Effect of serum metabolites on the risk of iridocyclitis: a bidirectional Mendelian randomization study.

Previous research has linked serum metabolite levels to iridocyclitis, yet their causal relationship remains unexplored. This study investigated this potential causality by analyzing pooled data from 7824 iridocyclitis patients in a Genome-Wide Association Study (GWAS) using Mendelian randomization (MR) and linkage disequilibrium score regression (LDSC). Employing rigorous quality control and comprehensive statistical methods, including sensitivity analyses, we examined the influence of 486 serum metabolites on iridocyclitis. Our MR analysis identified 23 metabolites with significant causal effects on iridocyclitis, comprising 17 known and 6 unidentified metabolites. Further refinement using Cochran's Q test and MR-PRESSO indicated 16 metabolites significantly associated with iridocyclitis risk. LDSC highlighted the heritability of certain metabolites, underscoring genetic influences on their levels. Notably, tryptophan, proline, theobromine, and 7-methylxanthine emerged as risk factors, while 3,4-dihydroxybutyrate appeared protective. These findings enhance our understanding of the metabolic interactions in iridocyclitis, offering insights for diagnosis, unraveling pathophysiological mechanisms, and informing potential avenues for prevention and personalized treatment.

Causal analysis of serum polyunsaturated fatty acids with juvenile idiopathic arthritis and ocular comorbidity.

BACKGROUND & OBJECTIVE: To investigate the causal effects of plasma Polyunsaturated fatty acids (PUFAs) on the risk of juvenile idiopathic arthritis (JIA) and ocular comorbidity through Mendelian randomization (MR) analysis. METHODS: Genetic variants (formerly single nucleotide polymorphisms, SNPs) that are strongly associated with PUFAs levels (P < 5×10-8) were selected as instrumental variables. Summary-level MR was performed with outcome estimates for JIA (n = 31,142) and JIA associated iridocyclitis (n = 94,197). The inverse variance-weighted (IVW) method was employed as the main approach to combine the estimation for each SNP. Two set of models with summary statistics were conducted and multiple sensitivity analyses were applied for testing of pleiotropic bias. RESULTS: In model 1, genetically predicted n-6 PUFAs linoleic acid (LA) and arachidonic acid (AA) were associated with lower and higher risk of JIA associated iridocyclitis using IVW (ORLA = 0.940, 95% CI: 0.895-0.988, P = 0.015; ORAA = 1.053, 95% CI: 1.007-1.101, P = 0.024). No such association was observed between each plasma PUFAs and JIA susceptibility (P > 0.05). In further MR analysis, results from model 2 also showed a consistent trend. Besides, multiple sensitivity analyses revealed that there was no obvious evidence for unknown pleiotropy (P > 0.05). CONCLUSIONS: Our MR study provides genetic evidence on the possible causality that plasma LA level might protect against JIA associated iridocyclitis, whereas AA was responsible for opposite effect.

Polymorphisms of the cytomegalovirus glycoprotein B genotype in patients with Posner-Schlossman syndrome.

AIMS: The aim of this observational study was to report the distribution of glycoprotein B (gB) genotypes in the eyes of cytomegalovirus (CMV) positive patients with Posner-Schlossman syndrome (PSS), and to investigate their clinical characteristics and outcomes. METHODS: We collected aqueous humour samples from 165 patients clinically diagnosed with PSS between 2017 and 2019. PCR was performed to analyse the CMV DNA and identify the gB genotypes in the samples. Clinical characteristics and responses to antiviral treatment were compared among patients with different gB genotypes. RESULTS: CMV DNA was detected in 94 (56.97%) of the 165 aqueous humour specimens analysed. Owing to the quantity requirement for CMV gB genotype analysis, results could be obtained from only 14 specimens. CMV gB type 1 was detected in 11 samples (78.6%), whereas CMV gB type 3 was detected in three samples (21.4%). No other gB genotypes or mixed genotypes were detected. Overall, 9.1% (1/11) of the patients in the gB type 1 group and 66.7% (2/3) of the patients in the gB type 3 group had bilateral attacks (p=0.093). The concentration of anti-CMV immunoglobulin G (IgG) in the type 1 group was 0.94±0.79 s/co (ratio of aqueous humour CMV IgG/serum CMV IgG to aqueous humour albumin concentration/serum albumin concentration), whereas that in the type 3 group was 0.67±0.71 s/co. CONCLUSION: Genotype 1 was the most prevalent genotype in the aqueous humour of CMV-infected patients with PSS. Bilateral attack was predominant among patients with gB genotype 3. CMV gB gene may be related to the pathogenicity of CMV virus strain in patients with PSS.

Polymorphisms of TNFAIP3 gene in a Chinese Han population with fuchs heterochromic iridocyclitis.

PURPOSE: This study was performed to evaluate the potential association of the tumor necrosis factor alpha inducible protein 3gene (TNFAIP3) polymorphisms with Fuchs' heterochromic iridocyclitis (Fuchs' Syndrome) in a Chinese Han population. METHODS: Five single-nucleotide polymorphisms (SNPs), rs10499194, rs610604, rs7753873, rs5029928 and rs9494885 of TNFAIP3 were genotyped in 225 Fuchs' syndrome patients and 651 healthy controls using a PCR-restriction fragment length polymorphism assay. All control subjects were matched ethnically and geographically with the patients. Genotype counts in patients and controls were analyzed by the χ² test. RESULTS: All genotypic and allelic frequencies of the tested TNFAIP3 polymorphisms were in Hardy-Weinberg equilibrium. The genotypic and allelic frequencies of rs10499194, rs610604, rs7753873, rs5029928 and rs9494885 of TNFAIP3 were not different between patients with Fuchs' syndrome and controls. CONCLUSIONS: Our results suggest that rs10499194, rs610604, rs7753873, rs5029928 and rs9494885 of TNFAIP3 are not associated with Fuchs' syndrome in a Chinese Han population.

Unusual presentation of presumed posterior polymorphous dystrophy associated with iris heterochromia, band keratopathy, and keratoconus.

PURPOSE: To report an unusual presentation of posterior polymorphous corneal dystrophy (PPCD) associated with band keratopathy, iridocorneal adhesions, heterochromia, keratoconus, and confocal microscopic findings suggestive of iridocorneal endothelial syndrome. METHODS: Confocal microscopy, corneal topography, electroretinography, and genetic analysis were performed in the proband and his siblings. RESULTS: A 23-year-old man presented with decreased vision in both eyes over 9 months. Examination revealed bilateral alterations in corneal endothelial mosaic with corneal edema and beaten metal appearance in the right eye and cystoid endothelial opacities in the left eye. Marked heterochromia, band keratopathy, and broad peripheral anterior synechiae were present in both eyes. Topographic features of keratoconus were noted. Electroretinography did not detect abnormal retinal function, as has been described with PPCD associated with VSX1 mutations. Diagnosis of PPCD was postulated on the basis of the examination of 3 of proband's brothers by confocal microscopy. Genetic analysis of 3 known PPCD genes, VSX1, COL8A2, and TCF8, did not detect any mutations. CONCLUSIONS: In severe cases, PPCD can resemble iridocorneal endothelial syndromes in both clinical appearance and imaging studies (confocal microscopy). There was a strong genetic phenotypic penetrance in the family, which was essential in the diagnostic decision making. A yet undetermined genotype is contributing to this unusual PPCD phenotype.

Ocular involvement in Adamantiades-Behçet's disease in Berlin, Germany.

BACKGROUND: Epidemiological studies demonstrate a prevalence of Adamantiades-Behçet's disease (ABD) in the range of 0.12-420 per 100,000 inhabitants, with the highest rates in Istanbul, Turkey, and the lowest rates in the USA. Ophthalmological data on the prevalence of ocular involvement are limited for ABD in Germany, because most epidemiological studies are based on rheumatological or dermatological data. Berlin is the city with the highest number of non-native German inhabitants, and its multi-ethnic character renders it uniquely appropriate for epidemiological studies on ABD. METHODS: We retrospectively analyzed all ABD patients seen in our department since 1982. All patients fulfilled the criteria of the International Study Group for Behçet's Disease. We found 140 patients (63 female, 77 male), with a mean follow-up of 6.4 years (0.5-22 years). RESULTS: The mean age was 23 at the first manifestation and 32 when the full-blown disease was noted. The mean age at onset of ocular involvement was 30. Most of the patients were of Turkish (n = 73) or German (n = 34) origin. Fifty-six percent developed ocular involvement, which was the first manifestation in 8.6% and the second manifestation in 19.3% of cases. CONCLUSIONS: More than half the patients developed ocular involvement. The calculated prevalence of ocular involvement in ABD is 1.77/100,000 inhabitants for the municipality of Berlin.

A suggestive association of fuchs heterochromic cyclitis with cytotoxic T cell antigen 4 gene polymorphism.

BACKGROUND: Fuchs heterochromic cyclitis (FHC) is a chronic inflammatory eye disease, usually presenting as unilateral anterior uveitis. Up to date no disease susceptibility genes have been described for FHC. METHODS: The allele frequency of HLA DRB1 and DQB1, polymorphisms of the tumour necrosis factor (TNF) alpha promoter region (-376, -308, -238), the promoter (-318), first exon (+49) and (AT)n repeat polymorphism of the cytotoxic T cell antigen 4 (CTLA4) gene were analysed in 44 FHC patients and 139 healthy controls. RESULTS: The CTLA4 -318 C/T genotype was increased in FHC patients [odds ratio (OR) 3.0, 95% confidence interval (CI) 1.4-6.5], as well as long CTLA4 (AT)n microsatellite alleles with more than 16 AT repeats (OR 2.6, 95% CI 1.3-5.3). A trend towards the -308 G/A TNF-alpha genotype was found in the patient cohort, whereas no difference in HLA class II allele distribution was observed. CONCLUSION: CTLA4 but not TNF-alpha or HLA class II DRB1 and DQB1 may represent a candidate gene for disease susceptibility in FHC.

Antibodies to the 45 kDa DEK nuclear antigen in pauciarticular onset juvenile rheumatoid arthritis and iridocyclitis: selective association with MHC gene.

OBJECTIVE: To study the frequency of autoantibodies to the 45 kDa DEK nuclear antigen, a putative oncoprotein, in a sample of patients with juvenile rheumatoid arthritis (JRA), and to make correlations with disease subtype and complications such as iridocyclitis. Class I and Class II HLA associations with reactivity to the antigen were also sought. METHODS: Sera from 146 HLA typed patients with JRA representing all subtypes were analyzed for reactivity with the 45 kDa DEK protein by immunoblotting. The antigen was purified to near homogeneity from nuclei of HeLa cells. RESULTS: Antibodies to DEK were found in 57% of all patients with JRA compared to 3% of controls (p < 0.0001). Antibodies were detected more frequently in pauciarticular onset (78%) than in polyarticular onset patients (29%; p < 0.01) and controls (3%; p < 0.0001). 97% of patients with JRA (regardless of onset subtype) and iridocyclitis had anti-DEK antibodies compared to 47% of patients without eye disease (p < 0.0001). Anti-DEK antibodies were found more frequently in females compared to males in the pauciarticular onset disease group (84 vs 42%; p < 0.01). The occurrence of anti-DEK antibodies was closely associated with positive antinuclear antibody serology, and a strong association with the Class I gene HLA-A2 was also observed. CONCLUSION: Antibodies to the 45 kDa DEK protein are characteristic of the pauciarticular onset subtype of JRA, particularly in patients with a history of iridocyclitis. The occurrence of anti-DEK antibodies is significantly but paradoxically associated with the presence of the HLA-A2 allele in such patients.

Association to HLA-DRB1*08, HLA-DPB1*0301 and homozygosity for an HLA-linked proteasome gene in juvenile ankylosing spondylitis.

To assess the role of HLA genes other than those encoding B27 in predisposing to JAS and AAS, we analyzed the distribution of B*4001, as well as the DRB1, DPB1, and LMP2 alleles, using PCR-based techniques in 63 JAS and 44 AAS patients (all B27 positive). The NBMDR (N = 4724) provided a source of controls matched with the patients for B27 (or other markers when necessary). We found an increase of the B*4001, DRB1*08, and DPB1*0301 alleles, as well as the LMP2 b/b genotype (the latter was most pronounced among patients with acute iridocyclitis), in JAS compared to B27-positive controls. The increase of DRB1*08 and DPB1*0301 was due to an increase of DRB1*08 and DPB1*0301 in combination, whereas the association with B*4001 could be due to linkage disequilibrium with LMP2b. None of these associations were detected in AAS. We conclude that in JAS, in addition to the association to B27, there are also weaker but distinct associations to the DRB1*08, DPB1*0301 alleles and homozygosity for LMP2b.

Waardenburg syndrome type II: phenotypic findings and diagnostic criteria.

The Waardenburg syndrome (WS) consists of at least two distinct autosomal dominant hereditary disorders. WS Type I has been mapped to the distal part of chromosome 2q and the gene identified as PAX3. Other gene(s) are responsible for WS Type II. Mapping WS Type II requires accurate diagnosis within affected families. To establish diagnostic criteria for WS Type II, 81 individuals from 21 families with Type II WS were personally studied, and compared with 60 personally studied patients from 8 families with Type I and 253 cases of WS (Type I or II) from the literature. Sensorineural hearing loss (77%) and heterochromia iridum (47%) were the two most important diagnostic indicators for WS Type II. Both were more common in Type II than in Type I. Other clinical manifestations, such as white forelock and skin patches, were more frequent in Type I. We estimate the frequency of phenotypic traits and propose diagnostic criteria for WS Type II. In practice, a diagnosis of WS Type II can be made with confidence given a family history of congenital hearing loss and pigmentary disorders, where individuals have been accurately measured for ocular distances to exclude dystopia canthorum.

A comparison of Blau's syndrome and sarcoidosis.

Blau's syndrome is a familial multisystem granulomatous inflammation which may be confused with childhood sarcoidosis because it presents with iridocyclitis, posterior uveitis, granulomatous skin disease, arthritis and elevated serum angiotensin-converting enzyme. They are distinguished by the absence of pulmonary involvement and a negative Kveim-Siltzbach skin test.

Class II alleles in juvenile arthritis in Czech children.

OBJECTIVE: Patients with pauciarticular and polyarticular onset rheumatoid factor (RF) negative juvenile arthritis (JA) have been reported to have a variety of HLA associations. The reason for the differences found in several recent studies is not known. We compare a new series of patients investigated in Prague, Czechoslovakia with those we reported from Dallas. METHODS: Czech patients with JA (N = 153) were classified clinically using the same criteria as in our studies in Dallas. The RF negative group included 56 patients that had persistent pauciarticular disease, 42 pauciarticular with polyarticular course and 39 with polyarticular onset. RF was present in 13 additional patients. HLA class II alleles were determined by oligotyping as previously described from our laboratory. RESULTS: DRB1*0801 was increased and DRB1*0701 was decreased in all the RF negative groups. The persistent pauciarticular group was associated with DRB1*11 and DPB1*0201 and lacked the association with DRB1*1301 seen in Dallas. Also found in Prague and not in Dallas were an increase in the frequency of DR2 in pauciarticular patients with early conversion and of DRB1*1201 in patients with iritis. Certain HLA associations (DRB1*0801, DPB1*0201) appear to be present in patients with JA in most studies; others (DRB1*1301, DPB1*0301) are more variable. CONCLUSION: The reason for differences in the HLA risk factors observed in our 2 populations is not known. Clinical heterogeneity not detected by our method seems the most likely explanation. Genetic and environmental factors may also play a role.

Human leukocyte antigen-DRB1*1104 in the chronic iridocyclitis of pauciarticular juvenile rheumatoid arthritis.

To determine whether genetic markers for chronic iridocyclitis could be identified, we used both serologic and oligonucleotide dot blot techniques to characterize immunogenetically 164 children with early-onset pauciarticular juvenile rheumatoid arthritis. Seventy-eight children (47.6%) had chronic iridocyclitis and 86 (52.4%) had not had evidence of eye disease during a mean follow-up period after the onset of arthritis of 15.8 years (minimum of 5.5 years). Control subjects were 218 healthy, unrelated individuals. The analysis was limited to alleles known to be associated with an increased or decreased risk of early-onset pauciarticular juvenile rheumatoid arthritis or of chronic iridocyclitis in this form of juvenile rheumatoid arthritis. Only one split of human leukocyte antigen (HLA)-DR5, HLA-DRB1* 1104, showed a statistically significant association with a risk of chronic iridocyclitis (chi-square value = 7.52; p = 0.036 adjusted; odds ratio 3.45); HLA-DQA1* 0501 and HLA-DQB1* 0301, both in linkage disequilibrium with HLA-DRB1* 1104, also were significantly associated with eye disease. Patients with both the DRB1* 1104 and DPB1* 0201 genes had a 7.7-fold increased risk for chronic iridocyclitis compared with that for other patients. The presence of HLA-DRB1* 1104 was about four times as specific, but only about one third as sensitive, as antinuclear antibodies in identifying patients at risk for eye disease. Although all children with early-onset pauciarticular juvenile rheumatoid arthritis should undergo periodic slit-lamp examinations, those with the HLA class II gene DRB1* 1104 are at particularly high risk for eye disease, and we recommend that they be monitored carefully for its evolution.

Is there a genetic basis for Fuchs' heterochromic uveitis? Discordance in monozygotic twins.

One pair, and probably two pairs, of monozygotic twins are reported with discordance for Fuchs' heterochromic uveitis (FHU). Regular Mendelian inheritance of this disease is now proved to be impossible. The heritability of FHU is low and may be zero. The possibility of any genetic predisposition to the disease and its association with 'simple' heterochromia are discussed.

Longitudinal analysis of HLA associated risks for iridocyclitis in juvenile rheumatoid arthritis.

The risk of iridocyclitis in children with early onset pauciarticular juvenile rheumatoid arthritis (EOPA-JRA) has been shown to be associated with certain HLA haplotypes. Our report contains an actuarial analysis, using one-year intervals, of 161 subjects and estimates haplotype specific risks. Individuals who possess the major susceptibility haplotype HLA-DR5 (11) developed eye disease earlier and with a greater frequency than did those with the protective HLA-DR1 haplotype. Highly significant differences were found between the resulting life-table curves for HLA-DR5 and HLA-DR1 positive subjects (p = 0.00003). These time oriented risk estimates may aid clinicians in determining more precisely the probability of iridocyclitis throughout the course of the disease in children with EOPA-JRA.

Congenital glaucoma in cutis marmorata teleangiectatica congenita.

A case of congenital glaucoma in cutis marmorata teleangiectatica congenita (CMTC, van Lohuizen syndrome) is described. The cutaneous anomaly and heterochromia iridium were noticed at birth. Brown discoloration of one iris was due to iris anterior layer dysplasia, resulting in unilateral glaucoma. Two trabeculotomies were performed until persistent normalization of intraocular pressure could be achieved. The possibility of a genetic basis and hereditary condition of CMTC and its association with congenital glaucoma is discussed. Patients with CMTC should regularly undergo ophthalmological follow-up to rule out development of glaucoma.