The 5-HTTLPR genotypes were in Hardy-Weinberg equilibrium, with no significant differences between subjects at baseline (). There was a non-significant trend for LA to be associated with lower PSQI scores ().
allele was associated with lower rates of MDD (Mantel-Cox Log Rank χ2(1)
= 4.3; p < 0.05), with the S/S genotype being the least resilient (). Pair-wise comparisons indicated that LA/
was different from S/S but not from S/LA
. Notably, the overall pattern was similar for both Caucasians and the nine African-Americans, with the LA/
genotype being the most resilient and S/S the most vulnerable in both groups. However, when solely examining Caucasians, the results only trended towards significance (χ2(1)
= 3.12; p = 0.077). When specifically comparing the S/S genotype vs. LA
in just Caucasians, the results were again significant (χ2 (1)
= 4.5; p < 0.05), consistent with association studies in which the S/S genotype is the most vulnerable (5
Development of MDD in patients starting interferon-alpha treatment.
Given uncertainty regarding the functional role of the rs25531 G allele, we combined LA and LG together. MDD incidence was similar (χ2 (1) = 4.06; p < 0.05) comparing 22 L/L 37 S/L and 12 S/S. Thus, rs25531 may have a small but present role. The effect was significantly mitigated when solely examining Caucasians (χ2 (1) = 2.46; p = 0.12). There was no relationship between the second intron VNTR and MDD incidence (Mantel-Cox Log Rankχ2 (1) = 0.005; n.s.).
We next examined BDI scores using a mixed-effect repeated-measures analysis. Individuals developing MDD received antidepressant treatment and/or had their INF-α held, potentially limiting any further increase in symptoms over time and resulting in a likely ‘ceiling’ effect. Despite this limitation, time was highly significant (F(137.8,5) = 3.7; p<0.005) with BDI increasing in all three genotypes during treatment (). Genotype was not significantly influential (F(75.8,2) = 1.7), nor was the interaction.
Development of increased BDI and PSQI self-report scores in patients starting interferon-alpha treatment. (Means +/− S.E.M. LA/LA = circles; S/LA or LA/LG = squares; S/S or S/LG=triangles).
Conversely, when assessing sleep quality (), genotype was influential (F(61.2,2) = 3.3; p<0.05), but time was not (F(95.5,5) =1.7), nor was the interaction. That is, sleep did not significantly worsen during interferon-alpha treatment, but those with the LA/LA genotype had better sleep quality throughout the study ().
Using Cox Regression analysis, we confirmed that genotype was related to MDD incidence (B=0.62 SE=0.27 p<0.05). We also confirmed that baseline neuroticism was strongly associated with MDD incidence (B=0.07 SE = 0.02 p<0.005). When genotype was included with neuroticism in the Cox Regression, both continued to be significantly associated with MDD incidence; with both neuroticism’s (B=0.07 SE = 0.02 p<0.005) and genotype’s (B=0.53 SE = 0.27 p<0.05) relationship relatively unchanged, indicating that neuroticism does not mediate the effect of 5-HTTLPR. Clinically, neuroticism could predict MDD (χ2 (2) = 9.7 p < 0.005; −2 Log Likelihood = 233.04), and genotyping slightly improved this predictive ability (χ2 (4) = 14.23 p < 0.005; −2 Log Likelihood = 228.41).
In Cox Regression analyses, both baseline PSQI and BDI were also associated with MDD incidence (PSQI: B=0.153 SE = 0.074 p<0.05 and BDI:B=0.067 SE = 0.034 p<0.05). When either PSQI or BDI was included with genotype using stepwise Cox Regression (both forward and backward conditional LR), only genotype remained significant (B = 0.73 SE = .37 p<0.05). Forcing all three into the same model, again only genotype remained associated (B=0.66 SE = 0.34 p<0.05), with the effects of PSQI (B=0.08 SE = 0.05 n.s.) and BDI (B=0.02 SE = 0.03 n.s.) no longer remaining. However, because baseline PSQI only trended toward a significant association with genotype (), actual mediation could not be concluded.
To ensure that we weren’t biasing our analyses by focusing purely on a DMS-IV based MDD diagnosis, we next examined the rate of development of all diagnosed “mood disorders” combined. After starting IFN- α, 24% ultimately developed categorical MDD by month four, but 45% total developed mood symptoms severe enough to prompt treatment (including one episode of mania). This group had “subsyndromal depression/irritability” as they did not have grandiosity, racing thoughts, increased goal-oriented activity, or decreased need for sleep – but did have insomnia, elevated anger, and irritability. When stratified by race; the LA allele remained dose-dependently associated with resiliency to this broader diagnosis (χ2 (1) = 5.74 p < 0.05). This association remained when examining solely Caucasians (χ2 (1) = 4.8 p < 0.05), but was lost when ignoring the role of the rs25531A/G SNP (χ2 (1) = 2.96 p = 0.085).