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. 2023 Aug 1;83(15):2572-2583.
doi: 10.1158/0008-5472.CAN-22-3713.

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Elom K Aglago  1 , Andre Kim  2 , Yi Lin  3 , Conghui Qu  3 , Marina Evangelou  1 , Yu Ren  1 , John Morrison  2 , Demetrius Albanes  4 , Volker Arndt  5 , Elizabeth L Barry  6 , James W Baurley  7   8 , Sonja I Berndt  4 , Stephanie A Bien  3 , D Timothy Bishop  9 , Emmanouil Bouras  10 , Hermann Brenner  5   11   12 , Daniel D Buchanan  13   14   15 , Arif Budiarto  7   16 , Robert Carreras-Torres  17   18 , Graham Casey  19 , Tjeng Wawan Cenggoro  7 , Andrew T Chan  20   21   22   23   24   25 , Jenny Chang-Claude  26   27 , Xuechen Chen  5   28 , David V Conti  2 , Matthew Devall  29 , Virginia Diez-Obrero  17   30   31   32   33 , Niki Dimou  34 , David Drew  22 , Jane C Figueiredo  2   35 , Steven Gallinger  36 , Graham G Giles  37   38   39 , Stephen B Gruber  40 , Andrea Gsur  41 , Marc J Gunter  34 , Heather Hampel  40 , Sophia Harlid  42 , Akihisa Hidaka  3 , Tabitha A Harrison  3 , Michael Hoffmeister  5 , Jeroen R Huyghe  3 , Mark A Jenkins  38 , Kristina Jordahl  3 , Amit D Joshi  22   24 , Eric S Kawaguchi  2 , Temitope O Keku  43 , Anshul Kundaje  44   45 , Susanna C Larsson  46 , Loic Le Marchand  47 , Juan Pablo Lewinger  2 , Li Li  29 , Brigid M Lynch  37   38   48 , Bharuno Mahesworo  7 , Marko Mandic  5   28 , Mireia Obón-Santacana  17   30   31 , Victor Moreno  17   30   31   32 , Neil Murphy  34 , Hongmei Nan  49   50 , Rami Nassir  51 , Polly A Newcomb  3   52 , Shuji Ogino  23   24   53   54 , Jennifer Ose  55   56 , Rish K Pai  57 , Julie R Palmer  58 , Nikos Papadimitriou  34 , Bens Pardamean  7 , Anita R Peoples  55   56 , Elizabeth A Platz  59 , John D Potter  3   52   60 , Ross L Prentice  3 , Gad Rennert  61   62   63 , Edward Ruiz-Narvaez  64 , Lori C Sakoda  3   65 , Peter C Scacheri  66 , Stephanie L Schmit  67 , Robert E Schoen  68 , Anna Shcherbina  44   45 , Martha L Slattery  69 , Mariana C Stern  2 , Yu-Ru Su  3 , Catherine M Tangen  70 , Stephen N Thibodeau  71 , Duncan C Thomas  2 , Yu Tian  26   72 , Cornelia M Ulrich  55   56 , Franzel Jb van Duijnhoven  73 , Bethany Van Guelpen  42   74 , Kala Visvanathan  59 , Pavel Vodicka  75   76   77 , Jun Wang  2 , Emily White  3   52 , Alicja Wolk  46 , Michael O Woods  78 , Anna H Wu  2 , Natalia Zemlianskaia  2 , Li Hsu #  3   79 , W James Gauderman #  2 , Ulrike Peters #  3   52 , Konstantinos K Tsilidis #  1   10 , Peter T Campbell #  80
Affiliations

A Genetic Locus within the FMN1/GREM1 Gene Region Interacts with Body Mass Index in Colorectal Cancer Risk

Elom K Aglago et al. Cancer Res. .

Abstract

Colorectal cancer risk can be impacted by genetic, environmental, and lifestyle factors, including diet and obesity. Gene-environment interactions (G × E) can provide biological insights into the effects of obesity on colorectal cancer risk. Here, we assessed potential genome-wide G × E interactions between body mass index (BMI) and common SNPs for colorectal cancer risk using data from 36,415 colorectal cancer cases and 48,451 controls from three international colorectal cancer consortia (CCFR, CORECT, and GECCO). The G × E tests included the conventional logistic regression using multiplicative terms (one degree of freedom, 1DF test), the two-step EDGE method, and the joint 3DF test, each of which is powerful for detecting G × E interactions under specific conditions. BMI was associated with higher colorectal cancer risk. The two-step approach revealed a statistically significant G×BMI interaction located within the Formin 1/Gremlin 1 (FMN1/GREM1) gene region (rs58349661). This SNP was also identified by the 3DF test, with a suggestive statistical significance in the 1DF test. Among participants with the CC genotype of rs58349661, overweight and obesity categories were associated with higher colorectal cancer risk, whereas null associations were observed across BMI categories in those with the TT genotype. Using data from three large international consortia, this study discovered a locus in the FMN1/GREM1 gene region that interacts with BMI on the association with colorectal cancer risk. Further studies should examine the potential mechanisms through which this locus modifies the etiologic link between obesity and colorectal cancer.

Significance: This gene-environment interaction analysis revealed a genetic locus in FMN1/GREM1 that interacts with body mass index in colorectal cancer risk, suggesting potential implications for precision prevention strategies.

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Figures

Figure 1. OR and 95% CI for colorectal cancer risk associated with BMI (per 5 kg/m2 increment). The OR and 95% CIs were calculated for individual participating studies and then meta-analyzed.
Figure 1.
OR and 95% CI for colorectal cancer risk associated with BMI (per 5 kg/m2 increment). The OR and 95% CIs were calculated for individual participating studies and then meta-analyzed.
Figure 2. LocusZoom plots for the interaction between rs58349661 (rs1975678 used as perfect LD proxy) and colorectal cancer. The genomic position is shown on the x-axis whereas the y-axis reports the −log10 of the P value of the interaction with BMI. Purple dot, rs1975678. The colors of the SNPs are based on their correlation with rs1975678. Previously known GWAS variants, with their references, are also included: rs17816465, rs1919364, rs12708491.
Figure 2.
LocusZoom plots for the interaction between rs58349661 (rs1975678 used as perfect LD proxy) and colorectal cancer. The genomic position is shown on the x-axis whereas the y-axis reports the −log10 of the P value of the interaction with BMI. Purple dot, rs1975678. The colors of the SNPs are based on their correlation with rs1975678. Previously known GWAS variants, with their references, are also included: rs17816465, rs1919364, rs12708491.
Figure 3. BMI in relation to colorectal cancer risk, stratified by genotype. Using normal BMI as the reference, risk for colorectal cancer was estimated for overweight and obesity across the genotypes of rs58349661.
Figure 3.
BMI in relation to colorectal cancer risk, stratified by genotype. Using normal BMI as the reference, risk for colorectal cancer was estimated for overweight and obesity across the genotypes of rs58349661.
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References

    1. Papadimitriou N, Markozannes G, Kanellopoulou A, Critselis E, Alhardan S, Karafousia V, et al. . An umbrella review of the evidence associating diet and cancer risk at 11 anatomical sites. Nat Commun 2021;12:4579. - PMC - PubMed
    1. Murphy N, Moreno V, Hughes DJ, Vodicka L, Vodicka P, Aglago EK, et al. . Lifestyle and dietary environmental factors in colorectal cancer susceptibility. Mol Aspects Med 2019;69:2–9. - PubMed
    1. Islami F, Goding Sauer A, Miller KD, Siegel RL, Fedewa SA, Jacobs EJ, et al. . Proportion and number of cancer cases and deaths attributable to potentially modifiable risk factors in the United States. CA Cancer J Clin 2018;68:31–54. - PubMed
    1. Goon S, Kim H, Giovannucci E. Population attributable risk for colorectal and breast cancer in England, Wales, Scotland, Northern Ireland, and the United Kingdom [version 1; peer review: 1 approved, 1 not approved]. AMRC Open Research 2021;3. - PMC - PubMed
    1. Campbell PT. Obesity: a certain and avoidable cause of cancer. Lancet 2014;384:727–8. - PubMed

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