Genetic, parental and lifestyle factors influence telomere length

The average length of telomere repeats (TL) declines with age and is considered to be a marker of biological ageing. Here, we measured TL in six blood cell types from 1046 individuals using the clinically validated Flow-FISH method. We identified remarkable cell-type-specific variations in TL. Host genetics, environmental, parental and intrinsic factors such as sex, parental age, and smoking are associated to variations in TL. By analysing the genome-wide methylation patterns, we identified that the association of maternal, but not paternal, age to TL is mediated by epigenetics. Single-cell RNA-sequencing data for 62 participants revealed differential gene expression in T-cells. Genes negatively associated with TL were enriched for pathways related to translation and nonsense-mediated decay. Altogether, this study addresses cell-type-specific differences in telomere biology and its relation to cell-type-specific gene expression and highlights how perinatal factors play a role in determining TL, on top of genetics and lifestyle.This project was funded by the BBMRI grant for measuring telomere length and by a Rosalind Franklin Fellowship to A.Z. The researchers participated in this project are supported by Netherlands Heart Foundation (IN-CONTROL CVON grants 2012-03 and 2018-27); the Netherlands Organization for Scientific Research (NWO) Gravitation Netherlands Organ-on-Chip Initiative to J.F. and C.W.; NWO Gravitation Exposome-NL (024.004.017) to J.F., A.K. and A.Z.; NWO-VIDI (864.13.013) and NWO-VICI (VI.C.202.022) to J.F.; NWO-VIDI (016.178.056) to A.Z.; NWO-VIDI (917.14.374) to L.F.; NWO-VENI (194.006) to D.V.Z.; NWO-VENI (192.029) to M.W.; NWO Spinoza Prize SPI 92–266 to C.W.; the European Research Council (ERC) (FP7/2007–2013/ERC Advanced Grant 2012-322698) to C.W.; ERC Starting grant 637640 to L.F.; ERC Starting Grant 715772 to A.Z.; ERC Consolidator Grant (grant agreement No. 101001678) to J.F.; and RuG Investment Agenda Grant Personalized Health to C.W. MM work is supported by RYC- 2017-22249 and PID2019-107937GA-I00 grants. T.S. holds scholarships from the Junior Scientific Masterclass, University of Groningen[grant no. 17–34]. AR is funded by a Formación Personal Investigador (FPI) grant [grant no. PRE2019-090193]. The Lifelines Biobank initiative has been made possible by a subsidy from the Dutch Ministry of Health, Welfare and Sport; the Dutch Ministry of Economic Affairs; the University Medical Centre Groningen (UMCG, the Netherlands); the University of Groningen and the Northern Provinces of the Netherlands.Peer reviewe

DRB1*03:01 Haplotypes: Differential Contribution to Multiple Sclerosis Risk and Specific Association with the Presence of Intrathecal IgM Bands

BACKGROUND: Multiple sclerosis (MS) is a multifactorial disease with a genetic basis. The strongest associations with the disease lie in the Human Leukocyte Antigen (HLA) region. However, except for the DRB1*15:01 allele, the main risk factor associated to MS so far, no consistent effect has been described for any other variant. One example is HLA-DRB1*03:01, with a heterogeneous effect across populations and studies. We postulate that those discrepancies could be due to differences in the diverse haplotypes bearing that allele. Thus, we aimed at studying the association of DRB1*03:01 with MS susceptibility considering this allele globally and stratified by haplotypes. We also evaluated the association with the presence of oligoclonal IgM bands against myelin lipids (OCMB) in cerebrospinal fluid. METHODS: Genotyping of HLA-B, -DRB1 and -DQA1 was performed in 1068 MS patients and 624 ethnically matched healthy controls. One hundred and thirty-nine MS patients were classified according to the presence (M+, 58 patients)/absence (M-, 81 patients) of OCMB. Comparisons between groups (MS patients vs. controls and M+ vs. M-) were performed with the chi-square test or the Fisher exact test. RESULTS: Association of DRB1*03:01 with MS susceptibility was observed but with different haplotypic contribution, being the ancestral haplotype (AH) 18.2 the one causing the highest risk. Comparisons between M+, M- and controls showed that the AH 18.2 was affecting only M+ individuals, conferring a risk similar to that caused by DRB1*15:01. CONCLUSIONS: The diverse DRB1*03:01-containing haplotypes contribute with different risk to MS susceptibility. The AH 18.2 causes the highest risk and affects only to individuals showing OCMB

Lack of association between the protein tyrosine phosphatase non-receptor type 22 R263Q and R620W functional genetic variants and endogenous non-anterior uveitis.

Journal Article;OBJECTIVE Endogenous uveitis is a major cause of visual loss mediated by the immune system. The protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene encodes a lymphoid-specific phosphatase that plays a key role in T-cell receptor (TCR) signaling. Two independent functional missense single nucleotide polymorphisms (SNPs) located within the PTPN22 gene (R263Q and R620W) have been associated with different autoimmune disorders. We aimed to analyze for the first time the influence of these PTPN22 genetic variants on endogenous non-anterior uveitis susceptibility. METHODS We performed a case-control study of 217 patients with endogenous non-anterior uveitis and 718 healthy controls from a Spanish population. The PTPN22 polymorphisms (rs33996649 and rs2476601) were genotyped using TaqMan allelic discrimination assays. The allele, genotype, carriers, and allelic combination frequencies were compared between cases and controls with χ(2) analysis or Fisher's exact test. RESULTS Our results showed no influence of the studied SNPs in the global susceptibility analysis (rs33996649: allelic P- value=0.92, odds ratio=0.97, 95% confidence interval=0.54-1.75; rs2476601: allelic P- value=0.86, odds ratio=1.04, 95% confidence interval=0.68-1.59). Similarly, the allelic combination analysis did not provide additional information. CONCLUSIONS Our results suggest that the studied polymorphisms of the PTPN22 gene do not play an important role in the pathophysiology of endogenous non-anterior uveitis.Ye

Frequency of the different <i>DRB1*03:01</i>-containing haplotypes in <i>DRB1*15:01</i> positive (+) and negative (−) multiple sclerosis (MS) patients and in controls; and case-control study for the total MS patients.

<p>% are referred to the total number of haplotypes analysed in each group (last row).</p><p>AH 18.2 includes haplotypes carrying <i>DRB1*03:01</i>, <i>DQB1*02:01</i>, <i>TNF -376A</i>, <i>TNF a1b5</i> and <i>B*18</i>. AH 8.1 includes haplotypes carrying <i>DRB1*03:01</i>, <i>DQB1*02:01</i>, <i>TNF -308A</i>, <i>TNF a2b3</i> and <i>B*8</i>. Haplotypes with all the remaining allelic combinations in those loci or markers are included as “non-conserved” haplotypes.</p>1<p>Excluding the <i>HLA-DRB1*15:01</i>-containing haplotypes.</p

A case of acute lumphoblastic leukemia presenting with migratory superficial thrombophlebitis

Venöz tromboemboHzm ve maliyn hastalıklar arasında bir ilişki olduğu yapılan çalışmalarda gösterilmiştir. Maliyniteli olguların %5-10'unda; derin ven trombozu, arteriyel tromboz, gezici tromboflebit, pulmoner emboli ve non-bakteriyel trombotik endokardit gibi tromboembolik olaylar gelişmektedir. Genellikle ileri evre kanserlerde görülen tromboz bazen kansere ait bulgular ortaya çıkmadan ilk bulgu olarak da saptanabilir. Sağ ayak bileği travması sonrası başvuran, ateş ve hiperlökositoz görülerek yatırılan olguda sağ bacak diz üstü iç yan bölgede yüzeyel tromboflebit olduğu saptandı. Hastanın yapılan periferik yaymasında %90 blast formunda lenfositler görüldü. Periferik kandan yapılan immünfenotipleme sonucu Pre B hücreli ALL ile uyumlu bulundu (CD-19 %93.74, CDL5 %98.73,CD-34 %87.58, CD-22 %63.59, CD-10 negatif). Yapılan kemik iliği biyopsisinde pre B hücreli ALL tanısı teyit edildi. Pre B hücreli lösemi tanısı alan hastanın ikinci günde sol bacakta da tromboflebit gelişti. Antitrombin III (%95) ve fibrinojen (3.7g/dL) düzeyleri normal olan, derin ven trombozu saptanmayan olgu nadir görülmesi ve gezici süperfisiyel tromboflebit ile akut lenfoblastik lösemi arasındaki ilişkiyi düşündürmesi açısından sunulmaya uygun bulunmuştur.The relationship between malignant diseases and venous thromboembolism was shown by different studies. In 10% of patients with malignancy thromboembolic events such as deep vein thrombosis, pulmonary emboli and nonthrombotic endocardit may occur. In high grade cancers, usually before the clinical findings, deep vein thrombosis may be diagnosed. The case who was admitted for right ankle trauma was hospitalized with fever and hyperleucocytosis. A peripheral blood examination revealed lymphocytosis with 90% blast cells. The patient was diagnosed as pre B-cell ALL by the immunophenotype (CD-19 %93.74, CD-45 %98.73, CD-34 %87.58, CD-22 %63.59, CD-10 negative). Pre B-cell ALL diagnosis was confirmed with bone marrow biopsy. The patient developed thrombophlebitis in left leg by the second day of the hospitalization. Antithrombin III (95%) and fibrinogen (3.7 g/dL) levels were in normal ranges and there was no evidence for deep vein thrombosis. The case is presented aş_it-,is d mre condition which indicates a possible association between migratory superficial thrombophlebitis and B-cell acute lymhoblastic leukemia

Two Functional Variants of <i>IRF5</i> Influence the Development of Macular Edema in Patients with Non-Anterior Uveitis

<div><p>Objective</p><p>Interferon (IFN) signaling plays a crucial role in autoimmunity. Genetic variation in interferon regulatory factor 5 (IRF5), a major regulator of the type I interferon induction, has been associated with risk of developing several autoimmune diseases. In the current study we aimed to evaluate whether three sets of correlated <i>IRF5</i> genetic variants, independently associated with SLE and with different functional roles, are involved in uveitis susceptibility and its clinical subphenotypes.</p> <p>Methods</p><p>Three <i>IRF5</i> polymorphisms, rs2004640, rs2070197 and rs10954213, representative of each group, were genotyped using TaqMan® allelic discrimination assays in a total of 263 non-anterior uveitis patients and 724 healthy controls of Spanish origin.</p> <p>Results</p><p>A clear association between two of the three analyzed genetic variants, rs2004640 and rs10954213, and the absence of macular edema was observed in the case/control analysis (<i>P</i>_<i>FDR</i>=5.07E-03, OR=1.48, CI 95%=1.14-1.92 and <i>P</i>_<i>FDR</i>=3.37E-03, OR=1.54, CI 95%=1.19-2.01, respectively). Consistently, the subphenotype analysis accordingly with the presence/absence of this clinical condition also reached statistical significance (rs2004640: <i>P</i>=0.037, OR=0.69, CI 95%=0.48-0.98; rs10954213: <i>P</i>=0.030, OR=0.67, CI 95%=0.47-0.96), thus suggesting that both <i>IRF5</i> genetic variants are specifically associated with the lack of macular edema in uveitis patients.</p> <p>Conclusion</p><p>Our results clearly showed for the first time that two functional genetic variants of <i>IRF5</i> may play a role in the development of macular edema in non-anterior uveitis patients. Identifying genetic markers for macular edema could lead to the possibility of developing novel treatments or preventive therapies.</p> </div

Influence of the IL6 Gene in Susceptibility to Systemic Sclerosis

Contains fulltext : 108354.pdf (publisher's version ) (Closed access)OBJECTIVE: Systemic sclerosis (SSc) is a genetically complex autoimmune disease; the genetic component has not been fully defined. Interleukin 6 (IL-6) plays a crucial role in immunity and fibrosis, both key aspects of SSc. We investigated the influence of IL6 gene in the susceptibility and phenotype expression of SSc. METHODS: We performed a large metaanalysis including a total of 2749 cases and 3189 controls from 6 white populations (Germany, The Netherlands, Norway, Spain, Sweden, and United Kingdom). Three IL6 single-nucleotide polymorphisms (SNP; rs2069827, rs1800795, and rs2069840) were selected by SNP tagging and genotyped using TaqMan((R)) allele discrimination technology. RESULTS: Individual SNP metaanalysis showed no evidence of association of the 3 IL6 genetic variants with the global disease. Phenotype analyses revealed a significant association between the minor allele of rs2069840 and the limited cutaneous SSc clinical form (Bonferroni p = 0.036, OR 1.14, 95% CI 1.04-1.25). A trend of association between the minor allele of the rs1800795 and the diffuse cutaneous SSc clinical form was also evident (Bonferroni p = 0.072, OR 0.86, 95% CI 0.77-0.96). In the IL6 allelic combination analyses, the GGC allelic combination rs2069827-rs1800795-rs2069840 showed an association with overall SSc (Bonferroni p = 0.016, OR 1.13, 95% CI 1.04-1.23). CONCLUSION: Our results suggest that the IL6 gene may influence the development of SSc and its progression