Polymorphisms in inflammation-related genes are associated with susceptibility to major depression and antidepressant response

Abstract

There are clinical parallels between the nature and course of depressive symptoms in major depressive disorder (MDD) and those of inflammatory disorders. However, the characterization of a possible immune system dysregulation in MDD has been challenging. Emerging data support the role of T-cell dysfunction. Here we report the association of MDD and antidepressant response to genes important in the modulation of the hypothalamic-pituitary-adrenal axis and immune functions in Mexican Americans with major depression. Specifically, single nucleotide polymorphisms (SNPs) in two genes critical for T-cell function are associated with susceptibility to MDD: PSMB4 (proteasome beta4 subunit), important for antigen processing, and TBX21 (T bet), critical for differentiation. Our analyses revealed a significant combined allele dose-effect: individuals who had one, two and three risk alleles were 2.3, 3.2 and 9.8 times more likely to have the diagnosis of MDD, respectively. We found associations of several SNPs and antidepressant response; those genes support the role of T cell (CD3E, PRKCH, PSMD9 and STAT3) and hypothalamic-pituitary-adrenal axis (UCN3) functions in treatment response. We also describe in MDD increased levels of CXCL10/IP-10, which decreased in response to antidepressants. This further suggests predominance of type 1 T-cell activity in MDD. T-cell function variations that we describe here may account for 47.8% of the attributable risk in Mexican Americans with moderate MDD. Immune function genes are highly variable; therefore, different genes might be implicated in distinct population groups.

Figure 1

Linkage disequilibrium pattern in TBX21 and PBSM4 genes. Standard color scheme: white, D′ < 1 and logarithm of odds (LOD) < 2; blue, D′ = 1 and LOD < 2; shades of pink/red, D′ < 1 and LOD≥2; bright red, D′ = 1 and LOD≥2. D′-values represent percentages and appeared inside each diamond; values of 100% are not labeled. At the top of the figure, gene structures are illustrated schematically by a thick horizontal white rectangle. Short vertical lines indicate genotyped single nucleotide polymorphisms (SNPs), which correspond to the numbers above the triangular image for genes TBX21 and PSMB4. Haplotype blocks were defined using the four game rule and haplotype tagging SNPs (htSNPs) are shown in bold. At the bottom of the triangular figures, haplotypes are shown in blocks with frequency and connections from one block to the next; only htSNPs are displayed. Blocks are connected with thin lines if frequency is > 5% and thick lines if > 10%. Between the blocks, a value of multiallelic D′ is shown. D′ is a measure of the recombination between the two blocks. TBX21: two haplotype blocks were defined; block 1 (1 kb; SNPs 3-5: rs17250953, rs11650354 and rs17244587) and block 2 (44 kb; SNPs 6-8: rs7502875, rs41515744 and rs2325717). Haplotype CCA in block 1 is the most significantly association with major depressive disorder (MDD) diagnosis (P < 0.0001). PSMB4: one haplotype block was defined; haplotype TCT was significantly associated with MDD diagnosis (P = 0.0001). *P < 0.05, **P < 0.01 and ***P≤0.0001.

Figure 2

Genotypes and relative reduction of Hamilton Depression Rating Scale (HAM-D) score in the patients treated with desipramine and fluoxetine. Histograms represent mean and standard error of mean for relative reduction of HAM-D21 score in major depressive disorder (MDD) patients who completed 8-week antidepressant treatment with desipramine (n = 68) or fluoxetine (n = 79) by genotypes (light blue, homozygous for minor allele; orange, heterozygote; dark blue, homozygous for major allele). A general linear model was used to detect allelic additive effects on treatment response after adjustment for age, sex and baseline HAM-D21 score. The analyses were performed using all treated patients (a), desipramine-treated patients (b) and fluoxetine-treated patients (c).

Figure 3

CXCL10 (IP10) and interleukin-13 (IL-13) levels in controls, major depressive disorder (MDD) patients and drug responders. (a) Histograms represent mean and standard error for CXCL10 and IL-13 levels in MDD patients before initiation of antidepressant treatment (n = 65) and controls (n = 14). Comparison levels between cases and controls were performed using general linear model after adjustment for age, sex and body mass index (BMI). Log arithmetic transformation was used for CXCL10 in our data analyses. (b) Histograms represent mean and standard error for CXCL10 and IL-13 levels before and after 8 weeks of antidepressant treatment in 19 antidepressant treatment responders (MDD patients who had higher than 50% reduction in Hamilton Depression Rating Scale (HAM-D21 score). Paired t-test was used to compare pre- and post-treatment levels in drug responders. Log arithmetic transformation was used for CXCL10 in our data analyses.

Figure 4

Schematic of sites where variations in TBX21 or PSMB4 could influence the T-cell arm of the adaptive immunity and contribute to susceptibility to major depressive disorder (MDD): Two crucial functions, specifically antigen processing and T cell-programmed differentiation are involved in Mexican Americans with MDD and are highlighted in red. A naive helper T-cell precursor (Th p) can become either a Th1 or Th2 cell under the instructive influence of interleukin-12 (IL-12) or IL-4, respectively; Th1 cell expresses TBX21 and Th2 expresses GATA3.