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Genes, Environment, Ion Transport, and Cystic Fibrosis

The basic defect in cystic fibrosis (CF) respiratory epithelium can be assessed by nasal potential difference measurement. Wallace and colleagues (1) report that they did not observe an association between ion conductance properties of CF nasal epithelium and lung disease severity, whereas we detected an association between residual chloride conductance and better lung function in F508 homozygous CF sibling pairs (2). To resolve the conflicting outcome of the two studies, we compared lung disease of the two cohorts, which exhibited the same mean age of 14 years (1, 2), in terms of FEVPerc (= the CF population percentiles of FEV₁% predicted [2, 3]). Our study cohort of F508 homozygotes covers the whole range of CF lung disease severity, whereas only 6 of the 30 F508-homozygous patients studied by Wallace and colleagues have an FEVPerc greater than 50 and qualify as above average when compared with the general CF patient population (1, 3) (see Table E1 in the online supplement). Besides this recruitment bias toward more severely affected patients, the inherent shortcomings of studies on single patients impede the detection of inherited components of lung disease in CF. We know from our CF sibling lung function data (3) that individual factors outweigh shared factors, and consequently these individual factors will mask a weak but significant association between basic defect and/or genetic modifiers and lung disease severity in an underpowered study on 30 unrelated F508 homozygotes. Emphasizing inherited components by studying concordant or discordant patient pairs with extreme phenotypes (3), we were able to detect associations of residual chloride conductance (2) and of modifier genes (4) with the CF phenotype. Our study confirms the rule applicable to all clinical research that the careful selection of informative cohorts is the key to uncovering the cause of disease.

Frauke Mekus and Burkhard Tümmler

Medizinische Hochschule Hannover Hannover, Germany

FOOTNOTES

Conflict of Interest Statement: F.M. and B.T. have no declared conflict of interest.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

REFERENCES

1. Wallace HL, Barker PM, Southern KW. Nasal airway ion transport and lung function in young people with cystic fibrosis. Am J Respir Crit Care Med 2003;168:594–600.[Abstract/Free Full Text]
2. Bronsveld I, Mekus F, Bijman J, Ballmann M, de Jonge H, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, et al. Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. J Clin Invest 2001;108:1705–1715.[CrossRef][Medline]
3. Mekus F, Ballmann M, Bronsveld I, Bijman J, Veeze HJ, Tümmler B. Categories of F508del homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res 2000;3:277–293.[CrossRef][Medline]
4. Mekus F, Laabs U, Veeze H, Tümmler B. Genes in the vicinity of CFTR modulate the cystic fibrosis phenotype in highly concordant or discordant F508del homozygous sib pairs. Hum Genet 2003;112:1–11.[CrossRef][Medline]

From the Authors:

Mekus and Tümmler have performed a more detailed subgroup analysis of our data by converting the FEV₁ to a percentile for age (which they term FEVPerc), in contrast to assigning the children as above or below average for their age group (1, 2). Their calculation of FEVPerc (from the European Cystic Fibrosis [CF] Registry using unpublished equations [3]) provides continuous data on which we can perform a separate univariate analysis. This demonstrates no relation between FEVPerc and either stable maximal potential difference (PD) or the response to perfusion with a zero Cl^- (zeroCl^-/iso) solution, confirming our original findings (see Figure E1 in the online supplement).

The European CF twins and siblings study (4) is a valuable body of work that has contributed to our understanding of CF. We agree with Mekus and Hümmler that by selecting a limited but informative cohort of patients they were able to demonstrate a small (but statistically significant) difference between the zero Cl^- response of patients with markedly different respiratory condition (although their practice of choosing the nostril with the greatest magnitude of Cl^- secretion is not conventional). We have no doubt that abnormal ion transport is the primary mechanism causing CF lung disease; however, our data do not support the hypothesis that the extent of the nasal airway ion transport abnormality is related to the severity of lung disease. The reanalysis of our data confirms this assertion, but demonstrates a more severely affected F508 cohort than initially presented. However, this does not negate that these young people with CF demonstrate a wide spectrum of disease (from the 3rd to the 93rd percentile) and are an informative group to study.

The bottom line is that, within a defined genotype, a young person with severe CF lung disease is as likely to have evidence of Cl^- secretion on nasal PD measurement as someone with mild disease. Does this matter? If nasal PD is being used as a surrogate explanatory end-point for new therapies, then it does.

Kevin W. Southern^a, Helen L. Wallace^a and Pierre M. Barker^b

^a University of Liverpool Liverpool, United Kingdom
^b University of North Carolina at Chapel Hill Chapel Hill, North Carolina

FOOTNOTES

Conflict of Interest Statement: K.W.S. has no declared conflict of interest; H.L.W. has no declared conflict of interest; P.M.B. has no declared conflict of interest.

This article has an online supplement, which is accessible from this issue's table of contents online at www.atsjournals.org

REFERENCES

1. Wallace HL, Barker PM, Southern KW. Nasal airway ion transport and lung function in young people with cystic fibrosis. Am J Respir Crit Care Med 2003;168:594–600.
2. Navarro J, Rainisio M, Harms HK, Hodson ME, Koch C, Mastella G, Strandvik B, McKenzie SG. Factors associated with poor pulmonary function: cross-sectional analysis of data from the ERCF. European Epidemiologic Registry of Cystic Fibrosis. Eur Respir J 2001;18:298–305.[Abstract/Free Full Text]
3. Mekus F, Ballmann M, Bronsveld I, Bijman J, Veeze HJ, Tümmler B. Categories of F508del homozygous cystic fibrosis twin and sibling pairs with distinct phenotypic characteristics. Twin Res 2000;3:277–293.
4. Bronsveld I, Mekus F, Bijman J, Ballmann M, de Jonge H, Laabs U, Halley DJ, Ellemunter H, Mastella G, Thomas S, et al. Chloride conductance and genetic background modulate the cystic fibrosis phenotype of Delta F508 homozygous twins and siblings. J Clin Invest 2001;108:1705–1715.

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