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Sex-Specific Association of Depression and a Haplotype in Leukotriene A4 Hydrolase Gene

From the Department of Biostatistics and Epidemiology (J.Z.), College of Public Health, University of Oklahoma Health Science Center, Oklahoma City, Oklahoma; Department of Medicine (A.A.Q., R.P., A.M.Z., E.V., L.H.S., L.J., V.V.), Division of Cardiology, Emory University School of Medicine, Atlanta, Georgia; and United States Department of Agriculture (S.O.), Agricultural Research Service, Stoneville, Mississippi.

Address correspondence and reprint requests to Jinying Zhao, Department of Biostatistics and Epidemiology, College of Public Health, University of Oklahoma Health Science Center, 801 NE 13th Street, Oklahoma City, OK 73104. E-mail: Jinying-Zhao{at}ouhsc.edu

Objective: To assess whether genetic variants involved in inflammation play a role in the sex difference in depression. Depression is, in part, genetically determined and inflammation has been implicated. Women are twice as likely to develop depression as men.

Methods: We examined the association, separately in men and women, between seven single nucleotide polymorphisms (SNPs) in the arachidonate 5-lipoxygenase-activating protein (ALOX5AP) gene and 12 SNPs in the leukotriene A4 hydrolase (LTA4H) gene and depression in 1368 white subjects (30.4% female) referred for cardiovascular evaluation. Depression was defined as a score of 10 in the Patient Health Questionnaire 9. Single marker analysis was assessed by the ² test. Haplotype-specific associations were performed, using likelihood ratio tests. Empirical significance levels were determined by permutation tests.

Results: Depressed individuals, comprising 14.5% of the total, were more likely to be female, current smokers, have a history of diabetes and myocardial infarction. None of the SNPs in the ALOX5AP gene, either singly or in combination, was associated with depression. The 12 SNPs in the LTA4H gene were not individually associated with depression. However, a six-SNP haplotype in LTA4H gene, named HapE, showed a significant protective effect on depression in women, but not in men, after correcting for cardiovascular effects. The interaction between HapE and sex on depression was statistically significant.

Conclusion: This study provides the first evidence for a sex-specific association of a novel haplotype in the LTA4H gene on depression. Although replication is needed, our study suggests that genetic variations may underlie sex differences in depression.

Key Words: depression • sex difference • SNP haplotype • leukotriene • genetic association

Abbreviations: SNPs = single nucleotide polymorphisms; ALOX5AP = arachidonate 5-lipoxygenase-activating protein; LTA4H = leukotriene A4 hydrolase; CAD = coronary artery disease; PHQ9 = Patient Health Questionnaire 9.