Quantification of the relative contribution of environmental and genetic factors to variation in cystic fibrosis lung function

Abstract

Objective: To assess the relative contributions of environmental and genetic factors to variation in cystic fibrosis (CF) lung disease.

Study design: Genetic and environmental contributions were quantified by use of intrapair correlations and differences in CF-specific forced expiratory volume in 1 second measures from 134 monozygous twins and 272 dizygous twins and siblings while in different living environments (ie, living with parents vs living alone), as well as by use of intraindividual differences in pulmonary function from a separate group of 80 siblings.

Results: Pulmonary function among monozygous twins was more similar than among dizygous twin and sibling pairs, regardless of living environment, affirming the role of genetic modifiers in CF pulmonary function. Regression modeling revealed that genetic factors account for 50% of pulmonary function variation, unique environmental or stochastic factors (36%), and shared environmental factors (14%; P < .0001). The intraindividual analysis produced similar estimates for the contributions of the unique and shared environment. The shared environment effects appeared primarily because of living with a sibling with CF (P = .003), rather than factors within the parental household (P = .310).

Conclusions: Genetic and environmental factors contribute equally to pulmonary function variation in CF. Environmental effects are dominated by unique and stochastic effects rather than common exposures.

FIGURE 1

Study Population Inclusion and Exclusion Criteria: Demographic characteristics of each group (A-F) can be found in Table 2 (online)

FIGURE 2. DZ twins and siblings show greater intra-pair differences in lung function (CF-specific FEV₁ percentiles) when living together and when living apart than MZ twins

The plots demonstrate the concordance in average lung function between the same pairs of family members when living together [A] and living apart [B]. Most PMZ twins within a pair either both experience improving or declining lung function over time; the same is not necessarily true for DZ twins and siblings where the members follow different trajectories.

FIGURE 3. Mean difference in lung function (CF-specific FEV₁ percentiles) increases between twins and siblings after they leave the parental home

Each point represents the mean absolute difference (± S.E.) in cross-sectional lung function between family members. The numbers above the datapoints represent the number of pairs contributing to that timepoint (Upper: DZ/Sib; Lower: MZ). Negative years represent the time leading up to leaving the parental home, positive years the time afterwards.

FIGURE 4. Differences in intra-individual lung function (CF-specific FEV₁ percentiles) between different living environments

Solid lines represent time spent in the parental home; dashed lines represent time spent outside the parental home. The lettered boxes refer to discrete periods of time for which lung function is averaged. A: Firstborn sibling from birth to leaving the parental home. B: First sibling after leaving home. C: Second sibling from birth to when the first sibling leaves the home. D: Second sibling from when the first sibling leaves home until the second sibling leaves home. E: Second sibling after leaving home. CF-specific FEV₁ percentiles for 40 pairs of siblings was averaged over each lettered time period, and mean absolute differences (± S.D.) between selected time periods are provided. Sibling pairs were included only if data existed for all lettered time periods. Siblings were not necessarily concordant for sex or born within 3 years of each other.

FIGURE 5. Summary of genetic and environmental effects on lung function variation using intra-pair and intra-individual differences

The data in this table are derived from the coefficients from the intra-pair and intra-individual regressions in the Results section. For the four leftmost bars, which are based on the intra-pair regression, the sources of variation are shown for each group. The rightmost bar is based on the intra-individual regression. Of note is that the genetic contribution to lung function (0.112) equals the environmental contribution (0.080 + 0.032) for the intra-pair regression. Also of note is that the estimates of the contributions of the common environment and unique environment from the intra-pair analysis are very similar those generated from the independent study sub-group used in the intra-individual analysis with a different regression strategy.