Association of FKBP5 gene haplotypes with completed suicide in the Japanese population

Abstract

Background

The hypothalamus–pituitary–adrenal (HPA) axis is known to have a role in suicidal behaviors in patients with affective disorders. However, the incomplete overlapping of the genetic factors of suicidal behaviors and the genetic factors of affective disorders suggest that the genes associated with predisposition to suicidal behaviors and affective disorders are different. There is increasing evidence that genes regulating the HPA axis have effects on suicidal behaviors. To test this idea, we examined the association of three HPA axis-related genes (glucocorticoid receptor (NR3C1), mineralocorticoid receptors (NR3C2), and FK506 binding protein 5 (FKBP5)) with suicide.

Methods

We selected 3 SNPs of the FKBP5 (rs3800373, rs1360780, and rs2395635), 2 SNPs of the NR3C1 (rs6196 and rs10052957), and 3 SNPs of the NR3C2 genes (rs5525, rs5522, and rs2070951) based on their frequency in the Japanese population. Using TaqMan probe assays, we determined these SNPs in 219 completed suicide victims and 228 age- and gender-matched healthy control subjects.

Results

No significant differences in genotypic distribution or allelic frequency of any single SNPs between the completed suicide and control groups were observed. The distributions of TT, TC, and GT haplotypes of the FKBP5 gene (comprised of rs3800373 and rs1360780) between the completed suicide and control groups were significantly different (p < 0.05 for each haplotype). The TC haplotype withstood correction for multiple comparisons (corrected p = 0.034).

Conclusion

Our results suggest that haplotypes in FKBP5 gene are associated with completed suicide. This finding needs to be confirmed using rigorous SNPs selection in a larger sample.

Introduction

Genetic factors have been shown to be involved in suicide attempts and completed suicide by family, twin and adoption studies (Roy et al., 1997). Both genetic and environmental factors likely play a crucial role in the pathogenesis of suicide (Brent and Mann, 2005, World Health Organization, 2005).

The hypothalamus–pituitary–adrenal (HPA) axis has been associated with suicidal behaviors in patients with affective disorders (Dorovini-Zis and Zis, 1987, Coryell, 1990, Roy, 1992, Westrin et al., 1999, Westrin, 2000, Mann, 2003, Pfennig et al., 2005, Mann et al., 2006, Lindqvist et al., 2008a, Lindqvist et al., 2008b) and other psychiatric disorders such as schizophrenia (De Luca et al., 2010). Suicidal patients in diagnostically heterogeneous populations exhibit HPA axis abnormalities, most commonly resistance to the dexamethasone suppression test (DST) (Inder et al., 1997, Van Heeringen et al., 2000, Coryell and Schlesser, 2001). Abnormal DST results predict higher suicide risk in affective disorder patients (Targum et al., 1983, Mann et al., 2006, Jokinen et al., 2007, Jokinen and Nordstrom, 2008, Jokinen and Nordstrom, 2009).

Although most suicide victims and suicide attempters have a diagnosable psychiatric illness (Robins et al., 1959, Beautrais et al., 1996, Shaffer et al., 1996, Van Heeringen, 2003), most patients never attempt suicide, indicating a predisposition to suicidal behaviors that is independent of the main psychiatric disorder (Mann, 1998, Mann, 2003, Rujescu et al., 2007, Ernst et al., 2009, Van Heeringen et al., 2000) including affective disorders. Suicidal depressive patients might represent a distinct subgroup with a different genetic background. The overlapping of genes thought to contribute to suicidal behaviors and affective disorders is incomplete, suggesting that separate genetic factors are involved in each disorder (Pfeffer et al., 1991, Mann, 2003, Jokinen et al., 2007). Studies have shown that HPA axis abnormalities may contribute to suicidal behaviors independently from the main psychiatric disorders (Szigethy et al., 1994, Dumser et al., 1998).

The involvement of the HPA axis in suicidal behaviors is thought to be mediated by stress response mechanisms (Westrin et al., 1999). Although environmental factors such as stressful life events are important components of suicidal behaviors, genetic components might also play a role in modifying suicide risk. HPA axis reactivity is regulated by feedback mechanisms mediated by the high affinity mineralocorticoid receptor (MR) and the lower affinity glucocorticoid receptor (GR). Functional polymorphisms in genes encoding these receptors most likely will affect the HPA axis reactivity, and thus the stress response (De Kloet et al., 2005, De Rijk and De Kloet, 2005, De Rijk and De Kloet, 2008, De Rijk et al., 2008, Claes, 2009, De Rijk, 2009, Van Leeuwen et al., 2010). GR is a nuclear receptor regulated by co-chaperone immunophilin FK506 binding protein 5 (encoded by FKBP5). Given FKBP5 role as a GR regulator, polymorphisms in FKBP5 might also affect HPA axis reactivity.

These findings suggested that polymorphisms in GR, MR (encoded by NR3C1 and NR3C2, respectively), and FKBP5 genes might underlie the contribution of the HPA axis to suicidal behaviors. To confirm this hypothesis, we conducted an association study on these genes in 219 completed suicide victims and 228 age- and gender-matched healthy control subjects. Out of the selected SNPs, rs1360780 and rs3800373 had been reported to affect FKBP5 expression levels by affecting the translation or protein stability (Binder et al., 2004, Tatro et al., 2009a). The rs5525, rs2070951, and rs10052957 have been associated with abnormal DST results (De Rijk et al., 2006, De Rijk, 2009, Van Leeuwen et al., 2010) which might be due to their effect on the receptors expression or affinity.