RESUMO
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.
Assuntos
Melanoma , Neoplasias Cutâneas , Austrália/epidemiologia , Humanos , Melanoma/etiologia , Melanoma/genética , Fatores de Risco , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Raios UltravioletaRESUMO
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.
Assuntos
Melanoma , Análise da Randomização Mendeliana , Estudo de Associação Genômica Ampla , Humanos , Melanoma/genética , Polimorfismo de Nucleotídeo Único/genética , Raios Ultravioleta/efeitos adversos , Vitamina DRESUMO
BACKGROUND: Melanoma develops as the result of complex interactions between sun exposure and genetic factors. However, data on these interactions from prospective studies are scant. OBJECTIVES: To quantify the association between ambient and personal ultraviolet exposure and incident melanoma in a large population-based prospective study of men and women residing in a setting of high ambient ultraviolet radiation, and to examine potential gene-environment interactions. METHODS: Data were obtained from the QSkin Sun and Health Study, a prospective cohort study of men and women aged 40-69 years, randomly sampled from the Queensland population in 2011. Participants were genotyped and assessed for ultraviolet exposure. RESULTS: Among participants with genetic data (n = 15 373), 420 (2·7%) developed cutaneous melanoma (173 invasive, 247 in situ) during a median follow-up time of 4·4 years. Country of birth, age at migration, having > 50 sunburns in childhood or adolescence, and a history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk. CONCLUSIONS: An interaction with polygenic risk was suggested: among people at low polygenic risk, markers of cumulative sun exposure (as measured by actinic damage) were associated with melanoma. In contrast, among people at high polygenic risk, markers of high-level early-life ambient exposure (as measured by place of birth) were associated with melanoma (hazard ratio for born in Australia vs. overseas 3·16, 95% confidence interval 1·39-7·22). These findings suggest interactions between genotype and environment that are consistent with divergent pathways for melanoma development. What's already known about this topic? The relationship between sun exposure and melanoma is complex, and exposure effects are highly modified by host factors and behaviours. The role of genotype on the relationship between ultraviolet radiation exposure and melanoma risk is poorly understood. What does this study add? We found that country of birth, age at migration, sunburns in childhood or adolescence, and history of keratinocyte cancer or actinic lesions were significantly associated with melanoma risk, while other measures of continuous or more intermittent patterns of sun exposure were not. We found evidence for gene-environment interactions that are consistent with divergent pathways for melanoma development. Linked Comment: Cust. Br J Dermatol 2020; 183:205-206. Plain language summary available online.
Assuntos
Melanoma , Neoplasias Cutâneas , Adulto , Idoso , Austrália/epidemiologia , Feminino , Humanos , Masculino , Melanoma/etiologia , Melanoma/genética , Pessoa de Meia-Idade , Estudos Prospectivos , Queensland/epidemiologia , Fatores de Risco , Neoplasias Cutâneas/etiologia , Neoplasias Cutâneas/genética , Luz Solar/efeitos adversos , Raios Ultravioleta/efeitos adversosRESUMO
BACKGROUND: To optimise predictive models for sentinal node biopsy (SNB) positivity, relapse and survival, using clinico-pathological characteristics and osteopontin gene expression in primary melanomas. METHODS: A comparison of the clinico-pathological characteristics of SNB positive and negative cases was carried out in 561 melanoma patients. In 199 patients, gene expression in formalin-fixed primary tumours was studied using Illumina's DASL assay. A cross validation approach was used to test prognostic predictive models and receiver operating characteristic curves were produced. RESULTS: Independent predictors of SNB positivity were Breslow thickness, mitotic count and tumour site. Osteopontin expression best predicted SNB positivity (P=2.4 × 10â»7), remaining significant in multivariable analysis. Osteopontin expression, combined with thickness, mitotic count and site, gave the best area under the curve (AUC) to predict SNB positivity (72.6%). Independent predictors of relapse-free survival were SNB status, thickness, site, ulceration and vessel invasion, whereas only SNB status and thickness predicted overall survival. Using clinico-pathological features (thickness, mitotic count, ulceration, vessel invasion, site, age and sex) gave a better AUC to predict relapse (71.0%) and survival (70.0%) than SNB status alone (57.0, 55.0%). In patients with gene expression data, the SNB status combined with the clinico-pathological features produced the best prediction of relapse (72.7%) and survival (69.0%), which was not increased further with osteopontin expression (72.7, 68.0%). CONCLUSION: Use of these models should be tested in other data sets in order to improve predictive and prognostic data for patients.
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Melanoma/diagnóstico , Melanoma/mortalidade , Biópsia de Linfonodo Sentinela , Neoplasias Cutâneas/diagnóstico , Neoplasias Cutâneas/mortalidade , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biomarcadores Tumorais/análise , Biomarcadores Tumorais/genética , Criança , Feminino , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Melanoma/genética , Melanoma/patologia , Pessoa de Meia-Idade , Modelos Teóricos , Prognóstico , Ensaios Clínicos Controlados Aleatórios como Assunto , Recidiva , Neoplasias Cutâneas/genética , Neoplasias Cutâneas/patologia , Análise de Sobrevida , Adulto JovemRESUMO
The power of genetic association studies to identify disease susceptibility alleles fundamentally relies on the variants studied. The standard approach is to determine a set of tagging-SNPs (tSNPs) that capture the majority of genomic variation in regions of interest by exploiting local correlation structures. Typically, tSNPs are selected from neutral discovery panels - collections of individuals comprehensively genotyped across a region. We investigated the implications of discovery panel design on tSNP performance in association studies using realistically-simulated sequence data. We found that discovery panels of 24 sequenced 'neutral' individuals (similar to NIEHS or HapMap ENCODE data) were sufficient to select well-powered tSNPs to identify common susceptibility alleles. For less common alleles (0.01-0.05 frequency) we found neutral panels of this size inadequate, particularly if low-frequency variants were removed prior to tSNP selection; superior tSNPs were found using panels of diseased individuals. Only large neutral panels (200 individuals) matched diseased panel performance in selecting well-powered tSNPs to detect both common and rarer alleles. The 1000 Genomes Project initiative may provide larger neutral panels necessary to identify rarer susceptibility alleles in association studies. In the interim, our results suggest investigators can boost power to detect such alleles by sequencing diseased individuals for tSNP selection.
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Doença/genética , Técnicas Genéticas , Variação Genética , Genoma Humano , Polimorfismo de Nucleotídeo Único , Predisposição Genética para Doença , Genética Populacional , Haplótipos , Humanos , Modelos GenéticosRESUMO
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.
Assuntos
Estudos de Associação Genética , Predisposição Genética para Doença/genética , Variação Genética/genética , Melanoma/genética , Doença de Parkinson/genética , Neoplasias Cutâneas/genética , Estudos de Coortes , Receptor DCC , Dopamina/biossíntese , Genótipo , Humanos , Melaninas/biossíntese , Glicoproteínas de Membrana/genética , Monofenol Mono-Oxigenase , Oxirredutases/genética , Pigmentação/genética , Receptor ErbB-4/genética , Receptores de Superfície Celular/genética , Risco , Proteínas Supressoras de Tumor/genética , Ubiquitina Tiolesterase/genéticaRESUMO
BACKGROUND: Rheumatoid arthritis (RA) is a heterogeneous condition affecting 1-2% of the population. Genetics account for 30% of disease susceptibility, with one third arising from the Major Histocompatibility Complex. The toll-like receptor 4 (TLR-4) gene which has been mapped to chromosome 9 (9q32-q33) is involved in innate immune recognition with subsequent proinflammatory cytokine release including TNF. A single nucleotide polymorphism (+896A-->G) resulting in the amino acid substitution (Asp299Gly) has been shown to interrupt TLR-4 mediated signalling. OBJECTIVE: We sought to determine if this TLR-4 polymorphism influences susceptibility to rheumatoid arthritis. METHODS: DNA was extracted from 879 healthy controls and 212 rheumatoid arthritis patients recruited from the north of England. Genotyping was performed using a 5' nuclease Taqman allelic discrimination assay. Allele frequencies were compared between the two groups. We also examined whether an association existed in non-carriers of the DRB1 shared epitope alleles. RESULTS: The frequency of the rare allele was 5.9% in the controls and 7% in the patients. Comparison of rare allele carriage between controls and patients revealed no significant difference p = 0.13. This was also the case in shared epitope negative individuals p = 0.92. CONCLUSION: The TLR-4 +896 polymorphism does not appear to influence susceptibility to rheumatoid arthritis.
Assuntos
Artrite Reumatoide/genética , Predisposição Genética para Doença , Glicoproteínas de Membrana/genética , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular/genética , Adulto , Idoso , Sequência de Bases , Estudos de Casos e Controles , Feminino , Marcadores Genéticos/genética , Humanos , Masculino , Pessoa de Meia-Idade , Dados de Sequência Molecular , Reação em Cadeia da Polimerase , Probabilidade , Valores de Referência , Sensibilidade e Especificidade , Receptor 4 Toll-Like , Receptores Toll-LikeRESUMO
The use of tagging SNPs (tSNPs) as a cost-effective means of capturing genetic diversity is widespread. However, the quality of the tSNPs selected is dependent on the initial sample in which they are characterized. If the initial marker set is too sparse the tSNPs chosen will capture less information than a naïve analysis suggests. A simple method has been proposed that should provide a better estimate of the performance of tSNPs. It is shown here that this approach is both unbiased and accurate, even for small numbers of typed markers. The effect of unknown phase is also investigated and it is shown that, excepting very small samples, this has little effect on the accuracy of the method.
Assuntos
Polimorfismo de Nucleotídeo Único , HumanosRESUMO
In assessing the power of an association study one needs to consider a variety of genetic models and to have some knowledge of the values of the relevant population parameters in those models. One's comparison of different models should be made such that these parameters are equal under each model. In practice one is most likely to have available estimates of the allele frequency (p) and of the relative risk to siblings of affected individuals (lambda(s)). In presenting power calculations for the transmission/disequilibrium test, previous authors have made comparisons of models which, while having the same gene frequency lead to completely different population outcomes, e.g. different values of lambda(s). Indeed, despite having the same values for their underlying parameters, these models do not necessarily provide the most useful comparison.
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Mapeamento Cromossômico , Interpretação Estatística de Dados , Desequilíbrio de Ligação , Modelos Genéticos , Projetos de PesquisaRESUMO
We show that the methods for calculating the power of the TDT of Risch & Merikangas (1996), McGinnis (1998, 2000), Tu & Whittemore (1999) and Knapp (1999) consist of three distinct approaches. The differences between the methods arise either by treating parental transmissions independently or not, and either conditioning on parental heterozygosity or not. Transmissions are only truly independent when the mode of inheritance of the disease is multiplicative, making this assumption invalid and the methods that assume them (Risch & Merikangas, 1996; McGinnis, 1998, 2000) inappropriate. We demonstrate a basic model that allows analytical comparisons of the methods, and suggest a new method that calculates power at least as accurately as any of the three previously published.
Assuntos
Doenças Genéticas Inatas/genética , Ligação Genética/genética , Modelos Genéticos , Predisposição Genética para Doença , Humanos , Desequilíbrio de Ligação/genética , Modelos EstatísticosRESUMO
1. A series of compounds has been prepared which are analogues of the transition state of the reaction catalysed by L-dopa decarboxylase (EC 4.1.1.28). 2. These compounds are reduced adducts of the substrate (L-dopa) and coenzyme (pyridoxal phosphate), as well as analogues of these substances (D-dopa, pyridoxal and salicaldehyde). 3. Compounds were also prepared with an oxazine link between the 3'-oxygen and the nitrogen attached to the 4'-carbon of the aldehyde moiety. 4. None of the D-dopa adducts produced any significant inhibition, but the L-dopa adducts were all active at millimolar levels, with the oxazine derivatives being more active than their parent compounds. 5. Inhibition was competitive with respect to L-dopa, but was neither competitive nor non-competitive with respect to pyridoxal phosphate. 6. The most active compound tested was the oxazine derivative of the L-dopa/salicaldehyde adduct, with an estimated Ki of 58.0 microM. 7. Increased inhibitory activity was observed when enzyme depleted of pyridoxal phosphate was used.
Assuntos
Inibidores das Descarboxilases de Aminoácidos Aromáticos , Inibidores Enzimáticos/classificação , Levodopa/análogos & derivados , Animais , Sítios de Ligação , Ligação Competitiva , Catálise , Rim/enzimologia , Modelos Teóricos , Fosfato de Piridoxal/isolamento & purificação , Fosfato de Piridoxal/fisiologia , SuínosRESUMO
We approached the simulation as though it were an international study with similar but not identical information being collected from different populations. In keeping with this we analyzed one replicate from each population. Initially we examined the risk of disease in relatives of cases to determine whether the disease appeared to be "more genetic" in one population than in the others and we examined the evidence for environmental risk factors in each population. Nonparametric linkage analysis and transmission/disequilibrium testing (TDT) were used to search for loci linked to the disease in each population. Using these methods we identified several candidate regions for a susceptibility gene which on examination of the answers are explicable in terms of the underlying model.