Fluctuation in self-perceived stress and increased risk of flare in patients with lupus nephritis carrying the serotonin receptor 1A -1019 G allele.

OBJECTIVE Stress is believed to be a risk factor for systemic lupus erythematosus (SLE) flare. Two serotonin-related gene polymorphisms, the serotonin receptor 1A (5-HT1A) polymorphism at -1019C>G and the serotonin transporter LS polymorphism, have been reported to affect stress-related behaviors. The purpose of this study was to assess the relationship between self-perceived stress (SPS), variability in SPS, and the 2 serotonin-related gene polymorphisms as risk factors for SLE flare. METHODS Seventy-seven SLE patients (50 with lupus nephritis) were evaluated every 2 months (mean +/- SD total followup 18.5 +/- 8.5 months), and patients recorded their daily SPS levels (0-10 scale). Values for mean SPS and coefficient of variation (CV) for SPS were calculated from the 60-day block of daily measurements between study visits. Serotonin-related gene polymorphism genotypes were determined by polymerase chain reaction-based methods. RESULTS Of the 77 patients, 53 experienced 80 flares of SLE (32 renal flares) based on prespecified criteria. Multivariate analysis revealed that whereas neither the serotonin-related gene polymorphisms nor the mean SPS was predictive of an SLE flare, an increased CV for SPS was predictive (P = 0.0031). Interaction between the CV for SPS and the 5-HT1A -1019C>G polymorphism was also found to be a predictor of SLE flare (P = 0.0039). Subset analysis revealed that only in lupus nephritis patients were increasing CVs for SPS (P = 0.0002) and the interaction between CVs for SPS and 5-HT1A (P < 0.0001) predictive of a flare. Odds ratio curves demonstrated that the predictive effect of increasing CVs for SPS required the presence of the 5-HT1A -1019 G allele, but appeared to be independent of the G allele number. CONCLUSION Fluctuation in the level of SPS is a risk factor for the onset of flare in SLE patients with major renal manifestations when it occurs on the background of a stress-related susceptibility gene (the 5-HT1A -1019 G allele).

[1]  P. Schur,et al.  Immune complexes, complement, and anti-DNA in exacerbations of systemic lupus erythematosus (SLE). , 1981, Medicine.

[2]  J F Fries,et al.  The 1982 revised criteria for the classification of systemic lupus erythematosus. , 1982, Arthritis and rheumatism.

[3]  A. Vingerhoets,et al.  Daily stressors and systemic lupus erythematosus: a longitudinal analysis--first findings. , 1991, Psychotherapy and psychosomatics.

[4]  E. Lewis,et al.  Serum C3 levels are diagnostically more sensitive and specific for systemic lupus erythematosus activity than are serum C4 levels. The Lupus Nephritis Collaborative Study Group. , 1991, American journal of kidney diseases : the official journal of the National Kidney Foundation.

[5]  D. Wallace,et al.  Can an earthquake cause flares of rheumatoid arthritis or lupus nephritis? , 1994, Arthritis and rheumatism.

[6]  K. Lesch,et al.  Association of Anxiety-Related Traits with a Polymorphism in the Serotonin Transporter Gene Regulatory Region , 1996, Science.

[7]  P Riederer,et al.  Allelic Variation of Human Serotonin Transporter Gene Expression , 1996, Journal of neurochemistry.

[8]  J. Esdaile,et al.  Psychosocial contributors to mental and physical health in patients with systemic lupus erythematosus. , 1998, Arthritis care and research : the official journal of the Arthritis Health Professions Association.

[9]  J. Levine,et al.  Repeated, but not acute, stress suppresses inflammatory plasma extravasation. , 1999, Proceedings of the National Academy of Sciences of the United States of America.

[10]  J John Mann,et al.  Role of the Serotonergic System in the Pathogenesis of Major Depression and Suicidal Behavior , 1999, Neuropsychopharmacology.

[11]  J. Esdaile,et al.  The role of stress in functional disability among women with systemic lupus erythematosus: a prospective study. , 1999, Arthritis care and research : the official journal of the Arthritis Health Professions Association.

[12]  D. Comings,et al.  A common C-1018G polymorphism in the human 5-HT1A receptor gene. , 1999, Psychiatric genetics.

[13]  D. Fuchs,et al.  Daily psychosocial stressors interfere with the dynamics of urine neopterin in a patient with systemic lupus erythematosus: an integrative single-case study. , 1999, Psychosomatic medicine.

[14]  T. Komori,et al.  Effects of repeated stress on expression of interleukin-6 (IL-6) and IL-6 receptor mRNAs in rat hypothalamus and midbrain. , 2000, Life sciences.

[15]  A. Picardi,et al.  Stressful Life Events and Skin Diseases: Disentangling Evidence from Myth , 2001, Psychotherapy and Psychosomatics.

[16]  M. Ward,et al.  Psychological distress and changes in the activity of systemic lupus erythematosus. , 2002, Rheumatology.

[17]  D. Fuchs,et al.  Daily psychosocial stressors and cyclic response patterns in urine cortisol and neopterin in a patient with systemic lupus erythematosus , 2003, Psychoneuroendocrinology.

[18]  H. Heiken,et al.  Flares in Patients with Systemic Lupus erythematosus Are Associated with Daily Psychological Stress , 2003, Psychotherapy and Psychosomatics.

[19]  K. Lesch,et al.  Allelic variation in 5-HT1A receptor expression is associated with anxiety- and depression-related personality traits , 2003, Journal of Neural Transmission.

[20]  Gustavo Turecki,et al.  Impaired Repression at a 5-Hydroxytryptamine 1A Receptor Gene Polymorphism Associated with Major Depression and Suicide , 2003, The Journal of Neuroscience.

[21]  A. Caspi,et al.  Influence of Life Stress on Depression: Moderation by a Polymorphism in the 5-HTT Gene , 2003, Science.

[22]  V. Arango,et al.  Human 5-HT1A receptor C(-1019)G polymorphism and psychopathology. , 2004, The international journal of neuropsychopharmacology.

[23]  M. Pérez-García,et al.  The Effects of Daily Stress and Stressful Life Events on the Clinical Symptomatology of Patients With Lupus Erythematosus , 2004, Psychosomatic medicine.

[24]  M. Burmeister,et al.  Meta‐analysis of the association between a serotonin transporter promoter polymorphism (5‐HTTLPR) and anxiety‐related personality traits , 2004, American journal of medical genetics. Part B, Neuropsychiatric genetics : the official publication of the International Society of Psychiatric Genetics.

[25]  Rajnish Mehrotra,et al.  Patient education and access of ESRD patients to renal replacement therapies beyond in-center hemodialysis. , 2005, Kidney international.

[26]  H. Nagaraja,et al.  Urine chemokines as biomarkers of human systemic lupus erythematosus activity. , 2005, Journal of the American Society of Nephrology : JASN.

[27]  T. Patterson,et al.  Major life stress, coping styles, and social support in relation to psychological distress in patients with systemic lupus erythematosus , 2005, Lupus.

[28]  P. Brantley,et al.  Stress, depression, and anxiety predict average symptom severity and daily symptom fluctuation in systemic lupus erythematosus , 1994, Journal of Behavioral Medicine.

[29]  H. Nagaraja,et al.  Clinical significance of fever in the systemic lupus erythematosus patient receiving steroid therapy. , 2005, Kidney international.

[30]  R. Mechoulam,et al.  Differential response to acute and repeated stress in cannabinoid CB1 receptor knockout newborn and adult mice , 2005, Behavioural pharmacology.

[31]  L. Hebert,et al.  Consumption of erythrocyte CR1 (CD35) is associated with protection against systemic lupus erythematosus renal flare , 2006, Clinical and experimental immunology.