A common missense variant of <i>LILRB₅</i> is associated with statin intolerance and myalgia

Aims A genetic variant in LILRB5 (leukocyte immunoglobulin-like receptor subfamily-B) (rs12975366: T > C: Asp247Gly) has been reported to be associated with lower creatine phosphokinase (CK) and lactate dehydrogenase (LDH) levels. Both biomarkers are released from injured muscle tissue, making this variant a potential candidate for susceptibility to muscle-related symptoms. We examined the association of this variant with statin intolerance ascertained from electronic medical records in the GoDARTS study. Methods and results In the GoDARTS cohort, the LILRB5 Asp247 variant was associated with statin intolerance (SI) phenotypes; one defined as having raised CK and being non-adherent to therapy [odds ratio (OR) 1.81; 95% confidence interval (CI): 1.34–2.45] and the other as being intolerant to the lowest approved dose of a statin before being switched to two or more other statins (OR 1.36; 95% CI: 1.07–1.73). Those homozygous for Asp247 had increased odds of developing both definitions of intolerance. Importantly the second definition did not rely on CK elevations. These results were replicated in adjudicated cases of statin-induced myopathy in the PREDICTION-ADR consortium (OR1.48; 95% CI: 1.05–2.10) and for the development of myalgia in the JUPITER randomized clinical trial of rosuvastatin (OR1.35, 95% CI: 1.10–1.68). A meta-analysis across the studies showed a consistent association between Asp247Gly and outcomes associated with SI (OR1.34; 95% CI: 1.16–1.54). Conclusion This study presents a novel immunogenetic factor associated with statin intolerance, an important risk factor for cardiovascular outcomes. The results suggest that true statin-induced myalgia and non-specific myalgia are distinct, with a potential role for the immune system in their development. We identify a genetic group that is more likely to be intolerant to their statins

Genetic predisposition to mosaic Y chromosome loss in blood.

Mosaic loss of chromosome Y (LOY) in circulating white blood cells is the most common form of clonal mosaicism1-5, yet our knowledge of the causes and consequences of this is limited. Here, using a computational approach, we estimate that 20% of the male population represented in the UK Biobank study (n = 205,011) has detectable LOY. We identify 156 autosomal genetic determinants of LOY, which we replicate in 757,114 men of European and Japanese ancestry. These loci highlight genes that are involved in cell-cycle regulation and cancer susceptibility, as well as somatic drivers of tumour growth and targets of cancer therapy. We demonstrate that genetic susceptibility to LOY is associated with non-haematological effects on health in both men and women, which supports the hypothesis that clonal haematopoiesis is a biomarker of genomic instability in other tissues. Single-cell RNA sequencing identifies dysregulated expression of autosomal genes in leukocytes with LOY and provides insights into why clonal expansion of these cells may occur. Collectively, these data highlight the value of studying clonal mosaicism to uncover fundamental mechanisms that underlie cancer and other ageing-related diseases.This research has been conducted using the UK Biobank Resource under application 9905 and 19808. This work was supported by the Medical Research Council [Unit Programme number MC_UU_12015/2]. Full study-specific and individual acknowledgements can be found in the supplementary information

A nhaD Na+/H+antiporter and a pcd homologues are among the Rhodothermus marinus complex I genes

AbstractThe NADH:menaquinone oxidoreductase (Nqo) is one of the enzymes present in the respiratory chain of the thermohalophilic bacterium Rhodothermus marinus. The genes coding for the R. marinus Nqo subunits were isolated and sequenced, clustering in two operons [nqo1 to nqo7 (nqoA) and nqo10 to nqo14 (nqoB)] and two independent genes (nqo8 and nqo9). Unexpectedly, two genes encoding homologues of a NhaD Na+/H+ antiporter (NhaD) and of a pterin-4α-carbinolamine dehydratase (PCD) were identified within nqoB, flanked by nqo13 and nqo14. Eight conserved motives to harbour iron–sulphur centres are identified in the deduced primary structures, as well as two consensus sequences to bind nucleotides, in this case NADH and FMN. Moreover, the open-reading-frames of the putative NhaD and PCD were shown to be co-transcribed with the other complex I genes encoded by nqoB. The possible role of these two genes in R. marinus complex I is discussed

Clinical manifestations, diagnosis, and treatment of Mycobacterium haemophilum infections.

Item does not contain fulltextMycobacterium haemophilum is a slowly growing acid-fast bacillus (AFB) belonging to the group of nontuberculous mycobacteria (NTM) frequently found in environmental habitats, which can colonize and occasionally infect humans and animals. Several findings suggest that water reservoirs are a likely source of M. haemophilum infections. M. haemophilum causes mainly ulcerating skin infections and arthritis in persons who are severely immunocompromised. Disseminated and pulmonary infections occasionally occur. The second at-risk group is otherwise healthy children, who typically develop cervical and perihilar lymphadenitis. A full diagnostic regimen for the optimal detection of M. haemophilum includes acid-fast staining, culturing at two temperatures with iron-supplemented media, and molecular detection. The most preferable molecular assay is a real-time PCR targeting an M. haemophilum-specific internal transcribed spacer (ITS), but another approach is the application of a generic PCR for a mycobacterium-specific fragment with subsequent sequencing to identify M. haemophilum. No standard treatment guidelines are available, but published literature agrees that immunocompromised patients should be treated with multiple antibiotics, tailored to the disease presentation and underlying degree of immune suppression. The outcome of M. haemophilum cervicofacial lymphadenitis in immunocompetent patients favors surgical intervention rather than antibiotic treatment.1 oktober 201