The SNP rs3128965 of HLA-DPB1 as a Genetic Marker of the AERD Phenotype

<div><p>Background</p><p>Two common clinical syndromes of acetylsalicylic acid (aspirin) hypersensitivity, aspirin-exacerbated respiratory disease (AERD) and aspirin-exacerbated cutaneous disease (AECD), were subjected to a genome-wide association study to identify strong genetic markers for aspirin hypersensitivity in a Korean population.</p><p>Methods</p><p>A comparison of SNP genotype frequencies on an Affymetrix Genome-Wide Human SNP array of 179 AERD patients and 1989 healthy normal control subjects (NC) revealed SNPs on chromosome 6 that were associated with AERD, but not AECD. To validate the association, we enrolled a second cohort comprising AERD (n = 264), NC (n = 238) and disease-control (aspirin tolerant asthma; ATA, n = 387) groups.</p><p>Results</p><p>The minor genotype frequency (AG or AA) of a particular SNP, rs3128965, in the HLA-DPB1 region was higher in the AERD group compared to the ATA or NC group (<i>P</i> = 0.001, <i>P</i> = 0.002, in a co-dominant analysis model, respectively). Comparison of rs3128965 alleles with the clinical features of asthmatics revealed that patients harboring the A allele had increased bronchial hyperresponsiveness to inhaled aspirin and methacholine, and higher 15-HETE levels, than those without the A allele (<i>P</i> = 0.039, 0.037, and 0.004, respectively).</p><p>Conclusions</p><p>This implies the potential of rs3128965 as a genetic marker for diagnosis and prediction of the AERD phenotype.</p></div

SNP rs3128965 of HLA-DPB1 as a target SNP for susceptibility to AERD.

<p>Negative logarithm <i>P</i> values are shown around the HLA-DPB1 region. Closed circles indicate the <i>P</i> value of each SNP in a comparison of AERD and NC. Open circles indicate the <i>P</i> value of each SNP in a comparison of AECD and NC.</p

Clinical features according to the SNP, rs3128965, in asthmatics (264 AERD and 387 ATA).

<p>Abbreviations: FEV1, forced expiratory volume in 1 s; IgE, immunoglobulin E; methacholine PC₂₀, the provocative concentration of methacholine required to cause a 20% fall in FEV1; 15-HETE, 15-hydroxyeicosatetraenoic acid; ECP, eosinophil cationic protein; LM score, Lund-Mackay CT score. Values are given as n (%) for categorical variables and as mean ± SD for continuous variables.</p>¶<p>count number/valid number.</p><p>*median ± std.</p>§<p><i>P</i> value were applied by Fisher exact test for categorical variable and T-test for continuous variable.</p><p>Bold character indicates significance.</p><p>Clinical features according to the SNP, rs3128965, in asthmatics (264 AERD and 387 ATA).</p

Genetic association of the SNP, rs3128965, with AERD phenotype.

<p>Abbreviations: AERD, aspirin-exacerbated respiratory disease; ATA, aspirin-tolerant asthma; NC, normal controls; NA; not applicable.</p>§<p>Each <i>P</i>-value was calculated for a co-dominant, dominant and recessive model. Logistic regression analysis was applied to control for age and gender as covariates.</p>¶<p>Odd ratio was given by co-dominant analysis model. Bold character indicates significance.</p><p>Genetic association of the SNP, rs3128965, with AERD phenotype.</p

A genome-wide Manhattan plot of GWAS in a comparison of AERD with NC.

<p>Distribution of negative logarithm <i>P</i> values are plotted against chromosomes.</p