{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,29]],"date-time":"2026-09-29T10:53:02Z","timestamp":1790679182893,"version":"4.1.0"},"reference-count":55,"publisher":"Wiley","issue":"4","license":[{"start":{"date-parts":[[2012,3,3]],"date-time":"2012-03-03T00:00:00Z","timestamp":1330732800000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/onlinelibrary.wiley.com\/termsAndConditions#vor"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["American J Hematol"],"published-print":{"date-parts":[[2012,4]]},"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Mutations in <jats:italic>GBA1<\/jats:italic> gene result in defective acid \u03b2\u2010glucosidase and the complex phenotype of Gaucher disease (GD) related to the accumulation of glucosylceramide\u2010laden macrophages. The phenotype is highly variable even among patients harboring identical <jats:italic>GBA1<\/jats:italic> mutations. We hypothesize that modifier gene(s) underlie phenotypic diversity in GD and performed a GWAS study in Ashkenazi Jewish patients with type 1 GD (GD1), homozygous for N370S mutation. Patients were assigned to mild, moderate, or severe disease categories using composite disease severity scoring systems. Whole\u2010genome genotyping for &gt;500,000 SNPs was performed to search for association signals using OQLS algorithm in 139 eligible patients. Several SNPs in linkage disequilibrium within the <jats:italic>CLN8<\/jats:italic> gene locus were associated with the GD1 severity: SNP rs11986414 was associated with GD1 severity at <jats:italic>P<\/jats:italic> value 1.26 \u00d7 10<jats:sup>\u22126<\/jats:sup>. Compared to mild disease, risk allele A at rs11986414 conferred an odds ratio of 3.72 for moderate\/severe disease. Loss of function mutations in <jats:italic>CLN8<\/jats:italic> causes neuronal ceroid\u2010lipofuscinosis, but our results indicate that its <jats:italic>increased<\/jats:italic> expression may protect against severe GD1. In cultured skin fibroblasts, the relative expression of <jats:italic>CLN8<\/jats:italic> was higher in mild GD compared to severely affected patients, in whom <jats:italic>CLN8<\/jats:italic> risk alleles were overrepresented. In an in vitro cell model of GD, <jats:italic>CLN8<\/jats:italic> expression was increased, which was further enhanced in the presence of bioactive substrate, glucosylsphingosine. Taken together, <jats:italic>CLN8<\/jats:italic> is a candidate modifier gene for GD1 that may function as a protective sphingolipid sensor and\/or in glycosphingolipid trafficking. Future studies should explore the role of <jats:italic>CLN8<\/jats:italic> in pathophysiology of GD. Am. J. Hematol., 2012. \u00a9 2012 Wiley Periodicals, Inc.<\/jats:p>","DOI":"10.1002\/ajh.23118","type":"journal-article","created":{"date-parts":[[2012,1,19]],"date-time":"2012-01-19T14:21:29Z","timestamp":1326982889000},"page":"377-383","source":"Crossref","is-referenced-by-count":53,"title":["Genome\u2010wide association study of N370S homozygous Gaucher disease reveals the candidacy of <i>CLN8<\/i> gene as a genetic modifier contributing to extreme phenotypic variation"],"prefix":"10.1002","volume":"87","author":[{"given":"Clarence K.","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Philip B.","family":"Stein","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jun","family":"Liu","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Zuoheng","family":"Wang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruhua","family":"Yang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Judy H.","family":"Cho","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter K.","family":"Gregersen","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Johannes M.F.G.","family":"Aerts","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hongyu","family":"Zhao","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gregory M.","family":"Pastores","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Pramod K.","family":"Mistry","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"311","published-online":{"date-parts":[[2012,3,3]]},"reference":[{"key":"e_1_2_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(08)61522-6"},{"key":"e_1_2_6_3_2","doi-asserted-by":"publisher","DOI":"10.1001\/archneur.1993.00540110088009"},{"key":"e_1_2_6_4_2","doi-asserted-by":"publisher","DOI":"10.2147\/BTT.S7582"},{"key":"e_1_2_6_5_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2004.05351.x"},{"key":"e_1_2_6_6_2","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M809500200"},{"key":"e_1_2_6_7_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.1003308107"},{"key":"e_1_2_6_8_2","volume-title":"Gaucher disease: Molecular biology and genotype\/phenotype correaltions in Gaucher disease","author":"Hruska KS"},{"key":"e_1_2_6_9_2","doi-asserted-by":"publisher","DOI":"10.1089\/gte.1997.1.5"},{"key":"e_1_2_6_10_2","doi-asserted-by":"publisher","DOI":"10.1006\/bcmd.2002.0535"},{"key":"e_1_2_6_11_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21362"},{"key":"e_1_2_6_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21888"},{"key":"e_1_2_6_13_2","doi-asserted-by":"publisher","DOI":"10.1023\/B:BOLI.0000042983.60840.f3"},{"key":"e_1_2_6_14_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-009-9024-7"},{"key":"e_1_2_6_15_2","first-page":"85","article-title":"Gaucher disease: Gene frequencies in the Ashkenazi Jewish population","volume":"52","author":"Beutler E","year":"1993","journal-title":"Am J Hum Genet"},{"key":"e_1_2_6_16_2","doi-asserted-by":"publisher","DOI":"10.1136\/jmg.2004.028019"},{"key":"e_1_2_6_17_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-011-9308-6"},{"key":"e_1_2_6_18_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hch036"},{"key":"e_1_2_6_19_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2010.10.007"},{"key":"e_1_2_6_20_2","doi-asserted-by":"publisher","DOI":"10.1172\/JCI116276"},{"key":"e_1_2_6_21_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0950-3536(97)80032-7"},{"key":"e_1_2_6_22_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi240"},{"key":"e_1_2_6_23_2","first-page":"33","article-title":"Phenotypic manifestations of Gaucher disease: Clinical features in 48 biochemically verified type 1 patients and comment on type 2 patients","volume":"95","author":"Kolodny EH","year":"1982","journal-title":"Prog Clin Biol Res"},{"key":"e_1_2_6_24_2","doi-asserted-by":"publisher","DOI":"10.1086\/302946"},{"key":"e_1_2_6_25_2","first-page":"986","article-title":"Polymorphisms in glucosylceramide (glucocerebroside) synthase and the Gaucher disease phenotype","volume":"4","author":"Beutler E","year":"2002","journal-title":"Isr Med Assoc J"},{"key":"e_1_2_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2010.07.009"},{"key":"e_1_2_6_27_2","doi-asserted-by":"publisher","DOI":"10.1093\/qjmed\/hcg097"},{"key":"e_1_2_6_28_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.cyto.2005.03.006"},{"key":"e_1_2_6_29_2","doi-asserted-by":"publisher","DOI":"10.1007\/s00246-009-9538-7"},{"key":"e_1_2_6_30_2","doi-asserted-by":"publisher","DOI":"10.1148\/radiol.2292020296"},{"key":"e_1_2_6_31_2","doi-asserted-by":"publisher","DOI":"10.1097\/00005792-199211000-00002"},{"key":"e_1_2_6_32_2","doi-asserted-by":"publisher","DOI":"10.1097\/GIM.0b013e3181c39194"},{"key":"e_1_2_6_33_2","doi-asserted-by":"publisher","DOI":"10.1086\/519795"},{"key":"e_1_2_6_34_2","doi-asserted-by":"publisher","DOI":"10.1002\/gepi.20418"},{"key":"e_1_2_6_35_2","doi-asserted-by":"publisher","DOI":"10.1086\/519497"},{"key":"e_1_2_6_36_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/bth457"},{"key":"e_1_2_6_37_2","doi-asserted-by":"publisher","DOI":"10.1093\/bioinformatics\/btn564"},{"key":"e_1_2_6_38_2","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pgen.1000214"},{"key":"e_1_2_6_39_2","doi-asserted-by":"publisher","DOI":"10.1194\/jlr.M200232-JLR200"},{"key":"e_1_2_6_40_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.joca.2009.02.006"},{"key":"e_1_2_6_41_2","doi-asserted-by":"publisher","DOI":"10.1042\/BC20040506"},{"key":"e_1_2_6_42_2","doi-asserted-by":"publisher","DOI":"10.1007\/s10545-006-0411-z"},{"key":"e_1_2_6_43_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0912176107"},{"key":"e_1_2_6_44_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0400782101"},{"key":"e_1_2_6_45_2","doi-asserted-by":"publisher","DOI":"10.1186\/gb-2009-10-11-r130"},{"key":"e_1_2_6_46_2","doi-asserted-by":"publisher","DOI":"10.1002\/ajh.21280"},{"key":"e_1_2_6_47_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1365-2141.2009.07872.x"},{"key":"e_1_2_6_48_2","doi-asserted-by":"publisher","DOI":"10.1038\/13868"},{"key":"e_1_2_6_49_2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/9.11.1691"},{"key":"e_1_2_6_50_2","doi-asserted-by":"publisher","DOI":"10.1002\/jnr.20133"},{"key":"e_1_2_6_51_2","doi-asserted-by":"publisher","DOI":"10.1091\/mbc.12.11.3417"},{"key":"e_1_2_6_52_2","doi-asserted-by":"publisher","DOI":"10.1002\/humu.21624"},{"key":"e_1_2_6_53_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.bcmd.2008.03.007"},{"key":"e_1_2_6_54_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMp078120"},{"key":"e_1_2_6_55_2","doi-asserted-by":"publisher","DOI":"10.1073\/pnas.0606016103"},{"key":"e_1_2_6_56_2","doi-asserted-by":"publisher","DOI":"10.1111\/j.1471-4159.2005.03376.x"}],"container-title":["American Journal of Hematology"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/api.wiley.com\/onlinelibrary\/tdm\/v1\/articles\/10.1002%2Fajh.23118","content-type":"unspecified","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/pdf\/10.1002\/ajh.23118","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,10,16]],"date-time":"2023-10-16T13:34:11Z","timestamp":1697463251000},"score":1,"resource":{"primary":{"URL":"https:\/\/onlinelibrary.wiley.com\/doi\/10.1002\/ajh.23118"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2012,3,3]]},"references-count":55,"journal-issue":{"issue":"4","published-print":{"date-parts":[[2012,4]]}},"alternative-id":["10.1002\/ajh.23118"],"URL":"https:\/\/doi.org\/10.1002\/ajh.23118","archive":["Portico"],"relation":{},"ISSN":["0361-8609","1096-8652"],"issn-type":[{"value":"0361-8609","type":"print"},{"value":"1096-8652","type":"electronic"}],"subject":[],"published":{"date-parts":[[2012,3,3]]}}}