{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,6]],"date-time":"2026-09-06T04:45:01Z","timestamp":1788669901284,"version":"build-2803163510"},"reference-count":35,"publisher":"National Academy of Sciences","issue":"22","content-domain":{"domain":["www.pnas.org"],"crossmark-restriction":true},"short-container-title":["Proc. Natl. Acad. Sci. U.S.A."],"published-print":{"date-parts":[[1997,10,28]]},"abstract":"<jats:p>\n                    Severe jaundice leading to kernicterus or death in the newborn is the most devastating consequence of glucose-6-phosphate dehydrogenase (EC\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"ec\" xlink:href=\"1.1.1.49\">1.1.1.49<\/jats:ext-link>\n                    ; G-6-PD) deficiency. We asked whether the TA repeat promoter polymorphism in the gene for uridinediphosphoglucuronate glucuronosyltransferase 1 (EC\n                    <jats:ext-link xmlns:xlink=\"http:\/\/www.w3.org\/1999\/xlink\" ext-link-type=\"ec\" xlink:href=\"2.4.1.17\">2.4.1.17<\/jats:ext-link>\n                    ; UDPGT1), associated with benign jaundice in adults (Gilbert syndrome), increases the incidence of neonatal hyperbilirubinemia in G-6-PD deficiency. DNA from term neonates was analyzed for UDPGT1 polymorphism (normal homozygotes, heterozygotes, variant homozygotes), and for G-6-PD Mediterranean deficiency. The variant UDPGT1 promoter allele frequency was similar in G-6-PD-deficient and normal neonates. Thirty (22.9%) G-6-PD deficient neonates developed serum total bilirubin \u2265 257 \u03bcmol\/liter, vs. 22 (9.2%) normals (\n                    <jats:italic>P<\/jats:italic>\n                    = 0.0005). Of those with the normal homozygous UDPGT1 genotype, the incidence of hyperbilirubinemia was similar in G-6-PD-deficients and controls (9.7% and 9.9%). In contrast, in the G-6-PD-deficient neonates, those with the heterozygous or homozygous variant UDPGT1 genotype had a higher incidence of hyperbilirubinemia than corresponding controls (heterozygotes: 31.6% vs. 6.7%,\n                    <jats:italic>P<\/jats:italic>\n                    &lt; 0.0001; variant homozygotes: 50% vs. 14.7%,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.02). Among G-6-PD-deficient infants the incidence of hyperbilirubinemia was greater in those with the heterozygous (31.6%,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.006) or variant homozygous (50%,\n                    <jats:italic>P<\/jats:italic>\n                    = 0.003) UDPGT1 genotype than in normal homozygotes. In contrast, among those normal for G-6-PD, the UDPGT1 polymorphism had no significant effect (heterozygotes: 6.7%; variant homozygotes: 14.7%). Thus, neither G-6-PD deficiency nor the variant UDPGT1 promoter, alone, increased the incidence of hyperbilirubinemia, but both in combination did. This gene interaction may serve as a paradigm of the interaction of benign genetic polymorphisms in the causation of disease.\n                  <\/jats:p>","DOI":"10.1073\/pnas.94.22.12128","type":"journal-article","created":{"date-parts":[[2002,7,26]],"date-time":"2002-07-26T10:42:40Z","timestamp":1027680160000},"page":"12128-12132","update-policy":"https:\/\/doi.org\/10.1073\/pnas.cm10313","source":"Crossref","is-referenced-by-count":272,"title":["Gilbert syndrome and glucose-6-phosphate dehydrogenase deficiency: A dose-dependent genetic interaction crucial  to neonatal\u2009hyperbilirubinemia"],"prefix":"10.1073","volume":"94","author":[{"given":"Michael","family":"Kaplan","sequence":"first","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Paul","family":"Renbaum","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ephrat","family":"Levy-Lahad","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Cathy","family":"Hammerman","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amnon","family":"Lahad","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ernest","family":"Beutler","sequence":"additional","affiliation":[{"name":"Department of Neonatology and Medical Genetics Laboratory and Department of Internal Medicine, Shaare Zedek Medical Center, Jerusalem 91031, Israel; Department of Family Medicine, Kupat Holim Clallit Health Fund, Jerusalem 93595, Israel; Medical School of the Hebrew University-Hadassah, Jerusalem 91010, Israel; and Department of Molecular and Experimental Medicine, The Scripps Research Institute, La Jolla, CA 92037"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"341","published-online":{"date-parts":[[1997,10,28]]},"reference":[{"key":"e_1_3_3_1_2","doi-asserted-by":"publisher","DOI":"10.1182\/blood.V84.11.3613.bloodjournal84113613"},{"key":"e_1_3_3_2_2","doi-asserted-by":"publisher","DOI":"10.2105\/AJPH.52.7.1101"},{"key":"e_1_3_3_3_2","doi-asserted-by":"publisher","DOI":"10.1136\/fn.71.1.F59"},{"key":"e_1_3_3_4_2","doi-asserted-by":"publisher","DOI":"10.1007\/BF00218277"},{"key":"e_1_3_3_5_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(61)91476-3"},{"key":"e_1_3_3_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(95)70510-4"},{"key":"e_1_3_3_7_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.96.4.734"},{"key":"e_1_3_3_8_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1651-2227.1994.tb13216.x"},{"key":"e_1_3_3_9_2","doi-asserted-by":"publisher","DOI":"10.1136\/adc.40.211.280"},{"key":"e_1_3_3_10_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.97.5.707"},{"key":"e_1_3_3_11_2","doi-asserted-by":"publisher","DOI":"10.1542\/peds.90.3.401"},{"key":"e_1_3_3_12_2","doi-asserted-by":"publisher","DOI":"10.1046\/j.1365-2141.1996.d01-1745.x"},{"key":"e_1_3_3_13_2","doi-asserted-by":"publisher","DOI":"10.1203\/00006450-196909000-00008"},{"key":"e_1_3_3_14_2","doi-asserted-by":"publisher","DOI":"10.1159\/000208087"},{"key":"e_1_3_3_15_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(60)92177-2"},{"key":"e_1_3_3_16_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0022-3476(96)80138-7"},{"key":"e_1_3_3_17_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(87)90123-5"},{"key":"e_1_3_3_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM199511023331802"},{"key":"e_1_3_3_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(96)91273-8"},{"key":"e_1_3_3_20_2","doi-asserted-by":"publisher","DOI":"10.1093\/nar\/16.3.1215"},{"key":"e_1_3_3_21_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.85.14.5171"},{"key":"e_1_3_3_22_2","first-page":"575","volume":"47","author":"Vives-Corrons J-L","year":"1990","unstructured":"J-L Vives-Corrons, W Kuhl, M A Pujades, E Beutler Am J Hum Genet 47, 575\u2013579 (1990).","journal-title":"Am J Hum Genet"},{"key":"e_1_3_3_23_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI113881"},{"key":"e_1_3_3_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0021-9258(19)50724-4"},{"key":"e_1_3_3_25_2","doi-asserted-by":"publisher","DOI":"10.1016\/0016-5085(93)90041-A"},{"key":"e_1_3_3_26_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJM196906052802303"},{"key":"e_1_3_3_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/0009-8981(86)90086-0"},{"key":"e_1_3_3_28_2","unstructured":"Bancroft J. D. Kreamer B. & Gourley G. R. (1997) J. Pediatr. in press."},{"key":"e_1_3_3_29_2","first-page":"937","volume":"66","author":"Chan T K","year":"1965","unstructured":"T K Chan, D Todd, C, C Wong J Lab Clin Med 66, 937\u2013941 (1965).","journal-title":"J Lab Clin Med"},{"key":"e_1_3_3_30_2","first-page":"338","volume":"32","author":"Brunetti P","year":"1960","unstructured":"P Brunetti, R Rossetti, G Broccia Clin Ther 32, 338\u2013350 (1960).","journal-title":"Clin Ther"},{"key":"e_1_3_3_31_2","first-page":"783","volume":"93","author":"Oluboyede O A","year":"1979","unstructured":"O A Oluboyede, G J F Esan, T I Francis, L Luzzatto J Lab Clin Med 93, 783\u2013789 (1979).","journal-title":"J Lab Clin Med"},{"key":"e_1_3_3_32_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.1957.72980250010016"},{"key":"e_1_3_3_33_2","first-page":"764","volume":"97","author":"Magon A M","year":"1981","unstructured":"A M Magon, R M Leipzig, V G Zannoni, G J Brewer J Lab Clin Med 97, 764\u2013770 (1981).","journal-title":"J Lab Clin Med"},{"key":"e_1_3_3_34_2","first-page":"30","volume":"45","author":"Dern R J","year":"1955","unstructured":"R J Dern, E Beutler, A S Alving J Lab Clin Med 45, 30\u201339 (1955).","journal-title":"J Lab Clin Med"},{"key":"e_1_3_3_35_2","first-page":"616","volume-title":"Hematology","author":"Beutler E","year":"1995","unstructured":"E Beutler Hematology, eds E Beutler, M A Lichtman, B S Coller, T J Kipps (McGraw\u2013Hill, New York), pp. 616\u2013654 (1995)."}],"container-title":["Proceedings of the National Academy of Sciences"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/pnas.org\/doi\/pdf\/10.1073\/pnas.94.22.12128","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,4,13]],"date-time":"2022-04-13T15:19:04Z","timestamp":1649863144000},"score":1,"resource":{"primary":{"URL":"https:\/\/pnas.org\/doi\/full\/10.1073\/pnas.94.22.12128"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[1997,10,28]]},"references-count":35,"journal-issue":{"issue":"22","published-print":{"date-parts":[[1997,10,28]]}},"alternative-id":["10.1073\/pnas.94.22.12128"],"URL":"https:\/\/doi.org\/10.1073\/pnas.94.22.12128","relation":{},"ISSN":["0027-8424","1091-6490"],"issn-type":[{"value":"0027-8424","type":"print"},{"value":"1091-6490","type":"electronic"}],"subject":[],"published":{"date-parts":[[1997,10,28]]},"assertion":[{"value":"1997-08-26","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"1997-10-28","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}