Allergy Asthma Immunol Res.  2012 Jul;4(4):199-205. 10.4168/aair.2012.4.4.199.

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

Affiliations
  • 1Department of Life Science, Sogang University, Seoul, Korea. hdshin@sogang.ac.kr
  • 2Department of Genetic Epidemiology, SNP Genetics Inc., Seoul, Korea.
  • 3Division of Allergy and Respiratory Medicine, Soonchunhyang University Seoul Hospital, Seoul, Korea.
  • 4Division of Allergy and Respiratory Medicine & Genome Research Center for Allergy and Respiratory Diseases, Soonchunhyang University Bucheon Hospital, Bucheon, Korea. schalr@schbc.ac.kr

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, Pcorr=0.01-0.04) and FEV1 decline after aspirin provocation (P=0.006-0.03, Pcorr=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.

Keyword

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

MeSH Terms

5' Untranslated Regions
Alleles
Aspirin
Asthma
Base Sequence
Centromere
Computer Simulation
Forced Expiratory Volume
Genetic Markers
Haplotypes
Humans
Inflammation
Major Histocompatibility Complex
Models, Genetic
Open Reading Frames
Polymorphism, Single Nucleotide
Risk Factors
5' Untranslated Regions
Aspirin
Genetic Markers

Figure

  • 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.


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