Functional polymorphisms in the interleukin-6 and serotonin transporter genes, and depression and fatigue induced by interferon-alpha and ribavirin treatment

Abstract

Depression and fatigue are frequent side effects of interferon-alpha (IFN-alpha) treatment, and there is compelling evidence that the inflammatory response system (including interleukin-6, IL-6) and the serotonergic system is important in the pathophysiology of such symptoms. Functional polymorphisms in the promoter region of the IL-6 gene (rs1800795) and serotonin transporter gene (5-HTTLPR) have been identified as regulating these systems. The present study aimed to determine if these polymorphisms were associated with the development of depression and fatigue during IFN-alpha and ribavirin treatment. Ninety-eight Caucasian patients receiving pegylated IFN-alpha and ribavirin treatment for chronic hepatitis C virus at King's College Hospital, London, and Emory University Hospital, Atlanta, participated in this prospective cohort study. Symptoms of depression and fatigue were measured before treatment and at weeks 4, 8, 12 and 24 during treatment. The 'low IL-6' synthesizing genotype (CC) was associated with significantly fewer symptoms of depression (effect size = 0.7 at week 24; F = 9.4, d.f. = 436, P = 0.002). The 'high transcription' serotonin transporter (5-HTT) genotype (LL) was also associated with significantly fewer symptoms of depression, but with a much smaller effect (effect size = 0.2 at week 24; F = 4.5, d.f. = 436, P = 0.03). Neither polymorphisms were associated with symptoms of fatigue (IL-6: F = 1.2, d.f. = 430, P = 0.2; 5-HTT: F = 0.5, d.f. = 430, P = 0.5). The smaller effects of the 5-HTT polymorphism on depression may be explained by an interaction between the genes (F = 5.0, d.f. = 434, P = 0.02): the 'protective' effect of the 5-HTTLPR polymorphism was evident only in the presence of the 'low IL-6' genotype (F = 5.4, d.f. = 64, P = 0.02), not in the presence of the 'high IL-6' genotype (F = 2.2, d.f. = 369, P = 0.1). The association between the IL-6 polymorphism and reduced risk of depressive symptoms confirms the role of the inflammatory response system in the pathophysiology of IFN-alpha-induced depression; in contrast, the effect of the 5-HTT gene was small and perhaps dependent on the status of the inflammatory response.

Figure 1

Depressive and fatigue symptom scores in the two interleukin-6 (IL-6) genotype groups. Symptoms are expressed as effect size (mean change from baseline ± s.e.m.) during 24 weeks of interferon-α (IFN-α) and ribavirin treatment. (a) Subjects with the CC genotype (n = 15) experienced significantly fewer depressive symptoms than the combined GG and GC genotype group (n = 83) (P = 0.002). (b) There was no difference in fatigue symptoms experienced by the CC genotype (n = 15) and the combined GG and GC genotype group (n = 83) (P = 0.3).

Figure 2

Depressive and fatigue symptom scores in the two 5-HTT genotype groups. Symptoms are expressed as effect size (mean change from baseline ± s.e.m.) during 24 weeks of interferon-α (IFN-α) and ribavirin treatment. (a) Subjects with the LL genotype (n = 45) experienced significantly fewer depressive symptoms than the combined SS and SL genotype group (n = 54) (P = 0.03). (b) There was no difference in fatigue symptoms experienced by the LL genotype (n = 45) and the combined SS and SL genotype group (n = 543) (P = 0.5).

Figure 3

Interaction between interleukin-6 (IL-6) and 5-HTT genotype on depressive symptom scores. Symptoms are expressed as effect size (mean change from baseline ± s.e.m.) during 24 weeks of interferon-α (IFN-α) and ribavirin treatment. There was a significant gene–gene interaction (P = 0.02). (a) Within the CC genotype group, LL genotype subjects (n = 5) experienced significantly fewer depressive symptoms than the SS/SL genotype subjects (n =7) (P = 0.02). (b) Within the GG/GC genotype group, there was no difference in depressive symptoms experienced by the LL genotype subjects (n = 33) and the SS/SL genotype subjects (n = 39) (P = 0.1).