Positive association between aspirin-intolerant asthma and genetic polymorphisms of FSIP1: a case-case study

Abstract

Background: Aspirin-intolerant asthma (AIA), which is caused by non-steroidal anti-inflammatory drugs (NSAIDs) such as aspirin, causes lung inflammation and reversal bronchi reduction, leading to difficulty in breathing. Aspirin is known to affect various parts inside human body, ranging from lung to spermatogenesis. FSIP1, also known as HDS10, is a recently discovered gene that encodes fibrous sheath interacting protein 1, and is regulated by amyloid beta precursor protein (APP). Recently, it has been reported that a peptide derived from APP is cleaved by alpha disintegrin and metalloproteinase 33 (ADAM33), which is an asthma susceptibility gene. It has also been known that the FSIP1 gene is expressed in airway epithelium.

Objectives: Aim of this study is to find out whether FSIP1 polymorphisms affect the onset of AIA in Korean population, since it is known that AIA is genetically affected by various genes.

Methods: We conducted association study between 66 single nucleotide polymorphisms (SNPs) of the FSIP1 gene and AIA in total of 592 Korean subjects including 163 AIA and 429 aspirin-tolerant asthma (ATA) patients. Associations between polymorphisms of FSIP1 and AIA were analyzed with sex, smoking status, atopy, and body mass index (BMI) as covariates.

Results: Initially, 18 SNPs and 4 haplotypes showed associations with AIA. However, after correcting the data for multiple testing, only one SNP showed an association with AIA (corrected P-value = 0.03, OR = 1.63, 95% CI = 1.23-2.16), showing increased susceptibility to AIA compared with that of ATA cases. Our findings suggest that FSIP1 gene might be a susceptibility gene for aspirin intolerance in asthmatics.

Conclusion: Although our findings did not suggest that SNPs of FSIP1 had an effect on the reversibility of lung function abnormalities in AIA patients, they did show significant evidence of association between the variants in FSIP1 and AIA occurrence among asthmatics in a Korean population.

Figure 1

A physical map of FSIP1 on chromosome 15q14. Exons, introns, UTR, and SNPs are shown. Coding exons are marked by shaded blocks; UTRs by white blocks. SNPs with complete LD are represented by r² = 1.

Figure 2

A graph of negative log of P-values of SNPs. After correction for multiple testing, all SNPs are calculated for the better representation of the values. The log = 0.0001 equals to P = 0.05. SNP rs7179742, which is the only SNP to have significant P-value after the multiple corrections, is highlighted in black.

Figure 3

Haplotypes and LDs of FSIP1 gene. (A) Haplotypes of FSIP1 in the Korean population. They are divided into 3 haplotype blocks. Only those with frequencies over 0.05 are shown. (B) LD coefficients graphical plot (|D'|) among SNPs based on the genotypes of whole study subjects in this study (n = 592).