Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development
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{"title"=>"Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development", "type"=>"journal", "authors"=>[{"first_name"=>"Christian M.", "last_name"=>"Lange"}, {"first_name"=>"Daiki", "last_name"=>"Miki"}, {"first_name"=>"Hidenori", "last_name"=>"Ochi"}, {"first_name"=>"Hans-Dieter", "last_name"=>"Nischalke"}, {"first_name"=>"Jörg", "last_name"=>"Bojunga"}, {"first_name"=>"Stéphanie", "last_name"=>"Bibert"}, {"first_name"=>"Kenichi", "last_name"=>"Morikawa"}, {"first_name"=>"Jérôme", "last_name"=>"Gouttenoire"}, {"first_name"=>"Andreas", "last_name"=>"Cerny"}, {"first_name"=>"Jean-François", "last_name"=>"Dufour"}, {"first_name"=>"Meri", "last_name"=>"Gorgievski-Hrisoho"}, {"first_name"=>"Markus H.", "last_name"=>"Heim"}, {"first_name"=>"Raffaele", "last_name"=>"Malinverni"}, {"first_name"=>"Beat", "last_name"=>"Müllhaupt"}, {"first_name"=>"Francesco", "last_name"=>"Negro"}, {"first_name"=>"David", "last_name"=>"Semela"}, {"first_name"=>"Zoltan", "last_name"=>"Kutalik"}, {"first_name"=>"Tobias", "last_name"=>"Müller"}, {"first_name"=>"Ulrich", "last_name"=>"Spengler"}, {"first_name"=>"Thomas", "last_name"=>"Berg"}, {"first_name"=>"Kazuaki", "last_name"=>"Chayama"}, {"first_name"=>"Darius", "last_name"=>"Moradpour"}, {"first_name"=>"Pierre-Yves", "last_name"=>"Bochud"}], "year"=>2013, "source"=>"PLoS ONE", "identifiers"=>{"doi"=>"10.1371/journal.pone.0064053", "pmid"=>"23734184", "issn"=>"1932-6203"}, "id"=>"dcefb7c4-eb2e-3918-93b1-c699c054762d", "abstract"=>"BACKGROUND: Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).\\n\\nMETHODOLOGY/PRINCIPAL FINDINGS: Associations between CYP2R1, GC, and DHCR7 genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D3) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between CYP2R1 (rs1993116, rs10741657), GC (rs2282679), and DHCR7 (rs7944926, rs12785878) genotypes and 25(OH)D3 serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D3 serum levels were found to be associated with HCV-related HCC (P = 0.07 [OR = 1.13, 95% CI = 0.99-1.28] for CYP2R1, P = 0.007 [OR = 1.56, 95% CI = 1.12-2.15] for GC, P = 0.003 [OR = 1.42, 95% CI = 1.13-1.78] for DHCR7; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (P>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (P>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D3 serum levels on hepatocarcinogenesis.\\n\\nCONCLUSIONS/SIGNIFICANCE: Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.", "link"=>"http://www.mendeley.com/research/genetic-analyses-reveal-role-vitamin-d-insufficiency-hcvassociated-hepatocellular-carcinoma-developm", "reader_count"=>23, "reader_count_by_academic_status"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>4}, "reader_count_by_user_role"=>{"Unspecified"=>1, "Professor > Associate Professor"=>3, "Researcher"=>3, "Student > Doctoral Student"=>4, "Student > Ph. D. Student"=>2, "Student > Postgraduate"=>1, "Student > Master"=>3, "Other"=>2, "Student > Bachelor"=>4}, "reader_count_by_subject_area"=>{"Unspecified"=>1, "Biochemistry, Genetics and Molecular Biology"=>1, "Nursing and Health Professions"=>1, "Mathematics"=>1, "Medicine and Dentistry"=>13, "Agricultural and Biological Sciences"=>6}, "reader_count_by_subdiscipline"=>{"Medicine and Dentistry"=>{"Medicine and Dentistry"=>13}, "Agricultural and Biological Sciences"=>{"Agricultural and Biological Sciences"=>6}, "Nursing and Health Professions"=>{"Nursing and Health Professions"=>1}, "Biochemistry, Genetics and Molecular Biology"=>{"Biochemistry, Genetics and Molecular Biology"=>1}, "Mathematics"=>{"Mathematics"=>1}, "Unspecified"=>{"Unspecified"=>1}}, "group_count"=>2}

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Figshare

  • {"files"=>["https://ndownloader.figshare.com/files/1070345"], "description"=>"<p>Allele 2 indicates the risk allele, according to Wang et al. <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064053#pone.0064053-Wang1\" target=\"_blank\">[9]</a>. <i>P</i>-values and ORs were calculated for risk genotypes using favorable genotypes as a reference, i.e. for <i>CYP2R1</i> by comparing GG <i>vs.</i> GA/AA genotypes, for <i>GC</i> by comparing TT/TG vs. GG genotypes, and for <i>DHCR7</i> by comparing TT vs. TC/CC genotypes.</p>#<p>Only patients from the SCCS and Japanese GWAS were included in the combined analysis for this locus, because of the different allele frequencies for rs12785878 in Japanese patients compared to Caucasian patients. Data remain significant after inclusion of the Bonn-Berlin cohort (P = 0.018, OR = 1.27 [95% CI = 1.04–1.56]). *Genotyping of this SNP failed in the Japanese Replication cohort due to limited amounts of DNA. Please note that the total number of patients with available genotypes is not equal between different loci due to limited amount of DNA or genotyping failure in some cases.</p>1<p>rs1993116 and rs10741657 are in complete LD in the Caucasian and Japanese population (R<sup>2</sup> = 0.95 and = 1.00, respectively), the major alleles of both SNPs have a similar impact on 25(OH)D<sub>3</sub> serum levels, indicating that both SNPs can be used equivalently <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064053#pone.0064053-Wang1\" target=\"_blank\">[9]</a>.</p>2<p>rs7944926 and rs12785878 are in complete LD in the Caucasian and Japanese population (R<sup>2</sup> = 1.00 and = 1.00, respectively), the major alleles of both SNPs have a similar impact on 25(OH)D<sub>3</sub> serum levels, indicating that both SNPs can be used equivalently <a href=\"http://www.plosone.org/article/info:doi/10.1371/journal.pone.0064053#pone.0064053-Wang1\" target=\"_blank\">[9]</a>.</p>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "associations", "snps", "hcv-related", "hepatocellular", "carcinoma"], "article_id"=>708816, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0064053.t002", "stats"=>{"downloads"=>5, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Summary_of_associations_between_SNPs_in_CYP2R1_GC_and_DHCR7_and_HCV_related_hepatocellular_carcinoma_development_/708816", "title"=>"Summary of associations between SNPs in <i>CYP2R1</i>, <i>GC</i>, and <i>DHCR7</i>, and HCV-related hepatocellular carcinoma development.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-29 02:26:56"}
  • {"files"=>["https://ndownloader.figshare.com/files/1070346"], "description"=>"*<p>FPR, liver fibrosis progression rate. Slow <i>vs.</i> fast FPR was defined as FPR</p>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "snps", "fibrosis", "progression", "patients"], "article_id"=>708817, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0064053.t003", "stats"=>{"downloads"=>1, "page_views"=>15, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_SNPs_in_CYP2R1_GC_and_DHCR7_with_liver_fibrosis_progression_rate_FPR_in_patients_with_chronic_hepatitis_C_/708817", "title"=>"Association of SNPs in <i>CYP2R1</i>, <i>GC</i>, and <i>DHCR7</i> with liver fibrosis progression rate (FPR) in patients with chronic hepatitis C.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-29 02:26:57"}
  • {"files"=>["https://ndownloader.figshare.com/files/1070347"], "description"=>"*<p>These comparisons between HCC cases and controls are statistically significant (<i>P</i><0.05). Repl, replication. The cohort labeling “Japanese GWAS” and “Japanese Replication” is based on the initial description of the cohorts in Miki <i>et al.</i>, for the present study both cohorts served as replication cohorts.</p>1<p>Age and sex data was missing in 5 patients in the Bonn/Berlin cohort. For the SCCS, age of infection is shown. Age of infection was unknown for the Bonn/Berlin cohort, for this cohort age at diagnosis is shown.</p>2<p>Alcohol consumption data was missing in 12 HCC and 290 non-HCC patients from the SCCS.</p>3<p>HCV genotype was missing in 5 HCC and 23 non-HCC patients from the SCCS, in 1 HCC and 2 non-HCC patients from the Japanese GWAS, and 50 HCC patients from the Japanese replication cohorts.</p>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "included"], "article_id"=>708818, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0064053.t001", "stats"=>{"downloads"=>1, "page_views"=>2, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Baseline_characteristics_of_included_patients_/708818", "title"=>"Baseline characteristics of included patients.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-29 02:26:58"}
  • {"files"=>["https://ndownloader.figshare.com/files/1070348", "https://ndownloader.figshare.com/files/1070349", "https://ndownloader.figshare.com/files/1070350"], "description"=>"<div><p>Background</p><p>Vitamin D insufficiency has been associated with the occurrence of various types of cancer, but causal relationships remain elusive. We therefore aimed to determine the relationship between genetic determinants of vitamin D serum levels and the risk of developing hepatitis C virus (HCV)-related hepatocellular carcinoma (HCC).</p><p>Methodology/Principal Findings</p><p>Associations between <i>CYP2R1</i>, <i>GC</i>, and <i>DHCR7</i> genotypes that are determinants of reduced 25-hydroxyvitamin D (25[OH]D<sub>3</sub>) serum levels and the risk of HCV-related HCC development were investigated for 1279 chronic hepatitis C patients with HCC and 4325 without HCC, respectively. The well-known associations between <i>CYP2R1</i> (rs1993116, rs10741657), <i>GC</i> (rs2282679), and <i>DHCR7</i> (rs7944926, rs12785878) genotypes and 25(OH)D<sub>3</sub> serum levels were also apparent in patients with chronic hepatitis C. The same genotypes of these single nucleotide polymorphisms (SNPs) that are associated with reduced 25(OH)D<sub>3</sub> serum levels were found to be associated with HCV-related HCC (<i>P</i> = 0.07 [OR = 1.13, 95% CI = 0.99–1.28] for <i>CYP2R1</i>, <i>P</i> = 0.007 [OR = 1.56, 95% CI = 1.12–2.15] for <i>GC</i>, <i>P</i> = 0.003 [OR = 1.42, 95% CI = 1.13–1.78] for <i>DHCR7</i>; ORs for risk genotypes). In contrast, no association between these genetic variations and liver fibrosis progression rate (<i>P</i>>0.2 for each SNP) or outcome of standard therapy with pegylated interferon-α and ribavirin (<i>P</i>>0.2 for each SNP) was observed, suggesting a specific influence of the genetic determinants of 25(OH)D<sub>3</sub> serum levels on hepatocarcinogenesis.</p><p>Conclusions/Significance</p><p>Our data suggest a relatively weak but functionally relevant role for vitamin D in the prevention of HCV-related hepatocarcinogenesis.</p></div>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "insufficiency", "hcv-associated", "hepatocellular", "carcinoma"], "article_id"=>708819, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>["https://dx.doi.org/10.1371/journal.pone.0064053.s001", "https://dx.doi.org/10.1371/journal.pone.0064053.s002", "https://dx.doi.org/10.1371/journal.pone.0064053.s003"], "stats"=>{"downloads"=>19, "page_views"=>18, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Genetic_Analyses_Reveal_a_Role_for_Vitamin_D_Insufficiency_in_HCV_Associated_Hepatocellular_Carcinoma_Development_/708819", "title"=>"Genetic Analyses Reveal a Role for Vitamin D Insufficiency in HCV-Associated Hepatocellular Carcinoma Development", "pos_in_sequence"=>0, "defined_type"=>4, "published_date"=>"2013-05-29 02:26:59"}
  • {"files"=>["https://ndownloader.figshare.com/files/1070343"], "description"=>"<p>The probability to develop HCC from the time of hepatitis C virus infection by <i>CYP2R1</i> rs1993116 genotypes (GG <i>vs</i>. GA/AA) was assessed by using cumulative incidence curves, with censoring of data at the date of last follow-up or death. Statistics are shown for univariate Cox regression analysis. CI, confidence interval; HR, hazard ratio.</p>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "hepatocellular", "carcinoma", "sccs", "patients", "duration", "rs1993116"], "article_id"=>708814, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0064053.g001", "stats"=>{"downloads"=>1, "page_views"=>12, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Risk_of_hepatocellular_carcinoma_HCC_development_in_SCCS_patients_with_chronic_hepatitis_C_and_known_duration_of_infection_according_to_CYP2R1_rs1993116_genotypes_/708814", "title"=>"Risk of hepatocellular carcinoma (HCC) development in SCCS patients with chronic hepatitis C and known duration of infection, according to <i>CYP2R1</i> rs1993116 genotypes.", "pos_in_sequence"=>0, "defined_type"=>1, "published_date"=>"2013-05-29 02:26:54"}
  • {"files"=>["https://ndownloader.figshare.com/files/1070344"], "description"=>"<p>Statistics are shown for logistic regression analyses based on the additive model of inheritance. The usage of other models of inheritance (recessive, dominant) did not result in significant associations as well (not shown).</p>", "links"=>[], "tags"=>["genetics", "population genetics", "Genetic polymorphism", "epidemiology", "Cancer epidemiology", "Gastroenterology and hepatology", "Liver diseases", "Infectious hepatitis", "Hepatitis C", "Gastrointestinal cancers", "Infectious diseases", "Viral diseases", "hepatitis", "nutrition", "vitamins", "oncology", "Cancers and neoplasms", "Gastrointestinal tumors", "Hepatocellular carcinoma", "Basic cancer research", "snps", "pegylated", "ribavirin", "patients"], "article_id"=>708815, "categories"=>["Medicine", "Biological Sciences"], "users"=>["Christian M. Lange", "Daiki Miki", "Hidenori Ochi", "Hans-Dieter Nischalke", "Jörg Bojunga", "Stephanie Bibert", "Kenichi Morikawa", "Jérôme Gouttenoire", "Andreas Cerny", "Jean-Francois Dufour", "Meri Gorgievski-Hrisoho", "Markus H. Heim", "Raffaele Malinverni", "Beat Müllhaupt", "Francesco Negro", "David Semela", "Zoltán Kutalik", "Tobias Müller", "Ulrich Spengler", "Thomas Berg", "Kazuaki Chayama", "Darius Moradpour", "Pierre-Yves Bochud"], "doi"=>"https://dx.doi.org/10.1371/journal.pone.0064053.t004", "stats"=>{"downloads"=>1, "page_views"=>17, "likes"=>0}, "figshare_url"=>"https://figshare.com/articles/_Association_of_SNPs_in_CYP2R1_GC_and_DHCR7_with_response_to_treatment_of_pegylated_interferon_and_ribavirin_in_patients_with_chronic_hepatitis_C_/708815", "title"=>"Association of SNPs in <i>CYP2R1</i>, <i>GC</i>, and <i>DHCR7</i> with response to treatment of pegylated interferon-α and ribavirin in patients with chronic hepatitis C.", "pos_in_sequence"=>0, "defined_type"=>3, "published_date"=>"2013-05-29 02:26:55"}

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Relative Metric

{"start_date"=>"2013-01-01T00:00:00Z", "end_date"=>"2013-12-31T00:00:00Z", "subject_areas"=>[{"subject_area"=>"/Biology and life sciences/Molecular biology", "average_usage"=>[272, 466, 589, 702, 806, 903, 995, 1086, 1176, 1258, 1347, 1422, 1493]}, {"subject_area"=>"/Medicine and health sciences/Nutrition", "average_usage"=>[273, 476, 611, 714, 821, 911, 1005, 1103, 1201, 1287, 1388, 1478, 1557]}]}
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