Results
SARP participants with asthma (n= 1401, SARP1-3) had whole genome
sequencing(after consent was attained) through the NHLBI-sponsored
TOPMed program. We extracted sequencing data on functional variation
spanning a 190.5Kb region of CFTR (hg19 position chromosome
7:117119040-117309560). Potentially pathogenic, low frequency-to-rareCFTR variants (allele frequency<0.05) were classified
as (1) CF-causing based on the CFTR2 database (cftr2.org), (2) having
varying clinical consequences on CF risk (VVCC) based on CFTR2, and (3)
likely pathogenic based on the American College of Medical Genetics
(ACMG)(acmg.net) assuming a recessive model (Figure 1 ). The
minor allele frequency of these potentially pathogenic CFTR variants and
regression-based models were stratified by self-reported racial/ethnic
group (African American and non-Hispanic whites). Regression-based
models tested for associations of potentially pathogenic genotypes with
clinical outcomes of interest including the comparison between (1)
individuals with no identifiable potentially pathogenic variation versus
1 potentially pathogenic variant, (2) one or more variants, or (3) 2
potentially pathogenic variants using collapsing-based burden tests.
Variant-specific models also compared individuals with and without
F508del and no other potentially pathogenic variants (i.e. F508del
heterozygotes).
Of 1401 total participants, 9.5% (134) were carriers of one potentially
pathogenic CFTR variant and these carriers were more likely to be
non-Hispanic white (NHW, 10.1% [84 of 831]) when compared to
African American individuals (AA, 5.2% [22 of 426]). The most
frequent potentially pathogenic CFTR variant identified was
F508del, found in 30 individuals, the majority of whom were NHW (3.5%
[29 of 831]). We found ≥2 potentially
pathogenic CFTR variants in 1.4% (19) of total participants
which occurred more frequently in African American (2.8%, n=12)
compared to NHW individuals (0.5%, n= 4 ). Potentially pathogenicCFTR variant genotypes (none versus ≥1 or ≥2 potentially
pathogenic variants), including F508del, were not cumulatively
associated with lung function measures or exacerbations requiring
corticosteroid bursts, ED visits, or hospitalizations. In four NHW
individuals, we found three with F508del compound heterozygosity with a
VVCC: two c.1210-11T>G(legacy: 5T;TG12), and one with
c.3208C>T(p.Arg1070Trp; legacy: R1070W; a CFTR modulator
therapy-eligible variant) and an individual homozygous for the VVCC
5T;TG12. All four individuals were females with a reduced
pre-bronchodilator forced expiratory volume in 1 second (FEV1)
percentage predicted (Table 1 ). All 12 AA with two potentially
pathogenic variants were carriers of the cis-variants
c.220C>T (p.Arg74Trp; legacy: R74W) and
c.3808G>A (p.Asp1270Asn; legacy: D1270N), both FDA-approved
targets for CFTR modulator therapy and highly likely to be
occurring in cis and in full linkage disequilibrium. The
CF-causing variants we identified in NHW and AA, especially F508del, had
a markedly higher minor allele frequencies (MAF) in SARP participants
compared to reference general populations (Table 2).