{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,22]],"date-time":"2026-09-22T18:20:56Z","timestamp":1790101256397,"version":"4.0.1"},"reference-count":20,"publisher":"American Diabetes Association","issue":"7","license":[{"start":{"date-parts":[[2017,6,21]],"date-time":"2017-06-21T00:00:00Z","timestamp":1498003200000},"content-version":"vor","delay-in-days":62,"URL":"http:\/\/www.diabetesjournals.org\/content\/license"}],"funder":[{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 DK54261"],"award-info":[{"award-number":["R01 DK54261"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 AG18728"],"award-info":[{"award-number":["R01 AG18728"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL69313"],"award-info":[{"award-number":["R01 HL69313"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 HL072515"],"award-info":[{"award-number":["U01 HL072515"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["U01 GM074518"],"award-info":[{"award-number":["U01 GM074518"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["R01 HL088119"],"award-info":[{"award-number":["R01 HL088119"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100000002","name":"National Institutes of Health","doi-asserted-by":"publisher","award":["P30 DK072488"],"award-info":[{"award-number":["P30 DK072488"]}],"id":[{"id":"10.13039\/100000002","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/100004440","name":"Wellcome Trust","doi-asserted-by":"publisher","award":["WT098051"],"award-info":[{"award-number":["WT098051"]}],"id":[{"id":"10.13039\/100004440","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["diabetesjournals.org"],"crossmark-restriction":true},"short-container-title":[],"published-print":{"date-parts":[[2017,7,1]]},"abstract":"<jats:p>Alleles associated with lower levels of LDL cholesterol (LDL-C) have recently been associated with an increased risk of type 2 diabetes (T2D), highlighting the complex relationship between LDL-C and diabetes. This observation begs the question of whether LDL-C\u2013raising alleles are associated with a decreased risk of T2D. This issue was recently addressed in a large familial hypercholesterolemia (FH) screening study, which reported a lower prevalence of self-reported diabetes in FH subjects than in age-matched relatives without FH. To extend this observation, we tested the association of FH with diabetes status and glycemia in a large Amish population enriched for the FH-associated APOB R3527Q variant that included 640 APOB R3527Q carriers and 4,683 noncarriers. Each copy of the R3527Q T allele was associated with a 74.9 mg\/dL increase in LDL-C. There was little difference in T2D prevalence between subjects with (5.2%) and without (4.5%) the R3527Q allele (P = 0.23), and there was no association between R3527Q variant and impaired fasting glucose, fasting glucose or insulin, or oral glucose tolerance test\u2013derived measures. Our data provide no evidence supporting an association between the APOB R3527Q variant and T2D or glycemia and highlight the asymmetry of the LDL-C\u2013T2D relationship and\/or the gene\/variant-dependent specificity of the LDL-C\u2013T2D association.<\/jats:p>","DOI":"10.2337\/db17-0173","type":"journal-article","created":{"date-parts":[[2017,4,21]],"date-time":"2017-04-21T00:25:37Z","timestamp":1492734337000},"page":"2054-2058","update-policy":"https:\/\/doi.org\/10.2337\/ada-journal-policies","source":"Crossref","is-referenced-by-count":29,"title":["Familial Hypercholesterolemia and Type 2 Diabetes in the Old Order Amish"],"prefix":"10.2337","volume":"66","author":[{"given":"Huichun","family":"Xu","sequence":"first","affiliation":[{"name":"Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kathleen A.","family":"Ryan","sequence":"additional","affiliation":[{"name":"Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4420-8703","authenticated-orcid":false,"given":"Thomas J.","family":"Jaworek","sequence":"additional","affiliation":[{"name":"Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lorraine","family":"Southam","sequence":"additional","affiliation":[{"name":"Wellcome Trust Sanger Institute, Hinxton, U.K."},{"name":"Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Jeffrey G.","family":"Reid","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"John D.","family":"Overton","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Aris","family":"Baras","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marja K.","family":"Puurunen","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Eleftheria","family":"Zeggini","sequence":"additional","affiliation":[{"name":"Wellcome Trust Centre for Human Genetics, University of Oxford, Oxford, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Simeon I.","family":"Taylor","sequence":"additional","affiliation":[{"name":"Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Alan R.","family":"Shuldiner","sequence":"additional","affiliation":[{"name":"Regeneron Genetics Center, Regeneron Pharmaceuticals, Inc., Tarrytown, NY"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Braxton D.","family":"Mitchell","sequence":"additional","affiliation":[{"name":"Program in Personalized and Genomic Medicine, and Division of Endocrinology, Diabetes & Nutrition, Department of Medicine, University of Maryland School of Medicine, Baltimore, MD"},{"name":"Geriatrics Research and Education Clinical Center, Baltimore VA Medical Center, Baltimore, MD"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1167","published-online":{"date-parts":[[2017,4,20]]},"reference":[{"key":"2022031303450247800_B1","doi-asserted-by":"crossref","first-page":"735","DOI":"10.1016\/S0140-6736(09)61965-6","article-title":"Statins and risk of incident diabetes: a collaborative meta-analysis of randomised statin trials","volume":"375","author":"Sattar","year":"2010","journal-title":"Lancet"},{"key":"2022031303450247800_B2","doi-asserted-by":"crossref","first-page":"351","DOI":"10.1016\/S0140-6736(14)61183-1","article-title":"HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis and randomised trials","volume":"385","author":"Swerdlow","year":"2015","journal-title":"Lancet"},{"key":"2022031303450247800_B3","doi-asserted-by":"crossref","first-page":"1383","DOI":"10.1001\/jama.2016.14568","article-title":"Association between low-density lipoprotein cholesterol-lowering genetic variants and risk of type 2 diabetes: a meta-analysis","volume":"316","author":"Lotta","year":"2016","journal-title":"JAMA"},{"key":"2022031303450247800_B4","doi-asserted-by":"crossref","first-page":"97","DOI":"10.1016\/S2213-8587(16)30396-5","article-title":"PCSK9 genetic variants and risk of type 2 diabetes: a mendelian randomisation study","volume":"5","author":"Schmidt","year":"2017","journal-title":"Lancet Diabetes Endocrinol"},{"key":"2022031303450247800_B5","doi-asserted-by":"crossref","first-page":"2144","DOI":"10.1056\/NEJMoa1604304","article-title":"Variation in PCSK9 and HMGCR and risk of cardiovascular disease and diabetes","volume":"375","author":"Ference","year":"2016","journal-title":"N Engl J Med"},{"key":"2022031303450247800_B6","doi-asserted-by":"crossref","first-page":"1029","DOI":"10.1001\/jama.2015.1206","article-title":"Association between familial hypercholesterolemia and prevalence of type 2 diabetes mellitus","volume":"313","author":"Besseling","year":"2015","journal-title":"JAMA"},{"key":"2022031303450247800_B7","doi-asserted-by":"crossref","first-page":"1850","DOI":"10.1001\/archinternmed.2010.384","article-title":"Familial defective apolipoprotein B-100 and increased low-density lipoprotein cholesterol and coronary artery calcification in the Old Order Amish","volume":"170","author":"Shen","year":"2010","journal-title":"Arch Intern Med"},{"key":"2022031303450247800_B8","doi-asserted-by":"crossref","DOI":"10.1126\/science.aaf6814","article-title":"Distribution and clinical impact of functional variants in 50,726 whole-exome sequences from the DiscovEHR study","volume":"354","author":"Dewey","year":"2016","journal-title":"Science"},{"key":"2022031303450247800_B9","doi-asserted-by":"crossref","first-page":"595","DOI":"10.2337\/diacare.23.5.595","article-title":"Diabetes in the Old Order Amish: characterization and heritability analysis of the Amish Family Diabetes Study","volume":"23","author":"Hsueh","year":"2000","journal-title":"Diabetes Care"},{"key":"2022031303450247800_B10","doi-asserted-by":"crossref","first-page":"308","DOI":"10.1359\/JBMR.0301223","article-title":"Reduced incidence of hip fracture in the Old Order Amish","volume":"19","author":"Streeten","year":"2004","journal-title":"J Bone Miner Res"},{"key":"2022031303450247800_B11","doi-asserted-by":"crossref","first-page":"717","DOI":"10.1161\/CIRCULATIONAHA.106.637512","article-title":"Determinants of coronary artery and aortic calcification in the Old Order Amish","volume":"115","author":"Post","year":"2007","journal-title":"Circulation"},{"key":"2022031303450247800_B12","doi-asserted-by":"crossref","first-page":"823","DOI":"10.1016\/j.ahj.2008.01.019","article-title":"The genetic response to short-term interventions affecting cardiovascular function: rationale and design of the Heredity and Phenotype Intervention (HAPI) Heart Study","volume":"155","author":"Mitchell","year":"2008","journal-title":"Am Heart J"},{"key":"2022031303450247800_B13","doi-asserted-by":"crossref","first-page":"116","DOI":"10.2174\/1570161113666150916094829","article-title":"The Pharmacogenomics of Anti-Platelet Intervention (PAPI) Study: variation in platelet response to clopidogrel and aspirin","volume":"14","author":"Bozzi","year":"2016","journal-title":"Curr Vasc Pharmacol"},{"key":"2022031303450247800_B14","unstructured":"MMAP user guide [article online], 2013. Available from http:\/\/edn.som.umaryland.edu\/mmap\/index.php. Accessed 8 April 2014"},{"key":"2022031303450247800_B15","doi-asserted-by":"crossref","first-page":"175","DOI":"10.1007\/s12471-011-0076-6","article-title":"Founder mutations in the Netherlands: geographical distribution of the most prevalent mutations in the low-density lipoprotein receptor and apolipoprotein B genes","volume":"19","author":"Kusters","year":"2011","journal-title":"Neth Heart J"},{"key":"2022031303450247800_B16","doi-asserted-by":"crossref","first-page":"S15","DOI":"10.1194\/jlr.R800054-JLR200","article-title":"Cholesterol feedback: from Schoenheimer\u2019s bottle to Scap\u2019s MELADL","volume":"50","author":"Brown","year":"2009","journal-title":"J Lipid Res"},{"key":"2022031303450247800_B17","doi-asserted-by":"crossref","first-page":"1084","DOI":"10.1172\/JCI1847","article-title":"Identification of the low density lipoprotein receptor-binding site in apolipoprotein B100 and the modulation of its binding activity by the carboxyl terminus in familial defective apo-B100","volume":"101","author":"Boren","year":"1998","journal-title":"J Clin Invest"},{"key":"2022031303450247800_B18","doi-asserted-by":"crossref","first-page":"5153","DOI":"10.1016\/S0021-9258(19)42341-7","article-title":"Binding and degradation of low density lipoproteins by cultured human fibroblasts. Comparison of cells from a normal subject and from a patient with homozygous familial hypercholesterolemia","volume":"249","author":"Goldstein","year":"1974","journal-title":"J Biol Chem"},{"key":"2022031303450247800_B19","doi-asserted-by":"crossref","first-page":"2676","DOI":"10.2337\/db14-1710","article-title":"Using genetic variants to assess the relationship between circulating lipids and type 2 diabetes","volume":"64","author":"Fall","year":"2015","journal-title":"Diabetes"},{"key":"2022031303450247800_B20","doi-asserted-by":"crossref","first-page":"692","DOI":"10.1001\/jamacardio.2016.1884","article-title":"Association of lipid fractions with risks for coronary artery disease and diabetes","volume":"1","author":"White","year":"2016","journal-title":"JAMA Cardiol"}],"container-title":["Diabetes"],"original-title":[],"language":"en","link":[{"URL":"http:\/\/diabetes.diabetesjournals.org\/syndication\/doi\/10.2337\/db17-0173","content-type":"unspecified","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/journals.org\/diabetes\/diabetes\/article-pdf\/66\/7\/2054\/537599\/db170173.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"syndication"},{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article-pdf\/66\/7\/2054\/537599\/db170173.pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2022,11,2]],"date-time":"2022-11-02T16:31:45Z","timestamp":1667406705000},"score":1,"resource":{"primary":{"URL":"https:\/\/diabetesjournals.org\/diabetes\/article\/66\/7\/2054\/39921\/Familial-Hypercholesterolemia-and-Type-2-Diabetes"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2017,4,20]]},"references-count":20,"journal-issue":{"issue":"7","published-online":{"date-parts":[[2017,4,20]]},"published-print":{"date-parts":[[2017,7,1]]}},"URL":"https:\/\/doi.org\/10.2337\/db17-0173","relation":{},"ISSN":["0012-1797","1939-327X"],"issn-type":[{"value":"0012-1797","type":"print"},{"value":"1939-327X","type":"electronic"}],"subject":[],"published":{"date-parts":[[2017,4,20]]}}}