The extrapituitary prolactin promoter polymorphism is associated with rheumatoid arthritis and anti-CCP antibodies in Mexican population (original) (raw)
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Introduction: Prolactin (PRL) is a 23-kDa protein that can be synthesized and secreted by pituitary and extrapituitary tissues such as immune cells due to its expression being regulated by two independent promoter regions. The promoter which is responsible for extrapituitary expression contains the single nucleotide polymorphism (SNP) –1149 G/T previously associated with autoimmune diseases in various populations. This study evaluates the relationship of PRL –1149 G/T polymorphism with PRL serum levels and clinical characteristics in systemic lupus erythematosus (SLE) patients from western Mexico. Material and methods: One hundred and sixty-three SLE patients classified according to the 1982 American College of Rheumatology (ACR) SLE classification criteria and 326 unrelated control subjects (CS), both from western Mexico, were included. The PRL –1149 G/T polymorphism was genotyped using the polymorphism was performed by the polymerase chain reaction restriction fragment length polymorphism technique, and both PRL serum levels and autoantibodies were measured by enzyme-linked immunosorbent assay (ELISA). Results: We found an association between the PRL –1149 TT genotype and SLE according to the recessive genetic model (OR = 2.26, 95% CI: 1.01–5.08, p = 0.04). The TT genotype was associated with anti-RNP antibodies (p = 0.04) and with higher scores of the Mex-SLEDAI (p = 0.02). Moreover, SLE patients showed elevated PRL serum levels (12.4 ng/ml; p < 0.01), and this condition was associated with renal activity and the presence of anti-RNP antibodies. Conclusions: PRL –1149 TT genotype is associated with susceptibility to SLE in a Mexican-Mestizo population, and high PRL serum levels are associated with anti-RNP antibodies and renal activity.
Peptidyl arginine deiminase IV (PADI4) enzyme catalyzes the citrullination of proteins, which are recognized by anti-cyclic citrullinated peptide antibodies (anti-CCP) in rheumatoid arthritis (RA) patients. Here, we determined the association between PADI4 gene polymorphisms and haplotypes with RA susceptibility and clinical characteristics in a western Mexican population. The relationship of PADI4 polymorphisms with anti-CCP and PADI4 mRNA expression was also evaluated. PADI4 89, PADI4 90 and PADI4 92 poly-morphisms were individually associated with RA susceptibility. The GTG haplotype was significantly associated with: RA susceptibility; disease onset at ≤40 years and anti-CCP antibodies. PADI4 expression was three fold higher in RA patients carrying the susceptibility haplotype (GTG) than in non-susceptibility haplotype carriers (ACC). In conclusion, polymorphisms and functional haplotype (GTG) in PADI4 are associated with RA susceptibility as well as anti-CCP antibodies in a Mexican population. This supports the role of PADI4 early in RA pathogenesis by promoting the generation of citrullinated autoantigens.
The Journal of Rheumatology, 2009
Objective.To determine the prevalence of anti-cyclic citrullinated peptide (anti-CCP) antibodies in unaffected relatives of North American Native probands with rheumatoid arthritis (RA); and the associations of the shared epitope (SE) and HLA-DRB1*0901 with RA and anti-CCP antibodies.Methods.The subjects were RA probands, affected relatives, unaffected first-degree (FDR) and more distant relatives, and unaffected controls from the same population. HLA-DRB1 typing was determined by DNA sequencing and anti-CCP antibodies were determined by ELISA.Results.DRB1*0901, SE, and SE/DRB1*0901 genotypes were all associated with RA. SE/DRB1*0901, but not other SE genotypes, was associated with disease onset at age < 16 years. The frequency of anti-CCP antibodies was 82% in RA probands, 17% in FDR, 11% in more distant relatives, and 3% in controls. Among unaffected relatives, a significant increased risk of anti-CCP was associated with SE/DRB1*0901 genotype, but not with SE.Conclusion.An inde...
Clinical and Experimental Rheumatology, 2007
Objective Citrullinated peptides produced by enzymatic deimination of arginine residues in proteins by peptidylarginine deiminases are of particular interest in the pathogenesis of rheumatoid arthritis (RA). One type of citrullinated protein-the cyclic citrullinated peptide-is the target of the anti-cyclic citrullinated peptide antibody, the most sensitive and specifi c autoantibody in RA. The peptidylarginine deiminase type 4 (PADI4) gene, which codes one of the PADI enzyme isotypes, has genetic variants that confer susceptibility to RA in Asian, but not in European populations. Methods Genetic associations were examined in 214 Hungarian RA patients characterized for the presence of anti-CCP and rheumatoid factor. The patients were characterized for the existing haplotypes of the PADI4 gene (defi ned by the combinations of 4 exonic padi4_89: 163G/A, padi4_90: 245T/C, padi4_92: 335C/G, padi4_104: 349T/C and 2 intronic padi4_94: 17535226C/T and padi4_102: 17546809C/T variants) by the PCR-RFLP method. Results None of the PADI4 haplotypes was accumulated in RA patients. One new fi nding was that we also did not detect the accumulation of any haplotypes either in the anti-CCP or in the RF-positive subgroups of patients. Conclusion The data presented here show that none of the naturally occurring haplotypes of the PADI4 gene conferred susceptibility to RA in an average group of Hungarian patients; this is in agreement with fi ndings for other European populations. In addition, none of the functional PADI4 haplotypes were associated with the pathologic immune response, which was evidenced by the absence of accumulation of anti-CCP-positive subjects in the specifi c PADI4 haplotypes.
Annals of The Rheumatic Diseases, 2007
Objective: To clarify the influence of the HLA-DRB1 locus on the susceptibility to rheumatoid arthritis and the production of anticyclic citrullinated peptide antibodies (anti-CCP) in a Portuguese population. Methods: 141 patients with rheumatoid arthritis fulfilling the American College of Rheumatology 1987 revised criteria for rheumatoid arthritis were compared with 150 healthy controls. Human leucocyte antigen (HLA)-DRB1 locus genotyping was assessed by polymerase chain reaction reverse probing assays and sequence-specific primers. Anti-CCP antibodies were quantified by ELISA in patients with rheumatoid arthritis. Frequencies between groups were compared by the two-sided Fisher's exact test and considered significant if p,0.05. Results: The HLA-DRB1*04 and HLA-DRB1*10 groups were highly associated with rheumatoid arthritis (p,0.001 and p = 0.031, respectively). High titres of anti-CCP antibodies were largely associated with the presence of HLA-DRB1*04/10. Conclusion: The well-recognised susceptibility alleles to rheumatoid arthritis, HLA-DRB1*04, were associated with rheumatoid arthritis in Portuguese patients. The relatively rare DRB1*10 was also associated with rheumatoid arthritis, as was described previously in other southern European countries. Both groups were associated with high anti-CCP titres, reinforcing its relevance to disease onset.
The influence of polygenic risk scores on heritability of anti-CCP level in RA
Genes and Immunity, 2014
Objective-To study genetic factors that influence quantitative anti-cyclic citrullinated peptide (anti-CCP) antibody levels in RA patients. Methods-We carried out a genome wide association study (GWAS) meta-analysis using 1,975 anti-CCP+ RA patients from 3 large cohorts, the Brigham Rheumatoid Arthritis Sequential Study (BRASS), North American Rheumatoid Arthritis Consortium (NARAC), and the Epidemiological Investigation of RA (EIRA). We also carried out a genome-wide complex trait analysis (GCTA) to estimate the heritability of anti-CCP levels. Results-GWAS-meta analysis showed that anti-CCP levels were most strongly associated with the human leukocyte antigen (HLA) region with a p-value of 2×10 −11 for rs1980493. There were 112 SNPs in this region that exceeded the genome-wide significance threshold of 5×10 −8 , and all were in linkage disequilibrium (LD) with the HLA-DRB1*03 allele with LD r 2 in the range of 0.25-0.88. Suggestive novel associations outside of the HLA region were also observed for rs8063248 (near the GP2 gene) with a p-value of 3×10 −7. None of the known RA risk alleles (~52 loci) were associated with anti-CCP level. Heritability analysis estimated that 44% of anti-CCP variation was attributable to genetic factors captured by GWAS variants. Conclusions-Anti-CCP level is a heritable trait. HLA-DR3 and GP2 are associated with lower anti-CCP levels. Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
Arthritis Research & Therapy, 2007
The PTPN22 1858C/T polymorphism has been associated with several autoimmune diseases including rheumatoid arthritis (RA). We have shown that carriage of the T variant (CT or TT) of PTPN22 in combination with anti-cyclic citrullinated peptide (anti-CCP) antibodies highly increases the odds ratio for developing RA. In the present study we analysed the association between the PTPN22 1858C/T polymorphism and early RA in patients from northern Sweden, related the polymorphism to autoantibodies and the HLA-DR shared epitope, and analysed their association with markers for disease activity and progression. The inception cohort includes individuals who also donated samples before disease onset. A case-control study was performed in patients (n = 505; 342 females and 163 males) with early RA (mean duration of symptoms = 6.3 months) and in population-based matched controls (n = 970) from northern Sweden. Genotyping of the PTPN22 1858C/T polymorphism was performed using a TaqMan instrument. HLAshared epitope alleles were identified using PCR sequence-specific primers. Anti-CCP2 antibodies were determined using enzyme-linked immunoassays. Disease activity (that is, the number of swollen and tender joints, the global visual analogue scale, and the erythrocyte sedimentation rate) was followed on a regular basis (that is, at baseline and after 6, 12, 18 and 24 months). Both the 1858T allele and the carriage of T were associated with RA (χ 2 = 23.84, P = 0.000001, odds ratio = 1.69, 95% confidence interval = 1.36-2.11; and χ 2 = 22.68, P = 0.000002, odds ratio = 1.79, 95% confidence interval = 1.40-2.29, respectively). Association of the 1858T variant with RA was confined to seropositive disease. Carriage of 1858T and the presence of anti-CCP antibodies was independently associated with disease onset at an earlier age (P < 0.05 and P < 0.01, respectively), while the combination of both resulted in an even earlier age at onset. Smoking was identified as a risk factor independent of the 1858T variant and anti-CCP antibodies.
Annals of the Rheumatic Diseases, 2012
Background Rheumatoid factors (RFs) and antibodies against cyclic citrullinated peptides (CCPs) of IgG, IgA and IgM isotype have been shown to precede disease onset by years. Objective To evaluate serological risk markers in fi rstdegree relatives from multicase families in relation to genetic and environmental risk factors. Methods 51 multicase families consisting of 163 individuals with rheumatoid arthritis (RA) (mean±SD age, 60±14 years; disease duration 21 years; 71.8% female) and with 157 fi rst-degree relatives unaffected by RA (54±17 years; 59.9% female) were recruited. Isotypes of antibodies against CCPs (IgG, IgA and IgM) and RFs (IgM and IgA) were determined using automated enzyme immunoassays. Cut-off levels were established using receiver operating characteristic curves based on values for 100 unrelated healthy controls. Results The concentrations and frequencies of all anti-CCP and RF isotypes were signifi cantly increased in fi rst-degree relatives and patients with RA compared with unrelated healthy controls. The relative distribution of IgA and IgM isotypes was higher than IgG in the relatives, whereas the IgG isotype dominated in patients with RA. The patients carried human leucocyte antigenshared epitope (HLA-SE) signifi cantly more often than the relatives (71.4% vs 53.9%, p=0.01), while the frequency of the PTPN22 T variant was similar. HLA-SE, combined with smoking, was signifi cantly related to all combinations of anti-CCP and RF isotypes in patients with RA. No such relationships were found for the fi rst-degree relatives. Conclusions All anti-CCP and RF isotypes analysed occurred more commonly in unaffected fi rst-degree relatives from multicase families than in controls, but with different isotype distribution from patients with RA.
The PRL -1149 G/T polymorphism and rheumatoid arthritis susceptibility
Arthritis & Rheumatism, 2009
Objectives-Prior evidence demonstrates that the PRL-1149 T (minor) allele decreases prolactin expression and may be associated with autoimmune diseases. Our goal was to determine the role of the PRL-1149 G/T polymorphism (rs1341239) in rheumatoid arthritis (RA) susceptibility. Methods-We examined the association between PRL-1149 G/T and RA risk in four separate collections consisting of 3,405 RA cases and 4,111 controls of self-described "white" European ancestry. Samples were genotyped using one of three genotyping platforms, and strict quality control metrics were applied. We tested for association with a two-tailed Cochran Mantel-Haenszel additive, fixed effects model. Results-In the individual collections, odds ratios for an association between PRL-1149 T and RA risk ranged from 0.80 to 0.97. In a joint meta-analysis across all four collections, the odds ratio for an association between PRL-1149 T and RA risk was 0.90 (95% CI 0.84-0.96) with p = 0.001. Conclusions-Our results suggest an association between the PRL-1149 T allele and decreased RA risk. The effect size is small but similar to odds ratios for other genetic polymorphisms associated with complex traits, including RA. Further studies will be necessary to confirm association unequivocally. Prolactin, an important hormone in lactogenesis, has immunomodulatory properties and may play an important role in the development of rheumatoid arthritis (RA). Prolactin binds to the prolactin receptor, a member of the class I cytokine superfamily, to induce lymphocyte proliferation, inhibit apoptosis and stimulate antibody formation (1). Extrapituitary prolactin, which is produced by lymphocytes and endometrial cells, increases IFN-γ production and enhances the effect of IL-2 in lymphocytes (2). RA is a chronic inflammatory synovitis of autoimmune etiology that is two to four times more common in women than men. Clinical studies support a potential role for prolactin in RA pathogenesis. During the postpartum period, the incidence of RA increases. This time period coincides with elevated prolactin levels in women who choose to breastfeed. However, prospective cohort studies have suggested an inverse relationship between duration of past breastfeeding and future RA susceptibility (3-6). These observations suggest that breastfeeding, and possibly prolactin, may have differential effects on acute and