Genome-wide association studies (GWAS) have identified ~20 melanoma susceptibility loci, most of which are not functionally characterized. Here we report an approach integrating massively-parallel ...reporter assays (MPRA) with cell-type-specific epigenome and expression quantitative trait loci (eQTL) to identify susceptibility genes/variants from multiple GWAS loci. From 832 high-LD variants, we identify 39 candidate functional variants from 14 loci displaying allelic transcriptional activity, a subset of which corroborates four colocalizing melanocyte cis-eQTL genes. Among these, we further characterize the locus encompassing the HIV-1 restriction gene, MX2 (Chr21q22.3), and validate a functional intronic variant, rs398206. rs398206 mediates the binding of the transcription factor, YY1, to increase MX2 levels, consistent with the cis-eQTL of MX2 in primary human melanocytes. Melanocyte-specific expression of human MX2 in a zebrafish model demonstrates accelerated melanoma formation in a BRAF
background. Our integrative approach streamlines GWAS follow-up studies and highlights a pleiotropic function of MX2 in melanoma susceptibility.
Myocardial fibrosis is fundamental in the pathogenesis of heart failure. Late gadolinium enhancement (LGE) with cardiac magnetic resonance (CMR) imaging is commonly assumed to represent myocardial ...fibrosis; however, comparative human histological data are limited, especially in non-ischaemic cardiac disease. Diffuse interstitial myocardial fibrosis is increasingly recognized as central in the pathogenesis of cardiomyopathy and can be quantified using newer CMR techniques such as T1 mapping. We evaluated the relationship of CMR assessment of regional and diffuse fibrosis with human histology.
Eleven patients on the waiting list for heart transplantation (43.5 ± 7.6 years, 64% male) and eight patients undergoing surgical myectomy for obstructive hypertrophic cardiomyopathy (57.1 ± 8.6 years, 63% male) were recruited and underwent CMR prior to cardiac transplantation or myectomy. Quantification of fibrosis in explanted hearts using digitally analysed Masson-trichrome-stained slides was validated against picrosirius red-stained slides analysed using Image J, with an excellent correlation (R = 0.95, P < 0.0001). Significant correlations were observed between LGE and histological fibrosis across a range of signal intensity thresholds in the explanted hearts (range: 2-10 standard deviations above reference myocardium), with maximal accuracy at a threshold of 6 SD (R = 0.91, P < 0.001). Assessment of interstitial myocardial fibrosis with post-contrast T1 times demonstrated a significant correlation on both segmental (R = -0.64, P = 0.002) and per-patient (R = -0.78, P = 0.003) analyses.
CMR provides accurate, non-invasive assessment of regional myocardial fibrosis using LGE, while diffuse interstitial myocardial fibrosis is accurately assessed with post-contrast T1 mapping.
Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection is associated with a range of persistent symptoms impacting everyday functioning, known as post-COVID-19 condition or long ...COVID. We undertook a retrospective matched cohort study using a UK-based primary care database, Clinical Practice Research Datalink Aurum, to determine symptoms that are associated with confirmed SARS-CoV-2 infection beyond 12 weeks in non-hospitalized adults and the risk factors associated with developing persistent symptoms. We selected 486,149 adults with confirmed SARS-CoV-2 infection and 1,944,580 propensity score-matched adults with no recorded evidence of SARS-CoV-2 infection. Outcomes included 115 individual symptoms, as well as long COVID, defined as a composite outcome of 33 symptoms by the World Health Organization clinical case definition. Cox proportional hazards models were used to estimate adjusted hazard ratios (aHRs) for the outcomes. A total of 62 symptoms were significantly associated with SARS-CoV-2 infection after 12 weeks. The largest aHRs were for anosmia (aHR 6.49, 95% CI 5.02-8.39), hair loss (3.99, 3.63-4.39), sneezing (2.77, 1.40-5.50), ejaculation difficulty (2.63, 1.61-4.28) and reduced libido (2.36, 1.61-3.47). Among the cohort of patients infected with SARS-CoV-2, risk factors for long COVID included female sex, belonging to an ethnic minority, socioeconomic deprivation, smoking, obesity and a wide range of comorbidities. The risk of developing long COVID was also found to be increased along a gradient of decreasing age. SARS-CoV-2 infection is associated with a plethora of symptoms that are associated with a range of sociodemographic and clinical risk factors.
Orchids are the most diverse family of angiosperms, with over 25 000 species, more than mammals, birds and reptiles combined. Tests of hypotheses to account for such diversity have been stymied by ...the lack of a fully resolved broad-scale phylogeny. Here, we provide such a phylogeny, based on 75 chloroplast genes for 39 species representing all orchid subfamilies and 16 of 17 tribes, time-calibrated against 17 angiosperm fossils. A supermatrix analysis places an additional 144 species based on three plastid genes. Orchids appear to have arisen roughly 112 million years ago (Mya); the subfamilies Orchidoideae and Epidendroideae diverged from each other at the end of the Cretaceous; and the eight tribes and three previously unplaced subtribes of the upper epidendroids diverged rapidly from each other between 37.9 and 30.8 Mya. Orchids appear to have undergone one significant acceleration of net species diversification in the orchidoids, and two accelerations and one deceleration in the upper epidendroids. Consistent with theory, such accelerations were correlated with the evolution of pollinia, the epiphytic habit, CAM photosynthesis, tropical distribution (especially in extensive cordilleras), and pollination via Lepidoptera or euglossine bees. Deceit pollination appears to have elevated the number of orchid species by one-half but not via acceleration of the rate of net diversification. The highest rate of net species diversification within the orchids (0.382 sp sp−1 My−1) is 6.8 times that at the Asparagales crown.
Summary
Background
Melanoma aetiology has been proposed to have two pathways, which are determined by naevi and type of sun exposure and related to the anatomical site where melanoma develops.
...Objectives
We examined associations with melanoma by anatomical site for a comprehensive set of risk factors including pigmentary and naevus phenotypes, ultraviolet radiation exposure and polygenic risk.
Methods
We analysed harmonized data from 2617 people with incident first invasive melanoma and 975 healthy controls recruited through two population‐based case–control studies in Australia and the UK. Questionnaire data were collected by interview using a single protocol, and pathway‐specific polygenic risk scores were derived from DNA samples. We estimated adjusted odds ratios using unconditional logistic regression that compared melanoma cases at each anatomical site with all controls.
Results
When cases were compared with control participants, there were stronger associations for many naevi vs. no naevi for melanomas on the trunk, and upper and lower limbs than on the head and neck (P‐heterogeneity < 0·001). Very fair skin (vs. olive/brown skin) was more weakly related to melanoma on the trunk than to melanomas at other sites (P‐heterogeneity = 0·04). There was no significant difference by anatomical site for polygenic risk. Increased weekday sun exposure was positively associated with melanoma on the head and neck but not on other sites.
Conclusions
We found evidence of aetiological heterogeneity for melanoma, supporting the dual pathway hypothesis. These findings enhance understanding of risk factors for melanoma and can guide prevention and skin examination education and practices.
What is already known about this topic?
Two main biological pathways have been proposed for the aetiology of melanoma – determined by naevi and type of sun exposure and related to the anatomical site at which melanoma develops.
Risk factors for melanoma may differ by anatomical site, but analyses are often limited by study sample size and most have focused on sun exposure.
What does this study add?
This study provides an examination of a comprehensive set of risk factors for melanoma by anatomical site, using a harmonized dataset from two population‐based studies with 3592 participants.
The presence of increased numbers of naevi was more strongly associated with melanomas on the trunk and limbs than on the head and neck.
Very fair skin was more weakly related to melanoma on the trunk than on other sites.
The association of pathway‐specific polygenic risk scores with melanoma did not differ by anatomical site.
Linked Comment: Ghiasvand. Br J Dermatol 2021; 184:995–996.
Abstract A shared genetic susceptibility between cutaneous malignant melanoma (CMM) and Parkinson's disease (PD) has been suggested. We investigated this by assessing the contribution of rare ...variants in genes involved in CMM to PD risk. We studied rare variation across 29 CMM risk genes using high-quality genotype data in 6875 PD cases and 6065 controls and sought to replicate findings using whole-exome sequencing data from a second independent cohort totaling 1255 PD cases and 473 controls. No statistically significant enrichment of rare variants across all genes, per gene, or for any individual variant was detected in either cohort. There were nonsignificant trends toward different carrier frequencies between PD cases and controls, under different inheritance models, in the following CMM risk genes: BAP1 , DCC , ERBB4, KIT , MAPK2 , MITF , PTEN , and TP53 . The very rare TYR p.V275F variant, which is a pathogenic allele for recessive albinism, was more common in PD cases than controls in 3 independent cohorts. Tyrosinase, encoded by TYR, is the rate-limiting enzyme for the production of neuromelanin, and has a role in the production of dopamine. These results suggest a possible role for another gene in the dopamine-biosynthetic pathway in susceptibility to neurodegenerative Parkinsonism, but further studies in larger PD cohorts are needed to accurately determine the role of these genes/variants in disease pathogenesis.
Background There are no systemic therapies approved in the United States to treat pediatric psoriasis. Objective We sought to evaluate long-term safety and efficacy of etanercept in children and ...adolescents with moderate to severe plaque psoriasis. Methods This 5-year, open-label extension study enrolled patients aged 4 to 17 years who had participated in a 48-week parent study. End points included occurrence of adverse events (AEs) and serious AEs including infections, and rates of 75% and 90% improvement in Psoriasis Area and Severity Index score and clear/almost clear on static physician global assessment. Results Of 182 patients enrolled, 181 received etanercept and 69 completed 264 weeks. Through week 264, 161 (89.0%) patients reported an AE, most commonly upper respiratory tract infection (37.6%), nasopharyngitis (26.0%), and headache (21.5%). Seven patients reported 8 serious AEs; only 1 (cellulitis) was considered treatment-related. No cases of opportunistic infections or malignancy were reported. Rates of 75% improvement in Psoriasis Area and Severity Index score (∼60%–70%) and 90% improvement in Psoriasis Area and Severity Index score (∼30%–40%) and static physician global assessment status clear/almost clear (∼40%–50%) were maintained through week 264. Limitations The number of patients remaining on study at week 264 was small. Conclusion Etanercept in pediatric patients was generally well tolerated and efficacy was maintained in those who remained in the study for up to 264 weeks.
Malignant hyperthermia (MH) is associated, in the majority of cases, with mutations in RYR1, the gene encoding the skeletal muscle ryanodine receptor. Our primary aim was to assess whether different ...RYR1 variants are associated with quantitative differences in MH phenotype.
The degree of in vitro pharmacological muscle contracture response and the baseline serum creatine kinase (CK) concentration were used to generate a series of quantitative phenotypes for MH. We then undertook the most extensive RYR1 genotype–phenotype correlation in MH to date using 504 individuals from 204 MH families and 23 RYR1 variants. We also determined the association between a clinical phenotype and both the laboratory phenotype and RYR1 genotype.
We report a novel correlation between the degree of in vitro pharmacological muscle contracture responses and the onset time of the clinical MH response in index cases (P<0.05). There was also a significant correlation between baseline CK concentration and clinical onset time (P=0.039). The specific RYR1 variant was a significant determinant of the severity of each laboratory phenotype (P<0.0001).
The MH phenotype differs significantly with different RYR1 variants. Variants leading to more severe MH phenotype are distributed throughout the gene and tend to lie at relatively conserved sites in the protein. Differences in phenotype severity between RYR1 variants may explain the variability in clinical penetrance of MH during anaesthesia and why some variants have been associated with exercise-induced rhabdomyolysis and heat stroke. They may also inform a mutation screening strategy in cases of idiopathic hyperCKaemia.
The success of genome-wide association studies relies on much of the risk of common diseases being due to common genetic variants; but evidence for this is inconclusive. The results of published ...genome-wide association studies are examined to see what can be learnt about the distribution of disease-associated variants and how this might influence future study design. Although replicated disease-associated variants tend to be very common and frequency is inversely correlated with estimated effect size, our simulations suggest that such observations are the result of power. We find that for studies conducted to date, the frequency and effect size of significantly associated alleles are likely to be similar to those of the underlying disease alleles that they represent. Little of the genetic variation of disease has been explained so far, but current studies are only adequately powered to detect very common alleles unless they greatly increase disease risk. Thus, although the truth of the common disease / common variant hypothesis remains undecided, recent successes suggest that there are many more common genetic disease-associated variants, requiring larger studies to be identified.
Summary
Background
Several preclinical studies have identified the antiproliferative effects of 25‐hydroxyvitamin D 25(OH)D; vitamin D. Ultraviolet radiation (UVR) is essential for vitamin D ...synthesis yet increases the risk of melanoma. Observational studies on the association of vitamin D levels with melanoma risk have reported inconclusive results, and are difficult to interpret owing to the potential confounding from the dual role of UVR.
Objectives
To determine whether there is a causal association between genetically predicted 25(OH)D concentrations and melanoma using a Mendelian randomization (MR) approach.
Methods
We performed MR using summary data from a large genome‐wide association study (GWAS) meta‐analysis of melanoma risk, consisting of 12 874 cases and 23 203 controls. Five single nucleotide polymorphisms associated with 25(OH)D concentration – rs12785878, rs10741657, rs2282679, rs6013897 and rs116970203 – were selected as instrumental variables. An inverse variance weighted method was used to access the evidence for causality. MR results from the melanoma meta‐analysis were combined with results from an MR study based on a melanoma risk GWAS using UK Biobank data.
Results
A 20 nmol L−1 decrease in 25(OH)D was not associated with melanoma risk odds ratio (OR) 1·06, 95% confidence interval (CI) 0·95–1·19. Results from the UK Biobank were concordant with this, with meta‐analysis of our and UK Biobank‐derived MR causal estimates showing no association (OR 1·02, 95% CI 0·92–1·13 for a 20 nmol L−1 decrease).
Conclusions
The results suggest that vitamin D levels may not be causally associated with the risk of melanoma.
What's already known about this topic?
Antitumour activity of vitamin D has been identified in preclinical studies.
Observational studies link vitamin D deficiency with an increased risk of a range of cancers.
There is a growing public interest for vitamin D supplementation.
Observational studies of melanoma are fraught with difficulties because while higher ultraviolet radiation levels increase vitamin D levels, such exposure is also associated with increased melanoma risk.
Results from observational studies are inconclusive regarding the effect of vitamin D on melanoma risk.
What does this study add?
Using Mendelian randomization, an approach to causal inference, which is analogous to a natural randomized controlled trial, we found no causal association between vitamin D levels and melanoma.
Plain language summary available online
Linked Comment: Bell. Br J Dermatol 2020; 182:13–14.
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