TY - JOUR
T1 - Pathway-Based analysis of a Melanoma Genome-Wide association study
T2 - Analysis of genes related to Tumour-Immunosuppression
AU - GenoMEL consortium
AU - Schoof, Nils
AU - Iles, Mark M.
AU - Bishop, D. Timothy
AU - Newton-Bishop, Julia A.
AU - Barrett, Jennifer H.
AU - Mann, Graham J.
AU - Hopper, John L.
AU - Aitken, Joanne F.
AU - Armstrong, Bruce K.
AU - Giles, Graham G.
AU - Kefford, Richard F.
AU - Cust, Anne
AU - Jenkins, Mark
AU - Aguilera, Paula
AU - Badenas, Celia
AU - Carrera, Cristina
AU - Cuellar, Francisco
AU - Gabriel, Daniel
AU - Martinez, Estefania
AU - Gonzalez, Melinda
AU - Iglesias, Pablo
AU - Malvehy, Josep
AU - Marti-Laborda, Rosa
AU - Mila, Montse
AU - Ogbah, Zighe
AU - Butille, Joan Anton Puig
AU - Puig, Susana
AU - Alós, Llúcia
AU - Arance, Ana
AU - ArguÃs, Pedro
AU - Campo, Antonio
AU - Castel, Teresa
AU - Conill, Carlos
AU - Palou, Jose
AU - Rull, Ramon
AU - Sánchez, Marcelo
AU - Vidal-Sicart, Sergi
AU - Vilalta, Antonio
AU - Vilella, Ramon
AU - Martin, Nicholas G.
AU - Montgomery, Grant W.
AU - Duffy, David
AU - Whiteman, David
AU - Macgregor, Stuart
AU - Hayward, Nicholas K.
AU - Webb, Penny
AU - Green, Adele
AU - Parsons, Peter
AU - Caron, Olivier
AU - Robert, Caroline
PY - 2011/12/27
Y1 - 2011/12/27
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84455172956&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0029451
DO - 10.1371/journal.pone.0029451
M3 - Article
C2 - 22216283
AN - SCOPUS:84455172956
SN - 1932-6203
VL - 6
JO - PLoS ONE
JF - PLoS ONE
IS - 12
M1 - e29451
ER -