Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10-11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10-8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10-8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10-8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.</p

Genome-wide meta-analysis points to CTC1 and ZNf676 as genes regulating telomere homeostasis in humans

Leukocyte telomere length (LTL) is associated with a number of common age-related diseases and is a heritable trait. Previous genome-wide association studies (GWASs) identified two loci on chromosomes 3q26.2 (TERC) and 10q24.33 (OBFC1) that are associated with the inter-individual LTL variation. We performed a meta-analysis of 9190 individuals from six independent GWAS and validated our findings in 2226 individuals from four additional studies. We confirmed previously reported associations with OBFC1 (rs9419958 P = 9.1 × 10-11) and with the telomerase RNA component TERC (rs1317082, P = 1.1 × 10-8). We also identified two novel genomic regions associated with LTL variation that map near a conserved telomere maintenance complex component 1 (CTC1; rs3027234, P = 3.6 × 10-8) on chromosome17p13.1 and zinc finger protein 676 (ZNF676; rs412658, P = 3.3 × 10-8) on 19p12. The minor allele of rs3027234 was associated with both shorter LTL and lower expression of CTC1. Our findings are consistent with the recent observations that point mutations in CTC1 cause short telomeres in both Arabidopsis and humans affected by a rare Mendelian syndrome. Overall, our results provide novel insights into the genetic architecture of inter-individual LTL variation in the general population.</p

The epidemiology of chronic pain in Libya: a cross-sectional telephone survey.

BACKGROUND: Chronic pain is a public health problem although there is a paucity of prevalence data from countries in the Middle East and North Africa. The aim of this study was to estimate the prevalence of chronic pain and neuropathic pain in a sample of the general adult population in Libya. METHODS: A cross-sectional telephone survey was conducted before the onset of the Libyan Civil War (February 2011) on a sample of self-declared Libyans who had a landline telephone and were at least 18 years of age. Random sampling of household telephone number dialling was undertaken in three major cities and interviews conducted using an Arabic version of the Structured Telephone Interviews Questionnaire on Chronic Pain previously used to collect data in Europe. In addition, an Arabic version of S-LANSS was used. 1212 individuals were interviewed (response rate = 95.1 %, mean age = 37.8 ± 13.9 years, female = 54.6 %). RESULTS: The prevalence of chronic pain ≥ 3 months was 19.6 % (95 % CI 14.6 % to 24.6 %) with a mean ± SD duration of pain of 6 · 5 ± 5 · 7 years and a higher prevalence for women. The prevalence of neuropathic pain in the respondents reporting chronic pain was 19 · 7 % (95 % CI 14 · 6-24 · 7), equivalent to 3 · 9 % (95 % CI 2 · 8 to 5 · 0 %) of the general adult population. Only, 71 (29 · 8 %) of respondents reported that their pain was being adequately controlled. CONCLUSIONS: The prevalence of chronic pain in the general adult population of Libya was approximately 20 % and comparable with Europe and North America. This suggests that chronic pain is a public health problem in Libya. Risk factors are being a woman, advanced age and unemployment. There is a need for improved health policies in Libya to ensure that patients with chronic pain receive effective management

A Genome-Wide Association Study Identifies rs2000999 as a Strong Genetic Determinant of Circulating Haptoglobin Levels

Haptoglobin is an acute phase inflammatory marker. Its main function is to bind hemoglobin released from erythrocytes to aid its elimination, and thereby haptoglobin prevents the generation of reactive oxygen species in the blood. Haptoglobin levels have been repeatedly associated with a variety of inflammation-linked infectious and non-infectious diseases, including malaria, tuberculosis, human immunodeficiency virus, hepatitis C, diabetes, carotid atherosclerosis, and acute myocardial infarction. However, a comprehensive genetic assessment of the inter-individual variability of circulating haptoglobin levels has not been conducted so far

Retinal Phenotype of Patients With Isolated Retinal Degeneration Due to CLN3 Pathogenic Variants in a French Retinitis Pigmentosa Cohort

Importance: Biallelic variants in CLN3 lead to a spectrum of diseases, ranging from severe neurodegeneration with retinal involvement (juvenile neuronal ceroid lipofuscinosis) to retina-restricted conditions. Objective: To provide a detailed description of the retinal phenotype of patients with isolated retinal degeneration harboring biallelic CLN3 pathogenic variants and to attempt a phenotype-genotype correlation associated with this gene defect. Design, Setting, and Participants: This retrospective cohort study included patients carrying biallelic CLN3 variants extracted from a cohort of patients with inherited retinal disorders (IRDs) investigated at the National Reference Center for Rare Ocular Diseases of the Centre Hospitalier National d'Ophtalmologie des Quinze-Vingts from December 2007 to August 2020. Data were analyzed from October 2019 to August 2020. Main Outcome and Measures: Functional (best-corrected visual acuity, visual field, color vision, and full-field electroretinogram), morphological (multimodal retinal imaging), and clinical data from patients were collected and analyzed. Gene defect was identified by either next-generation sequencing or whole-exome sequencing and confirmed by Sanger sequencing, quantitative polymerase chain reaction, and cosegregation analysis. Results: Of 1533 included patients, 843 (55.0%) were women and 690 (45.0%) were men. A total of 15 cases from 11 unrelated families harboring biallelic CLN3 variants were identified. All patients presented with nonsyndromic IRD. Two distinct patterns of retinal disease could be identified: a mild rod-cone degeneration of middle-age onset (n = 6; legal blindness threshold reached by 70s) and a severe retinal degeneration with early macular atrophic changes (n = 9; legal blindness threshold reached by 40s). Eleven distinct pathogenic variants were detected, of which 4 were novel. All but 1, p.(Arg405Trp), CLN3 point variants and their genotypic associations were clearly distinct between juvenile neuronal ceroid lipofuscinosis and retina-restricted disease. Mild and severe forms of retina-restricted CLN3-linked IRDs also had different genetic background. Conclusions and Relevance: These findings suggest CLN3 should be included in next-generation sequencing panels when investigating patients with nonsyndromic rod-cone dystrophy. These results document phenotype-genotype correlations associated with specific variants in CLN3. However, caution seems warranted regarding the potential neurological outcome if a pathogenic variant in CLN3 is detected in a case of presumed isolated IRD for the onset of neurological symptoms could be delayed

Retinal Cell Biology Further Insights Into GPR179: Expression, Localization, and Associated Pathogenic Mechanisms Leading to Complete Congenital Stationary Night Blindness

PURPOSE. Mutations in GPR179, which encodes the G protein-coupled receptor 179, lead to autosomal recessive complete (c) congenital stationary night blindness (CSNB), which is characterized by an ON-bipolar retinal cell dysfunction. This study further defined the exact site of Gpr179 expression and its protein localization in human retina and elucidated the pathogenic mechanism of the reported missense and splice site mutations. METHODS. RNA in situ hybridization was performed with mouse retinal sections. A commercially available antibody was validated with GPR179-overexpressing COS-1 cells and applied to human retinal sections. Live-cell extracellular staining along with subsequent intracellular immunolocalization and ELISA studies were performed using mammalian cells overexpressing wild-type or missense mutated GPR179. Wild-type and splice site-mutated mini-gene constructs were transiently transfected, and RNA was extracted. RT-PCR-amplified products were cloned, and Sanger sequenced. RESULTS. Mouse Gpr179 transcript was expressed in the upper part of the inner nuclear layer, and the respective human protein localized at the dendritic tips of bipolar cells in human retina. The missense mutations p.Tyr220Cys, p.Gly455Asp, and p.His603Tyr led to severely reduced cell surface localization, whereas p.Asp126His did not. The mutated splice donor site altered GPR179 splicing. CONCLUSIONS. Our findings indicate that the site of expression and protein localization of human and mouse GPR179 is similar to that of other proteins implicated in cCSNB. For most of the mutations identified so far, loss of the GPR179 protein function seems to be the underlying pathogenic mechanism leading to this form of cCSNB. Keywords: GPR179, expression and localization, cCSNB, pathogenicity, trafficking defect, mini-gene approach C ongenital stationary night blindness (CSNB) is a clinically and genetically heterogeneous disorder, which is characterized by impaired night vision and is often associated with other ocular problems such as decreased visual acuity, nystagmus, high myopia, and strabismus. 1 Clinically, this disorder can be classified according to two forms distinguished by particular full-field electroretinogram (ERG) abnormalities. 2 Patients with Riggs-type ERG responses reveal a reduced a-and b-wave, whereas patients with the Schubert-Bornschein-type of ERG are characterized by an electronegative scotopic ERG response in which the a-wave is larger than the b-wave. 3,4 The latter type can be further divided into the incomplete (ic) and complete (c) forms. In the former form, the patient shows reduced scotopic b-wave and severely reduced 30-Hz flicker and single-flash photopic ERG responses; in the latter form, the patient shows severely reduced scotopic b-wave and squareshaped a-wave photopic ERG responses with relatively preserved amplitude. 6-10 and one gene that causes autosomal recessive (ar) CSNB (SLC24A1

Developing institutions for cancer care in low-income and middle-income countries:From cancer units to comprehensive cancer centres

Global cancer centres operate across different sizes, scales, and ecosystems. Understanding the essential aspects of the creation, organisation, accreditation, and activities within these settings is crucial for developing an affordable, equitable, and quality cancer care, research, and education system. Robust guidelines are scarce for cancer units, cancer centres, and comprehensive cancer centres in low-income and middle-income countries. However, some robust examples of the delivery of complex cancer care in centres in emerging economies are available. Although it is impossible to create an optimal system to fit the unique needs of all countries for the delivery of cancer care, we summarise what has been published about the development and management of cancer centres in low-income and middle-income countries so far and highlight the need for clinical and political leadership