Genome-wide significant associations with FEV1 were observed in CHARGE for numerous SNPs spanning at least three genes on chromosome 4q24, and these associations were significant for all eight SNPs tested for replication in SpiroMeta. There is moderate to strong linkage disequilibrium among the chromosome 4q24 SNPs, and the specific genes influencing FEV1 remain speculative. The genes are ordered INTS12-GSTCD-NPNT along chromosome 4q24, and joint meta-analysis with SpiroMeta showed that SNPs from the genes INTS12 and GSTCD had the most significant associations with FEV1. The product of INTS12 is a subunit of the Integrator complex that associates with the C-terminal domain of RNA polymerase II and mediates 3’-end processing of small nuclear RNAs44. GSTCD (glutathione S-transferase, C-terminal domain) could influence lung function via mechanisms involving the detoxification by glutathione S-transferases of xenobiotics that might damage the lungs.
