WDR46 is a Genetic Risk Factor for Aspirin-Exacerbated Respiratory Disease in a Korean Population

Abstract

Purpose: The human WD repeat-containing protein 46 (WDR46; also known as C6orf11), located at the disease-relevant centromere side of the class II major histocompatibility complex region, is hypothesized to be associated with risk of aspirin-exacerbated respiratory disease (AERD) as well as a decline in forced expiratory volume in the first second (FEV1), an important diagnostic marker of asthma.

Methods: To investigate the association between WDR46 and AERD, five single-nucleotide polymorphisms (SNPs) were genotyped in 93 AERD cases and 96 aspirin-tolerant asthma controls of Korean ethnicity. Three major haplotypes were inferred from pairwise comparison of the SNPs, and one was included in the association analysis. Differences in the frequency distribution of WDR46 SNPs and haplotype were analyzed using logistic and regression models via various modes of genetic inheritance.

Results: Depending on the genetic model, the logistic and regression analyses revealed significant associations between rs463260, rs446735, rs455567, rs469064, and WDR46_ht2 and the risk of AERD (P=0.007-0.04, P(corr)=0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, P(corr)=0.01-0.03). Furthermore, functional analysis in silico showed that the G>A allele of rs463260 located in the 5' untranslated region potentially matched a nucleotide sequence within an upstream open reading frame of WDR46.

Conclusions: These findings show for the first time that WDR46 is an important genetic marker of aspirin-induced airway inflammation and may be useful for formulating new disease-management strategies.

Keywords: Aspirin exacerbated respiratory disease; FEV1; WDR46; haplotype; single-nucleotide polymorphism.

Figure

Physical map, linkage disequilibrium, and haplotypes of WDR46. (A) Schematic gene map and single-nucleotide polymorphisms (SNPs) of WDR46 on chromosome 6p21.3 (10.11 kbp). Black blocks represent coding exons and white blocks represent 5' and 3' untranslated regions. The first base of translation sites are denoted as nucleotide +1. SNPs in absolute linkage are indicated by brackets (r²=1). (B) LD coefficient (|D'|) among WDR46 SNPs in a Korean population. (C) Haplotypes of WDR46.