Multicentric Genome-Wide Association Study for Primary Spontaneous Pneumothorax

Abstract

Despite elevated incidence and recurrence rates for Primary Spontaneous Pneumothorax (PSP), little is known about its etiology, and the genetics of idiopathic PSP remains unexplored. To identify genetic variants contributing to sporadic PSP risk, we conducted the first PSP genome-wide association study. Two replicate pools of 92 Portuguese PSP cases and of 129 age- and sex-matched controls were allelotyped in triplicate on the Affymetrix Human SNP Array 6.0 arrays. Markers passing quality control were ranked by relative allele score difference between cases and controls (|RASdiff|), by a novel cluster method and by a combined Z-test. 101 single nucleotide polymorphisms (SNPs) were selected using these three approaches for technical validation by individual genotyping in the discovery dataset. 87 out of 94 successfully tested SNPs were nominally associated in the discovery dataset. Replication of the 87 technically validated SNPs was then carried out in an independent replication dataset of 100 Portuguese cases and 425 controls. The intergenic rs4733649 SNP in chromosome 8 (between LINC00824 and LINC00977) was associated with PSP in the discovery (P = 4.07E-03, ORC[95% CI] = 1.88[1.22–2.89]), replication (P = 1.50E-02, ORC[95% CI] = 1.50[1.08–2.09]) and combined datasets (P = 8.61E-05, ORC[95% CI] = 1.65[1.29–2.13]). This study identified for the first time one genetic risk factor for sporadic PSP, but future studies are warranted to further confirm this finding in other populations and uncover its functional role in PSP pathogenesis.

An evidence‐based review of primary spontaneous pneumothorax in the adolescent population

“…[30][31][32] Approximately 10% of patients with PSP have a positive family history of pneumothorax, 33,34 although no specific genetic mutations have been associated with sporadic PSP. 35 Loeys-Dietz syndrome. [36][37][38] In these syndromes, pneumothorax is believed to result from the lower tensile strength of the visceral pleural.…”

The Genetics of Pneumothorax

“…To investigate whether nonapical lung cysts might herald FLCN mutations among patients with spontaneous pneumothorax, Johannesma and colleagues screened 40 patients with nonfamilial and familial spontaneous pneumothorax with chest CT imaging; indeed, all three subjects with cysts below the carina had FLCN mutations (11). To determine whether common genetic variants play a role in pneumothorax risk, Sousa and colleagues performed a genomewide association study of spontaneous pneumothorax (12). No SNPs met the Bonferroni correction threshold in the replication dataset.…”

LINC01414/LINC00824 genetic polymorphisms in association with the susceptibility of chronic obstructive pulmonary disease

“…LINC00824, located at chromosome 8q24.21, is also known as LINC01263. Genome-wide association studies reported that LINC00824 polymorphisms were associated with primary spontaneous pneumothorax and rheumatoid arthritis [ 18 , 19 ]. Here, we firstly found that rs699467 in LINC01414 and rs7815944 in LINC00824 might be protective factors for COPD occurrence, while LINC01414 rs298207 increased the risk of COPD in the whole population.…”