We examined whether polymorphisms in the SOD3 gene were associated with COPD susceptibility and the specific COPD-related phenotypes of lung function and quantitative CT measurements in a well-characterized case-control cohort, and we tried to replicate our findings in two large family-based studies. We were not able to replicate previously published associations with COPD status and lung function. However, we found that polymorphisms in the SOD3 gene were associated with CT emphysema in two independent populations, suggesting that SOD3 may particularly be important to the emphysema subtype of COPD. To our knowledge, this is the first study to assess the associations between SOD3 and quantitative CT measurements. Our results also demonstrate the relevance of accurate phenotyping, for instance using quantitative CT analysis, in genetic studies of heterogeneous lung disorders such as COPD.
Our findings add to and expand the current knowledge on SOD3 and its role in COPD susceptibility. Several previous studies have identified associations between variations in SOD3
and COPD-related phenotypes. The most studied SOD3
SNP in COPD is the rare functional variant R213G (9
). This SNP has a marked impact on plasma levels of SOD3, and Juul et al showed that heterozygous carriers of R213G had reduced risk of COPD in the Danish general population (10
). The protective effect was demonstrated in smokers, but not in non-smokers. Another study observed that the R213G polymorphism was more common among smokers who did not develop COPD, so-called “resistant smokers”, also suggesting that this variant may have a protective effect against COPD development (12
). Recently, a Dutch study demonstrated a slower decline in FEV1
in R213G carriers, but only among never-smokers (11
). Dahl and colleagues identified the two novel polymorphisms E1 and I1, and showed that homozygous individuals had reduced FVC % predicted in two studies from the general population in Denmark (8
). In the Dutch study, a trend for lower VC among individuals homozygous for I1 was found (11
COPD is a heterogeneous disease, with several disease processes contributing to the clinical manifestations of the disease. It has long been observed that there are clinical subtypes of COPD, such as airway- or emphysema-predominant disease. Quantitative measurements of emphysema severity and distribution on chest CT scan, as well as determinations of airway wall thickness, have made better phenotyping of COPD subjects possible. Our results demonstrate that using more specific and well-defined phenotypes in COPD studies can improve our ability to detect genetic associations, and possibly also suggest which disease process the genes are most likely to affect. We found that polymorphisms in the SOD3 gene were determinants of emphysema severity in COPD, but they were not significantly associated with lung function variables or COPD status. Our results suggest that SOD3 may be important in the emphysema subtype of COPD.
The CT protocols for NETT and ICGN were not uniform, and the difference in slice thickness limits our ability to compare the %LAA950 values between the two studies. We did not directly compare %LAA950 values across studies in any analysis, but this methodological difference should be noted when interpreting characteristics of the study subjects. Even though ICGN relatives have a higher %LAA950 value than NETT cases, it is unlikely that they have more severe emphysema. Rather, this is a consequence of different CT protocols being used in the two studies.
The limitations of our study should be acknowledged. First of all, the low minor allele frequencies gave us limited power to detect associations, especially for the rare coding variant. Also, the NETT cases are a highly selected group of COPD subjects, with a narrow range of lung function. This may have contributed to the lack of replication of previous associations with lung function variables in the NETT study. The replication of the association between E1 and emphysema in ICGN was not robust to adjustment for clinical center. Although there was a non-significant trend in the same direction, we cannot fully exclude the possibility that clinical site differences may have biased our results. The functional relevance of E1 and I1 is unclear. These SNPs may be functionally relevant, or they may be in LD with other functional variants. By testing only 3 SNPs, we are not capturing the total genetic variation in the SOD3 gene, and other polymorphisms that we did not genotype may influence COPD-related phenotypes.
In summary, we demonstrated an association between polymorphisms in the SOD3 gene and emphysema severity on chest CT scan in two independent populations. However, we were not able to replicate previous prior associations between SOD3 variants and COPD susceptibility or lung function. Our findings suggest a role for SOD3 in the emphysema subtype of COPD, and also emphasize the importance of precise phenotyping in clinical COPD studies. Our study shows that well-defined phenotypes like quantitative CT measurements may enable us to detect genetic associations that otherwise may have gone unnoticed.