Paula A. Correa

CCL3L1 gene-containing segmental duplications and polymorphisms in CCR5 affect risk of systemic lupus erythaematosus

Objectives: There is an enrichment of immune response genes that are subject to copy number variations (CNVs). However, there is limited understanding of their impact on susceptibility to human diseases. CC chemokine ligand 3 like-1 (CCL3L1) is a potent ligand for the HIV coreceptor, CC chemokine receptor 5 (CCR5), and we have demonstrated previously an association between CCL3L1-gene containing segmental duplications and polymorphisms in CCR5 and HIV/AIDS susceptibility. Here, we determined the association between these genetic variations and risk of developing systemic lupus erythaematosus (SLE), differential recruitment of CD3+ and CD68+ leukocytes to the kidney, clinical severity of SLE reflected by autoantibody titres and the risk of renal complications in SLE. Methods: We genotyped 1084 subjects (469 cases of SLE and 615 matched controls with no autoimmune disease) from three geographically distinct cohorts for variations in CCL3L1 and CCR5. Results: Deviation from the average copy number of CCL3L1 found in European populations increased the risk of SLE and modified the SLE-influencing effects of CCR5 haplotypes. The CCR5 human haplogroup (HH)E and CCR5-Δ32-bearing HHG*2 haplotypes were associated with an increased risk of developing SLE. An individual’s CCL3L1–CCR5 genotype strongly predicted the overall risk of SLE, high autoantibody titres, and lupus nephritis as well as the differential recruitment of leukocytes in subjects with lupus nephritis. The CCR5 HHE/HHG*2 genotype was associated with the maximal risk of developing SLE. Conclusion: CCR5 haplotypes HHE and HHG*2 strongly influence the risk of SLE. The copy number of CCL3L1 influences risk of SLE and modifies the SLE-influencing effects associated with CCR5 genotypes. These findings implicate a key role of the CCL3L1–CCR5 axis in the pathogenesis of SLE.

Interleukin-1β polymorphisms in Colombian patients with autoimmune rheumatic diseases

Interleukin-1 beta (IL-1β) exerts a range of inflammatory and immunomodulatory activities that are important in host defense and autoimmune response. The IL-1β gene, located on chromosome 2 (2q13), is polymorphic. The influence of its polymorphism on 355 patients with autoimmune rheumatic diseases was examined. To this effect, 172 patients with rheumatoid arthritis (RA), 114 with systemic lupus erythematosus (SLE), and 69 with primary Sjögrens syndrome (pSS) were studied. The control group consisted of 392 matched healthy individuals. Genotyping of IL-1β single-nucleotide polymorphisms (SNPs) at positions −511 (C/T) and +3953 (C/T) was performed by the polymerase chain reaction-restriction fragment length polymorphism technique. In addition, levels of IL-1β were measured by immunoassay in supernatants of lipopolysaccharide (LPS)-stimulated and nonstimulated peripheral blood monocytes (PBM) obtained from 19 homozygous individuals for the three most common IL-1β likely haplotypes, all belonging to the control group. Allele+3953T was protective for SLE (odds ratio (OR)=0.57, 95% confidence intervals (CI)=0.34–0.88, P=0.01) as was the haplotype −511C+3953T (OR=0.43, 95%CI=0.25–0.74, pc=0.006). The latter was associated with a lower LPS-stimulated-PBM IL-1β secretion. Results suggest that IL-1β polymorphism influences the susceptibility to acquire SLE in our population. The protective association might be explained by the observed inhibitory effect of IL-1β +3953T allele on the secretion of IL-1β under inflammatory circumstances.

Rheumatoid arthritis association in Colombian population is restricted to HLA-DRB1*04 QRRAA alleles

In most ethnic groups genetic susceptibility to rheumatoid arthritis (RA) is associated with certain HLA-DRB1 alleles encoding a similar sequence motif called the ‘shared epitope’ (SE) spanning amino acid positions 70 to 74 in the third diversity region of the outermost domain of the HLA-DRB1 molecule. We examined the association of the SE and RA in 83 Colombian women with established RA and 90 healthy controls. The group HLA-DRB1*04 was associated with RA with respect to controls (47% vs 18%, respectively. OR: 4.1, 95%CI: 2.1–8.2, P < 0.001). HLA-DRB1 alleles carrying the SE QRRAA, but not those carrying QKRAA or RRRAA, were associated with disease (OR: 3.7, 95%CI: 1.73–7.83, P = 0.0009). This association was stronger among HLA-DRB1*04 carriers (OR: 23, 95%CI: 1.3–414, P = 0.002). In our population, the SE QRRAA expressed in DRB1*04 alleles appears critical in identifying women with increased susceptibility to RA.

TAP1 and TAP2 polymorphisms analysis in northwestern Colombian patients with systemic lupus erythematosus

Objective: To determine the influence of TAP1 and TAP2 alleles in northwestern Colombian patients with systemic lupus erythematosus (SLE). Methods: Unselected patients with SLE (n=140) and controls (n=120) matched for sex, age, and ethnicity were analysed. Clinical manifestations, clinical activity, and severity of disease were recorded. Autoantibodies were detected by enzyme linked immunosorbent assay (ELISA). TAP1 and TAP2 polymorphisms were determined by amplification refractory mutation system-polymerase chain reaction. A Hardy-Weinberg equilibrium test, microdifferentiation analysis, linkage disequilibrium analysis, and haplotype and allele frequency comparisons were performed. Results: The TAP2 variant Val379/Ala565/Ala665 (allele TAP2*0201) was associated with SLE (56% v 39%; odds ratio=2, 95% confidence interval 1.22 to 3.30, pc=0.03). There was no stratification between patient and control samples. Linkage disequilibrium between TAP1 and TAP2 loci was found in controls but not in patients. An excess in the number of heterozygotes in the TAP2 locus was found in patients. No association between TAP1 and TAP2 variants and the presence of autoantibodies, clinical expression, or severity of disease was found. Conclusions: The TAP2 locus influences susceptibility to SLE in our patient group; however, it has no significant effect on the immune response or on the clinical course of the disease.

Anti-cyclic citrullinated peptide antibodies in patients with primary Sjögren’s syndrome

Primary Sjogren’s syndrome (pSS) is an autoimmune late onset disease characterised mainly by sicca symptoms. Lymphocytic infiltrate of the minor salivary glands and the presence of autoantibodies are the hallmarks of disease.1 The spectrum of pSS extends from an organ-specific autoimmune disorder (autoimmune exocrinopathy) to a systemic process that may involve the musculoskeletal system, leading to arthralgias and arthritis. In the latter case differential diagnosis with other autoimmune diseases like rheumatoid arthritis (RA) is a challenge. In these situations, specific antibodies may be useful for making a correct diagnosis and, consequently, guide treatment. Anti-cyclic citrullinated peptide (anti-CCP) antibodies …

The simultaneous presence of IL-1B and TNFA two-positions risk haplotypes enhances the susceptibility for celiac disease

To assess the joint contribution of interleukin 1 beta (IL-1B) and tumor necrosis factor alpha (TNFalpha) to the genetic risk of developing celiac disease (CD), we analyzed four biallelic polymorphisms of TNFA and IL-1B genes in 228 patients and 244 healthy controls. The individual contribution of TNFA -308A and IL-1B -511C alleles was weak (OR 1.47 and 1.66, respectively) and was null for TNFA -238 A/G and IL-1B +3953 C/T single nucleotide polymorphisms (SNPs). Due to the potential linkage disequilibrium between TNFA, human leukocyte antigen (HLA) -DQA1 and HLA-DQB1 genes, only individuals carrying DQ2 antigen (DQ2-positive) were considered to perform haplotype analyses. Two-position risk haplotypes were first defined by the combined presence of -511C and +3953T alleles for IL-1B (OR 9.402) or -308A and -238A alleles for TNFA (OR 15.389). The TNFA/IL-1B combined haplotype-stratified association analysis showed that the simultaneous presence of TNFA risk and IL-1B non-risk haplotypes (OR 13.32) but not TNFA non-risk and IL-1B risk haplotypes (OR 0.71) is associated with CD. Interestingly, our data suggest that the coexistence of both risk haplotypes seems to work synergistically (OR 29.59), which enhances the risk of developing CD.