Beyond GWAS of Colorectal Cancer: Evidence of Interaction with Alcohol Consumption and Putative Causal Variant for the 10q24.2 Region.
Journal
Cancer epidemiology, biomarkers & prevention : a publication of the American Association for Cancer Research, cosponsored by the American Society of Preventive Oncology
ISSN: 1538-7755
Titre abrégé: Cancer Epidemiol Biomarkers Prev
Pays: United States
ID NLM: 9200608
Informations de publication
Date de publication:
04 05 2022
04 05 2022
Historique:
received:
20
08
2021
revised:
30
10
2021
accepted:
15
02
2022
pubmed:
20
4
2022
medline:
6
5
2022
entrez:
19
4
2022
Statut:
ppublish
Résumé
Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer. Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models. For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif. Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region. The study identifies multifaceted evidence of a possible functional effect for rs1318920.
Sections du résumé
BACKGROUND
Currently known associations between common genetic variants and colorectal cancer explain less than half of its heritability of 25%. As alcohol consumption has a J-shape association with colorectal cancer risk, nondrinking and heavy drinking are both risk factors for colorectal cancer.
METHODS
Individual-level data was pooled from the Colon Cancer Family Registry, Colorectal Transdisciplinary Study, and Genetics and Epidemiology of Colorectal Cancer Consortium to compare nondrinkers (≤1 g/day) and heavy drinkers (>28 g/day) with light-to-moderate drinkers (1-28 g/day) in GxE analyses. To improve power, we implemented joint 2df and 3df tests and a novel two-step method that modifies the weighted hypothesis testing framework. We prioritized putative causal variants by predicting allelic effects using support vector machine models.
RESULTS
For nondrinking as compared with light-to-moderate drinking, the hybrid two-step approach identified 13 significant SNPs with pairwise r2 > 0.9 in the 10q24.2/COX15 region. When stratified by alcohol intake, the A allele of lead SNP rs2300985 has a dose-response increase in risk of colorectal cancer as compared with the G allele in light-to-moderate drinkers [OR for GA genotype = 1.11; 95% confidence interval (CI), 1.06-1.17; OR for AA genotype = 1.22; 95% CI, 1.14-1.31], but not in nondrinkers or heavy drinkers. Among the correlated candidate SNPs in the 10q24.2/COX15 region, rs1318920 was predicted to disrupt an HNF4 transcription factor binding motif.
CONCLUSIONS
Our study suggests that the association with colorectal cancer in 10q24.2/COX15 observed in genome-wide association study is strongest in nondrinkers. We also identified rs1318920 as the putative causal regulatory variant for the region.
IMPACT
The study identifies multifaceted evidence of a possible functional effect for rs1318920.
Identifiants
pubmed: 35438744
pii: 694506
doi: 10.1158/1055-9965.EPI-21-1003
pmc: PMC9081195
mid: NIHMS1783982
doi:
Substances chimiques
COX15 protein, human
EC 1.9.3.1
Electron Transport Complex IV
EC 1.9.3.1
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Research Support, U.S. Gov't, P.H.S.
Langues
eng
Sous-ensembles de citation
IM
Pagination
1077-1089Subventions
Organisme : NCI NIH HHS
ID : R01 CA059045
Pays : United States
Organisme : NIEHS NIH HHS
ID : P30 ES010126
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA182883
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA137088
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA164930
Pays : United States
Organisme : NCI NIH HHS
ID : U01 CA206110
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA201407
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA196569
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA206279
Pays : United States
Organisme : NCI NIH HHS
ID : UG1 CA189974
Pays : United States
Informations de copyright
©2022 American Association for Cancer Research.
Références
PLoS Genet. 2016 Oct 10;12(10):e1006296
pubmed: 27723779
Cancers (Basel). 2018 Jan 30;10(2):
pubmed: 29385712
Genet Epidemiol. 2008 Apr;32(3):255-63
pubmed: 18200600
Am J Hum Genet. 2007 Sep;81(3):607-14
pubmed: 17701906
Gigascience. 2015 Feb 25;4:7
pubmed: 25722852
Bioinformatics. 2016 Jul 15;32(14):2196-8
pubmed: 27153584
Nat Commun. 2015 Jul 07;6:7138
pubmed: 26151821
Hum Genet. 2012 May;131(5):747-56
pubmed: 22143225
Am J Epidemiol. 2019 Apr 1;188(4):760-767
pubmed: 30649161
Nature. 2015 Feb 19;518(7539):317-30
pubmed: 25693563
Alcohol. 2017 Jun;61:25-31
pubmed: 28599714
Nat Commun. 2017 Feb 07;8:14400
pubmed: 28169291
Nat Methods. 2020 Jun;17(6):629-635
pubmed: 32483332
Int J Cancer. 2020 Feb 1;146(3):861-873
pubmed: 31037736
Proc Natl Acad Sci U S A. 1997 Nov 25;94(24):13209-14
pubmed: 9371825
Cell. 2018 Nov 29;175(6):1701-1715.e16
pubmed: 30449622
Am J Epidemiol. 2009 Jan 15;169(2):219-26
pubmed: 19022827
Biomark Med. 2012 Jun;6(3):297-300
pubmed: 22731903
Cell. 2016 Dec 15;167(7):1853-1866.e17
pubmed: 27984732
Nat Genet. 2016 Oct;48(10):1284-1287
pubmed: 27571263
Genet Epidemiol. 2008 May;32(4):361-9
pubmed: 18271029
Cell Mol Gastroenterol Hepatol. 2021;12(1):181-197
pubmed: 33601062
Nat Rev Genet. 2011 Nov 18;12(12):881; author reply 881
pubmed: 22094952
Genet Epidemiol. 2011 Feb;35(2):102-10
pubmed: 21254217
Mol Genet Genomics. 2014 Jun;289(3):253-69
pubmed: 24395673
Cancer Res. 2012 Apr 15;72(8):2036-44
pubmed: 22367214
Atherosclerosis. 2006 May;186(1):113-20
pubmed: 16055129
Hepatology. 2009 Oct;50(4):1241-50
pubmed: 19637192
Nat Genet. 2019 Jan;51(1):76-87
pubmed: 30510241
Gastrointest Endosc. 2017 Jul;86(1):93-104.e5
pubmed: 28011280
Methods Mol Biol. 2018;1856:157-172
pubmed: 30178251
Mutagenesis. 2020 Jul 11;35(3):221-231
pubmed: 31605533
Stat Med. 2001 Dec 30;20(24):3875-89
pubmed: 11782040
Curr Protoc Bioinformatics. 2014 Sep 08;47:11.12.1-34
pubmed: 25199790
Hepatogastroenterology. 2012 Nov-Dec;59(120):2552-6
pubmed: 22534544
Bioinformatics. 2010 Sep 15;26(18):2336-7
pubmed: 20634204
Sci Rep. 2021 Jan 11;11(1):432
pubmed: 33432071
J Natl Cancer Inst. 2019 Feb 1;111(2):146-157
pubmed: 29917119
Bioinformatics. 2021 Apr 20;37(3):422-423
pubmed: 32745185
Am J Clin Nutr. 2008 Oct;88(4):1097-103
pubmed: 18842799
Genome Biol. 2007;8(2):R24
pubmed: 17324271
Bioinformatics. 2019 Jul 15;35(14):i173-i182
pubmed: 31510661
Nature. 2021 Feb;590(7845):290-299
pubmed: 33568819
Nat Protoc. 2017 Dec;12(12):2478-2492
pubmed: 29120462