Bartłomiej Kisiel

M34T and V37I mutations in GJB2 associated hearing impairment: Evidence for pathogenicity and reduced penetrance

Despite research the role of the M34T and V37I variants of GJB2 in causing hearing impairment (HI) remains controversial. Our purpose was to test a hypothesis that M34T and V37I are pathogenic but have distinct features resulting in a reduced penetrance. We screened for known GJB2/GJB6 mutations 233 Polish consecutive unrelated subjects with non‐syndromic, sensorineural HI who were previously found to carry 35delG mutation on one chromosome. The most frequent mutations were also analyzed in ∼1,000 controls. We found that M34T and V37I were significantly (P ≪ 10−6) overrepresented among patients, but their penetrance was estimated as 1/10 relative to mutations of undisputed pathogenicity. This finding apparently could not be explained by low degree of HI associated with M34T and V37I since another mutation causing comparably mild HI (L90P) did not have reduced penetrance. Subsequent analyses showed that the patients with M34T/35delG and V37I/35delG had significantly later onset of HI than patients with other genotypes (P < 10−6) including the L90P/35delG (P = 0.006). Also, among these patients (but not others) a strong correlation between the degree of HI and its duration was found (r = 0.79, P < 10−5). We tentatively suggest that M34T and V37I might cause mild HI characterized by relatively late onset and progression.

Polymorphism of the oestrogen receptor beta gene (ESR2) is associated with susceptibility to Graves' disease.

Objective  To investigate whether a polymorphism in the ESR2 gene (rs4986938, previously associated with endometriosis, ovulatory dysfunction and premature onset of coronary heart disease) increases the risk of Graves’ disease (GD).

Vitamin D status and its association with quality of life, physical activity, and disease activity in rheumatoid arthritis patients.

BackgroundVitamin D deficiency is common in rheumatoid arthritis (RA) and may be related to disease activity. Population-based studies have shown the influence of vitamin D deficiency on quality of life (QoL), but it was not investigated in RA patients. ObjectivesThe aim of the study was to determine possible relationship between vitamin D deficiency, QoL, physical activity (PA), and disease activity in RA. MethodsIn 97 consecutive RA patients without vitamin D supplementation (86 women and 11 men, aged 59.4 ± 12 years), serum 25-hydroxycholecalciferol (25(OH)D), calcium, phosphorus, and parathyroid hormone were measured. The patients completed Short Form 36 (SF-36), Beck Depression Inventory, and Health Assessment Questionnaire, assessed the intensity of pain, fatigue, and PA. Disease Activity Score in 28 Joints was used to assess disease activity. A comparison control group consisted of 28 osteoarthritis patients (25 women and 3 men aged 56.2 ± 15 years). ResultsVitamin D deficiency was detected in 76.3% of RA and in 78.6% of osteoarthritis patients (P = 0.75). There was a negative correlation between 25(OH)D serum concentration and Disease Activity Score in 28 Joints in patients with active arthritis. There was a positive correlation between serum 25(OH)D and the level of PA and most aspects of SF-36, and negative correlation between serum 25(OH)D and Health Assessment Questionnaire and Beck Depression Inventory in patients with disease duration of 1 year or longer. After inclusion of PA into multivariable analysis, only the correlations between 25(OH)D and SF-36 mental subscale (MCS) and pain remained significant. ConclusionsVitamin D deficiency is highly prevalent in RA patients and is associated with higher disease activity and worse QoL indices. Regular PA correlates with higher vitamin D titers and better QoL in RA. Further studies are needed to explain possible influence of vitamin D on RA activity.

Methotrexate, Cyclosporine A, and Biologics Protect against Atherosclerosis in Rheumatoid Arthritis

Introduction. The risk of cardiovascular disease is increased in rheumatoid arthritis (RA). A meta-analysis showed increased intima media thickness (IMT) in RA. It has been shown that disease modifying antirheumatic drugs (DMARDs) may influence the progression of atherosclerosis. However, it was suggested that biologics may be more efficient than other DMARDs (including methotrexate—MTX) in protecting against atherosclerosis. Objectives. The aim of this study was to assess the influence of different RA characteristics and treatment regimens on IMT and atherosclerotic plaques. Patients and Methods. 317 RA patients and 111 controls were included in the study. IMT was measured in carotid (CIMT) and femoral (FIMT) arteries. Arteries were screened for the presence of plaques. Results. CIMT, FIMT, and prevalence of plaques were lower in patients treated with methotrexate (MTX) ≥ 20 mg/wk, cyclosporine (CsA), or biologics than in patients treated with lower doses of MTX and other disease modifying antirheumatic drugs. No differences in IMT between patients treated with MTX ≥ 20 mg/wk, biologics, or CsA were found. Conclusions. We found a beneficial effect of MTX ≥ 20 mg/wk, biologics, and CsA on atherosclerosis. We do not confirm a stronger influence of biologics on IMT compared with therapeutic doses of MTX.

The association between 38 previously reported polymorphisms and psoriasis in a Polish population: High predicative accuracy of a genetic risk score combining 16 loci

Objectives To confirm the association of previously discovered psoriasis (Ps) risk loci with the disease in a Polish population and to create predictive models based on the combination of these single nucleotide polymorphisms (SNPs). Material and methods Thirty-eight SNPs were genotyped in 480 Ps patients and 490 controls. Alleles distributions were compared between patients and controls, as well as between different Ps sub-phenotypes. The genetic risk score (GRS) was calculated to assess the cumulative risk conferred by multiple loci. Results We confirmed associations of several loci with Ps: HLA-C, REL, IL12B, TRIM39/RPP21, POU5F1, MICA. The analysis of ROC curves showed that GRS combining 16 SNPs at least nominally (uncorrected P<0.05) associated with Ps (GRS-N) had significantly better discriminative power than GRS combining SNPs associated with Ps after the Bonferroni correction (AUC 0.776 vs. 0.750, P = 1 x 10−4) or HLA-C (AUC 0.776 vs. 0.694, P<1 x 10−5). On the other hand, adding additional SNPs to the model did not improve its discriminatory ability (AUC 0.782 for GRS combining all SNPs, P>0.05). In order to assess the total risk conferred by GRS-N, we calculated ORs according to GRS-N quartile ˗ the Ps OR for top vs. bottom GRS-N quartiles was 12.29 (P<1 x 10−6). The analysis of different Ps sub-phenotypes showed an association of GRS-N with age of onset and family history of Ps. Conclusions We confirmed the association of Ps with several previously identified genetic risk factors in a Polish population. We found that a GRS combining 16 SNPs at least nominally associated with Ps had a significantly better discriminatory ability than HLA-C or GRS combining SNPs associated with Ps after the Bonferroni correction. In contrast, adding additional SNPs to GRS did not increase significantly the discriminative power.

Value of multilocus genetic risk score for atrial fibrillation in end-stage kidney disease patients in a Polish population

Genetic factors play a key role in the pathogenesis of atrial fibrillation (AF). We would like to establish an association between previously described single-nucleotide polymorphisms (SNPs) and AF in haemodialysed patients with end-stage kidney disease (ESKD-HD) as well as to assess the cumulative effect of all genotyped SNPs on AF risk. Sixteen SNPs were genotyped in 113 patients with AF-ESKD-HD and in 157 controls: without AF (NAF) and with ESKD-HD. The distribution of the risk alleles was compared in both groups and between different sub-phenotypes. The multilocus genetic risk score (GRS) was calculated to estimate the cumulative risk conferred by all SNPs. Several loci showed a trend toward an association with permanent AF (perm-AF): CAV1, Cx40 and PITX2. However, GRS was significantly higher in the AF and perm-AF groups, as compared to NAF. Three of the tested variables were independently associated with AF: male sex, history of myocardial infarction (MI) and GRS. The GRS, which combined 13 previously described SNPs, showed a significant and independent association with AF in a Polish population of patients with ESKD-HD and concomitant AF. Further studies on larger groups of patients are needed to confirm the associations.

Ultrasonography versus magnetic resonance imaging in detecting and grading common extensor tendon tear in chronic lateral epicondylitis

Objectives To investigate the diagnostic performance and reliability of ultrasonography (US) in detecting and grading common extensor tendon (CET) tear in patients with chronic lateral epicondylitis (LE), using magnetic resonance imaging (MRI) as the reference standard. Materials and methods The study comprised fifty-eight chronic LE patients. Each patient underwent US and MRI. CET status was classified as: high-grade tear (≥50% thickness), low-grade tear (<50% thickness), suspected tear (possible but not evident tear), no tear. Additionally, the following dichotomous scale was used: confirmed or unconfirmed CET tear. Relative US parameters (versus MRI) for detecting CET tear included: sensitivity, specificity, positive predictive value (PPV), negative predictive value (NPV) and accuracy. The agreement between US and MRI findings was measured using the weighted Cohen kappa coefficient (κ). Results US showed moderate agreement with MRI in detecting and grading CET tear (κ = 0.49). Sensitivity, specificity, and accuracy in CET tear detecting by US were 64.52%, 85.19%, and 72.73%, respectively. PPV and NPV of US were 83.33% and 67.65%, respectively. No patient with unconfirmed CET tear on US had high-grade CET tear on MRI. Conclusion Ultrasonography is a valuable imaging modality that can be used as a screening tool to exclude high-grade CET tear in chronic LE patients. Once a tear is evident on US, MRI should be considered to assess precisely the extent of tendon injury.

Treat-to-target therapy does not prevent excessive progression of carotid intima media thickness during the first year of therapy in early rheumatoid arthritis

Introduction The aim of the study was to investigate the presence of subclinical atherosclerosis and predictors of change in carotid intima-media measures in early rheumatoid arthritis patients (eRA) as compared to chronic RA patients and patients without arthritis. Material and methods Fifty-five consecutive eRA patients were assessed at the time of diagnosis and after 1 year of therapy. Fifty-five sex- and age-matched chronic RA patients and 29 patients without inflammatory disease were used as controls. Carotid artery intima-media thickness (CIMT) and carotid plaques were measured at baseline and after follow-up. In eRA patients ultrasound assessment of hand joints was performed before and after treatment. Carotid artery intima-media thickness was assessed again after 2 years in 44 eRA patients. Results Carotid artery intima-media thickness progression after 1 year of therapy was higher in eRA patients compared to both control groups (p = 0.017) and correlated with symptoms duration (p = 0.017) and DMARD monotherapy (p = 0.015). Ultrasound progression of hand joint erosions was associated with longer symptoms duration (p = 0.006). After 2 years of observation CIMT progression was similar in all examined groups. Conclusions We observed rapid CIMT progression during the first year of RA therapy. Longer symptoms duration and less aggressive therapy were associated with CIMT increase.