Association of MC1R Variants and host phenotypes with melanoma risk in CDKN2A mutation carriers: a GenoMEL study

<p><b>Background</b> Carrying the cyclin-dependent kinase inhibitor 2A (CDKN2A) germline mutations is associated with a high risk for melanoma. Penetrance of CDKN2A mutations is modified by pigmentation characteristics, nevus phenotypes, and some variants of the melanocortin-1 receptor gene (MC1R), which is known to have a role in the pigmentation process. However, investigation of the associations of both MC1R variants and host phenotypes with melanoma risk has been limited.</p> <p><b>Methods</b> We included 815 CDKN2A mutation carriers (473 affected, and 342 unaffected, with melanoma) from 186 families from 15 centers in Europe, North America, and Australia who participated in the Melanoma Genetics Consortium. In this family-based study, we assessed the associations of the four most frequent MC1R variants (V60L, V92M, R151C, and R160W) and the number of variants (1, ≥2 variants), alone or jointly with the host phenotypes (hair color, propensity to sunburn, and number of nevi), with melanoma risk in CDKN2A mutation carriers. These associations were estimated and tested using generalized estimating equations. All statistical tests were two-sided.</p> <p><b>Results</b> Carrying any one of the four most frequent MC1R variants (V60L, V92M, R151C, R160W) in CDKN2A mutation carriers was associated with a statistically significantly increased risk for melanoma across all continents (1.24 × 10−6 ≤ P ≤ .0007). A consistent pattern of increase in melanoma risk was also associated with increase in number of MC1R variants. The risk of melanoma associated with at least two MC1R variants was 2.6-fold higher than the risk associated with only one variant (odds ratio = 5.83 [95% confidence interval = 3.60 to 9.46] vs 2.25 [95% confidence interval = 1.44 to 3.52]; Ptrend = 1.86 × 10−8). The joint analysis of MC1R variants and host phenotypes showed statistically significant associations of melanoma risk, together with MC1R variants (.0001 ≤ P ≤ .04), hair color (.006 ≤ P ≤ .06), and number of nevi (6.9 × 10−6 ≤ P ≤ .02).</p> <p><b>Conclusion</b> Results show that MC1R variants, hair color, and number of nevi were jointly associated with melanoma risk in CDKN2A mutation carriers. This joint association may have important consequences for risk assessments in familial settings.</p&gt

DNA methylation in peripheral tissues and left-handedness

This is the final version. Available on open access from Nature Research vis the DOI in this recordData availability: The HumanMethylation450 BeadChip data from the NTR are available as part of the Biobank-based Integrative Omics Studies (BIOS) Consortium in the European Genome-phenome Archive (EGA), under the accession code EGAD00010000887 (https://ega-archive.org/datasets/EGAD00010000887). The Infinium MethylationEPIC from NTR are available from the Netherlands Twin Register on reasonable request (https://tweelingenregister.vu.nl/information_for_researchers/working-with-ntr-data). DNA methylation data from ALSPAC are available at ALSPAC and can be provided on request. The study website contains details of all the data that is available through a fully searchable data dictionary and variable search tool (http://www.bristol.ac.uk/alspac/researchers/our-data). The code used to perform the primary and secondary analyses is available at https://github.com/MRCIEU/handedness-ewas. The pipeline for the DNA methylation array analysis developed by the Biobank-based Integrative Omics Study (BIOS) consortium are available here: https://molepi.github.io/DNAmArray_workflow/. EWAS summary statistics for the top 100 CpGs are given in Supplemental Tables 6–11 and 15–29. The full EWAS summary statistics from the meta-analysis with basic and adjusted model are provided in Supplemental Tables 32 and 33. The full summary statistics for all other analyses are available upon request from the corresponding author.Handedness has low heritability and epigenetic mechanisms have been proposed as an etiological mechanism. To examine this hypothesis, we performed an epigenome-wide association study of left-handedness. In a meta-analysis of 3914 adults of whole-blood DNA methylation, we observed that CpG sites located in proximity of handedness-associated genetic variants were more strongly associated with left-handedness than other CpG sites (P = 0.04), but did not identify any differentially methylated positions. In longitudinal analyses of DNA methylation in peripheral blood and buccal cells from children (N = 1737), we observed moderately stable associations across age (correlation range [0.355-0.578]), but inconsistent across tissues (correlation range [- 0.384 to 0.318]). We conclude that DNA methylation in peripheral tissues captures little of the variance in handedness. Future investigations should consider other more targeted sources of tissue, such as the brain

The Relevance of Fatalism in the Study of Latinas’ Cancer Screening Behavior: A Systematic Review of the Literature

# The Author(s) 2010. This article is published with open access at Springerlink.com Background Fatalism has been identified as a dominant belief among Latinos and is believed to act as a barrier to cancer prevention. However, controversy exists over the utility of the construct in explaining health disparities experienced by disadvantaged populations above the influence of structural barriers such as low socioeconomic status (SES) and limited access to health care. Purpose This paper reviews the empirical research on fatalism and Latinas ’ participation in cancer screening in an attempt to determine whether fatalism predicts participation in cancer screening after accounting for structural barriers

Pathway-Based Analysis of a Melanoma Genome-Wide Association Study: Analysis of Genes Related to Tumour-Immunosuppression

Systemic immunosuppression is a risk factor for melanoma, and sunburn-induced immunosuppression is thought to be causal. Genes in immunosuppression pathways are therefore candidate melanoma-susceptibility genes. If variants within these genes individually have a small effect on disease risk, the association may be undetected in genome-wide association (GWA) studies due to low power to reach a high significance level. Pathway-based approaches have been suggested as a method of incorporating a priori knowledge into the analysis of GWA studies. In this study, the association of 1113 single nucleotide polymorphisms (SNPs) in 43 genes (39 genomic regions) related to immunosuppression have been analysed using a gene-set approach in 1539 melanoma cases and 3917 controls from the GenoMEL consortium GWA study. The association between melanoma susceptibility and the whole set of tumour-immunosuppression genes, and also predefined functional subgroups of genes, was considered. The analysis was based on a measure formed by summing the evidence from the most significant SNP in each gene, and significance was evaluated empirically by case-control label permutation. An association was found between melanoma and the complete set of genes (pemp = 0.002), as well as the subgroups related to the generation of tolerogenic dendritic cells (pemp = 0.006) and secretion of suppressive factors (pemp = 0.0004), thus providing preliminary evidence of involvement of tumour-immunosuppression gene polymorphisms in melanoma susceptibility. The analysis was repeated on a second phase of the GenoMEL study, which showed no evidence of an association. As one of the first attempts to replicate a pathway-level association, our results suggest that low power and heterogeneity may present challenges

A922 Sequential measurement of 1 hour creatinine clearance (1-CRCL) in critically ill patients at risk of acute kidney injury (AKI)

Meeting abstrac

The genetics of myopia

Myopia is the most common eye condition worldwide and its prevalence is increasing. While changes in environment, such as time spent outdoors, have driven myopia rates, within populations myopia is highly heritable. Genes are estimated to explain up to 80% of the variance in refractive error. Initial attempts to identify myopia genes relied on family studies using linkage analysis or candidate gene approaches with limited progress. More genome-wide association study (GWAS) approaches have taken over, ultimately resulting in the identification of hundreds of genes for refractive error and myopia, providing new insights into its molecular machinery. These studies showed myopia is a complex trait, with many genetic variants of small effect influencing retinal signaling, eye growth and the normal process of emmetropization. The genetic architecture and its molecular mechanisms are still to be clarified and while genetic risk score prediction models are improving, this knowledge must be expanded to have impact on clinical practice

Tunable Klein-like tunnelling of high-temperature superconducting pairs into graphene

Superconductivity can be induced in a normal material via the 'leakage' of superconducting pairs of charge carriers from an adjacent superconductor. This so-called proximity effect is markedly influenced by graphene's unique electronic structure, both in fundamental and technologically relevant ways. These include an unconventional form1,2 of the 'leakage' mechanism- the Andreev reflection3-and the potential of supercurrent modulation through electrical gating4. Despite the interest of high-temperature superconductors in that context5,6, realizations have been exclusively based on low-temperature ones. Here we demonstrate a gate-tunable, high-temperature superconducting proximity effect in graphene. Notably, gating effects result fromthe perfect transmission of superconducting pairs across an energy barrier-a form of Klein tunnelling7,8, up to nowobserved only for non-superconducting carriers9,10- and quantum interferences controlled by graphene doping. Interestingly, we find that this type of interference becomesdominant without the need of ultraclean graphene, in stark contrast to the case of low-temperature superconductors11. These results pave the way to a new class of tunable, high-temperature Josephson devices based on large-scale graphene