The Interplay between Natural Selection and Susceptibility to Melanoma on Allele 374F of SLC45A2 Gene in a South European Population

We aimed to study the selective pressures interacting on SLC45A2 to investigate the interplay between selection and susceptibility to disease. Thus, we enrolled 500 volunteers from a geographically limited population (Basques from the North of Spain) and by resequencing the whole coding region and intron 5 of the 34 most and the 34 least pigmented individuals according to the reflectance distribution, we observed that the polymorphism Leu374Phe (L374F, rs16891982) was statistically associated with skin color variability within this sample. In particular, allele 374F was significantly more frequent among the individuals with lighter skin. Further genotyping an independent set of 558 individuals of a geographically wider population with known ancestry in the Spanish population also revealed that the frequency of L374F was significantly correlated with the incident UV radiation intensity. Selection tests suggest that allele 374F is being positively selected in South Europeans, thus indicating that depigmentation is an adaptive process. Interestingly, by genotyping 119 melanoma samples, we show that this variant is also associated with an increased susceptibility to melanoma in our populations. The ultimate driving force for this adaptation is unknown, but it is compatible with the vitamin D hypothesis. This shows that molecular evolution analysis can be used as a useful technology to predict phenotypic and biomedical consequences in humans

Involvement of ANXA5 and ILKAP in Susceptibility to Malignant Melanoma

Single nucleotide-polymorphisms (SNPs) are a source of diversity among human population, which may be responsible for the different individual susceptibility to diseases and/or response to drugs, among other phenotypic traits. Several low penetrance susceptibility genes associated with malignant melanoma (MM) have been described, including genes related to pigmentation, DNA damage repair and oxidative stress pathways. In the present work, we conducted a candidate gene association study based on proteins and genes whose expression we had detected altered in melanoma cell lines as compared to normal melanocytes. The result was the selection of 88 loci and 384 SNPs, of which 314 fulfilled our quality criteria for a case-control association study. The SNP rs6854854 in ANXA5 was statistically significant after conservative Bonferroni correction when 464 melanoma patients and 400 controls were analyzed in a discovery Phase I. However, this finding could not be replicated in the validation phase, perhaps because the minor allele frequency of SNP rs6854854 varies depending on the geographical region considered. Additionally, a second SNP (rs6431588) located on ILKAP was found to be associated with melanoma after considering a combined set of 1,883 MM cases and 1,358 disease-free controls. The OR was 1.29 (95% CI 1.12–1.48; p-value = 4×10−4). Both SNPs, rs6854854 in ANXA5 and rs6431588 in ILKAP, show population structure, which, assuming that the Spanish population is not significantly structured, suggests a role of these loci on a specific genetic adaptation to different environmental conditions. Furthermore, the biological relevance of these genes in MM is supported by in vitro experiments, which show a decrease in the transcription levels of ANXA5 and ILKAP in melanoma cells compared to normal melanocyte

Sensibilización alérgica por tatuajes de henna = Hennazko tatuaiek eragindako sentsibilizazio alergikoa: a propósito de tres casos = hiru kasu

Los tatuajes de henna son objeto de una popularidad creciente debido a su aparente inocuidad y a su corta duración en el tiempo. Sin embargo, las mezclas de henna negra de uso comercial pueden contener alergenos añadidos, como la parafenilendiamina (PPD), capaces de provocar dermatitis de contacto e incluso sensibilización permanente a estas sustancias. Esto podría dar lugar en el futuro a reacciones cruzadas frente a tintes, colorantes textiles y algunos fármacos. Los eccemas de contacto por estos aditivos son cada vez más referidos en las publicaciones, aunque existen pocos casos descritos en población infantil y sólo hemos encontrado cinco en el ámbito nacional(1,2), dos de ellos de publicación muy reciente(3). En una población de 1.300 niños menores de 14 años observamos 3 casos sucedidos en los meses de verano de 2004 que podrían ser el exponente de un número mayor de niños afectados. Creemos que la práctica de tatuajes de henna en niños debe ser abandonada ya que no está exenta de riesgos

SNP association results.

<p>The –log10 of the allelic p-values from 314 SNPs comparing 464 melanoma patients and 400 controls of Spanish origin at Phase I are represented. The chromosomal SNP distribution is shown. The SNP rs6854854 in <i>ANXA5</i> remained statistically significant after Bonferroni correction (p-<i>value</i> <0.00015).</p

Western blot analysis for Annexin A5 in melanoma cell lines and primary melanocytes.

<p>(A) Western blotting shows a decrease in Annexin A5 protein levels in melanoma cell lines with respect to primary melanocytes; γ-tubulin was used as the internal control. (B) Histogram showing the relative expression levels of Annexin A5 in melanoma cell lines and primary melanocytes.</p

Haplotypes in the promoter region of <i>ILKAP</i> gene in different populations obtained from 1000 Genomes Project.

<p>Although we detected three different haplotypes among the melanoma cell lines and the primary melanocytes studied (underlined haplotypes), a total of six different haplotypes have been reported worldwide. Each haplotype is represented with a circle, whose size is proportional to their frequency in the global population. The genealogic relationship suggests the existence of two different main lineages, showed in green and red circles.</p

Data of the SNPs analyzed in Phase II.

<p>Chrom. Chromosome; OR (95% CI) Odds ratio (95% confidence interval).</p

<i>ANXA5</i> and <i>ILKAP</i> mRNA expression in human melanoma cell lines and primary melanocytes.

<p>A) <i>ANXA5</i> relative expression levels. B) <i>ILKAP</i> relative expression levels. Results are expressed as mean relative expression fold ± standard deviation (SD) in the histograms, calculated on six replicates of each sample. The relative expression fold values are reported in boxes below histograms. The average expression of primary melanocytes is shown with a dashed line. Statistically significant differences of each melanoma cell line with respect to primary melanocytes: * p-<i>value</i> ≤0.05; ** p-<i>value</i> ≤0.01.</p