CFTR gene variants, air pollution, and childhood asthma in a California Medicaid population

Abstract

Carriers of the cystic fibrosis transmembrane conductance regulator (CFTR) gene ("carriers") have been found to have an increased risk of persistent asthma. However, it is unclear at what level of CFTR function this risk exists and whether it is modified by asthmogens, such as air pollution. We conducted a retrospective cohort study of children born in California between July 2007 and December 2013, linking CFTR genotype data from the California newborn screening program to Medicaid claims records through March 17, 2020 to identify asthma cases, and to air pollution data from CalEnviroScreen 3.0 to identify levels of particulate matter with diameter 2.5 microns or smaller (PM 2.5 ). Log-binomial regression models for asthma risk were fitted, adjusting for race/ethnicity and sex. Compared to population controls, carriers had higher risk of asthma (adjusted risk ratio (aRR) = 1.29, 95% confidence interval (CI): 0.98, 1.69; p < 0.1). Other non-CF-causing variants on the second allele did not appear to further increase risk. Genotypes with the greatest asthma risk were F508del with an intron 10 T7 or (TG)11T5 in trans (aRR=1.52, 95% CI: 1.10, 2.12). This association was higher among children living in areas at or above (aRR = 1.80) versus below (aRR = 1.37) the current national air quality standard for PM 2.5 , though this difference was not statistically significant (p interaction > 0.2). These results suggest carriers with CFTR functional levels between 25% and 45% of wildtype are at increased risk of asthma. Knowledge of CFTR genotype in asthmatics may be important to open new CFTR-related treatment options for these patients.

The Association between CFTR Gene Mutation Heterozygosity and Asthma Development: A Systematic Review

“…A total of 17 studies that examined the association of CFTR mutation heterozygosity with asthma development were included in this systematic review. Three studies were conducted in India [ 10 , 17 , 18 ], two in Greece [ 19 , 20 ], two in Denmark [ 7 , 21 ], two in the USA [ 2 , 6 ], one in Italy [ 12 ], one in Spain [ 8 ], one in France [ 13 ], one in Singapore [ 9 ], one in China [ 22 ], one in Korea [ 15 ], one in Norway [ 14 ], and one study was multinational [ 23 ].…”

“…The majority of the studies ( n = 13) were case-control [ 8 , 9 , 10 , 12 , 13 , 14 , 15 , 17 , 18 , 19 , 20 , 22 , 23 ], two cross-sectional [ 7 , 21 ], and two retrospective cohort studies [ 2 , 6 ].…”

“…The sample sizes ranged from 54 to 99,010 participants, with the age range being 9 months to 93 years. Eight out of 17 studies enrolled adults as participants [ 7 , 8 , 9 , 12 , 20 , 21 , 22 , 23 ], five studies children exclusively [ 2 , 14 , 15 , 17 , 18 ], three both adults and children [ 6 , 13 , 19 ], and one study did not report the participants’ age [ 10 ].…”

“…According to asthma diagnosis, in eight studies asthma was diagnosed by a physician [ 2 , 8 , 9 , 10 , 14 , 15 , 20 , 22 ], in four studies through asthma questionnaires [ 7 , 12 , 23 ] or self-report [ 13 ], in two studies asthma cases should follow the criteria of receiving asthma medication; hospitalization; current wheezing; and presenting with a first episode of wheeze along with a positive family history of asthma [ 17 , 18 ], and in three studies there was no report about the way asthma was diagnosed [ 6 , 19 , 21 ].…”

“…Asthma is a heterogeneous disease, characterized by chronic airway inflammation, caused by complex interactions between genetic and environmental factors [ 1 ]. Various genes have been implicated in the development of asthma; among them is cystic fibrosis transmembrane conductance regulator (CFTR) gene [ 2 ]. CFTR regulates chloride and bicarbonate transport across epithelial surface of multiple organs, including the lungs.…”