Journal Article

<i>XRCC1</i>, <i>XRCC3</i>, <i>XPD</i> gene polymorphisms, smoking and <sup>32</sup>P-DNA adducts in a sample of healthy subjects

Giuseppe Matullo, Domenico Palli, Marco Peluso, Simonetta Guarrera, Sonia Carturan, Egidio Celentano, Vittorio Krogh, Armelle Munnia, Rosario Tumino, Silvia Polidoro, Alberto Piazza and Paolo Vineis

in Carcinogenesis

Volume 22, issue 9, pages 1437-1445
Published in print September 2001 | ISSN: 0143-3334
Published online September 2001 | e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/22.9.1437
XRCC1, XRCC3, XPD gene polymorphisms, smoking and 32P-DNA adducts in a sample of healthy subjects

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DNA repair genes have an important role in protecting individuals from cancer-causing agents. Polymorphisms in several DNA repair genes have been identified and individuals with non-dramatic reductions in the capacity to repair DNA damage are observed in the population, but the impact of specific genetic variants on repair phenotype and cancer risk has not yet been clarified. In 308 healthy Italian individuals belonging to the prospective European project EPIC, we have investigated the relationship between DNA damage, as measured by 32P-DNA adduct levels, and three genetic polymorphisms in different repair genes: XRCC1-Arg399Gln (exon 10), XRCC3-Thr241Met (exon 7) and XPD-Lys751Gln (exon 23). DNA adduct levels were measured as relative adduct level (RAL) per 109 normal nucleotides by DNA 32P-post-labelling assay in white blood cells from peripheral blood. Genotyping was performed by PCR–RFLP analysis. The XRCC3-241Met variant was significantly associated with higher DNA adduct levels, whereas XRCC1-399Gln and XPD-751Gln were associated with higher DNA adduct levels only in never-smokers. XRCC3-241Met homozygotes had an average DNA adduct level of 11.44 ± 1.48 (±SE) compared with 7.69 ± 0.88 in Thr/Met heterozygotes and 6.94 ± 1.11 in Thr/Thr homozygotes (F = 3.206, P = 0.042). Never-smoking XRCC1-399Gln homozygotes had an average DNA adduct level of 15.60 ± 5.42 compared with 6.16 ± 0.97 in Gln/Arg heterozygotes and 6.78 ± 1.10 in Arg/Arg homozygotes (F = 5.237, P = 0.007). A significant odds ratio (3.81, 95% CI 1.02–14.16) to have DNA adduct levels above median value was observed for XPD-751Gln versus XPD-751Lys never-smoking homozygotes after adjustment for several confounders. These data show that all the analysed polymorphisms could result in deficient DNA repair and suggest a need for further investigation into the possible interactions between these polymorphisms, smoking and other risk factors.

Keywords: BER, base excision repair; EPIC, European Prospective Investigation into Cancer and Nutrition; NER, nucleotide excision repair; OR, odds ratio; RAL, relative adduct level; SE, standard error; WBC, white blood cells; XPD, xeroderma pigmentosum-D gene; XRCC 1–3, X-ray repair cross complementing groups 1–3.

Journal Article.  5931 words.  Illustrated.

Subjects: Clinical Cytogenetics and Molecular Genetics

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