A Genome-Wide Association Study Identifies UGT 1 A 1 as a Regulator of Serum Cell-Free DNA in Young Adults : The Cardiovascular Risk in Young Finns Study

Introduction: Circulating cell-free DNA (cf-DNA) is a useful indicator of cell death, and it can also be used to predict outcomes in various clinical disorders. Several innate immune mechanisms are known to be involved in eliminating DNA and chromatin-related material as part of the inhibition of potentially harmful autoimmune responses. However, the exact molecular mechanism underlying the clearance of circulating cf-DNA is currently unclear. Methods: To examine the mechanisms controlling serum levels of cf-DNA, we carried out a genome-wide association analysis (GWA) in a cohort of young adults (aged 24–39 years; n = 1841; 1018 women and 823 men) participating in the Cardiovascular Risk in Young Finns Study. Genotyping was performed with a custom-built Illumina Human 670 k BeadChip. The Quant-iT high sensitivity DNA assay was used to measure cf-DNA directly from serum. Results: The results revealed that 110 single nucleotide polymorphisms (SNPs) were associated with serum cf-DNA with genome-wide significance (p,5610). All of these significant SNPs were localised to chromosome 2q37, near the UDPglucuronosyltransferase 1 (UGT1) family locus, and the most significant SNPs localised within the UGT1 polypeptide A1 (UGT1A1) gene region. Conclusion: The UGT1A1 enzyme catalyses the detoxification of several drugs and the turnover of many xenobiotic and endogenous compounds by glucuronidating its substrates. These data indicate that UGT1A1-associated processes are also involved in the regulation of serum cf-DNA concentrations. Citation: Jylhävä J, Lyytikäinen L-P, Kähönen M, Hutri-Kähönen N, Kettunen J, et al. (2012) A Genome-Wide Association Study Identifies UGT1A1 as a Regulator of Serum Cell-Free DNA in Young Adults: The Cardiovascular Risk in Young Finns Study. PLoS ONE 7(4): e35426. doi:10.1371/journal.pone. 0035426 Editor: Marie-Pierre Dubé, Universite de Montreal, Canada Received July 5, 2011; Accepted March 16, 2012; Published April 12, 2012 Copyright: 2012 Jylhävä et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited. Funding: The Young Finns Study was financially supported by the Academy of Finland: grants no. 126925, 121584, 124282, 129378 (Salve), 117787 (Gendi), and 41071 (Skidi), the Social Insurance Institution of Finland, the Turku University Foundation, the Finnish Cultural Foundation, the Yrjö Jahnsson Foundation, the Emil Aaltonen Foundation (T.L.), Medical Research Fund of Tampere University Hospital (grant no. 9M048), the Turku University Central Hospital Medical Fund, the Juho Vainio Foundation, and the Finnish Foundation for Cardiovascular Research and Tampere Tuberculosis Foundation. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. Competing Interests: The authors have declared that no competing interests exist. * E-mail: juulia.jylhava@uta.fi . These authors contributed equally to this work. " These authors also contributed equally to this work.