PLoS ONE (Jan 2013)

Polymorphisms in DNA-repair genes in a cohort of prostate cancer patients from different areas in Spain: heterogeneity between populations as a confounding factor in association studies.

  • Luis Alberto Henríquez-Hernández,
  • Almudena Valenciano,
  • Palmira Foro-Arnalot,
  • María Jesús Alvarez-Cubero,
  • José Manuel Cozar,
  • José Francisco Suárez-Novo,
  • Manel Castells-Esteve,
  • Adriana Ayala-Gil,
  • Pablo Fernández-Gonzalo,
  • Montse Ferrer,
  • Ferrán Guedea,
  • Gemma Sancho-Pardo,
  • Jordi Craven-Bartle,
  • María José Ortiz-Gordillo,
  • Patricia Cabrera-Roldán,
  • Estefanía Herrera-Ramos,
  • Pedro C Lara

DOI
https://doi.org/10.1371/journal.pone.0069735
Journal volume & issue
Vol. 8, no. 7
p. e69735

Abstract

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BackgroundDifferences in the distribution of genotypes between individuals of the same ethnicity are an important confounder factor commonly undervalued in typical association studies conducted in radiogenomics.ObjectiveTo evaluate the genotypic distribution of SNPs in a wide set of Spanish prostate cancer patients for determine the homogeneity of the population and to disclose potential bias.Design setting and participantsA total of 601 prostate cancer patients from Andalusia, Basque Country, Canary and Catalonia were genotyped for 10 SNPs located in 6 different genes associated to DNA repair: XRCC1 (rs25487, rs25489, rs1799782), ERCC2 (rs13181), ERCC1 (rs11615), LIG4 (rs1805388, rs1805386), ATM (rs17503908, rs1800057) and P53 (rs1042522). The SNP genotyping was made in a Biotrove OpenArray® NT Cycler.Outcome measurements and statistical analysisComparisons of genotypic and allelic frequencies among populations, as well as haplotype analyses were determined using the web-based environment SNPator. Principal component analysis was made using the SnpMatrix and XSnpMatrix classes and methods implemented as an R package. Non-supervised hierarchical cluster of SNP was made using MultiExperiment Viewer.Results and limitationsWe observed that genotype distribution of 4 out 10 SNPs was statistically different among the studied populations, showing the greatest differences between Andalusia and Catalonia. These observations were confirmed in cluster analysis, principal component analysis and in the differential distribution of haplotypes among the populations. Because tumor characteristics have not been taken into account, it is possible that some polymorphisms may influence tumor characteristics in the same way that it may pose a risk factor for other disease characteristics.ConclusionDifferences in distribution of genotypes within different populations of the same ethnicity could be an important confounding factor responsible for the lack of validation of SNPs associated with radiation-induced toxicity, especially when extensive meta-analysis with subjects from different countries are carried out.