Background

The diagnosis of Cystic Fibrosis (CF) is by consensus based on the same parameters in all patients, yet the influence of ethnicity has only scarcely been studied. We aimed at elucidating the impact of Asian descent on the diagnosis of CF.Ethnicity impacts the cystic fibrosis diagnosis.

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Methods

We performed a retrospective analysis of the CFTR2 and UK CF databases for clinical phenotype, sweat chloride values and CFTR mutations and compared the diagnostic characteristics of Asian to non-Asian patients with CF.Ethnicity impacts the cystic fibrosis diagnosis.

Results

Asian patients with CF do not have a worse clinical phenotype. The repeatedly reported lower FEV₁ of Asian patients with CF is attributable to the influence of ethnicity on lung function in general. However, pancreatic sufficiency is more common in Asian patients with CF. The diagnosis of CF in people with Asian ancestry is heterogeneous as mean sweat chloride values are lower (92 ± 26 versus 99 ± 22 mmol/L in controls) and 14% have sweat chloride values below 60 mmol/L (versus 6% in non-Asians). Also, CFTR mutations differ from those in Caucasians: 55% of British Asian patients with CF do not have one mutation included in the routine newborn screening panel.Ethnicity impacts the cystic fibrosis diagnosis.

Conclusions

Bringing together the largest cohort of patients with CF and Asian ethnicity, we demonstrate that Asian roots impact on all three CF diagnostic pillars. These findings have implications for clinical practice in the increasingly ethnically diverse Western population.Ethnicity impacts the cystic fibrosis diagnosis.

In consensus documents, the diagnosis of Cystic Fibrosis (CF) is based on uniform parameters for all patients: their clinical phenotype plus a positive test result (an elevated sweat chloride value, two CF-causing mutations or CFTR dysfunction on nasal potential difference measurement [1]). Additionally, most CF newborn screening (NBS) programs e.g. the United Kingdom (UK) apply the same mutation panel to every newborn regardless of his or her racial background. This might not be equally sensitive when used for patients of different ethnicities.Ethnicity impacts the cystic fibrosis diagnosis.

Conversely, inter-individual variability in outcome [2] and treatment response [3] is increasingly being reported. Also in the search for a cure (https://www.cff.org/treatments/Pipeline/), CF is refined to ‘precision’ medicine [4].

We therefore evaluated if a more inclusive approach, accounting for ethnic differences, should be considered in the CF diagnosis too. Asians have been reported to have a lower incidence of CF, but a worse clinical course [5]. We studied whether Asian ethnicity impacts the three main CF diagnostic pillars: 1) clinical phenotype; 2) sweat chloride value and 3) the spectrum of CFTR mutations.Ethnicity impacts the cystic fibrosis diagnosis.

We retrospectively analyzed CFTR2 and the UK CF database for Asians with CF.

Both registries approved the use of their de-identified data.

‘Asians’ are patients with at least one parent with registered Asian origin (included Asian countries are listed in Supplementary Table 1). Ethnicity information was made available by the submitting registries and is usually patient self-reported.Ethnicity impacts the cystic fibrosis diagnosis.

CFTR2 is the largest database for patients with CF in the world and includes patients from different countries, including Asian countries. This allows (partially) to compensate for potential confounders such as diet on e.g. sweat chloride. Yet, CFTR2 can only be analyzed as pooled group data (e.g. Asian/non-Asian). Studying the UK CF database separately allowed matching individual patients for age, gender (all 234 UK Asians to 468 controls) and genotype (53 F508del-homozygous).Ethnicity impacts the cystic fibrosis diagnosis.

Clinical phenotype was assessed by lung function (forced expiratory volume in 1 s (FEV₁) as % predicted (%pred) according to Wang [6] and Hankinson [7] (W–H)); pancreatic status (pancreatic sufficiency (PS) or insufficiency (PI)); and Pseudomonas aeruginosa (P. a.) infection status. For details on these definitions see the registries’ websites (www.cftr2.org; www.cysticfibrosis.org.uk).Ethnicity impacts the cystic fibrosis diagnosis.

CF registries customarily use W–H equations to express lung function. However, the Global Lung Initiative (GLI) task force has clearly shown that healthy Asians have lower W–H spirometric values [8]. Using the UK data and GLI equations, we therefore calculated ethnicity-corrected FEV₁%pred per individual patient.Ethnicity impacts the cystic fibrosis diagnosis.

For the laboratory CF diagnostic analyses, we used sweat chloride value and CFTR mutation results. Typically a sweat chloride ≥ 60 mmol/L is considered diagnostic [1].

All statistical analyses were performed in SPSS 22.0.0.0 (IBM®) using t-tests for continuous and χ²-tests for categorical parameters; p ≤ 0.05 was considered significant.

Among the 92,741 patients with CF thus compiled, 86,979 had their ethnicity reported; 0.6% was Asian.

The UK cohort allowed matching for age, gender (panel 2A) and genotype (panel 2B).Ethnicity impacts the cystic fibrosis diagnosis.