ABCC1 polymorphisms contribute to level and decline of lung function in two population-based cohorts.
OBJECTIVE
The ATP-binding cassette transporter ABCC1 [i.e. multidrug resistance-associated protein 1 (MRP1)] is a membrane-bound pump excreting a variety of xenobiotics from the cell, and thus ABCC1 may play an important role in smoking-related lung function loss and development of chronic obstructive pulmonary disease (COPD). We earlier showed that bronchial epithelium of COPD patients have lower ABCC1 expression than that of healthy controls, with even further decrements in more severe COPD stages. In line with these results, we now aimed to assess effects of ABCC1 single nucleotide polymorphisms (SNPs) on both the level and the longitudinal course of lung function in the general population.


METHODS
All 51 prevalent (minor allele frequency >5%) and noncorrelated (r<0.8) ABCC1 SNPs were analyzed in two independent, prospective, population-based cohorts, that is, Doetinchem (n = 1152) and Vlagtwedde-Vlaardingen (n = 1390) studies (three and seven median lung function measurements, respectively, per patient), using linear regression and linear mixed-effect models.


RESULTS
SNPs rs4148382 and rs212093 in the 3'-ABCC1 region were significantly associated with a higher and lower forced expiratory volume in 1 s (FEV1), respectively, in both the cohorts. Another rs35621 SNP (intron 14) was significantly associated with a highly excessive FEV1 decline in both cohorts. All replicated associations were additionally confirmed by permutation testing.


CONCLUSIONS
This is the first study showing a significant relationship between ABCC1 SNPs and lung function in two independent cohorts. These SNPs are therefore putative candidates for studies aiming to prevent COPD and investigating pharmacogenetics in established COPD.
Siedlinski
Mateusz
M
Departments of Epidemiology, University Medical Center, Groningen, The Netherlands.
Boezen
H M
HM
Boer
Jolanda M A
JM
Smit
Henriette A
HA
Postma
Dirkje S
DS
D000328:Adult; D000368:Aged; D015331:Cohort Studies; D005260:Female; D005541:Forced Expiratory Volume / Q000235:genetics*; D005828:Genetics, Population; D005838:Genotype; D006801:Humans; D008297:Male; D008875:Middle Aged; D027425:ATP-Binding Cassette, Sub-Family C Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011446:Prospective Studies; D029424:Pulmonary Disease, Chronic Obstructive / Q000453:epidemiology / Q000235:genetics*; D012129:Respiratory Function Tests; D012307:Risk Factors
D027425:ATP-Binding Cassette, Sub-Family C Proteins; C421109:multidrug resistance-associated protein 1