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Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

ABSTRACT: High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-control study within EPIC including 727 cases diagnosed between 1992 and 2003 and 727 matched controls selected according to an incidence-density sampling protocol. Baseline CRP concentrations were measured in plasma samples by a high sensitivity assay. Tagging single nucleotide polymorphisms (SNPs) in the CRP gene (rs1205, rs1800947, rs1130864, rs2808630, rs3093077) were identified via HapMap. The causal effect of CRP on colorectal cancer risk was examined in a Mendelian Randomization approach utilizing multiple CRP genetic variants as instrumental variables. The SNPs rs1205, rs1800947, rs1130864 and rs3093077 were significantly associated with CRP concentrations and were incorporated in a CRP allele score which was associated with 13% higher CRP concentrations per allele count (95% confidence interval 8-19%). Using the CRP-score as instrumental variable, genetically twofold higher CRP concentrations were associated with higher risk of colorectal cancer (odds ratio 1.74, 95% confidence interval 1.06-2.85). Similar observations were made using alternative definitions of instrumental variables. Our findings give support to the hypothesis that elevated circulating CRP may play a direct role in the etiology of colorectal cancer.

SUBMITTER: Nimptsch K

PROVIDER: S-EPMC6284796 | biostudies-literature | 2015 Mar

REPOSITORIES: biostudies-literature

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Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

Nimptsch Katharina K Aleksandrova Krasimira K Boeing Heiner H Janke Jürgen J Lee Young-Ae YA Jenab Mazda M Bueno-de-Mesquita H Bas HB Jansen Eugène H J M EH Tsilidis Konstantinos K KK Trichopoulou Antonia A Weiderpass Elisabete E Wu Chunsen C Overvad Kim K Tjønneland Anne A Boutron-Ruault Marie-Christine MC Dossus Laure L Racine Antoine A Kaaks Rudolf R Canzian Federico F Lagiou Pagona P Trichopoulos Dimitrios D Palli Domenico D Agnoli Claudia C Tumino Rosario R Vineis Paolo P Panico Salvatore S Johansson Anders A Van Guelpen Bethany B Khaw Kay-Tee KT Wareham Nick N Peeters Petra H PH Quirós J Ramón JR Venceslá García Adoración A Molina-Montes Esther E Dorronsoro Miren M Chirlaque María-Dolores MD Barricarte Gurrea Aurelio A Key Timothy J TJ Duarte-Salles Talita T Stepien Magdalena M Gunter Marc J MJ Riboli Elio E Pischon Tobias T

International journal of cancer 20140728 5

High blood concentrations of C-reactive protein (CRP) have been associated with elevated risk of colorectal cancer in several prospective studies including the European Prospective Investigation into Cancer and Nutrition (EPIC), but it is unknown whether these observations reflect a causal relationship. We aimed to investigate whether CRP genetic variants associated with lifelong higher CRP concentrations translate into higher colorectal cancer risk. We conducted a prospective nested case-contro ...[more]

PMID: 25043606

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Project description:BackgroundHigh sensitivity C-reactive protein (hsCRP) levels are shown to be influenced by genetic variants in Europeans; however, little is explored in Indian population.MethodsHerein, we comprehensively evaluated association of all previously reported genetic determinants of hsCRP levels, including 18 cis (proximal to CRP gene) and 73 trans-acting (distal to CRP gene) variants in 4,200 North Indians of Indo-European ethnicity. First, we evaluated association of 91 variants from 12 candidate loci with hsCRP levels in 2,115 North Indians (1,042 non-diabetic subjects and 1,073 patients with type 2 diabetes). Then, cis and trans-acting variants contributing maximally to hsCRP level variation were further replicated in an independent 2,085 North Indians (1,047 patients with type 2 diabetes and 1,038 non-diabetic subjects).ResultsWe found association of 12 variants from CRP, LEPR, IL1A, IL6, and IL6R with hsCRP levels in non-diabetic subjects. However, only rs3093059-CRP [β = 0.33, P = 9.6×10⁻⁵] and the haplotype harboring rs3093059 risk allele [β = 0.32 µg/mL, P = 1.4×10⁻⁴/P(perm) = 9.0×10⁻⁴] retained significance after correcting for multiple testing. The cis-acting variant rs3093059-CRP had maximum contribution to the variance in hsCRP levels (1.14%). Among, trans-acting variants, rs1892534-LEPR was observed to contribute maximally to hsCRP level variance (0.59%). Associations of rs3093059-CRP and rs1892534-LEPR were confirmed by replication and attained higher significance after meta-analysis [β(meta) = 0.26/0.22; P(meta) = 4.3×10⁻⁷/7.4×10⁻³ and β(meta) = -0.15/-0.12; P(meta) = 2.0×10⁻⁶/1.6×10⁻⁶ for rs3093059 and rs1892534, respectively in non-diabetic subjects and all subjects taken together].ConclusionIn conclusion, we identified rs3093059 in CRP and rs1892534 in LEPR as major cis and trans-acting contributor respectively, to the variance in hsCRP levels in North Indian population.

Dataset Information

Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

Publications

Association of CRP genetic variants with blood concentrations of C-reactive protein and colorectal cancer risk.

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