title: Distribution of PTPN22 polymorphisms in SLE from western Mexico: correlation with mRNA expression and disease activity.
abstract: Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune inflammatory disease characterized by loss of self-tolerance with hyperactivation of autoreactive T and B cells. Protein tyrosine phosphatase non-receptor type 22 (PTPN22) encodes for lymphoid-specific phosphatase (Lyp), which is a key negative regulator of T lymphocyte activation. The aim of this study was to evaluate the genetic contribution of PTPN22 -1123G>C and +1858C>T polymorphisms and their haplotypes in SLE patients, as well as mRNA expression according to -1123G>C promoter polymorphism and disease activity. One hundred and fifty SLE patients and 150 unrelated healthy controls (HC), both Mexican mestizos, were genotyped by PCR-RFLP technique for the PTPN22 -1123G>C and +1858C>T polymorphisms. PTPN22 mRNA expression levels were determined by real-time PCR from PBMCs of thirty patients with SLE and fifteen HC carrying different genotypes. Distributions of genotype and allelic frequencies were similar between SLE and HC. The most frequent alleles were -1123 G and +1858 C in both groups (69 vs. 66 % and 97 vs. 98 %, in SLE and HC, respectively). However, the recessive model of inheritance analysis showed a lower frequency of -1123 CC genotype in SLE patients (7 vs. 15 %), suggesting a protection effect to develop SLE (OR 0.41, CI 1.10-5.28, p = 0.02). Haplotype analysis showed strong linkage disequilibrium D' = 0.98 for PTPN22 -1123G>C and +1858C>T polymorphisms, but haplotypes were not associated with SLE. The PTPN22 mRNA expression did not show differences among -1123G>C genotypes; nevertheless, a significant negative correlation with disease activity was found (r = -0.64, p < 0.01). SLE inactive patients showed similar PTPN22 mRNA expression levels to healthy controls, whereas in patients with severe flare, the expression was nearly depleted. In conclusion, we found a lack of association of PTPN22 -1123G>C and +1858C>T polymorphisms with the risk of developing SLE in a Mexican population. Moreover, decreased or absent PTPN22 mRNA expression in SLE patients with severe flare suggests that Lyp plays an important regulatory role, and its absence contributes to the inflammatory response and disease activity in SLE. However, further analysis in a prospective study could help us determine its usefulness as a genetic marker of disease activity in SLE.
authors.affiliation: Departamento de Clínicas Médicas, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Colina Farnese 3470, Colonia Colinas de Atemajac, C.P. 45170, Zapopan, Jalisco, Mexico.
authors.forename: Jesús René
authors.initials: JR
authors.lastname: Machado-Contreras
authors.affiliation: Departamento de Clínicas Médicas, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Colina Farnese 3470, Colonia Colinas de Atemajac, C.P. 45170, Zapopan, Jalisco, Mexico.
authors.forename: José Francisco
authors.initials: JF
authors.lastname: Muñoz-Valle
authors.affiliation: Departamento de Clínicas Médicas, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Colina Farnese 3470, Colonia Colinas de Atemajac, C.P. 45170, Zapopan, Jalisco, Mexico.
authors.forename: Alvaro
authors.initials: A
authors.lastname: Cruz
authors.affiliation: Departamento de Clínicas Médicas, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Colina Farnese 3470, Colonia Colinas de Atemajac, C.P. 45170, Zapopan, Jalisco, Mexico.
authors.forename: Diana Celeste
authors.initials: DC
authors.lastname: Salazar-Camarena
authors.affiliation: Departamento de Inmunología y Reumatología del Hospital General de Occidente, Secretaria de Salud Jalisco, Zapopan, Jalisco, Mexico.
authors.forename: Miguel
authors.initials: M
authors.lastname: Marín-Rosales
authors.affiliation: Departamento de Clínicas Médicas, Instituto de Investigación en Ciencias Biomédicas (IICB), Centro Universitario de Ciencias de la Salud, Universidad de Guadalajara, Colina Farnese 3470, Colonia Colinas de Atemajac, C.P. 45170, Zapopan, Jalisco, Mexico. kklaumx@yahoo.com.|Departamento de Inmunología y Reumatología del Hospital General de Occidente, Secretaria de Salud Jalisco, Zapopan, Jalisco, Mexico. kklaumx@yahoo.com.
authors.forename: Claudia Azucena
authors.initials: CA
authors.lastname: Palafox-Sánchez
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D016022:Case-Control Studies; D005260:Female; D020869:Gene Expression Profiling; D005787:Gene Frequency; D020022:Genetic Predisposition to Disease; D060005:Genotyping Techniques; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000235:genetics* / Q000473:pathology*; D008297:Male; D008800:Mexico; D008875:Middle Aged; D016133:Polymerase Chain Reaction; D012150:Polymorphism, Restriction Fragment Length; D020641:Polymorphism, Single Nucleotide; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22 / Q000235:genetics*; D012333:RNA, Messenger / Q000096:biosynthesis*; D055815:Young Adult
chemical_list: D012333:RNA, Messenger; C516765:PTPN22 protein, human; D054596:Protein Tyrosine Phosphatase, Non-Receptor Type 22
keywords: Low PTPN22 gene expression; PTPN22; Single nucleotide polymorphisms; Systemic lupus erythematosus