title: Analysis of SNPs and haplotypes in vitamin D pathway genes and renal cancer risk.
abstract: In the kidney vitamin D is converted to its active form. Since vitamin D exerts its activity through binding to the nuclear vitamin D receptor (VDR), most genetic studies have primarily focused on variation within this gene. Therefore, analysis of genetic variation in VDR and other vitamin D pathway genes may provide insight into the role of vitamin D in renal cell carcinoma (RCC) etiology. RCC cases (N = 777) and controls (N = 1,035) were genotyped to investigate the relationship between RCC risk and variation in eight target genes. Minimum-p-value permutation (Min-P) tests were used to identify genes associated with risk. A three single nucleotide polymorphism (SNP) sliding window was used to identify chromosomal regions with a False Discovery Rate of <10%, where subsequently, haplotype relative risks were computed in Haplostats. Min-P values showed that VDR (p-value = 0.02) and retinoid-X-receptor-alpha (RXRA) (p-value = 0.10) were associated with RCC risk. Within VDR, three haplotypes across two chromosomal regions of interest were identified. The first region, located within intron 2, contained two haplotypes that increased RCC risk by approximately 25%. The second region included a haplotype (rs2239179, rs12717991) across intron 4 that increased risk among participants with the TC (OR = 1.31, 95% CI = 1.09-1.57) haplotype compared to participants with the common haplotype, TT. Across RXRA, one haplotype located 3' of the coding sequence (rs748964, rs3118523), increased RCC risk 35% among individuals with the variant haplotype compared to those with the most common haplotype. This study comprehensively evaluated genetic variation across eight vitamin D pathway genes in relation to RCC risk. We found increased risk associated with VDR and RXRA. Replication studies are warranted to confirm these findings.
authors.affiliation: Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health (NIH), Department of Health and Human Services (DHHS), Bethesda, Maryland, USA. karamis@mail.nih.gov
authors.forename: Sara
authors.initials: S
authors.lastname: Karami
authors.forename: Paul
authors.initials: P
authors.lastname: Brennan
authors.forename: Philip S
authors.initials: PS
authors.lastname: Rosenberg
authors.forename: Marie
authors.initials: M
authors.lastname: Navratilova
authors.forename: Dana
authors.initials: D
authors.lastname: Mates
authors.forename: David
authors.initials: D
authors.lastname: Zaridze
authors.forename: Vladimir
authors.initials: V
authors.lastname: Janout
authors.forename: Helena
authors.initials: H
authors.lastname: Kollarova
authors.forename: Vladimir
authors.initials: V
authors.lastname: Bencko
authors.forename: Vsevolod
authors.initials: V
authors.lastname: Matveev
authors.forename: Neonila
authors.initials: N
authors.lastname: Szeszenia-Dabrowska
authors.forename: Ivana
authors.initials: I
authors.lastname: Holcatova
authors.forename: Meredith
authors.initials: M
authors.lastname: Yeager
authors.forename: Stephen
authors.initials: S
authors.lastname: Chanock
authors.forename: Idan
authors.initials: I
authors.lastname: Menashe
authors.forename: Nathaniel
authors.initials: N
authors.lastname: Rothman
authors.forename: Wong-Ho
authors.initials: WH
authors.lastname: Chow
authors.forename: Paolo
authors.initials: P
authors.lastname: Boffetta
authors.forename: Lee E
authors.initials: LE
authors.lastname: Moore
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D006239:Haplotypes; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D011110:Polymorphism, Genetic; D020641:Polymorphism, Single Nucleotide; D018167:Receptors, Calcitriol / Q000235:genetics*; D047490:Retinoid X Receptor alpha / Q000235:genetics*; D014807:Vitamin D / Q000378:metabolism
chemical_list: D018167:Receptors, Calcitriol; D047490:Retinoid X Receptor alpha; D014807:Vitamin D