{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,10,24]],"date-time":"2026-10-24T01:40:33Z","timestamp":1792806033499,"version":"4.5.0"},"reference-count":81,"publisher":"MDPI AG","issue":"1","license":[{"start":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T00:00:00Z","timestamp":1546560000000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom\u00eda y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)","award":["CIBER 06\/03"],"award-info":[{"award-number":["CIBER 06\/03"]}],"id":[{"id":"https:\/\/ror.org\/01txxn211","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom\u00eda y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)","award":["PRX17\/00500"],"award-info":[{"award-number":["PRX17\/00500"]}],"id":[{"id":"https:\/\/ror.org\/01txxn211","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom\u00eda y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)","award":["PI16\/00366"],"award-info":[{"award-number":["PI16\/00366"]}],"id":[{"id":"https:\/\/ror.org\/01txxn211","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom\u00eda y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)","award":["PI06\/1326"],"award-info":[{"award-number":["PI06\/1326"]}],"id":[{"id":"https:\/\/ror.org\/01txxn211","id-type":"ROR","asserted-by":"crossref"}]},{"name":"Spanish Ministry of Health (Instituto de Salud Carlos III) and the Ministerio de Econom\u00eda y Competitividad-Fondo Europeo de Desarrollo Regional (FEDER)","award":["SAF2016\u201380532-R"],"award-info":[{"award-number":["SAF2016\u201380532-R"]}],"id":[{"id":"https:\/\/ror.org\/01txxn211","id-type":"ROR","asserted-by":"crossref"}]},{"name":"University Jaume I","award":["P1\u20131B2013\u201354"],"award-info":[{"award-number":["P1\u20131B2013\u201354"]}]},{"name":"University Jaume I","award":["COGRUP\/2016\/06"],"award-info":[{"award-number":["COGRUP\/2016\/06"]}]},{"DOI":"10.13039\/100008666","name":"Fundaci\u00f3 La Marat\u00f3 de TV3","doi-asserted-by":"publisher","award":["538\/U\/2016"],"award-info":[{"award-number":["538\/U\/2016"]}],"id":[{"id":"10.13039\/100008666","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100013721","name":"Real Colegio Complutense at Harvard University","doi-asserted-by":"publisher","award":["Dolores Corella research stay"],"award-info":[{"award-number":["Dolores Corella research stay"]}],"id":[{"id":"10.13039\/100013721","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["PROMETEO2017\/017"],"award-info":[{"award-number":["PROMETEO2017\/017"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100003359","name":"Generalitat Valenciana","doi-asserted-by":"publisher","award":["AEST\/2018\/044"],"award-info":[{"award-number":["AEST\/2018\/044"]}],"id":[{"id":"10.13039\/501100003359","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["Nutrients"],"abstract":"<jats:p>Although, for decades, increased serum bilirubin concentrations were considered a threatening sign of underlying liver disease and had been associated with neonatal jaundice, data from recent years show that bilirubin is a powerful antioxidant and suggest that slightly increased serum bilirubin concentrations are protective against oxidative stress-related diseases, such as cardiovascular diseases. Therefore, a better understanding of the gene-diet interactions in determining serum bilirubin concentrations is needed. None of the previous genome-wide association studies (GWAS) on bilirubin concentrations has been stratified by sex. Therefore, considering the increasing interest in incorporating the gender perspective into nutritional genomics, our main aim was to carry out a GWAS on total serum bilirubin concentrations in a Mediterranean population with metabolic syndrome, stratified by sex. Our secondary aim was to explore, as a pilot study, the presence of gene-diet interactions at the GWAS level. We included 430 participants (188 men and 242 women, aged 55\u201375 years, and with metabolic syndrome) in the PREDIMED Plus-Valencia study. Global and sex-specific GWAS were undertaken to analyze associations and gene-diet interaction on total serum bilirubin. Adherence (low and high) to the Mediterranean diet (MedDiet) was analyzed as the dietary modulator. In the GWAS, we detected more than 55 SNPs associated with serum bilirubin at p &lt; 5 \u00d7 10\u22128 (GWAS level). The top-ranked were four SNPs (rs4148325 (p = 9.25 \u00d7 10\u221224), rs4148324 (p = 9.48 \u00d7 10\u221224), rs6742078 (p = 1.29 \u00d7 10\u221223), rs887829 (p = 1.39 \u00d7 10\u221223), and the rs4148324 (p = 9.48 \u00d7 10\u221224)) in the UGT1A1 (UDP glucuronosyltransferase family 1 member A1) gene, which replicated previous findings revealing the UGT1A1 as the major locus. In the sex-specific GWAS, the top-ranked SNPs at the GWAS level were similar in men and women (the lead SNP was the rs4148324-UGT1A1 in both men (p = 4.77 \u00d7 10\u221211) and women (p = 2.15 \u00d7 10\u221214), which shows homogeneous genetic results for the major locus. There was more sex-specific heterogeneity for other minor genes associated at the suggestive level of GWAS significance (p &lt; 1 \u00d7 10\u22125). We did not detect any gene-MedDiet interaction at p &lt; 1 \u00d7 10\u22125 for the major genetic locus, but we detected some gene-MedDiet interactions with other genes at p &lt; 1 \u00d7 10\u22125, and even at the GWAS level for the IL17B gene (p = 3.14 \u00d7 10\u22128). These interaction results, however, should be interpreted with caution due to our small sample size. In conclusion, our study provides new data, with a gender perspective, on genes associated with total serum bilirubin concentrations in men and women, and suggests possible additional modulations by adherence to MedDiet.<\/jats:p>","DOI":"10.3390\/nu11010090","type":"journal-article","created":{"date-parts":[[2019,1,4]],"date-time":"2019-01-04T11:34:26Z","timestamp":1546601666000},"page":"90","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":37,"title":["Genome-Wide Association Study (GWAS) on Bilirubin Concentrations in Subjects with Metabolic Syndrome: Sex-Specific GWAS Analysis and Gene-Diet Interactions in a Mediterranean Population"],"prefix":"10.3390","volume":"11","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-4518-8495","authenticated-orcid":false,"given":"Oscar","family":"Coltell","sequence":"first","affiliation":[{"name":"Department of Computer Languages and Systems, Universitat Jaume I, 12071 Castell\u00f3n, Spain"},{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eva M.","family":"Asensio","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-0130-2006","authenticated-orcid":false,"given":"Jos\u00e9 V.","family":"Sorl\u00ed","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-8072-3791","authenticated-orcid":false,"given":"Rocio","family":"Barrag\u00e1n","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Rebeca","family":"Fern\u00e1ndez-Carri\u00f3n","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Olga","family":"Portol\u00e9s","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carolina","family":"Ortega-Azor\u00edn","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raul","family":"Mart\u00ednez-LaCruz","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jos\u00e9 I.","family":"Gonz\u00e1lez","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1179-1592","authenticated-orcid":false,"given":"Vicente","family":"Zan\u00f3n-Moreno","sequence":"additional","affiliation":[{"name":"Area of Health Sciences, Valencian International University, 46002 Valencia, Spain"},{"name":"Red Tem\u00e1tica de Investigaci\u00f3n Cooperativa OftaRed, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Ophthalmology Research Unit \u201cSantiago Grisolia\u201d, Dr. Peset University Hospital, 46017 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ignacio","family":"Gimenez-Alba","sequence":"additional","affiliation":[{"name":"Department of Preventive Medicine and Public Health, School of Medicine, University of Valencia, 46010 Valencia, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Montserrat","family":"Fit\u00f3","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Instituto Hospital del Mar de Investigaciones M\u00e9dicas, 08003 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2573-1294","authenticated-orcid":false,"given":"Emilio","family":"Ros","sequence":"additional","affiliation":[{"name":"CIBER Fisiopatolog\u00eda de la Obesidad y Nutrici\u00f3n, Instituto de Salud Carlos III, 28029 Madrid, Spain"},{"name":"Lipid Clinic, Endocrinology and Nutrition Service, Institut d\u2019Investigacions Biom\u00e8diques August Pi Sunyer (IDIBAPS), Hospital Cl\u00ednic, University of Barcelona, 08036 Barcelona, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jose M.","family":"Ordovas","sequence":"additional","affiliation":[{"name":"Nutrition and Genomics Laboratory, JM-USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA 02111, USA"},{"name":"Department of Cardiovascular Epidemiology and Population Genetics, Centro Nacional de Investigaciones Cardiovasculares (CNIC), 28029 Madrid, Spain"},{"name":"IMDEA Alimentaci\u00f3n, 28049 Madrid, Spain"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2366-4104","authenticated-orcid":false,"given":"Dolores","family":"Corella","sequence":"additional","affiliation":[{"name":"CIBER 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