Background and objective: A wide range of common loci have been extensively screened and evaluated for their associations with various complex diseases; however, the relevance of rare variants causing missense substitutions in the protein-coding genes in human diseases is still poorly understood.
Methods: In this study, we conducted a two-stage retrospective study of a total of 1791 patients with COPD and 1940 controls in southern and eastern Chinese to test relevancies of five rare variants (i.e. p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) of human mitogen-activated protein kinase kinase 7 (MAP2K7) to COPD susceptibility. The effects of these loci on lung function were further estimated.
Results: The p.Glu116Lys rare variant had significant associations with COPD risk. Compared to individuals with Glu/Glu wild-genotype, those with 116Lys rare variants (Lys/Glu+Lys/Lys) had an increased risk of COPD (OR = 3.83, 95% CI: 2.64-5.56; P = 1.45 × 10-12 ). Meanwhile, the carriers with 116Lys rare variants (Lys/Glu+Lys/Lys) had lower pre-forced expiratory volume in 1 s (pre-FEV1 : 1.74 ± 0.70 vs 2.00 ± 0.68; P = 3.97 × 10-5 ) and lower pre-FEV1 to pre-forced vital capacity ratio (pre-FEV1 /FVC: 0.68 ± 0.14 vs 0.75 ± 0.12; P = 2.40 × 10-10 ) than those with Glu/Glu genotype. However, for other rare variants, no significant association with either COPD risk or lung function was observed.
Conclusion: Our data strongly suggest that the p.Glu116Lys rare variant in MAP2K7 predisposes its carriers to develop COPD, which would provide a useful genetic biomarker for COPD susceptibility in Chinese.
Keywords: case-control study; chronic obstructive pulmonary disease; mitogen-activated protein kinase kinase 7; rare variant; susceptibility.
© 2017 Asian Pacific Society of Respirology.