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      The RS4939827 polymorphism in the SMAD7 GENE and its association with Mediterranean diet in colorectal carcinogenesis

      research-article
      1 , 2 , , 3 , 1 , 1 , 4 , 5 , 4 , 5 , 3 , 4 , 4 , 6 , 7 , 8 , 4 , 9 , 4 , 10 , 4 , 11 , 4 , 12 , 13 , 1 , 3 , 4 , 10 , 4 , 5 , 14 , 4 , 5 ,   4 , 15 , 4 , 16 , 17 , 18 , 4 , 16 , 17 , 18 , 19 , 4 , 6 , 7 , 8 , 4 , 20
      BMC Medical Genetics
      BioMed Central
      Colorectal cancer, SMAD7, rs4939827, Mediterranean diet, Gene-environment

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          Abstract

          Background

          The objective of our investigation is to study the relationship between the rs4939827 SNP in the SMAD7 gene, Mediterranean diet pattern and the risk of colorectal cancer.

          Methods

          We examined 1087 cases of colorectal cancer and 2409 population controls with available DNA samples from the MCC-Spain study, 2008–2012. Descriptive statistical analyses, and multivariate logistic mixed models were performed. The potential synergistic effect of rs4939827 and the Mediterranean diet pattern was evaluated with logistic regression in different strata of of adherence to the Mediterranean diet and the genotype.

          Results

          High adherence to Mediterrenean diet was statistically significantly associated with colorectal cancer risk. A decreased risk for CRC cancer was observed for the CC compared to the TT genotype (OR = 0.65 and 95% CI = 0.51–0.81) of the rs4939827 SNP Also, we could show an association between the Mediterranean diet pattern (protective factor) and rs4939827. Although the decreased risk for the CC genotype was slightly more pronounced in subjects with high adherence to Mediterrenean diet, there was no statistically significant synergistic effect between genotype CC and adherence to the Mediterranean dietary pattern factors.

          Conclusion

          The SMAD7 gene and specifically the allele C could be protective for colorectal cancer. An independent protective association was also observed between high adherence Mediterranean diet pattern and CRC risk. Findings form this study indicate that high adherence to Mediterranean diet pattern has a protective role for CRC cancer probably involving the Tumor Growth Factor- β pathway in this cancer.

          Electronic supplementary material

          The online version of this article (10.1186/s12881-017-0485-5) contains supplementary material, which is available to authorized users.

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          Most cited references26

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          International trends in colorectal cancer incidence rates.

          Previous studies have documented significant variations in colorectal cancer incidence rates and trends regionally and across countries. However, no study has examined the worldwide pattern using the most recently updated incidence data from the IARC. We obtained sex-specific colorectal cancer incidence for 1953-57 through 1998-2002 by cancer registry from Cancer Incidence in Five Continents (CI5) databases. For 51 cancer registries with long-term incidence data, we assessed the change in the incidence rates over the past 20 years by calculating the ratio of the incidence rates in 1998-2002 to that in 1983-87. Colorectal cancer incidence rates for both males and females statistically significantly increased from 1983-87 to 1998-2002 for 27 of 51 cancer registries considered in the analysis, largely confined to economically transitioning countries including Eastern European countries, most parts of Asia, and select countries of South America. These increases were more prominent for men than for women. We also observed substantial variations in colorectal cancer incidence trends within countries such as Japan. Similarly, trends in Israel and Singapore varied significantly according to ethnicity. The United States is the only country where colorectal cancer incidence rates declined in both males and females. Colorectal cancer incidence rates continue to increase in economically transitioning countries, with incidence rates among men in the Czech Republic and Slovakia exceeding the peak incidence observed in the United States and other long-standing developed nations. Targeted prevention and early detection programs could help reverse the trend in these countries.
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            Genome-wide association scan identifies a colorectal cancer susceptibility locus on 11q23 and replicates risk loci at 8q24 and 18q21.

            In a genome-wide association study to identify loci associated with colorectal cancer (CRC) risk, we genotyped 555,510 SNPs in 1,012 early-onset Scottish CRC cases and 1,012 controls (phase 1). In phase 2, we genotyped the 15,008 highest-ranked SNPs in 2,057 Scottish cases and 2,111 controls. We then genotyped the five highest-ranked SNPs from the joint phase 1 and 2 analysis in 14,500 cases and 13,294 controls from seven populations, and identified a previously unreported association, rs3802842 on 11q23 (OR = 1.1; P = 5.8 x 10(-10)), showing population differences in risk. We also replicated and fine-mapped associations at 8q24 (rs7014346; OR = 1.19; P = 8.6 x 10(-26)) and 18q21 (rs4939827; OR = 1.2; P = 7.8 x 10(-28)). Risk was greater for rectal than for colon cancer for rs3802842 (P < 0.008) and rs4939827 (P < 0.009). Carrying all six possible risk alleles yielded OR = 2.6 (95% CI = 1.75-3.89) for CRC. These findings extend our understanding of the role of common genetic variation in CRC etiology.
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              Smad7 Protein Interacts with Receptor-regulated Smads (R-Smads) to Inhibit Transforming Growth Factor-β (TGF-β)/Smad Signaling.

              TGF-β is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes. TGF-β signaling is spatiotemporally fine-tuned. As a key negative regulator of TGF-β signaling, Smad7 exerts its inhibitory effects by blocking receptor activity, inducing receptor degradation or interfering with Smad-DNA binding. However, the functions and the molecular mechanisms underlying the actions of Smad7 in TGF-β signaling are still not fully understood. In this study we report a novel mechanism whereby Smad7 antagonizes TGF-β signaling at the Smad level. Smad7 oligomerized with R-Smad proteins upon TGF-β signaling and directly inhibited R-Smad activity, as assessed by Gal4-luciferase reporter assays. Mechanistically, Smad7 competes with Smad4 to associate with R-Smads and recruits the E3 ubiquitin ligase NEDD4L to activated R-Smads, leading to their polyubiquitination and proteasomal degradation. Similar to the R-Smad-Smad4 oligomerization, the interaction between R-Smads and Smad7 is mediated by their mad homology 2 (MH2) domains. A positive-charged basic region including the L3/β8 loop-strand module and adjacent amino acids in the MH2 domain of Smad7 is essential for the interaction. These results shed new light on the regulation of TGF-β signaling by Smad7.
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                Author and article information

                Contributors
                jalonm00@estudiantes.unileon.es
                cgonzd00@estudiantes.unileon.es
                camilo.palazuelos@unican.es
                tferv@unileon.es
                lnagarciaramos@gmail.com
                mpollan@isciii.es
                naragones@isciii.es
                javier.llorca@unican.es
                mhalonso@iconcologia.net
                atardon@uniovi.es
                epicss-san@euskadi.eus
                jjmoleon@ugr.es
                peiro_ros@gva.es
                rocio.capelo@dbasp.uhu.es
                ajmolt@unileon.es
                ines.gomez@unican.es
                mp.guevara.eslava@navarra.es
                bperez@isciii.es
                vicarvajal@isciii.es
                jmhuerta.carm@gmail.com
                gcastano@creal.cat
                kogevinas@creal.cat
                v.moreno@iconcologia.net
                vicente.martin@unileon.es
                Journal
                BMC Med Genet
                BMC Med. Genet
                BMC Medical Genetics
                BioMed Central (London )
                1471-2350
                30 October 2017
                30 October 2017
                2017
                : 18
                : 122
                Affiliations
                [1 ]ISNI 0000 0001 2187 3167, GRID grid.4807.b, Grupo de Investigación en Interacciones Gen-Ambiente y Salud. Instituto de Biomedicina (IBIOMED), , Universidad de León, ; León, Spain
                [2 ]ISNI 0000 0001 2187 3167, GRID grid.4807.b, Centro de Investigación Biomédica en Red (CIBERESP) and Oviedo University; Departamento de Ciencias Biomédicas. Universidad de León. Campus de Vegazana, ; León, Spain
                [3 ]ISNI 0000 0004 1770 272X, GRID grid.7821.c, Universidad de Cantabria, ; Santander, Spain
                [4 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, CIBER Epidemiología y Salud Pública (CIBERESP), ; Madrid, Spain
                [5 ]ISNI 0000 0000 9314 1427, GRID grid.413448.e, Cancer and Environmental Epidemiology Unit, National Centre for Epidemiology, Carlos III Institute of Health, ; Madrid, Spain
                [6 ]Cancer Prevention and Control Program, Catalan Institute of Oncology, Hospitalet de Llobregat, Barcelona, Spain
                [7 ]ISNI 0000 0004 1937 0247, GRID grid.5841.8, Department of Clinical Sciences, Faculty of Medicine, , University of Barcelona, ; Barcelona, Spain
                [8 ]GRID grid.417656.7, Colorectal Cancer Group, Bellvitge Biomedical Research Institute (IDIBELL). Hospitalet de Llobregat, ; Barcelona, Spain
                [9 ]ISNI 0000 0001 2164 6351, GRID grid.10863.3c, Oncology Institute IUOPA, , Universidad de Oviedo, ; Oviedo, Asturias Spain
                [10 ]ISNI 0000 0004 0375 9231, GRID grid.419126.9, Instituto de Salud Pública de Navarra, ; Pamplona, Navarra Spain
                [11 ]Instituto de Investigación Biosanitaria de Granada (ibs.GRANADA), Hospitales Universitarios de Granada/Universidad de Granada, Granada, Spain
                [12 ]Dirección General de Salud Pública, Fundación para el fomento de la investigación sanitaria y biomédica de la Comunidad Valenciana, FISABIO-Salud Pública, Barcelona, Spain
                [13 ]ISNI 0000 0004 1769 8134, GRID grid.18803.32, Centro de Investigación en Salud y Medio Ambiente (CYSMA), , Universidad de Huelva, ; Huelva, Spain
                [14 ]GRID grid.476442.7, Cancer Epidemiology Research Group, Oncology and Hematology Area, IIS Puerta De Hierro, ; Madrid, Spain
                [15 ]GRID grid.452553.0, Department of Epidemiology, Murcia Regional Health Council, IMIB-Arrixaca, ; Murcia, Spain
                [16 ]ISGlobal, Centre for Research in Environmental Epidemiology (CREAL), Barcelona, Spain
                [17 ]ISNI 0000 0004 1767 8811, GRID grid.411142.3, IMIM (Hospital del Mar Medical Research Institute), ; Barcelona, Spain
                [18 ]ISNI 0000 0001 2172 2676, GRID grid.5612.0, Universitat Pompeu Fabra (UPF), ; Barcelona, Spain
                [19 ]School of Public Health, Athens, Greece
                [20 ]ISNI 0000 0001 2187 3167, GRID grid.4807.b, Grupo de Investigación en Interacciones Gen-Ambiente y Salud de la Universidad de León, ; León, Spain
                Author information
                http://orcid.org/0000-0001-6212-1797
                Article
                485
                10.1186/s12881-017-0485-5
                5661920
                29084532
                47289a21-9f63-4157-b451-5c3885b74136
                © The Author(s). 2017

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 November 2016
                : 18 October 2017
                Funding
                Funded by: Accion Transversal del Cancer
                Funded by: Instituto de Salud Carlos III-FEDER
                Funded by: Fundación Marqués de Valdecilla
                Funded by: ICGC International Cancer Genome Consortium CLL
                Funded by: Junta de Castilla y León (LE22A10-2)
                Funded by: Consejería de Salud of the Junta de Andalucía (2009-S0143)
                Funded by: Conselleria de Sanitat of the Generalitat Valenciana (AP_061/10)
                Funded by: Recercaixa (2010ACUP 00310)
                Funded by: Regional Government of the Basque Country
                Funded by: Consejería de Sanidad de la Región de Murcia
                Funded by: European Commission grants FOOD-CT-2006-036224-HIWATE
                Funded by: Association Against Cancer (AECC) Scientific Foundation
                Funded by: Catalan Government DURSI grant 2014SGR647
                Funded by: Fundación Caja de Ahorros de Asturias
                Funded by: FundRef http://dx.doi.org/10.13039/501100006382, Universidad de Oviedo;
                Categories
                Research Article
                Custom metadata
                © The Author(s) 2017

                Genetics
                colorectal cancer,smad7,rs4939827,mediterranean diet,gene-environment
                Genetics
                colorectal cancer, smad7, rs4939827, mediterranean diet, gene-environment

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