Exon sequencing identifies a novel CHRNA3-CHRNA5-CHRNB4 variant that increases the risk for chronic obstructive pulmonary disease

Background and objective: Recent genome-wide association studies have established that single nucleotide polymorphisms in the CHRNA3-CHRNA5-CHRNB4 genes are susceptibility loci for chronic obstructive pulmonary disease COPD. However, further effort is still required to reveal their genetic contribution to COPD, considering the existence of 'missing heritability', which may be mediated by variants that are of a low frequency or rare. Here we aimed to identify genetic variants in the coding regions of the CHRNA3-CHRNA5-CHRNB4 genes and determine their associations with COPD risk in Chinese.

Methods: We directly sequenced the coding regions of the CHRNA3-CHRNA5-CHRNB4 genes in 160 Chinese subjects, and then genotyped the missense or synonymous variants that have previously been reported to be associated with COPD risk in a two-stage case-control study involving 1013 COPD cases and 1030 controls of southern Chinese.

Results: We found nine variants, three of which were missense variations (Ser140Gly, His462Gln and Asp398Asn), while two were synonymous variants (Tyr215Tyr and Val53Val). The variants Ser140Gly, Tyr215Tyr and Asp398Asn were significantly associated with COPD risk. By combining these variants, the number of risk genotypes significantly increased the risk for COPD in a dose-dependent manner (Ptrend = 5.00 × 10(-4) ). The risk genotype number was also significantly correlated with several lung function parameters, including forced expiratory volume in 1 s (FEV1 ), FEV1 % predicted, FEV1 /forced vital capacity ratio and peak expiratory flow.

Conclusions: The present study identified a novel exon variant Ser140Gly, and two previously reported variants Tyr215Tyr and Asp398Asn are significantly associated with COPD risk in Chinese. These variants may be genetic biomarkers for predicting COPD risk in Chinese. Validation in other ethnicities is warranted.