Discussion
The increased allele frequency of potentially pathogenic CFTR variation
we report may be partially attributed to the smaller sample size of the
deeply characterized SARP cohort, but is consistent with prior reports
of a higher frequency of potentially pathogenic CFTR variants,
especially F508del, in individuals with asthma from the general
population.(2, 3) In NHW individuals from SARP, the
allele frequency for F508del was >5-fold higher than that
reported in European general populations (Table
2 ).(5) Although we hypothesized biologic
plausibility, we found no evidence that CFTR variation influences
asthma severity. The lack of an association could result from a lack of
pathogenicity data. For example, we identified 91 coding variants in the
exons of CFTR of which we were only able to find 62 catalogued in
CFTR2 or by ACMG. Another potential reason for a lack of a severity
association is that determinants of asthma are heterogeneous and complex
stemming from numerous genes potentially masking anyCFTR -specific effects in SARP.
Twelve African American individuals carried two African descentcis potentially pathogenic variants in perfect linkage
disequilibrium that were both CFTR variant targets for CFTR
modulators. This phenomenon of potentially pathogenic cis-occurring
variants has been described previously in the literature and results in
a complex allele with additive effects for these and other European
descent variants associated with CF or congenital bilateral absence of
the vas deferens(CBAVD).(6) Interestingly, when
associated with CBAVD or mild CF there is usually an additional in cis
variant (c.601G>A; p.Val201Met; legacy: V201M) that we did
not find in these individuals.(6) Even though we found
a smaller number of potentially pathogenic CFTR variants in AA
individuals, we found a substantial number of African ancestry-specific
variants in AA that we were unable to categorize because current
databases primarily consist of data from European descent white
individuals. Of the variants we identified with confirmed or potential
pathogenicity, eight were found in AA while 21 were found in NHW
individuals. A similar lack of identifiable pathogenic variation was
described in both individuals with clinical CF from Puerto Rico and the
Dominican Republic.
Four non-Hispanic white individuals with asthma of varying severity were
either homozygous or compound heterozygous for potentially pathogenic
CFTR variation of which three would have qualified for CFTR modulator
therapy in the appropriate clinical setting. None of the potentially
pathogenic genotypes we identified consisted of two CF-causing variants,
but always had at least one VVCC. In the absence of concomitant
demonstration of measured CFTR dysfunction, these individuals would not
meet criteria for a confirmed diagnosis of CF. However, the clinical
significance of these CFTR genotypes might relate to CF
masquerading as asthma in individuals with CF-asthma overlap or as an
asthma disease-modifying genotype in the absence of CF, and further
evaluation for CF would be warranted in such individuals.
The analysis of next-generationCFTR sequencing data in larger asthma and general populations
will be required and are currently underway (
https://topmed.nhlbi.nih.gov/) to further characterize and confirm
our findings.