Studio di associazione caso-controllo per l'identificazione di pathways rilevanti per il rischio di cancro colorettale

Il tumore al colon retto è una patologia diffusa nei paesi sviluppati. Si calcola che annualmente 850.000 persone sviluppano tumore e 500.000 ne muoiono.. Il 92% dei casi riguarda individui di 50 anni di età ed oltre. Il 20% dei casi di tumore è di tipo familiare-ereditario, mentre il restante 70% è di tipo sporadico. Il tumore sporadico subisce l’influenza di fattori sia ambientali che genetici. Si ritiene che una dieta ricca di grassi e povera di frutta e verdura, la sedentarietà, il fumo e l’alcool siano tra i principali fattori di rischio. Si ritiene anche che polimorfismi genetici coinvolti nei processi infiammatori, nella riparazione dei danni al DNA, nella fisiologia dell’apparato digerente e nel metabolismo degli xenobiotici passono modulare la sucettibilità genetica a sviluppare il tumore. Lo scopo del presente studio è quello di individuare polimorfismi di geni coinvolti nei diversi processi cellulari sopra menzionati che possano essere associati alla predisposizione individuale a sviluppare il tumore al colon retto sporadico. E’ stato cosi’ effettuato uno studio esplorativo di tipo caso-controllo su 115 casi affetti da tumore al colon retto e 115 controlli. Il DNA dei casi e dei controlli è stato estratto a partire da sangue periferico. L’utilizzo di PCR multiplex seguita da tecnica Apex (Arrayed Primer Extension) basata sui micro-arrays è stata utilizzata per la genotipizzazione simultanea di 278 polimorfismi a singolo nucleotide (SNPs) di 108 geni candidati coinvolti nei processi metabolici e cellulari descritti. Per ciascun polimorfismo tramite l’analisi di regressione logistica e’ stato calcolato l’Odd Ratio, il relativo intervallo di confidenza e il livello di probabilita’ dell’associazione. Al fine di caratterizzare quale dei pathways considerati avesse maggiore rilevanza per il rischio, i geni sono stati classificati in base alla loro funzione e raggruppati in pathways secondo un approccio bioinformatico. Il peso relativo di ciascun pathway e’ stato valutato in relazione al numero di polimorfismi che mostravano associazione statisticamente significativa. I risultati sono anche stati verificati e messi in relazione alla letteratura scientifica sul tema

Variants at the 9p21 locus and melanoma risk

Background: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). Methods: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. Results: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3' UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A-allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). Conclusions: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes

Variants at chromosome 20 (ASIP locus) and melanoma risk

Agouti signaling protein (ASIP) locus on chromosome 20q11 is implicated, as shown by genome-wide association studies, in phenotype variation and melanoma risk. We genotyped 837 melanoma cases and 1,154 controls for 21 single nucleotide polymorphisms (SNPs) informative for 495 polymorphisms at the locus. Our data showed an increased risk of melanoma (odds ratio [OR] 1.27, 95% confidence interval [95% CI] 1.03-1.57) in carriers of the rs4911414 variant, located 120 kb upstream of ASIP. The main effect of rs4911414, as reported previously, was in tandem with a 10 kb adjacent polymorphism rs1015362; two constituted risk-associated haplotype/diplotype. Except for rs1015363, none of the 12 tagging SNPs, genotyped to cover 239.9 kb region with polymorphisms linked to rs4911414 and rs1015362, were associated with melanoma. Our data confirmed a previous association of melanoma risk (OR 1.82, 95% CI 1.37-2.41) with rs4911442, located in intron 5 of the nuclear receptor coactivator 6 (NCOA6) gene. The rs910871, one of the six variants, genotyped to cover NCOA6, showed an association with melanoma risk (OR 1.33, 95% CI 1.04-1.70). Both, rs4911442 and rs910871 were in moderate linkage with a, previously reported, risk-associated rs910873 polymorphism. A haplotype from the variants within NCOA6 showed an association with risk of melanoma (OR 1.49, 95% CI 1.17-1.88). Interaction between risk-associated polymorphisms and previously genotyped melanocortin receptor 1 (MC1R) variants, in our study, was not statistically significant. Nevertheless, the carriers of the variant alleles over the background of MC1R variants were at a higher risk than the carriers not enriched for MC1R variants. Our data confirmed the association of different variants at chromosome 20q11 with melanoma risk

Additional file 4: of Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Distribution of the number of diaries and months available per subject. (DOCX 14 kb

Additional file 2: of Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Flow diagram describing the study population. (DOCX 27 kb

Additional file 5: of Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Seasonal prevalence patterns for each symptom indicator. (DOCX 61 kb

Additional file 1: of Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Details into the AWIS study and the sub-cohort. (DOCX 20 kb

Additional file 3: of Obesity and risk of respiratory tract infections: results of an infection-diary based cohort study

Development of the nutrition score to assess more favourable and unfavourable dietary pattern. (DOCX 112 kb

Variants at the 9p21 locus and melanoma risk

BACKGROUND: The influence of variants at the 9p21 locus on melanoma risk has been reported through investigation of CDKN2A variants through candidate gene approach as well as by genome wide association studies (GWAS). METHODS: In the present study we genotyped, 25 SNPs that tag 273 variants on chromosome 9p21 in 837 melanoma cases and 1154 controls from Spain. Ten SNPs were selected based on previous associations, reported in GWAS, with either melanocytic nevi or melanoma risk or both. The other 15 SNPs were selected to fine map the CDKN2A gene region. RESULTS: All the 10 variants selected from the GWAS showed statistically significant association with melanoma risk. Statistically significant association with melanoma risk was also observed for the carriers of the variant T-allele of rs3088440 (540 C>T) at the 3’ UTR of CDKN2A gene with an OR 1.52 (95% CI 1.14-2.04). Interaction analysis between risk associated polymorphisms and previously genotyped MC1R variants, in the present study, did not show any statistically significant association. Statistical significant association was observed for the interaction between phototypes and the rs10811629 (located in intron 5 of MTAP). The strongest association was observed between the homozygous carrier of the A–allele and phototype II with an OR of 15.93 (95% CI 5.34-47.54). CONCLUSIONS: Our data confirmed the association of different variants at chromosome 9p21 with melanoma risk and we also found an association of a variant with skin phototypes