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Re: Authors' reply

Dear Editor

Morten Dahl and Børge G. Nordestgaard argue against selection bias, if genotyping is performed after lung function tests because a newborn with PiMZ genotype does not change to PiZZ later in life. The latter is obviously true and not the issue. The reason for possible selection bias is that some persons may fail to have genotype performed due to a characteristic of the lung function tests under study and this may affect the result of a longitudinal study.

If we assume that PiMZ persons have a very fast FEV1 decline with premature death, a number of PiMZ persons may have attended the first examinations, but did not live long enough to show up to the last visit with genotyping. These persons would not be included in the analysis of FEV1 decline and the result would be an underestimate of FEV1 decline with the possible conclusion that PiMZ is not a risk factor for lung disease. This is usually called a survivor effect.

The opposite may also be true. Suppose a reverse relationship between pulmonary function and compliance to study visits, that is persons with normal FEV1, normal FEV1 decline, and no lung symptoms may not show up to the last visit because they feel well. This would tend to exaggerate any increased decline in FEV1 and the conclusion could be that PiMZ is an important risk factor for lung disease.

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Re: "MZ Alpha1-Antitrypsin Genotype Unaffected by Age"

Dear Editor

In a recent otherwise excellent editorial in Thorax [1], Dr. Seersholm indicated that our previous results on FEV1 decline based on the Copenhagen City Heart Study [2] are biased. We disagree, and rather believe that our study of the general population is prone to less bias than case-control or family-based studies.

Dr. Seersholm argues that because we genotyped study participants after measurement of FEV1 in 1976-1978, 1981-1984, and 1991-1994, our results are biased [1]. Certainly, if conventional risk factors are measured after development of disease, the disease might be the cause of the risk factor, rather than vice versa. However, an alpha1-antitrypsin MZ genotype in a newborn does not change into a ZZ genotype by age. Therefore, Pi MZ genotype preceded FEV1 outcomes in our study, even though genotypes were determined after FEV1 measurements. Using identical logic, genotype preceded outcomes in a similar manner in other previous studies [3-6].

Selection bias could potentially be a reason for discrepancies between studies on Pi MZ and COPD [1,7]. In our study where genotype distribution was in Hardy Weinberg equilibrium, we found no evidence for selection against any alpha1-antitrypsin genotype [2,8]. Therefore, as also pointed out by Dr. Seersholm [1], selection bias is more likely in case-control and family-based studies than in cohort studies of the general population.

Morten Dahl and Børge G. Nordestgaard. Dept of Clinical Biochemistry, Herlev University Hospital, Copenhagen, Denmark.

References

(1) Seersholm N. Pi MZ and COPD: will we ever know? Thorax 2004;59:823-825.

(2) Dahl M, Tybjærg-Hansen A, Lange P, Vestbo J, Nordestgaard BG.Change in lung function and morbidity from chronic obstructive pulmonary disease in alpha1-antitrypsin MZ heterozygotes. A longitudinal study of the general population. Ann Intern Med 2002;136:270-279.

(3) Juul K, Tybjærg-Hansen A, Steffensen R, Kofoed S, Jensen G, Nordestgaard BG. Factor V leiden: The Copenhagen City Heart Study and 2 meta-analyses. Blood 2002;100:3-10.

(4) Bojesen SE, Tybjærg-Hansen A, Nordestgaard BG. Integrin beta3Leu33Pro homozygosity and risk of cancer. J Natl Cancer Inst 2003;95:1150-1157.

(5) Dahl M, Tybjærg-Hansen A, Schnohr P, Nordestgaard BG. A population -based study of morbidity and mortality in mannose-binding lectin deficiency. J Exp Med 2004;199:1391-1399.

(6) Wadsworth MEJ, Vinall LE, Jones AL, Hardy RJ, Whitehouse DB, Butterworth SL, Hilder WS, Lovegrove JU, Swallow DM. Alpha-1-antitrypsin as a risk factor for infant and adult respiratory outcomes in a national birth cohort. Am J Respir Cell Mol Biol (in press).

(7) Hersh CP, Dahl M, Ly CS, Nordestgaard BG, Silverman EK. Chronic obstructive pulmonary disease in alpha1-antitrypsin PI MZ heterozygotes: a meta-analysis. Thorax 2004;59:843-849.