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American Journal of Human Genetics logoLink to American Journal of Human Genetics
letter
. 2006 Jul;79(1):184–186. doi: 10.1086/505268

The SERPINE2 Gene and Chronic Obstructive Pulmonary Disease

Sally Chappell 1, Leslie Daly 1, Kevin Morgan 1, Tamar Guetta Baranes 1, Josep Roca 1, Roberto Rabinovich 1, Ann Millar 1, Seamas C Donnelly 1, Vera Keatings 1, William MacNee 1, Jan Stolk 1, Pieter S Hiemstra 1, Massimo Miniati 1, Simonetta Monti 1, Clare M O’Connor 1,*, Noor Kalsheker 1,*
PMCID: PMC1474124  PMID: 16773582

To the Editor: In the February 2006 issue of the Journal, DeMeo et al.1 identified SERPINE2 as a positional candidate gene for susceptibility to chronic obstructive pulmonary disease (COPD [MIM 606963]) and reported on the association of polymorphic variants of this gene with early-onset disease in a family-based study and with severe disease in a case-control study. With early prior information provided by the authors, we have independently tested for an association of the SERPINE2 gene with COPD in the largest case-control study reported to date. Our study consists of 1,018 COPD cases and 911 controls prospectively recruited from six European centers. We have provided details about the patients elsewhere.2 The study population was screened for genotypes at the Medical Research Council (United Kingdom) Gene Services Unit for five SNPs (table 1) in the SERPINE2 gene. All the SNPs evaluated were reported in the study by DeMeo et al. as associated with disease, with three of the five associated with disease in both the family and case-control study cohorts they assessed.

Table 1. .

LD between SERPINE2 SNPs Expressed as r2[Note]

r2 for SNP
SNP rs1438831 rs920251 rs6747096a rs3795879
rs920251 .952 (1.0)
rs6747096a .140 .148
rs3795879a .140 (.145) .145 (.145) .964
ss49785625a .020 .023 .054 .055

Note.— The r2 values in parentheses are values obtained from HapMap and compared with our own data in controls. ss49785625 and rs6747096 are not in HapMap.

a

SNP reported by DeMeo et al.1 to be associated with disease in both family and case-control cohorts.

We examined linkage disequilibrium (LD) between the SNPs (table 1) and evaluated SNP and haplotype associations as described elsewhere.2 DeMeo et al. did not report specific LD values between SNPs or noncontiguous SNPs contributing to haplotypes. SNPs and genotype frequencies in the study population are shown in table 2. We found no significant deviation from Hardy-Weinberg equilibrium in frequencies for any of the SNPs.

Table 2. .

SERPINE2 Genotype and Allele Frequencies in Controls and COPD Cases

Frequencyof Allele
Frequencyof Genotype
SNP and
Sample
C T CC CT TT
rs1438831:
 COPD case .66 .34 .43 .45 .12
 Control .66
.34
.43
.46
.11
A
G
AA
AG
GG
rs920251:
 COPD case .35 .65 .13 .45 .42
 Control .35
.65
.12
.46
.42
A
G
AA
AG
GG
rs6747096:
 COPD case .79 .21 .61 .35 .04
 Control .79
.21
.63
.33
.04
C
T
CC
CT
TT
rs3795879:
 COPD case .78 .22 .60 .36 .05
 Control .79
.21
.62
.33
.05
A
G
AA
AG
GG
ss49785625:
 COPD case .54 .46 .30 .48 .22
 Control .53 .47 .29 .48 .23

We found no association between any of the SERPINE2 SNPs and disease, in examining both the allelic and genotype distributions, although our study was well powered to detect associations of the magnitude observed by DeMeo et al., and we would have expected to see these frequency differences with the SNPs that we studied. We also failed to find a relationship between any haplotypes of these SNPs and disease (data not shown). It was of interest that the allele and genotype frequencies observed in our control and patient groups were virtually identical to those observed in control subjects by DeMeo et al., indicating a common distribution of SERPINE2 variants in the European and North American populations studied. Our previous study has also shown that there is no evidence of population stratification in our sample.

Patients evaluated in both the family-based and case-control studies reported by DeMeo et al. represent a severe subset of the disease spectrum. To determine whether the association with SERPINE2 noted by DeMeo et al. was related to disease severity, we also analyzed SNP allele and genotype frequencies in the subgroup of our patients with forced expiratory volume at 1 s ⩽45% (n=388), a group that represents severe disease, but we failed to observe any association.

Our inability to replicate the observations of DeMeo et al. in a more highly powered case-control study may be related to differences in the disease phenotype of the patients studied, because our patients included those with and without emphysema. The possibility, however, that the associations reported by DeMeo et al. represent false-positive results must also be considered. In this respect, it is of note that, in the study by DeMeo et al., different associations were reported for SNPs that are in linkage disequilibrium with one another. For example, rs3795879 and rs3795877 have an r2 value of 1 in HapMap, yet different associations with quantitative spirometric phenotypes were reported for the family study. Similarly, rs1438831 and rs920251 are in complete LD, with an r2 value of 1 in HapMap and 0.95 in our study; however, in DeMeo et al.’s case-control study, the allele and genotype frequencies of rs920251 were found to be significantly associated with disease (P values of 0.015 and 0.011, respectively), whereas no similar association was observed for rs1438831. In both instances, the almost complete linkage between these pairs of SNPs would be expected to result in similar associations.

These results underline the importance of replication in other large independent studies before SERPINE2 can be unequivocally assigned as a candidate gene for COPD. It is becoming apparent that, to detect modest genetic effects for complex diseases, several independent studies may be required and the data may need to be subjected to meta-analysis. For example, this approach has been used to study Alzheimer disease (see Alzheimer's Association Web site). Similar approaches need to be adopted for COPD. It would also be helpful to have similar criteria adapted for phenotypic selection and to plan prospective studies on this basis.

Acknowledgments

We thank Ed Silverman and Dawn DeMeo for providing us with detailed information about the SERPINE2 SNPs. This work was supported by European Union 5th Framework Programme grant QLG1-CT-2001-01012.

Web Resources

The URLs for data presented herein are as follows:

  1. Alzheimer's Association, http://www.alz.org/
  2. Online Mendelian Inheritance in Man (OMIM), http://www.ncbi.nlm.nih.gov/Omim/ (for COPD) [PubMed]

References

  • 1.DeMeo DL, Mariani TJ, Lange C, Srisuma S, Litonjua AA, Celedon JC, Lake SL, Reilly JJ, Chapman HA, Mecham BH, Haley KJ, Sylvia JS, Sparrow D, Spira AE, Beane J, Pino-Plata V, Speizer FE, Shapiro SD, Weiss ST, Silverman EK (2006) The SERPINE2 gene is associated with chronic obstructive pulmonary disease. Am J Hum Genet 78:253–264 [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 2.Chappell S, Daly L, Morgan K, Guetta Baranes T, Roca J, Rabinovich R, Millar A, Donnelly S, Keatings V, MacNee W, Stolk J, Hiemstra P, Miniati M, Monti S, O’Connor CM, Kalsheker N (2006) Cryptic haplotypes of SERPINA1 confer susceptibility to chronic obstructive pulmonary disease. Hum Mutat 27:103–109 10.1002/humu.20275 [DOI] [PubMed] [Google Scholar]

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