A higher prevalence of depression in systemic lupus erythematosus (SLE) patients has been reported, though the mechanism underlying this phenomenon remains unclear. The present study was conducted to explore whether the polymorphism and methylation status of the serotonin transporter gene (5HTT) promoter region (PR-5HTT) contribute to depression in SLE patients from both genetic and epigenetic perspectives. In this study, 96 SLE patients and 96 healthy controls (HCs) were recruited. Depression levels of all subjects were evaluated using the Hamilton Depression Rating Scale (HDRS). The serotonin transporter-linked polymorphism (5HTTLPR) and the DNA methylation status of PR-5HTT were detected in peripheral lymphocytes of SLE patients and HCs. The differences in 5HTTLPR and DNA methylation of PR-5HTT between SLEs and HCs were compared. In SLE patients, the frequencies of short allele (S) and SS genotype of 5HTTLPR were higher in depressive SLE (SLE-D) patients than in non-depressive SLE (SLE-ND) patients. The mean HDRS score of SS homozygote patients was higher than that of patients with SL/LL genotypes. Conversely, PR-5HTT was hypomethylated in HCs as well as SLE patients. There was no difference in the methylation status between HCs and SLEs. Thus, the functional expression of PR-5HTT may be primarily regulated by gene polymorphism and not by DNA methylation. The risk allele of 5HTTLPR appears to be a major contributor to depression in SLE patients.
KremerJMRynesRIBartholomewLE. Non-organic non-psychotic psychopathology (NONPP) in patients with systemic lupus erythematosus. Semin Arthritis Rheum1981; 11: 182–189.
2.
ShortallEIsenbergDNewmanSP. Factors associated with mood and mood disorders in SLE. Lupus1995; 4: 272–279.
3.
OmdalRHusbyGMellgrenSI. Mental health status in systemic lupus erythematosus. Scand J Rheumatol1995; 24: 142–145.
4.
IshikuraRMorimotoNTanakaK. Factors associated with anxiety, depression and suicide ideation in female outpatients with SLE in Japan. Clin Rheumatol2001; 20: 394–400.
5.
HayEMBlackDHuddyA. Psychiatric disorder and cognitive impairment in systemic lupus erythematosus. Arthritis Rheum1992; 35: 411–416.
6.
AinialaHLoukkolaJPeltolaJKorpelaMHietaharjuA. The prevalence of neuropsychiatric syndromes in systemic lupus erythematosus. Neurology2001; 57: 496–500.
7.
NeryFGBorbaEFHatchJPSoaresJCBonfáENetoFL. Major depressive disorder and disease activity in systemic lupus erythematosus. Compr Psychiatry2007; 48: 14–19.
8.
GaoHXCampbellSRCuiMH. Depression is an early disease manifestation in lupus-prone MRL/lpr mice. J Neuroimmunol2009; 207: 45–56.
9.
WangCSandlingJKHagbergN. Genome-wide profiling of target genes for the systemic lupus erythematosus-associated transcription factors IRF5 and STAT4. Ann Rheum Dis2013; 72: 96–103.
10.
PiotrowskiPLianeriMWudarskiMOlesińskaMJagodzińskiPP. Contribution of STAT4 gene single-nucleotide polymorphism to systemic lupus erythematosus in the Polish population. Mol Biol Rep2012; 39: 8861–8866.
11.
NicolasCSPeineauSAmiciM. The Jak/STAT pathway is involved in synaptic plasticity. Neuron2012; 73: 374–390.
12.
OrosziGLaptevaLDavisE. The Met66 allele of the functional Val66Met polymorphism in the brain-derived neurotrophic factor gene confers protection against neurocognitive dysfunction in systemic lupus erythematosus. Ann Rheum Dis2006; 65: 1330–1335.
13.
TsankovaNRenthalWKumarANestlerEJ. Epigenetic regulation in psychiatric disorders. Nat Rev2007; 8: 355–367.
14.
KuratomiGIwamotoKBundoM. Aberrant DNA methylation associated with bipolar disorder identified from discordant monozygotic twins. Mol Psychiatry2008; 13: 429–441.
15.
SunHKennedyPJNestlerEJ. Epigenetics of the depressed brain: Role of histone acetylation and methylation. Neuropsychopharmacology2013; 38: 124–137.
16.
SchroederMKrebsMOBleichSFrielingH. Epigenetics and depression: Current challenges and new therapeutic options. Curr Opin Psychiatry2010; 23: 588–592.
17.
PetersAHSchübelerD. Methylation of histones: Playing memory with DNA. Curr Opin Cell Biol2005; 17: 230–238.
18.
JaenischRBirdA. Epigenetic regulation of gene expression: How the genome integrates intrinsic and environmental signals. Nat Genet2003; 33 (Suppl): 245–254.
19.
JanuchowskiRProkopJJagodzinskiPP. Role of epigenetic DNA alterations in the pathogenesis of systemic lupus erythematosus. J Appl Genet2004; 45: 237–248.
20.
PanYSawalhaAH. Epigenetic regulation and the pathogenesis of systemic lupus erythematosus. Transl Res2009; 153: 4–10.
21.
PellegrinoTCBayerBM. Specific serotonin reuptake inhibitor-induced decreases in lymphocyte activity require endogenous serotonin release. Neuroimmunomodulation2001; 8: 179–187.
22.
FrankMGJohnsonDRHendricksSEFrankJL. Monocyte 5-HT1A receptors mediate pindobind suppression of natural killer cell activity: Modulation by catalase. Int immunopharmacol2001; 1: 247–253.
23.
StefuljJJernejBCicin-SainLRinnerISchauensteinK. mRNA expression of serotonin receptors in cells of the immune tissues of the rat. Brain Behav Immun2000; 14: 219–224.
24.
LeschKPBallingUGrossJ. Organization of the human serotonin transporter gene. J Neural Transm Gen Sect1994; 95: 157–162.
25.
LeschKPBengelDHeilsA. Association of anxiety-related traits with a polymorphism in the serotonin transporter gene regulatory region. Science1996; 274: 1527–1531.
26.
LevinsonDF. The genetics of depression: A review. Biol Psychiatry2006; 60: 84–92.
27.
RischNHerrellRLehnerT. Interaction between the serotonin transporter gene (5-HTTLPR), stressful life events, and risk of depression: A meta-analysis. JAMA2009; 301: 2462–2471.
28.
LeschKPWolozinBLMurphyDLReidererP. Primary structure of the human platelet serotonin uptake site: Identity with the brain serotonin transporter. J Neurochem1993; 60: 2319–2322.
29.
Gross-IsseroffRIsraeliMBiegonA. Autoradiographic analysis of tritiated imipramine binding in the human brain post mortem: Effects of suicide. Arch Gen Psychiatry1989; 46: 237–241.
30.
LawrenceKMFalkowskiJJacobsonRRHortonRW. Platelet 5-HT uptake sites in depression: Three concurrent measures using [3H] imipramine and [3H] paroxetine. Psychopharmacology (Berl)1993; 110: 235–239.
31.
LimaLUrbinaM. Serotonin transporter modulation in blood lymphocytes from patients with major depression. Cell Mol Neurobiol2002; 22: 797–804.
32.
LimaLMataSUrbinaM. Allelic isoforms and decrease in serotonin transporter mRNA in lymphocytes of patients with major depression. Neuroimmunomodulation2005; 12: 299–306.
33.
UrbinaMPinedaSPiñangoLCarreiraILimaL. [3H]Paroxetine binding to human peripheral lymphocyte membranes of patients with major depression before and after treatment with fluoxetine. Int J Immunopharmacol1999; 21: 631–646.
34.
Philibert RA, Sandhu H, Hollenbeck N, Gunter T, Adams W, Madan A. The relationship of 5HTT (SLC6A4) methylation and genotype on mRNA expression and liability to major depression and alcohol dependence in subjects from the Iowa Adoption Studies. Am J Med Genet B Neuropsychiatr Genet 2008; 147B: 543–549.
35.
van IJzendoornMHCaspersKBakermans-KranenburgMJBeachSRPhilibertR. Methylation matters: Interaction between methylation density and serotonin transporter genotype predicts unresolved loss or trauma. Biol Psychiatry, 68: 405–407.
XuJZhangGChengY. Hypomethylation of the HTR1A promoter region and high expression of HTR1A in the peripheral blood lymphocytes of patients with systemic lupus erythematosus. Lupus2011; 20: 678–689.
38.
HochbergMC. Updating the American College of Rheumatology revised criteria for the classification of systemic lupus erythematosus. Arthritis Rheum1997; 40: 1725–1725.
39.
HamiltonM. A rating scale for depression. J Neurol Neurosurg Psychiatry1960; 23: 56–62.
40.
Klauck SM, Poustka F, Benner A, Lesch KP, Poustka A. Serotonin transporter (5-HTT) gene variants associated with autism? Human molecular genetics 1997; 6: 2233–2238.
41.
Cook EH, Jr., Courchesne R, Lord C, et al. Evidence of linkage between the serotonin transporter and autistic disorder. Molecular psychiatry 1997; 2: 247–250.
42.
LindseyJCAndertonJALusherMECliffordSC. Epigenetic events in medulloblastoma development. Neurosurg Focus2005; 19: E10–E10.
NoblePBCuttsJH. Separation of blood leukocytes by Ficoll gradient. Can Vet J1967; 8: 110–111.
45.
KanedaMOkanoMHataK. Essential role for de novo DNA methyltransferase Dnmt3a in paternal and maternal imprinting. Nature2004; 429: 900–903.
46.
EhrichMZollSSurSvan den BoomD. A new method for accurate assessment of DNA quality after bisulfite treatment. Nucleic Acids Res2007; 35: e29–e29.
47.
FrommerMMcDonaldLEMillarDS. A genomic sequencing protocol that yields a positive display of 5-methylcytosine residues in individual DNA strands. Proc Natl Acad Sci USA1992; 89: 1827–1831.
48.
ClarkSJHarrisonJPaulCLFrommerM. High sensitivity mapping of methylated cytosines. Nucleic Acids Res1994; 22: 2990–2997.
ZhangYJeltschA. The application of next generation sequencing in DNA methylation analysis. Genes2010; 1: 85–101.
51.
WilleitMPraschak-RiederNNeumeisterA. A polymorphism (5-HTTLPR) in the serotonin transporter promoter gene is associated with DSM-IV depression subtypes in seasonal affective disorder. Mol Psychiatry2003; 8: 942–946.
52.
KargKBurmeisterMSheddenKSenS. The serotonin transporter promoter variant (5-HTTLPR), stress, and depression meta-analysis revisited: Evidence of genetic moderation. Arch Gen Psychiatry2011; 68: 444–454.
53.
OtteCMcCafferyJAliSWhooleyMA. Association of a serotonin transporter polymorphism (5-HTTLPR) with depression, perceived stress, and norepinephrine in patients with coronary disease: The Heart and Soul Study. Am J Psychiatry2007; 164: 1379–1384.
54.
GreenbergBDTolliverTJHuangSJLiQBengelDMurphyDL. Genetic variation in the serotonin transporter promoter region affects serotonin uptake in human blood platelets. Am J Med Genet1999; 88: 83–87.
55.
StoltenbergSFTwitchellGRHannaGL. Serotonin transporter promoter polymorphism, peripheral indexes of serotonin function, and personality measures in families with alcoholism. Am J Med Genet2002; 114: 230–234.
56.
SingalRGinderGD. DNA methylation. Blood1999; 93: 4059–4070.
57.
BirdA. DNA methylation patterns and epigenetic memory. Genes Dev2002; 16: 6–21.
58.
Naveh-ManyTCedarH. Active gene sequences are undermethylated. Proc Natl Acad Sci USA1981; 78: 4246–4250.
59.
KressCThomassinHGrangeT. Local DNA demethylation in vertebrates: How could it be performed and targeted?FEBS Lett2001; 494: 135–140.
60.
DengCLuQZhangZ. Hydralazine may induce autoimmunity by inhibiting extracellular signal-regulated kinase pathway signaling. Arthritis Rheum2003; 48: 746–756.
61.
SawalhaAHJeffriesM. Defective DNA methylation and CD70 overexpression in CD4+T cells in MRL/lpr lupus-prone mice. Eur J Immunol2007; 37: 1407–1413.
62.
YungRLQuddusJChrispCEJohnsonKJRichardsonBC. Mechanism of drug-induced lupus. I. Cloned Th2 cells modified with DNA methylation inhibitors in vitro cause autoimmunity in vivo. J Immunol1995; 154: 3025–3035.
63.
SawalhaAHJeffriesMWebbR. Defective T-cell ERK signaling induces interferon-regulated gene expression and overexpression of methylation-sensitive genes similar to lupus patients. Genes Immun2008; 9: 368–378.
64.
GorelikGRichardsonB. Aberrant T cell ERK pathway signaling and chromatin structure in lupus. Autoimmun Rev2009; 8: 196–198.
65.
EyreHBauneBT. Neuroplastic changes in depression: A role for the immune system. Psychoneuroendocrinology2012; 37: 1397–1416.
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