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Sex-specific association of epidermal growth factor gene polymorphisms with acute respiratory distress syndrome

¹ Dept of Environmental Health, Harvard School of Public Health, ⁴ Pulmonary and Critical Care Unit, Dept of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, ³ Division of Pulmonary and Critical Care Medicine, Mount Sinai School of Medicine, New York, NY, USA, ² Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan, ⁵ Both authors contributed equally to this article.

CORRESPONDENCE: D. C. Christiani, Dept of Environmental Health, Harvard School of Public Health, 665 Huntington Avenue, Room I-1407, Boston, MA 02115, USA. Fax: 1 6174326981. E-mail: dchris{at}hsph.harvard.edu

Keywords: Acute respiratory distress syndrome, epidermal growth factor, genetic susceptibility, haplotypes, lung injury, molecular epidemiology

Received: June 16, 2008
Accepted October 13, 2008

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance and inflammation, and is regulated by sex hormones. An unmatched, nested case–control study was conducted to evaluate the associations of EGF variants with acute respiratory distress syndrome (ARDS) and the role of sex on the associations between EGF variants and ARDS.

Patients with ARDS risk factors upon intensive care unit admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1,052 Caucasians who did not develop ARDS. Cases were followed for clinical outcomes and 60-day mortality. One functional single nucleotide polymorphism (SNP), rs4444903, and six haplotype-tagging SNPs spanning the entire EGF gene were genotyped.

No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Sex-stratified analyses showed opposite effects of EGF variants on ARDS in males versus in females. SNPs rs4444903, rs2298991, rs7692976 and rs4698803, and haplotypes GGCGTC and ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs6533485 significantly interacted with sex for ARDS risk.

The present study suggests that associations of epidermal growth factor gene variants with acute respiratory distress syndrome risk are modified by sex. The current findings should be replicated in other populations.