AKR1C4 gene variant linked to reduced progesterone and mood irritability in men with BD
MedWire News: A variant of the aldoketoreductase-type-4 gene (AKR1C4) is associated with reduced serum levels of progesterone and manic/hypomanic irritability in euthymic men with bipolar disorder (BD), research shows.
"Irritable mood during mood elevation is common in BD [and] the progesterone metabolite allopregnanolone (ALLO) has been implicated in other disorders presenting with irritability," explain Anette Johansson and colleagues from the Karolinska Institute in Stockholm, Sweden.
For the current study, the researchers investigated whether mood irritability in patients with BD is associated with reduced progesterone levels. They also assessed whether single nucleotide polymorphisms (SNPs) in the steroidogenetic enzyme genes AKR1C4, 3β-hydroxysteroid dehydrogenase (HSD3B2), and steroid-5-alpha-reductase (SRD5A1) are associated with mood irritability and/or with serum progesterone in such patients.
The team recruited 178 euthymic patients (71 men) with bipolar I or II disorder to participate in the study.
All of the patients were genotyped, and assessed for hypomanic/manic irritability using relevant questions from the Affective Disorders Evaluation. They also supplied blood samples for analysis of progesterone levels.
In total, 54 men, aged an average of 41.7 years, and 78 women, aged an average of 36.9 years, had a history of hypomanic/manic irritability.
The researchers found that in men, those with a history of manic/hypomanic irritability had significantly lower serum progesterone concentrations than those without such a history, after accounting for age and comorbid anxiety disorders. No such association was observed in women.
Three SNPs in AKRIC4 (rs17306779, rs3829125, and rs10904440) were significantly associated with manic/hypomanic irritability in men. Of these, rs3829125 - a missense variation due to a cystine to serine change at position 145 - was also associated with lower serum progesterone concentrations. Again, no such associations were observed in women.
Johansson and team conclude in the Journal of Affective Disorders: "Low progesterone levels and a cystine to serine change at position 145 in AKR1C4 gene are associated with manic/hypomanic irritability in males."
They add: "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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By Mark Cowen