title: SIRT1 promoter polymorphisms as clinical modifiers on systemic lupus erythematosus.
abstract: Silent mating type Information Regulator 2 homolog 1 (SIRT1) is a deacetylase protein that participates in several physiological processes with importance in transcriptional silencing, apoptosis, immune system regulation and inflammation. Systemic lupus erythematosus (SLE) is an inflammatory autoimmune disease in which upregulated expression of SIRT1 on CD4+ T lymphocytes of active patients has been reported. Also, global hypoacetylation of histones H3 and H4, with H3 hypoacetylation was correlated with a higher disease activity index. SIRT1 promoter rs12778366 and rs3758391 may account for differential expression of this molecule and the role of these variants was investigated in SLE susceptibility and morbidity. Genomic DNA was extracted from peripheral blood of 367 SLE patients and 290 healthy controls of a Southern Brazilian population. SIRT1 rs12778366 and rs3758391 were amplified through PCR and genotyped through sequencing. No statistically significant differences were observed between patients and controls for allelic, genotypic or haplotypic frequencies. Nevertheless, SIRT1 rs3758391 was not in Hardy-Weinberg equilibrium, presenting a paucity of CT heterozygous both in patients and controls. SLE patients with TT and CT genotypes displayed a higher chance of developing lupus nephritis (Pc = 0.012, OR = 2.04 95 % CI 1.32-3.14) and presented a higher disease activity index (Mean rank 170.95 vs 137.26, Pc = 0.006) when compared with CC homozygous patients. Our results suggest that SIRT1 rs3758391 modifies SLE morbidity, with rs3758391 T allele being a risk factor for nephritis and a higher SLEDAI. Nevertheless, it remains to be elucidated how SIRT1 rs3758391 functionally influences SLE severity.
authors.affiliation: Immunogenetics Laboratory, Genetics Department, Genetics and Molecular Biology Post-Graduate Program, Institute of Biosciences, Universidade Federal do Rio Grande do Sul, Av. Bento Gonçalves 9500 Prédio 43323, Porto Alegre, RS, CEP 91501-970, Brazil.
authors.forename: Camila Rosat
authors.initials: CR
authors.lastname: Consiglio
authors.forename: Schauren
authors.initials: S
authors.lastname: Juliana da Silveira
authors.forename: Odirlei André
authors.initials: OA
authors.lastname: Monticielo
authors.forename: Ricardo Machado
authors.initials: RM
authors.lastname: Xavier
authors.forename: João Carlos Tavares
authors.initials: JC
authors.lastname: Brenol
authors.forename: José Artur Bogo
authors.initials: JA
authors.lastname: Chies
mesh_terms: D000328:Adult; D000483:Alleles; D016022:Case-Control Studies; D005260:Female; D005787:Gene Frequency; D005838:Genotype; D006579:Heterozygote; D006720:Homozygote; D006801:Humans; D015810:Linkage Disequilibrium; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011401:Promoter Regions, Genetic; D012720:Severity of Illness Index; D056564:Sirtuin 1 / Q000235:genetics*
chemical_list: C447939:SIRT1 protein, human; D056564:Sirtuin 1