Type 2 Diabetes Risk Variants and Colorectal Cancer Risk: the Multiethnic Cohort and PAGE Studies

Overview

Journal Gut

Specialty Gastroenterology

Date 2011 May 24

PMID 21602532

Citations 24

Authors

Iona Cheng

Christian P Caberto

Annette Lum-Jones

Ann Seifried

Lynne R Wilkens

Fredrick R Schumacher

Kristine R Monroe

Unhee Lim

Maarit Tiirikainen

Laurence N Kolonel

Brian E Henderson

Daniel O Stram

Christopher A Haiman

Loic Le Marchand

Affiliations

Soon will be listed here.

Abstract

Background: Diabetes has been positively associated with the risk of colorectal cancer. This study investigated whether recently established risk variants for diabetes also have effects on colorectal cancer.

Methods: 19 single nucleotide repeats (SNPs) associated with type 2 diabetes in genome-wide association studies were tested in a case-control study of 2011 colorectal cancer cases and 6049 controls nested in the Multiethnic Cohort study as part of the Population Architecture using Genomics and Epidemiology (PAGE) initiative. ORs and 95% CIs were estimated by unconditional logistic regression to evaluate the association between SNPs and colorectal cancer risk, adjusting for age, sex and race/ethnicity. Permutation testing was conducted to correct for multiple hypothesis testing.

Results: Four type 2 diabetes SNPs were associated with colorectal cancer risk: rs7578597 (THADA), rs864745 (JAZF1), rs5219 (KCNJ11) and rs7961581 (TSPAN8, LGR5). The strongest association was for the rs7578597 (THADA) Thr1187Ala missense polymorphism (P(trend)=0.004 adjusted for multiple testing), with the high risk allele for colorectal cancer being the low risk allele for diabetes. Similar patterns of associations were seen with further adjustment for diabetes status and body mass index. The association of diabetes status with colorectal cancer risk was somewhat weakened after adjustment for these SNPs.

Conclusion: The findings suggest that diabetes risk variants also influence colorectal cancer susceptibility, possibly through mechanisms different from those for diabetes.

Citing Articles

Unraveling the potential effects of non-synonymous single nucleotide polymorphisms (nsSNPs) on the Protein structure and function of the human gene on type 2 diabetes and colorectal cancer: An approach.

Uddin M, Hossain M, Hossain M, Ahsan A, Shamim K, Hossen M Heliyon. 2024; 10(17):e37280.

PMID: 39296124 PMC: 11408818. DOI: 10.1016/j.heliyon.2024.e37280.

Associations between Diabetes Mellitus and Selected Cancers.

Pliszka M, Szablewski L Int J Mol Sci. 2024; 25(13).

PMID: 39000583 PMC: 11242587. DOI: 10.3390/ijms25137476.

THADA inhibits autophagy and increases 5-FU sensitivity in gastric cancer cells via the PI3K/AKT/mTOR signaling pathway.

Lin X, Pan J, Hamoudi H, Yu J Iran J Basic Med Sci. 2024; 27(2):195-202.

PMID: 38234670 PMC: 10790288. DOI: 10.22038/IJBMS.2023.72055.15668.

Exploring genetic loci of type 2 diabetes and cancer: a review.

Endicott M, Thirlwell C, Webster A Endocr Oncol. 2023; 3(1):e220094.

PMID: 37529774 PMC: 10388678. DOI: 10.1530/EO-22-0094.

TCF7L2, CASC8, and GREM1 polymorphism and colorectal cancer in south-eastern Romanian population.

Mitroi A, Leopa N, Dumitru E, Dumitru A, Tocia C, Popescu I Medicine (Baltimore). 2023; 102(7):e33056.

PMID: 36800588 PMC: 9936048. DOI: 10.1097/MD.0000000000033056.

References

Unoki H, Takahashi A, Kawaguchi T, Hara K, Horikoshi M, Andersen G . SNPs in KCNQ1 are associated with susceptibility to type 2 diabetes in East Asian and European populations. Nat Genet. 2008; 40(9):1098-102. DOI: 10.1038/ng.208. View

Stancakova A, Kuulasmaa T, Paananen J, Jackson A, Bonnycastle L, Collins F . Association of 18 confirmed susceptibility loci for type 2 diabetes with indices of insulin release, proinsulin conversion, and insulin sensitivity in 5,327 nondiabetic Finnish men. Diabetes. 2009; 58(9):2129-36. PMC: 2731523. DOI: 10.2337/db09-0117. View

LeRoy E, Moore J, Hu C, Martinez M, Lance P, Duggan D . Genes in the insulin and insulin-like growth factor pathway and odds of metachronous colorectal neoplasia. Hum Genet. 2011; 129(5):503-12. DOI: 10.1007/s00439-010-0942-0. View

He J, Stram D, Kolonel L, Henderson B, Le Marchand L, Haiman C . The association of diabetes with colorectal cancer risk: the Multiethnic Cohort. Br J Cancer. 2010; 103(1):120-6. PMC: 2905298. DOI: 10.1038/sj.bjc.6605721. View

Johansson A, Marroni F, Hayward C, Franklin C, Kirichenko A, Jonasson I . Common variants in the JAZF1 gene associated with height identified by linkage and genome-wide association analysis. Hum Mol Genet. 2008; 18(2):373-80. PMC: 2638782. DOI: 10.1093/hmg/ddn350. View

Greco C, Bralet M, Ailane N, Dubart-Kupperschmitt A, Rubinstein E, Le Naour F . E-cadherin/p120-catenin and tetraspanin Co-029 cooperate for cell motility control in human colon carcinoma. Cancer Res. 2010; 70(19):7674-83. DOI: 10.1158/0008-5472.CAN-09-4482. View

Kosoy R, Nassir R, Tian C, White P, Butler L, Silva G . Ancestry informative marker sets for determining continental origin and admixture proportions in common populations in America. Hum Mutat. 2008; 30(1):69-78. PMC: 3073397. DOI: 10.1002/humu.20822. View

Drieschner N, Belge G, Rippe V, Meiboom M, Loeschke S, Bullerdiek J . Evidence for a 3p25 breakpoint hot spot region in thyroid tumors of follicular origin. Thyroid. 2006; 16(11):1091-6. DOI: 10.1089/thy.2006.16.1091. View

Sandhu M, Weedon M, Fawcett K, Wasson J, Debenham S, Daly A . Common variants in WFS1 confer risk of type 2 diabetes. Nat Genet. 2007; 39(8):951-3. PMC: 2672152. DOI: 10.1038/ng2067. View

10.

Yasuda K, Miyake K, Horikawa Y, Hara K, Osawa H, Furuta H . Variants in KCNQ1 are associated with susceptibility to type 2 diabetes mellitus. Nat Genet. 2008; 40(9):1092-7. DOI: 10.1038/ng.207. View

11.

Soranzo N, Rivadeneira F, Chinappen-Horsley U, Malkina I, Richards J, Hammond N . Meta-analysis of genome-wide scans for human adult stature identifies novel Loci and associations with measures of skeletal frame size. PLoS Genet. 2009; 5(4):e1000445. PMC: 2661236. DOI: 10.1371/journal.pgen.1000445. View

12.

Folsom A, Pankow J, Peacock J, Bielinski S, Heiss G, Boerwinkle E . Variation in TCF7L2 and increased risk of colon cancer: the Atherosclerosis Risk in Communities (ARIC) Study. Diabetes Care. 2008; 31(5):905-9. PMC: 2577771. DOI: 10.2337/dc07-2131. View

13.

Hazra A, Fuchs C, Chan A, Giovannucci E, Hunter D . Association of the TCF7L2 polymorphism with colorectal cancer and adenoma risk. Cancer Causes Control. 2008; 19(9):975-80. PMC: 2719293. DOI: 10.1007/s10552-008-9164-3. View

14.

Landi D, Moreno V, Guino E, Vodicka P, Pardini B, Naccarati A . Polymorphisms affecting micro-RNA regulation and associated with the risk of dietary-related cancers: a review from the literature and new evidence for a functional role of rs17281995 (CD86) and rs1051690 (INSR), previously associated with.... Mutat Res. 2010; 717(1-2):109-15. DOI: 10.1016/j.mrfmmm.2010.10.002. View

15.

Scott L, Mohlke K, Bonnycastle L, Willer C, Li Y, Duren W . A genome-wide association study of type 2 diabetes in Finns detects multiple susceptibility variants. Science. 2007; 316(5829):1341-5. PMC: 3214617. DOI: 10.1126/science.1142382. View

16.

Slattery M, Folsom A, Wolff R, Herrick J, Caan B, Potter J . Transcription factor 7-like 2 polymorphism and colon cancer. Cancer Epidemiol Biomarkers Prev. 2008; 17(4):978-82. PMC: 2587179. DOI: 10.1158/1055-9965.EPI-07-2687. View

17.

Zeggini E, Scott L, Saxena R, Voight B, Marchini J, Hu T . Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes. Nat Genet. 2008; 40(5):638-45. PMC: 2672416. DOI: 10.1038/ng.120. View

18.

Timpson N, Lindgren C, Weedon M, Randall J, Ouwehand W, Strachan D . Adiposity-related heterogeneity in patterns of type 2 diabetes susceptibility observed in genome-wide association data. Diabetes. 2008; 58(2):505-10. PMC: 2628627. DOI: 10.2337/db08-0906. View

19.

Thomas G, Jacobs K, Yeager M, Kraft P, Wacholder S, Orr N . Multiple loci identified in a genome-wide association study of prostate cancer. Nat Genet. 2008; 40(3):310-5. DOI: 10.1038/ng.91. View

20.

Pare G, Chasman D, Parker A, Nathan D, Miletich J, Zee R . Novel association of HK1 with glycated hemoglobin in a non-diabetic population: a genome-wide evaluation of 14,618 participants in the Women's Genome Health Study. PLoS Genet. 2008; 4(12):e1000312. PMC: 2596965. DOI: 10.1371/journal.pgen.1000312. View