title: Comprehensive evaluation of one-carbon metabolism pathway gene variants and renal cell cancer risk.
abstract: BACKGROUND
  Folate and one-carbon metabolism are linked to cancer risk through their integral role in DNA synthesis and methylation. Variation in one-carbon metabolism genes, particularly MTHFR, has been associated with risk of a number of cancers in epidemiologic studies, but little is known regarding renal cancer.
  
  
  METHODS
  Tag single nucleotide polymorphisms (SNPs) selected to produce high genomic coverage of 13 gene regions of one-carbon metabolism (ALDH1L1, BHMT, CBS, FOLR1, MTHFR, MTR, MTRR, SHMT1, SLC19A1, TYMS) and the closely associated glutathione synthesis pathway (CTH, GGH, GSS) were genotyped for 777 renal cell carcinoma (RCC) cases and 1,035 controls in the Central and Eastern European Renal Cancer case-control study. Associations of individual SNPs (n = 163) with RCC risk were calculated using unconditional logistic regression adjusted for age, sex and study center. Minimum p-value permutation (Min-P) tests were used to identify gene regions associated with risk, and haplotypes were evaluated within these genes.
  
  
  RESULTS
  The strongest associations with RCC risk were observed for SLC19A1 (P(min-P) = 0.03) and MTHFR (P(min-P) = 0.13). A haplotype consisting of four SNPs in SLC19A1 (rs12483553, rs2838950, rs2838951, and rs17004785) was associated with a 37% increased risk (p = 0.02), and exploratory stratified analysis suggested the association was only significant among those in the lowest tertile of vegetable intake.
  
  
  CONCLUSIONS
  To our knowledge, this is the first study to comprehensively examine variation in one-carbon metabolism genes in relation to RCC risk. We identified a novel association with SLC19A1, which is important for transport of folate into cells. Replication in other populations is required to confirm these findings.
authors: Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland, United States of America. gibsontm@mail.nih.gov
authors: Todd M
authors: TM
authors: Gibson
authors: Paul
authors: P
authors: Brennan
authors: Summer
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authors: Han
authors: Sara
authors: S
authors: Karami
authors: David
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authors: Zaridze
authors: Vladimir
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authors: Janout
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authors: Kollarova
authors: Vladimir
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authors: Bencko
authors: Marie
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authors: Navratilova
authors: Neonila
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authors: Szeszenia-Dabrowska
authors: Dana
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authors: Mates
authors: Alena
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authors: Slamova
authors: Ruth M
authors: RM
authors: Pfeiffer
authors: Rachael Z
authors: RZ
authors: Stolzenberg-Solomon
authors: Susan T
authors: ST
authors: Mayne
authors: Meredith
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authors: Yeager
authors: Stephen
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authors: Chanock
authors: Nat
authors: N
authors: Rothman
authors: Wong-Ho
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authors: Chow
authors: Philip S
authors: PS
authors: Rosenberg
authors: Paolo
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authors: Boffetta
authors: Lee E
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authors: Moore
mesh_terms: D002244:Carbon / Q000378:metabolism*; D020411:Oligonucleotide Array Sequence Analysis; D012275:Oryza / Q000235:genetics* / Q000378:metabolism; D059467:Transcriptome
chemical_list: D002244:Carbon