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Epigenome-wide association studies have shown a consistent association between smoking exposure and hypomethylation in the aryl hydrocarbon receptor repressor ( AHRR ) gene (cg05575921). We tested the hypothesis that  AHRR  hypomethylation is associated with low lung function, steeper lung function decline, and respiratory symptoms in the general population.   AHRR  methylation extent was measured in 9113 individuals from the 1991–1994 examination of the Copenhagen City Heart Study, using bisulfite-treated leukocyte DNA. Spirometry at the time of blood sampling was available for all individuals. Lung function was measured again for 4532 of these individuals in 2001–2003.  Cross-sectionally, a 10% lower methylation extent was associated with a 0.2 z-score (95% CI 0.1–0.2) lower forced expiratory volume in 1 s (FEV 1 ) after multivariable adjustment including smoking. Hypomethylation was also associated with a lower z-score for both forced vital capacity (FVC) and FEV 1 /FVC. In prospective analyses, individuals in the lowest  versus  highest tertile of methylation extent had a steeper decline in FEV 1 /height 3  (p for examination×methylation interaction=0.003) and FVC/height 3  (p=0.01), but not FEV 1 /FVC (p=0.08). Multivariable-adjusted odds ratios per 10% lower methylation extent were 1.31 (95% CI 1.18–1.45) for chronic bronchitis and 1.21 (95% CI 1.13–1.30) for any respiratory symptoms.   AHRR  hypomethylation was associated with low lung function, steeper lung function decline, and respiratory symptoms.

AHRR hypomethylation, lung function, lung function decline and respiratory symptoms