OBJECTIVE: An understanding of the etiologic heterogeneity of colorectal cancer (CRC) is critical for improving precision prevention, including individualized screening recommendations and the discovery of novel drug targets and repurposable drug candidates for chemoprevention. Known differences in molecular characteristics and environmental risk factors among tumors arising in different locations of the colorectum suggest partly distinct mechanisms of carcinogenesis. The extent to which the contribution of inherited genetic risk factors for CRC differs by anatomical subsite of the primary tumor has not been examined. DESIGN: To identify new anatomical subsite-specific risk loci, we performed genome-wide association study (GWAS) meta-analyses including data of 48 214 CRC cases and 64 159 controls of European ancestry. We characterised effect heterogeneity at CRC risk loci using multinomial modelling. RESULTS: We identified 13 loci that reached genome-wide significance (p<5×10-8) and that were not reported by previous GWASs for overall CRC risk. Multiple lines of evidence support candidate genes at several of these loci. We detected substantial heterogeneity between anatomical subsites. Just over half (61) of 109 known and new risk variants showed no evidence for heterogeneity. In contrast, 22 variants showed association with distal CRC (including rectal cancer), but no evidence for association or an attenuated association with proximal CRC. For two loci, there was strong evidence for effects confined to proximal colon cancer. CONCLUSION: Genetic architectures of proximal and distal CRC are partly distinct. Studies of risk factors and mechanisms of carcinogenesis, and precision prevention strategies should take into consideration the anatomical subsite of the tumour.
- MeSH
- alely MeSH
- běloši genetika MeSH
- cékum MeSH
- celogenomová asociační studie MeSH
- colon ascendens MeSH
- colon descendens MeSH
- colon sigmoideum MeSH
- colon transversum MeSH
- dospělí MeSH
- genetická heterogenita * MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus MeSH
- kolon * MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- nádory rekta diagnóza genetika MeSH
- nádory tračníku diagnóza genetika MeSH
- rizikové faktory MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- studie případů a kontrol MeSH
- věk při počátku nemoci MeSH
- věkové rozložení MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
To further dissect the genetic architecture of colorectal cancer (CRC), we performed whole-genome sequencing of 1,439 cases and 720 controls, imputed discovered sequence variants and Haplotype Reference Consortium panel variants into genome-wide association study data, and tested for association in 34,869 cases and 29,051 controls. Findings were followed up in an additional 23,262 cases and 38,296 controls. We discovered a strongly protective 0.3% frequency variant signal at CHD1. In a combined meta-analysis of 125,478 individuals, we identified 40 new independent signals at P < 5 × 10-8, bringing the number of known independent signals for CRC to ~100. New signals implicate lower-frequency variants, Krüppel-like factors, Hedgehog signaling, Hippo-YAP signaling, long noncoding RNAs and somatic drivers, and support a role for immune function. Heritability analyses suggest that CRC risk is highly polygenic, and larger, more comprehensive studies enabling rare variant analysis will improve understanding of biology underlying this risk and influence personalized screening strategies and drug development.
- MeSH
- celogenomová asociační studie metody MeSH
- genetická predispozice k nemoci genetika MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus genetika MeSH
- kolorektální nádory genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- rizikové faktory MeSH
- RNA dlouhá nekódující genetika MeSH
- senioři MeSH
- signální transdukce genetika MeSH
- studie případů a kontrol MeSH
- Check Tag
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
Objective: Determinants of the increased risk of diffuse large B-cell lymphoma (DLBCL) in SLE are unclear. Using data from a recent lymphoma genome-wide association study (GWAS), we assessed whether certain lupus-related single nucleotide polymorphisms (SNPs) were also associated with DLBCL. Methods: GWAS data on European Caucasians from the International Lymphoma Epidemiology Consortium (InterLymph) provided a total of 3857 DLBCL cases and 7666 general-population controls. Data were pooled in a random-effects meta-analysis. Results: Among the 28 SLE-related SNPs investigated, the two most convincingly associated with risk of DLBCL included the CD40 SLE risk allele rs4810485 on chromosome 20q13 (OR per risk allele=1.09, 95% CI 1.02 to 1.16, p=0.0134), and the HLA SLE risk allele rs1270942 on chromosome 6p21.33 (OR per risk allele=1.17, 95% CI 1.01 to 1.36, p=0.0362). Of additional possible interest were rs2205960 and rs12537284. The rs2205960 SNP, related to a cytokine of the tumour necrosis factor superfamily TNFSF4, was associated with an OR per risk allele of 1.07, 95% CI 1.00 to 1.16, p=0.0549. The OR for the rs12537284 (chromosome 7q32, IRF5 gene) risk allele was 1.08, 95% CI 0.99 to 1.18, p=0.0765. Conclusions: These data suggest several plausible genetic links between DLBCL and SLE.
- Publikační typ
- časopisecké články MeSH
Previous genome-wide association studies (GWAS) have identified six risk loci for renal cell carcinoma (RCC). We conducted a meta-analysis of two new scans of 5,198 cases and 7,331 controls together with four existing scans, totalling 10,784 cases and 20,406 controls of European ancestry. Twenty-four loci were tested in an additional 3,182 cases and 6,301 controls. We confirm the six known RCC risk loci and identify seven new loci at 1p32.3 (rs4381241, P=3.1 × 10-10), 3p22.1 (rs67311347, P=2.5 × 10-8), 3q26.2 (rs10936602, P=8.8 × 10-9), 8p21.3 (rs2241261, P=5.8 × 10-9), 10q24.33-q25.1 (rs11813268, P=3.9 × 10-8), 11q22.3 (rs74911261, P=2.1 × 10-10) and 14q24.2 (rs4903064, P=2.2 × 10-24). Expression quantitative trait analyses suggest plausible candidate genes at these regions that may contribute to RCC susceptibility.
- MeSH
- běloši genetika MeSH
- celogenomová asociační studie * MeSH
- dospělí MeSH
- fenotyp MeSH
- genetická predispozice k nemoci * MeSH
- genetické lokusy MeSH
- jednonukleotidový polymorfismus MeSH
- karcinom z renálních buněk genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- nádory ledvin genetika MeSH
- senioři MeSH
- zárodečné mutace MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mladý dospělý MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
Evidence from a small number of studies suggests that longer telomere length measured in peripheral leukocytes is associated with an increased risk of non-Hodgkin lymphoma (NHL). However, these studies may be biased by reverse causation, confounded by unmeasured environmental exposures and might miss time points for which prospective telomere measurement would best reveal a relationship between telomere length and NHL risk. We performed an analysis of genetically inferred telomere length and NHL risk in a study of 10 102 NHL cases of the four most common B-cell histologic types and 9562 controls using a genetic risk score (GRS) comprising nine telomere length-associated single-nucleotide polymorphisms. This approach uses existing genotype data and estimates telomere length by weighing the number of telomere length-associated variant alleles an individual carries with the published change in kb of telomere length. The analysis of the telomere length GRS resulted in an association between longer telomere length and increased NHL risk [four B-cell histologic types combined; odds ratio (OR) = 1.49, 95% CI 1.22-1.82,P-value = 8.5 × 10(-5)]. Subtype-specific analyses indicated that chronic lymphocytic leukemia or small lymphocytic lymphoma (CLL/SLL) was the principal NHL subtype contributing to this association (OR = 2.60, 95% CI 1.93-3.51,P-value = 4.0 × 10(-10)). Significant interactions were observed across strata of sex for CLL/SLL and marginal zone lymphoma subtypes as well as age for the follicular lymphoma subtype. Our results indicate that a genetic background that favors longer telomere length may increase NHL risk, particularly risk of CLL/SLL, and are consistent with earlier studies relating longer telomere length with increased NHL risk.
- MeSH
- B-buněčný lymfom genetika patologie MeSH
- dospělí MeSH
- genetická predispozice k nemoci * MeSH
- genetické asociační studie metody MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- prospektivní studie MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- telomery patologie MeSH
- věkové faktory MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mladiství MeSH
- mužské pohlaví MeSH
- senioři nad 80 let MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, N.I.H., Intramural MeSH
- Research Support, U.S. Gov't, Non-P.H.S. MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
OBJECTIVE: To use the rs1229984 variant in the alcohol dehydrogenase 1B gene (ADH1B) as an instrument to investigate the causal role of alcohol in cardiovascular disease. DESIGN: Mendelian randomisation meta-analysis of 56 epidemiological studies. PARTICIPANTS: 261 991 individuals of European descent, including 20 259 coronary heart disease cases and 10 164 stroke events. Data were available on ADH1B rs1229984 variant, alcohol phenotypes, and cardiovascular biomarkers. MAIN OUTCOME MEASURES: Odds ratio for coronary heart disease and stroke associated with the ADH1B variant in all individuals and by categories of alcohol consumption. RESULTS: Carriers of the A-allele of ADH1B rs1229984 consumed 17.2% fewer units of alcohol per week (95% confidence interval 15.6% to 18.9%), had a lower prevalence of binge drinking (odds ratio 0.78 (95% CI 0.73 to 0.84)), and had higher abstention (odds ratio 1.27 (1.21 to 1.34)) than non-carriers. Rs1229984 A-allele carriers had lower systolic blood pressure (-0.88 (-1.19 to -0.56) mm Hg), interleukin-6 levels (-5.2% (-7.8 to -2.4%)), waist circumference (-0.3 (-0.6 to -0.1) cm), and body mass index (-0.17 (-0.24 to -0.10) kg/m(2)). Rs1229984 A-allele carriers had lower odds of coronary heart disease (odds ratio 0.90 (0.84 to 0.96)). The protective association of the ADH1B rs1229984 A-allele variant remained the same across all categories of alcohol consumption (P=0.83 for heterogeneity). Although no association of rs1229984 was identified with the combined subtypes of stroke, carriers of the A-allele had lower odds of ischaemic stroke (odds ratio 0.83 (0.72 to 0.95)). CONCLUSIONS: Individuals with a genetic variant associated with non-drinking and lower alcohol consumption had a more favourable cardiovascular profile and a reduced risk of coronary heart disease than those without the genetic variant. This suggests that reduction of alcohol consumption, even for light to moderate drinkers, is beneficial for cardiovascular health.
- MeSH
- alkoholdehydrogenasa genetika MeSH
- biologické markery krev MeSH
- cévní mozková příhoda krev etiologie genetika MeSH
- dospělí MeSH
- genetické markery MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus * MeSH
- koronární nemoc krev etiologie genetika MeSH
- lidé středního věku MeSH
- lidé MeSH
- mendelovská randomizace MeSH
- pití alkoholu škodlivé účinky genetika MeSH
- senioři MeSH
- statistické modely MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- práce podpořená grantem MeSH
- Research Support, N.I.H., Extramural MeSH
- Research Support, U.S. Gov't, P.H.S. MeSH
Diffuse large B cell lymphoma (DLBCL) is the most common lymphoma subtype and is clinically aggressive. To identify genetic susceptibility loci for DLBCL, we conducted a meta-analysis of 3 new genome-wide association studies (GWAS) and 1 previous scan, totaling 3,857 cases and 7,666 controls of European ancestry, with additional genotyping of 9 promising SNPs in 1,359 cases and 4,557 controls. In our multi-stage analysis, five independent SNPs in four loci achieved genome-wide significance marked by rs116446171 at 6p25.3 (EXOC2; P = 2.33 × 10(-21)), rs2523607 at 6p21.33 (HLA-B; P = 2.40 × 10(-10)), rs79480871 at 2p23.3 (NCOA1; P = 4.23 × 10(-8)) and two independent SNPs, rs13255292 and rs4733601, at 8q24.21 (PVT1; P = 9.98 × 10(-13) and 3.63 × 10(-11), respectively). These data provide substantial new evidence for genetic susceptibility to this B cell malignancy and point to pathways involved in immune recognition and immune function in the pathogenesis of DLBCL.
- MeSH
- běloši genetika MeSH
- celogenomová asociační studie MeSH
- difúzní velkobuněčný B-lymfom genetika MeSH
- genetická predispozice k nemoci genetika MeSH
- genetické lokusy genetika MeSH
- genotyp MeSH
- jednonukleotidový polymorfismus genetika MeSH
- lidé MeSH
- lokus kvantitativního znaku genetika MeSH
- mapování chromozomů MeSH
- pravděpodobnostní funkce MeSH
- výpočetní biologie MeSH
- Check Tag
- lidé MeSH
- Publikační typ
- časopisecké články MeSH
- metaanalýza MeSH
- Research Support, N.I.H., Intramural MeSH
Human papillomavirus (HPV) infections have been implicated in lung carcinogenesis, but causal associations remain uncertain. We evaluated a potential causal role for HPV infections in lung cancer through an analysis involving serology, tumor DNA, RNA, and p16 protein expression. Association between type-specific HPV antibodies and risk of lung cancer was examined among 3,083 cases and 4,328 controls in two case-control studies (retrospective) and one nested case-control study (prospective design). Three hundred and thirty-four available tumors were subjected to pathologic evaluation and subsequent HPV genotyping following stringent conditions to detect all high-risk and two low-risk HPV types. All HPV DNA-positive tumors were further tested for the expression of p16 protein and type-specific HPV mRNA. On the basis of the consistency of the results, although HPV11 and HPV31 E6 antibodies were associated with lung cancer risk in the retrospective study, no association was observed in the prospective design. Presence of type-specific antibodies correlated poorly with the presence of the corresponding HPV DNA in the tumor. Although nearly 10% of the lung tumors were positive for any HPV DNA (7% for HPV16 DNA), none expressed the viral oncogenes. No association was observed between HPV antibodies or DNA and lung cancer survival. In conclusion, we found no supportive evidence for the hypothesized causal association between HPV infections and lung cancer.
- MeSH
- DNA virů analýza genetika MeSH
- dospělí MeSH
- infekce papilomavirem etiologie genetika virologie MeSH
- lidé středního věku MeSH
- lidé MeSH
- lidský papilomavirus 11 imunologie MeSH
- lidský papilomavirus 16 imunologie MeSH
- lidský papilomavirus 18 imunologie MeSH
- lidský papilomavirus 6 imunologie MeSH
- nádorové proteiny biosyntéza MeSH
- nádory plic komplikace mortalita virologie MeSH
- onkogenní proteiny virové genetika imunologie MeSH
- Papillomaviridae genetika MeSH
- prospektivní studie MeSH
- protilátky virové imunologie MeSH
- retrospektivní studie MeSH
- RNA virová biosyntéza MeSH
- senioři MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- senioři MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
Cíl Naším cílem bylo zjistit vliv kouření cigaret na riziko nádorů zařazených do International Agency for Research on Cancer mezi nádory v kauzální souvislosti s kouřením, označovaných jako zhoubné nádory související s tabákem (TRC). Metody Populaci studie tvořilo 441 211 účastníků (133 018 mužů a 308 193 žen) ze studie European Prospective Investigation Into Cancer and Nutrition. Hodnotili jsme 14 563 účastníků, u nichž došlo k rozvoji TRC, s dobou sledování v průměru 11 let. Vliv kouření cigaret na riziko zhoubného nádoru byl posouzen pomocí populační atributivní frakce (AFp), která byla vypočtena z korigovaných poměrů rizik (HR) a 95% CI pro stávající a bývalé kuřáky, a dále buď z prevalence kouření u případů zhoubného nádoru nebo odhadů vypočtených z průzkumů v reprezentativních vzorcích populace ve všech jednotlivých zemích. Výsledky Podíl všech TRC způsobených kouřením cigaret byl 34,9 % (95% CI, 32,5–37,4) podle výpočtu na základě prevalence kouření u případů a 36,2 % (95% CI, 33,7–38,6) na základě prevalence kouření v populaci. Hodnoty AFp byly vyšší než 80 % pro karcinomy plic a hrtanu, mezi 20 % a 50 % pro většinu zhoubných nádorů dýchacích cest a gastrointestinálního traktu a nádorů z dolních močových cest a méně než 20 % pro ostatní TRC. Závěr Na základě údajů o incidenci zhoubných nádorů z roku 2008 a našich odhadů AFp je možno působením kouření cigaret vysvětlit přibližně 270 000 nových diagnóz zhoubných nádorů za 1 rok v osmi evropských zemích, v nichž byly dostupné údaje pro muže i ženy (Itálie, Španělsko, Velká Británie, Nizozemsko, Řecko, Německo, Švédsko, Dánsko).
- MeSH
- časové faktory MeSH
- hodnocení rizik MeSH
- incidence MeSH
- kohortové studie MeSH
- kouření * epidemiologie škodlivé účinky MeSH
- lidé MeSH
- nádory podle lokalizace * MeSH
- nádory * epidemiologie MeSH
- Check Tag
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Geografické názvy
- Dánsko MeSH
- Itálie MeSH
- Německo MeSH
- Nizozemsko MeSH
- Řecko MeSH
- Španělsko MeSH
- Spojené království MeSH
- Švédsko MeSH