80%. Like many complex diseases, no single gene or polymorphism accounts for the hereditary effect on AR. Instead, many genes and several variants, each with small effects, are believed to contribute to disease initiation, persistence, and severity. In this section, the current literature on the genetics of AR is reviewed, including candidate gene studies and recent large-scale genome-wide association studies (GWASs). In addition, gene environment interaction effects and epigenetics studies are briefly covered. Single-nucleotide polymorphisms associated with AR GWASs.: GWASs with an unbiased approach that include hundreds of thousands of common gene variants, or single-nucleotide polymorphisms (SNPs), have successfully identified important variants for complex diseases over the past decade. Five GWASs on AR (or hay fever) have been published as of September 2016, as summarized in Table VI.A. SNPs in leucine-rich repeat-containing protein 32 ( LRRC32 ) have been strongly associated with AR in 3 of the GWASs, 486-488 and with asthma, 487,489 eczema, 488,490 and other allergy-related comorbidities. 486,489,491 At the protein level, LRRC32 is known to regulate T-cell proliferation, cytokine secretion, and TGF- β activation. 492 These associations suggest shared genetic mechanisms for AR and other allergy-related diseases, evidence further supported by the large-scale GWAS on self-reported cat, HDM, and pollen allergies (as well as AR), which revealed 16 shared susceptibility loci with strong association ( p < 5 × 10 −8 ; TLR -locus top hit). 487 In an accompanying GWAS on allergic sensitization, there was strong overlap between top hits for sensitization and self-reported allergies. 487,493 In the GWAS by Ferreira et al., 489 11 variants were associated with the combined asthma phenotype and hay fever below the genome-wide significance level ( HLA-DQB1 top hit). TLRs play a crucial role in immune regulation and SNPs in different TLRs have been associated with AR in both GWASs ( TLR1 , TLR6 , TLR10 ) 486,487 and candidate gene studies ( TLR8 ), as discussed in the next paragraph. 494 In addition to shared genetic effects between different allergy-related diseases, a significant overlap between susceptibility loci for allergy and autoimmune diseases has been observed. 495 Candidate gene studies.— The candidate gene approach for selecting disease-relevant genes is based on previous associations reported from GWAS or biological features which could be relevant for disease risk. Studies on AR using this approach have found several well-replicated genes as summarized previously. 496-498 Notably, SNPs in genes involved in antigen presentation (for example HLA-DQA1 ), pathogen recognition ( TLR2 , TLR7 , TLR8 ), IL signaling and proinflammation ( IL13 , IL18 , and TSLP ) are considered important susceptibility variants for AR. 496-502 Recently, functional evidence in blood immune cells for genetic variants in brain-derived neurotrophic factor ( BDNF ), a secretory proinflammatory protein implicated in AR pathogenesis, was reported. 503 However, many of

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