A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations

Sırt Ağrısı ile Başvuran Adölesan Bir Hastada Saptanan Pott Hastalığı

Giriş: Spinal kemik tüberkülozu olarak da bilinen Pott hastalığı, endemik ülkelerde erişkin yaş gruplarında sık bildirilse de çocuk yaş grubu için sık görülen bir durum değildir. Burada başvuru değerlendirmesi ile skrofuloderma ön tanısı alan ve izleminde Pott apsesi de saptanan adölesan bir olgu sunulmaktadır. Olgu: On dört yaşında kız hasta, 5 ay önce sağ meme altında başlayan akıntılı yara ve sırt ağrsı şikayetiyle dermatoloji kliniğine başvurmuş. Bilinen psöriazis tanılı hasta, uygulanan çeşitli tedavilere rağmen devam eden yakınmaları nedeniyle tarafımıza yönlendirilmiş. Sistem muayenelerinde patoloji olmayan hastada birkaç adet psöriyatik lezyon ile sağ ve sol aksiller bölgede sırasıyla 2x2 cm ve 1x1,5 cm lenfadenopati saptandı. Sağ meme altında 5x3 cm boyutlu inflame görünümde akıntılı endüre lezyon izlendi(Şekil 1). Babasında geçirilmiştüberküloz hastalığı olduğu öğrenildi. Laboratuvar tetkikleri mikrositer anemi ile uyumlu olan hastada akut faz reaktanları negatif sonuçlandı. Meme altındaki lezyondan alınan biyopsi örneği yoğun granülamatöz nekrotik enflamasyon olarak raporlandı. Skrofuloderma ön tanısı ile alınan örneğe ait kültür sonuçları beklenirken tüberküloza yönelik tetkikler planlandı. Bacillus Calmette-Guérin skarı izlenmeyen hastanın tüberkülin deri testi 17 mm sonuçlandı. Aile taramasında aktif tüberküloz hastalığı saptanmadı. Toraks tomografisinde patolojik lenf nodu veya parankim dokusu olmayan hastanın T10-11 vertebra korpusları sağ yarımı ve 11. kostovertebral bileşkeyi infiltre ederek T11 vertebra korpusunda fraktüre sebep olup spinal kanalı daraltan, 48x40 mm ölçülen kitle lezyonu izlendi(Şekil 2). Ayrıca sağ 5. kosta anteriorunda kostayı infiltre ederek cilde açılan 32x26 cm boyutlu lezyon da görüldü. Yara yerinden alınan örneğin kültür sonuçunda M. tuberculosis üremesi olduğu saptandı. Nöroşirurji ile de konsulte edilen hastanın spinal bölgedeki lezyonu Pott apsesi ile uyumlu bulundu. Kemik tüberkülozu tanısı alan hastaya dörtlü antitüberküloz tedavi başlandı. Sonuç: Nadir görüldüğü bu yaş grubunda tanıda gecikmenin de etkisiyle paraplejiye varabilecek yıkıcı sonuçlar meydana gelebilir. Sırt ağrısı gibi spesifik olmayan bir semptomla başvuran hastalarda ayırıcı tanıda mutlaka akla gelmelidir

Phenotypes Determined by Cluster Analysis and Their Survival in the Prospective European Scleroderma Trials and Research Cohort of Patients With Systemic Sclerosis

Objective Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained. Methods A total of 11,318 patients were registered in the EUSTAR database, and 6,927 were included in the study. Twenty-four clinical and serologic variables were used for clustering. Results Clustering analyses provided a first delineation of 2 clusters showing moderate stability. In an exploratory attempt, we further characterized 6 homogeneous groups that differed with regard to their clinical features, autoantibody profile, and mortality. Some groups resembled usual dcSSc or lcSSc prototypes, but others exhibited unique features, such as a majority of lcSSc patients with a high rate of visceral damage and antitopoisomerase antibodies. Prognosis varied among groups and the presence of organ damage markedly impacted survival regardless of cutaneous involvement. Conclusion Our findings suggest that restricting subsets of SSc patients to only those based on cutaneous involvement may not capture the complete heterogeneity of the disease. Organ damage and antibody profile should be taken into consideration when individuating homogeneous groups of patients with a distinct prognosis

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study.

Objective To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice. Methods We performed a prospective study including patients with SSc from the European Scleroderma Trials and Research (EUSTAR) network treated with rituximab and matched with untreated patients with SSc. The main outcomes measures were adverse events, skin fibrosis improvement, lung fibrosis worsening and steroids use among propensity score-matched patients treated or not with rituximab. Results 254 patients were treated with rituximab, in 58% for lung and in 32% for skin involvement. After a median follow-up of 2 years, about 70% of the patients had no side effect. Comparison of treated patients with 9575 propensity-score matched patients showed that patients treated with rituximab were more likely to have skin fibrosis improvement (22.7 vs 14.03 events per 100 person-years; OR: 2.79 [1.47-5.32]; p=0.002). Treated patients did not have significantly different rates of decrease in forced vital capacity (FVC)&gt;10% (OR: 1.03 [0.55-1.94]; p=0.93) nor in carbon monoxide diffusing capacity (DLCO) decrease. Patients having received rituximab were more prone to stop or decrease steroids (OR: 2.34 [1.56-3.53], p&lt;0.0001). Patients treated concomitantly with mycophenolate mofetil had a trend for better outcomes as compared with patients receiving rituximab alone (delta FVC: 5.22 [0.83-9.62]; p=0.019 as compared with controls vs 3 [0.66-5.35]; p=0.012). Conclusion Rituximab use was associated with a good safety profile in this large SSc-cohort. Significant change was observed on skin fibrosis, but not on lung. However, the limitation is the observational design. The potential stabilisation of lung fibrosis by rituximab has to be addressed by a randomised trial

Phenotypes determined by cluster analysis and their survival in the prospective european scleroderma trials and research cohort of patients with systemic sclerosis

Systemic sclerosis (SSc) is a heterogeneous connective tissue disease that is typically subdivided into limited cutaneous SSc (lcSSc) and diffuse cutaneous SSc (dcSSc) depending on the extent of skin involvement. This subclassification may not capture the entire variability of clinical phenotypes. The European Scleroderma Trials and Research (EUSTAR) database includes data on a prospective cohort of SSc patients from 122 European referral centers. This study was undertaken to perform a cluster analysis of EUSTAR data to distinguish and characterize homogeneous phenotypes without any a priori assumptions, and to examine survival among the clusters obtained

Outcomes of patients with systemic sclerosis treated with rituximab in contemporary practice: a prospective cohort study

To assess the safety and efficacy of rituximab in systemic sclerosis (SSc) in clinical practice

A genome-wide association search for type 2 diabetes genes in African Americans.

African Americans are disproportionately affected by type 2 diabetes (T2DM) yet few studies have examined T2DM using genome-wide association approaches in this ethnicity. The aim of this study was to identify genes associated with T2DM in the African American population. We performed a Genome Wide Association Study (GWAS) using the Affymetrix 6.0 array in 965 African-American cases with T2DM and end-stage renal disease (T2DM-ESRD) and 1029 population-based controls. The most significant SNPs (n = 550 independent loci) were genotyped in a replication cohort and 122 SNPs (n = 98 independent loci) were further tested through genotyping three additional validation cohorts followed by meta-analysis in all five cohorts totaling 3,132 cases and 3,317 controls. Twelve SNPs had evidence of association in the GWAS (P<0.0071), were directionally consistent in the Replication cohort and were associated with T2DM in subjects without nephropathy (P<0.05). Meta-analysis in all cases and controls revealed a single SNP reaching genome-wide significance (P<2.5×10(-8)). SNP rs7560163 (P = 7.0×10(-9), OR (95% CI) = 0.75 (0.67-0.84)) is located intergenically between RND3 and RBM43. Four additional loci (rs7542900, rs4659485, rs2722769 and rs7107217) were associated with T2DM (P<0.05) and reached more nominal levels of significance (P<2.5×10(-5)) in the overall analysis and may represent novel loci that contribute to T2DM. We have identified novel T2DM-susceptibility variants in the African-American population. Notably, T2DM risk was associated with the major allele and implies an interesting genetic architecture in this population. These results suggest that multiple loci underlie T2DM susceptibility in the African-American population and that these loci are distinct from those identified in other ethnic populations