The functional MICA-129 polymorphism is associated with skin but not joint manifestations of psoriatic disease independently of HLA-B and HLA-C.

A methionine/valine polymorphism at amino acid 129 of the major histocompatibility complex class I chain-related gene A (MICA-129) categorizes alleles into strong and weak binders of the natural killer (NK) and T-cell receptor NKG2D. We investigated whether MICA-129 is differentially associated with skin and joint manifestations of psoriatic disease (PsD) independently of human leukocyte antigen (HLA)-C and HLA-B in patients and controls from Toronto and St. John's. The MICA-129 methionine (Met) allele, particularly Met/Met homozygosity, was strongly associated with both cutaneous psoriasis (PsC) and psoriatic arthritis (PsA) independently of HLA-B and HLA-C in Toronto patients, and was also associated with PsA in St. John's patients, but with no additional effect of Met/Met homozygosity. No association remained after adjustment for HLA alleles in St. John's patients. MICA-129 was not associated with PsA when compared with PsC. We conclude that MICA-129 is a marker of skin manifestations of PsD that is independent of HLA class I in Toronto patients.

Differential major histocompatibility complex class I chain-related A allele associations with skin and joint manifestations of psoriatic disease.

About 30% of patients with psoriasis have psoriatic arthritis (PsA), an inflammatory arthritis that can affect both axial and peripheral joints. Major histocompatibility complex class I chain-related A (MICA) alleles have previously been shown to be associated with PsA; however it is unclear whether there is a differential association of MICA alleles with skin and joint manifestations of PsA. Here, we describe a case-control study that aims to validate previously reported MICA allele associations with PsA and determine whether MICA alleles differentiate patients with PsA from those with psoriasis without PsA. Two hundred forty-nine unrelated Caucasian PsA patients, 243 psoriasis patients without arthritis, and 248 healthy controls were genotyped for 55 MICA alleles using PCR-SSP, and for human leucocyte antigen (HLA)-B and HLA-C alleles by PCR-SSO reverse line blot. Allele frequencies were calculated and logistic regressions were performed, adjusting for HLA-B and HLA-C alleles previously shown to be associated with psoriasis and/or PsA. Several MICA alleles were associated with psoriatic disease, PsA, and psoriasis compared with controls, and PsA compared with psoriasis in univariate analyses. Haplotype analysis showed evidence of strong linkage disequilibrium (LD) between PsA and psoriasis risk alleles of HLA-C, HLA-B, and MICA. After adjusting for significant HLA-B and HLA-C alleles in multivariate analyses, MICA*016 remained significantly associated with psoriasis [odds ratio (OR) = 5.5, P = 0.008]. MICA*00801 homozygosity was associated with susceptibility to PsA when compared with patients with psoriasis alone (OR = 2.26, P = 0.009). We conclude that most MICA allele associations with psoriasis and PsA are dependent on LD with HLA-B and HLA-C risk alleles. Independent of HLA, only MICA*016 influences the risk of developing psoriasis without arthritis, and homozygosity for MICA*00801 increases the risk of developing PsA in patients with psoriasis.

Familial aggregation of psoriatic arthritis.

OBJECTIVES: The aim of this study was to determine the recurrence risk of psoriatic arthritis (PsA) and uncomplicated psoriasis in first-degree relatives (FDRs) of patients with PsA. METHODS: All available FDRs (full siblings, parents and children) of 100 consecutive consenting patients attending a PsA clinic were evaluated for the presence of psoriasis and PsA using a standard protocol. The protocol included a screening questionnaire, physical examination by a rheumatologist, and radiographic and laboratory assessment. The prevalence of PsA and psoriasis in FDRs of the index cases was determined, and the recurrence risk ratio (lambda) was calculated, assuming a population prevalence of PsA of 0.25%, and a population prevalence of psoriasis of 2%. RESULTS: The 100 probands had 533 relatives. Eighty-four of them were deceased and 53 were unavailable (age <16 years). Of the remaining 396 FDRs, 107 did not participate (living too far away/did not consent). Thus, 289/396 (73%) of the available FDRs participated in the study. There were 130 siblings, 108 parents and 51 children. The prevalence of PsA and psoriasis among FDRs was 7.6% and 15.2%, respectively. The lambda(1 )was 30.4 for PsA and 7.6 for psoriasis. The prevalence of PsA and psoriasis in siblings was 7.7% and 17.7%, respectively. The lambda(S) was 30.8 for PsA and 8.8 for psoriasis. CONCLUSIONS: The recurrence risk ratio for both PsA and psoriasis is high in FDRs and siblings of patients with PsA. These results confirm that both PsA and psoriasis have a strong heritable component.

KIRs and autoimmune disease: studies in systemic lupus erythematosus and scleroderma.

We investigated killer immunoglobulin-like receptors (KIRs) and the human leukocyte antigen (HLA)-C ligands for the corresponding inhibitory KIRs in Caucasian patients, 304 with systemic lupus erythematosus (SLE) and 90 with scleroderma [or progressive systemic sclerosis (PSS)] compared with 416 Caucasian controls. Compared with controls, KIR2DS1 in the absence of KIR2DS2 was increased in both SLE (P= 0.04) and PSS (P= 0.02). Only 42% of KIR2DS1-positive PSS patients had the appropriate HLA-C ligand for the corresponding inhibitory KIR compared with 61% of KIR2DS1 positive controls (P= 0.02). In the PSS group the presence of at least either activating KIR2DS1 and/or 2DS2 was significantly increased in patients when compared with controls (P= 0.001). This suggests that KIR receptors play a role in susceptibility to both PSS and SLE.

TNFalpha polymorphisms and risk of psoriatic arthritis.

BACKGROUND: Tumour necrosis factor alpha (TNFalpha) is a cytokine of critical importance in psoriatic arthritis. OBJECTIVES: (1) To examine the association between TNFalpha promoter gene polymorphisms and psoriatic arthritis in two well characterised Canadian populations with the disease; (2) to carry out a meta-analysis of all TNFalpha association studies in white psoriatic arthritis populations. METHODS: DNA samples were genotyped for five TNF variants by time of flight mass spectrometry using the Sequenom platform. All five single nucleotide polymorphisms were in the 5' flanking region of TNFalpha gene at the following positions: -1031 (T-->C), -863 (C-->A), -857 (C-->T), -308 (G-->A), and -238 (G-->A). Primary analyses were based on logistic regression. Summary estimates of disease/genotype relations from several studies were derived from random effects meta-analyses. RESULTS: 237 psoriatic arthritis subjects and 103 controls from Newfoundland and 203 psoriatic arthritis subjects and 101 controls from Toronto were studied. A combined analysis of data from both populations, showed a significant association between disease status and the -238(A) variant (p=0.01). The meta-analysis estimate for the -238(A) TNFalpha variant in eight psoriatic arthritis populations was also significant (odds ratio=2.29 (95% confidence interval, 1.48 to 3.55)). CONCLUSIONS: Analysis of TNFalpha variants in psoriatic arthritis populations shows that the -238 (A) variant is a significant risk factor for this disease.

Association of SEEK1 and psoriatic arthritis in two distinct Canadian populations.

OBJECTIVE: To examine the relationship between SNP +39604 in SEEK1 and psoriatic arthritis (PsA) in two distinct Canadian populations. METHODS: 103 patients with PsA and 105 ethnically matched controls from Newfoundland and 202 patients with PsA and 100 controls from Ontario were studied. Patients and controls were genotyped for SNP +39604 of SEEK1 by time of flight mass spectrometry, using the Sequenom platform. Genomic DNA was amplified by the Dynal RELI SSO HLA-Cw* typing kit for HLA-C typing. RESULTS: The frequency of the minor SEEK1(T) allele in subjects with PsA and controls was 48.5% and 32.4%, respectively (odds ratio (OR) = 2.0; p = 0.017), in the Newfoundland population and 46.5% and 38.0%, respectively (OR = 1.4; p = 0.16), in the Ontario population. Although SEEK1 is associated with PsA, particularly in the Newfoundland population, multivariate analysis showed that SEEK1 does not seem to be a further susceptibility factor if the HLA-Cw*0602 status is already known. No association was noted between SEEK1(T) allele and onset of psoriasis, PsA, or arthritis pattern. CONCLUSION: SEEK1 is associated with PsA in the Newfoundland founder population. This association is probably due to linkage disequilibrium between SEEK1 and HLA-Cw*0602 in this population.

CARD15: a pleiotropic autoimmune gene that confers susceptibility to psoriatic arthritis.

A recent genomewide scan in psoriatic arthritis (PsA) revealed a susceptibility locus at 16q. This region overlaps CARD15, a susceptibility gene in Crohn disease. The possibility of a common susceptibility gene between PsA and Crohn disease is further supported by epidemiological studies that note an increased incidence of psoriasis in subjects with Crohn. We screened 187 patients with PsA and 136 healthy controls, all from Newfoundland, for the three common, independent sequence variants of CARD15 (R702W, leu1007fsinsC, and G908R), which were detected by polymerase chain reaction by use of allele-specific primers and visualized through gel electrophoresis. In total, 53/187 (28.3%) probands with PsA had at least one variant of the CARD15 gene, compared with 16/136 (11.8%) controls (odds ratio 2.97; 95% confidence interval 1.61-5.47; P=.0005). Allele frequencies of R702W, leu1007fsinsC, and G908R were 10.43%, 3.21%, and 1.61%, respectively, in patients with PsA, compared with 3.31%, 2.57%, and 0.37%, respectively, in the control patients. CARD15 conferred susceptibility to PsA independent of HLA-Cw*0602. Thus, CARD15 represents a pleiotropic autoimmune gene and is the first non-MHC gene to be associated with PsA.

HLA-DRB1*04 alleles in psoriatic arthritis: comparison with rheumatoid arthritis and healthy controls.

Psoriatic arthritis (PsA) is an inflammatory arthritis associated with psoriasis usually seronegative for rheumatoid factor. An increased frequency of HLA-DR4 has been noted in PsA, particularly among patients with a rheumatoid arthritis like (RA) arthritis. The aim of the current investigation was to compare HLA-DRB1*04 alleles in patients with PsA, patients with RA, and healthy controls. Sample size calculations based on the frequency of HLA-DR4 suggested that 90 individuals in each patient group would be sufficient to address our question. Therefore, 90 HLA-DRB1*04 positive patients from each patient group underwent high resolution molecular typing and were included in this study. Although HLA-DRB1*0401 was the most frequent allele in all groups, its frequency among the PsA patients was lower than that of RA patients and controls. HLA-DRB1*0402 was higher among patients with PsA. Patients with RA were more likely to have more than one shared epitope allele than either PsA or the healthy control group. HLA-DQB1 alleles did not contribute further information. We suggest that the differences in the class II HLA epitope(s) may also be related to interaction specificity with another molecule functioning in the immune response to a putative arthritogenic antigen and result in differences in disease expression.

Use of acoustic reflectometry in the detection of middle ear effusion.

The purpose of the present investigation was to compare the performance of the acoustic otoscope/DPU-411 printer and acoustic immittance with otoscopic examinations by a physician for the detection of middle ear effusion (MEE). Three hundred and two patients (11 months to 69 years) were evaluated with the acoustic otoscope, acoustic immittance, and otoscopic examinations. The patients were divided into two age groups for data analysis: 1 to 12 years (children) and 13 to 69 years (adults). Reflectivity and angle data were evaluated at different cut-off points and receiver operating characteristics (ROC) curves were determined. The variables were analyzed in different combinations for each study group. Sensitivity and specificity were poorest for the acoustic otoscope in children. Furthermore, acoustic immittance data compared more favorably with otoscopy than did the acoustic otoscope for all ages.

Ultraviolet radiation and chemical requirements for experimental contact photosensitivity.

Contact photosensitivity to tetrachlorsalicylanilide was induced in albino guinea pigs. For the induction process, different types of ultraviolet radiation were employed and the effect of different doses of chemical was measured. Dose responses for ultraviolet radiation and chemical were determined for the production of positive photopatch tests in photosensitized animals. Successful contact photosensitivity was achieved when UVA alone was used for induction. Contrary to previously published reports, we found that UVB, chemical or physical irritation or immune potentiation were not required. In order to detect all photosensitized animals 0.1 ml of 1% TCSA and 1.65 J/cm2 of UVA were required to produce positive photopatch tests.