title: AKR1C4 gene variant associated with low euthymic serum progesterone and a history of mood irritability in males with bipolar disorder.
abstract: 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.
  
  
  CONCLUSIONS
  Relatively small sample sizes.
  
  
  CONCLUSIONS
  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.
authors.affiliation: Division of Psychiatry, Department of Clinical Neuroscience, Karolinska Institutet, Stockholm, Sweden. Anette.Johansson.2@ki.se
authors.forename: Anette G M
authors.initials: AG
authors.lastname: Johansson
authors.forename: Pernilla
authors.initials: P
authors.lastname: Nikamo
authors.forename: Martin
authors.initials: M
authors.lastname: Schalling
authors.forename: Mikael
authors.initials: M
authors.lastname: Landén
mesh_terms: D000328:Adult; D000339:Affect; D001714:Bipolar Disorder / Q000097:blood / Q000235:genetics* / Q000523:psychology; D001921:Brain; D003527:Cyclothymic Disorder; D039721:Diagnostic and Statistical Manual of Mental Disorders; D005260:Female; D006801:Humans; D007508:Irritable Mood; D008297:Male; D008875:Middle Aged; D019964:Mood Disorders / Q000523:psychology; D010088:Oxidoreductases / Q000235:genetics*; D017354:Point Mutation; D011280:Pregnanolone; D011374:Progesterone / Q000097:blood*; D011569:Psychiatric Status Rating Scales
chemical_list: D011374:Progesterone; D011280:Pregnanolone; D010088:Oxidoreductases; C048338:trans-1,2-dihydrobenzene-1,2-diol dehydrogenase