AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder.

BACKGROUND:Irritable mood during mood elevation is common in bipolar disorder. The progesterone metabolite allopregnanolone (ALLO) has been implicated in other disorders presenting with irritability. This study aimed to test whether a history of manic/hypomanic irritability is associated with low serum progesterone levels; and whether single nucleotide polymorphisms (SNPs) in gene coding for steroidogenetic enzymes (HSD3B2, SRD5A1 and AKR1C4 were coupled to previous manic irritability and/or with serum progesterone concentrations. METHODS:Morning serum progesterone concentrations during euthymic phase of bipolar illness types 1 and 2 were assessed in 71 males and 107 females. Previous manic/hypomanic irritability was assessed using the Affective Disorders Evaluation. Selected SNPs were analyzed: i) aldoketoreductase-type-4 (AKR1C4 - rs17306779, rs3829125, rs10904440, rs12762017, and rs11253048), ii) 3-β-hydroxysteroid-dehydrogenase (HSD3B2 - rs4659174, rs2854964, and rs3765948), iii) steroid-5-α-reductase (SRD5A1 - rs8192139, rs181807, rs3822430, and rs3736316). RESULTS:In males, progesterone concentrations were lower in those who had shown manic/hypomanic irritability compared with nonirritable (F=7.05, p=0.0099). SNPs rs17306779, rs3829125, and rs10904440 were associated with manic/hypomanic irritability. A cystine to serine change at position 145 in AKR1C4 (rs3829125) was associated with lower serum progesterone (F=6.34, p=0.014). There were no associations in females. LIMITATIONS:Relatively small sample sizes. CONCLUSION:Low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene are associated with manic/hypomanic irritability in males. Given that the enzyme AKR1C4 has both dehydrogenating and reductive activities in the steroidogenetic pathway, a missense variation in the gene may predispose to manic/hypomanic irritability by altering the relationship between progesterone and ALLO concentrations in the brain.

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