{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,10]],"date-time":"2026-07-10T20:46:52Z","timestamp":1783716412452,"version":"3.55.0"},"reference-count":51,"publisher":"Oxford University Press (OUP)","issue":"10","license":[{"start":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T00:00:00Z","timestamp":1675036800000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by-nc\/4.0\/"}],"funder":[{"name":"Netherlands Organization of Scientific Research","award":["#91615080"],"award-info":[{"award-number":["#91615080"]}]},{"DOI":"10.13039\/100000957","name":"Alzheimer's Association Research","doi-asserted-by":"crossref","award":["AARG-19-616534"],"award-info":[{"award-number":["AARG-19-616534"]}],"id":[{"id":"10.13039\/100000957","id-type":"DOI","asserted-by":"crossref"}]},{"name":"European Research Council Starting Grant","award":["101041677"],"award-info":[{"award-number":["101041677"]}]},{"DOI":"10.13039\/501100005039","name":"Leiden University Medical Center","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100005039","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001717","name":"Leiden University","doi-asserted-by":"publisher","id":[{"id":"10.13039\/501100001717","id-type":"DOI","asserted-by":"publisher"}]},{"name":"DutchScience Organization","award":["916.14.023"],"award-info":[{"award-number":["916.14.023"]}]},{"name":"King Abdullah Scholarship Program and King Faisal Specialist Hospital & Research Center","award":["1012879283"],"award-info":[{"award-number":["1012879283"]}]},{"DOI":"10.13039\/501100001826","name":"Netherlands Organization for Health Research and Development","doi-asserted-by":"crossref","award":["10-000-1002"],"award-info":[{"award-number":["10-000-1002"]}],"id":[{"id":"10.13039\/501100001826","id-type":"DOI","asserted-by":"crossref"}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":[],"published-print":{"date-parts":[[2023,5,5]]},"abstract":"<jats:title>Abstract<\/jats:title>\n               <jats:p>Tandem cytosine-adenine-guanine (CAG) repeat sizes of 36 or more in the huntingtin gene (HTT) cause Huntington's disease (HD). Apart from neuropsychiatric complications, the disease is also accompanied by metabolic dysregulation and weight loss, which contribute to a progressive functional decline. Recent studies also reported an association between repeats below the pathogenic threshold (&amp;lt;36) for HD and body mass index (BMI), suggesting that HTT repeat sizes in the non-pathogenic range are associated with metabolic dysregulation. In this study, we hypothesized that HTT repeat sizes &amp;lt;\u200936 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n\u2009=\u200910\u2009228) with genotyped HTT CAG repeat size and metabolomic measurements. All 145 metabolites were measured on the same targeted platform in all studies. Multilevel mixed-effects analysis using the CAG repeat size in HTT identified 67 repeat size metabolite associations. Overall, the metabolomic profile associated with larger CAG repeat sizes in HTT were unfavorable\u2014similar to those of higher risk of coronary artery disease and type 2 diabetes\u2014and included elevated levels of amino acids, fatty acids, low-density lipoprotein (LDL)-, very low-density lipoprotein- and intermediate density lipoprotein (IDL)-related metabolites while with decreased levels of very large high-density lipoprotein (HDL)-related metabolites. Furthermore, the associations of 50 metabolites, in particular, specific very large HDL-related metabolites, were mediated by lower BMI. However, no mediation effect was found for 17 metabolites related to LDL and IDL. In conclusion, our findings indicate that large non-pathogenic CAG repeat sizes in HTT are associated with an unfavorable metabolomic profile despite their association with a lower BMI.<\/jats:p>","DOI":"10.1093\/hmg\/ddad020","type":"journal-article","created":{"date-parts":[[2023,1,30]],"date-time":"2023-01-30T21:26:38Z","timestamp":1675113998000},"page":"1741-1752","source":"Crossref","is-referenced-by-count":12,"title":["Normal range CAG repeat size variations in the <i>HTT<\/i> gene are associated with an adverse lipoprotein profile partially mediated by body mass index"],"prefix":"10.1093","volume":"32","author":[{"ORCID":"https:\/\/orcid.org\/0000-0001-8026-2251","authenticated-orcid":false,"given":"Tariq O","family":"Faquih","sequence":"first","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"N Ahmad","family":"Aziz","sequence":"additional","affiliation":[{"name":"Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE) , Bonn 53175 , Germany"},{"name":"Department of Neurology, Bonn University Hospital , Bonn 53175 , Germany"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sarah L","family":"Gardiner","sequence":"additional","affiliation":[{"name":"Department of Neurology, Amsterdam UMC , Amsterdam 1080 HZ , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ruifang","family":"Li-Gao","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"},{"name":"Metabolon, Inc. , Morrisville, NC 27560 , USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ren\u00e9e","family":"de Mutsert","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuri","family":"Milaneschi","sequence":"additional","affiliation":[{"name":"Department of Psychiatry, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam 1081 HZ , The Netherlands"},{"name":"Amsterdam Public Health, Mental Health Program , Amsterdam 1081 HZ , The Netherlands"},{"name":"Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program , Amsterdam 1081 HZ , The Netherlands"},{"name":"Amsterdam Neuroscience, Complex Trait Genetics , Amsterdam 1081 HV , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stella","family":"Trompet","sequence":"additional","affiliation":[{"name":"Department of Internal Medicine, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"J Wouter","family":"Jukema","sequence":"additional","affiliation":[{"name":"Department of Cardiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Frits R","family":"Rosendaal","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"van Hylckama Vlieg","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ko Willems","family":"van Dijk","sequence":"additional","affiliation":[{"name":"Department of Human Genetics, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"},{"name":"Department of Internal Medicine , Division of Endocrinology, , Leiden 2300 RC , The Netherlands"},{"name":"Leiden University Medical Center , Division of Endocrinology, , Leiden 2300 RC , The Netherlands"},{"name":"Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dennis O","family":"Mook-Kanamori","sequence":"additional","affiliation":[{"name":"Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"},{"name":"Department of Public Health and Primary Care, Leiden University Medical Center , Leiden 2300 RC , The Netherlands"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2023,1,30]]},"reference":[{"key":"2023050516324082900_ref1","doi-asserted-by":"crossref","first-page":"24","DOI":"10.1111\/ene.13413","article-title":"Huntington's disease: a clinical review","volume":"25","author":"McColgan","year":"2018","journal-title":"Eur. 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