title: The effect of common genetic variation in 11β-hydroxysteroid dehydrogenase type 1 on hypothalamic-pituitary-adrenal axis activity and incident depression.
abstract: BACKGROUND
  Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11β-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression.
  
  
  METHODS
  Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression.
  
  
  RESULTS
  rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03-1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels.
  
  
  CONCLUSIONS
  We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11β-HSD1 is implicated in human HPA axis regulation and susceptibility to depression.
authors: Department of Internal Medicine, Erasmus Medical Center, P.O. Box 2040, 3000 CA Rotterdam, The Netherlands.
authors: M J H J
authors: MJ
authors: Dekker
authors: H
authors: H
authors: Tiemeier
authors: H J
authors: HJ
authors: Luijendijk
authors: M
authors: M
authors: Kuningas
authors: A
authors: A
authors: Hofman
authors: F H
authors: FH
authors: de Jong
authors: P M
authors: PM
authors: Stewart
authors: J W
authors: JW
authors: Koper
authors: S W J
authors: SW
authors: Lamberts
mesh_terms: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1 / Q000235:genetics* / Q000378:metabolism; D000368:Aged; D000369:Aged, 80 and over; D015331:Cohort Studies; D003866:Depressive Disorder / Q000453:epidemiology* / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation / Q000502:physiology; D006801:Humans; D006854:Hydrocortisone / Q000378:metabolism; D007030:Hypothalamo-Hypophyseal System / Q000378:metabolism*; D015994:Incidence; D008297:Male; D008875:Middle Aged; D010913:Pituitary-Adrenal System / Q000378:metabolism*; D020641:Polymorphism, Single Nucleotide / Q000502:physiology
chemical_list: D043205:11-beta-Hydroxysteroid Dehydrogenase Type 1; D006854:Hydrocortisone