Gender-specific association of Epidermal Growth Factor gene polymorphisms with ARDS

¹ Dept of Environmental Health, Harvard School of Public Health, Boston, MA, USA.; and Division of Pulmonary and Critical Care Medicine, Kaohsiung Medical University Hospital, Kaohsiung Medical University, Kaohsiung, Taiwan
² Dept of Environmental Health, Harvard School of Public Health, Boston, MA, USA.
³ Division of Pulmonary and Critical Care Medicine, Mount Sinai School of Medicine, New York, USA.
⁴ Pulmonary and Critical Care Unit, Dept of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.
⁵ Dept of Environmental Health, Harvard School of Public Health, Boston, MA, USA.; and Pulmonary and Critical Care Unit, Dept of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA.

^* To whom correspondence should be addressed. E-mail: dchris{at}hsph.harvard.edu.

	Abstract

Epidermal growth factor (EGF) is involved in alveolar epithelial repair, lung fluid clearance, 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 gender on the associations between EGF variants and ARDS.

Patients with ARDS risk factors upon ICU admission were enrolled. Cases were 416 Caucasians who developed ARDS and controls were 1052 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 entire EGF gene were genotyped with TaqMan assays.

No individual SNP or haplotype was associated with ARDS risk or outcomes in all subjects. Gender-stratified analyses showed opposite effects of EGF variants on ARDS in males versus in females. SNPs rs4444903, rs2298991, rs7692976, rs4698803, and haplotypes GGCGTC, ATCAAG were associated with ARDS risk in males. No associations were observed in females. Interaction analysis showed that rs4444903, rs2298991, rs7692976 and rs4533485 significantly interacted with gender for ARDS risk.

This study suggests that genetic associations of EGF with ARDS risk are modified by gender. Our findings should be replicated in other populations.