Genetic Variation in Genes Encoding Airway Epithelial Potassium Channels Is Associated with Chronic Rhinosinusitis in a Pediatric Population

<div><p>Background</p><p>Apical potassium channels regulate ion transport in airway epithelial cells and influence air surface liquid (ASL) hydration and mucociliary clearance (MCC). We sought to identify whether genetic variation within genes encoding airway potassium channels is associated with chronic rhinosinusitis (CRS).</p><p>Methods</p><p>Single nucleotide polymorphism (SNP) genotypes for selected potassium channels were derived from data generated on the Illumnia HumanHap550 BeadChip or Illumina Human610-Quad BeadChip for 828 unrelated individuals diagnosed with CRS and 5,083 unrelated healthy controls from the Children's Hospital of Philadelphia (CHOP). Statistical analysis was performed with set-based tests using PLINK, and corrected for multiple testing.</p><p>Results</p><p>Set-based case control analysis revealed the gene <i>KCNMA1</i> was associated with CRS in our Caucasian subset of the cohort (598 CRS cases and 3,489 controls; p = 0.022, based on 10,000 permutations). In addition there was borderline evidence that the gene <i>KCNQ5</i> (p = 0.0704) was associated with the trait in our African American subset of the cohort (230 CRS cases and 1,594 controls). In addition to the top significant SNPs rs2917454 and rs6907229, imputation analysis uncovered additional genetic variants in <i>KCNMA1</i> and in <i>KCNQ5</i> that were associated with CRS.</p><p>Conclusions</p><p>We have implicated two airway epithelial potassium channels as novel susceptibility loci in contributing to the pathogenesis of CRS.</p></div

Demographics and clinical features of study groups.

<p>For Age, mean ± standard deviation is shown.</p

Quantitative association studies (PLINK) for log(TG) (<i>P</i><10⁻⁶).

<p>Quantitative association studies (PLINK) for log(TG) (<i>P</i><10⁻⁶).</p

Results of gene set-based analyses of 44 potassium channel genes.

<p>NSNP: number of SNPs within the gene and its upstream and downstream 20 kb genomic region; NSIG: number of significant SNPs; ISIG: number of independent significant SNPs; adj. P-value: P-value adjusted for multiple testing.</p

List of analyzed potassium channels.

<p>List of analyzed potassium channels.</p

Significantly associated SNPs in genes <i>KCNMA1</i> and <i>KCNQ5</i>.

<p>SNP = single nucleotide polymorphism; Chr = chromosome; bp = base pair; MAF = minor allele frequency; OR = odds ratio; SE = standard error.</p

Regulatory elements at the significant loci in gene <i>KCNQ5</i>.

<p>r² and D′ are measures of LD between the indicated SNP and significant SNPs rs6907229 or rs9343015.</p

Distribution of triglyceride levels in “cases” (TG>200mg/dL) and “controls” (TG<150mg/dL) for binary GWAS and pathway association analyses.

<p>Distribution of triglyceride levels in “cases” (TG>200mg/dL) and “controls” (TG<150mg/dL) for binary GWAS and pathway association analyses.</p

Imputed variants in gene <i>KCNMA1</i> with p-value<10⁻⁴ in the Caucasian cohort.

<p>Chr = chromosome; Pos = Position; OR = odds ratio; CI = confidence interval.</p

Schematic drawing of ciliated epithelial airway ion transport.

<p>Schematic drawing of ciliated epithelial airway ion transport.</p