Normal range CAG repeat size variations in the HTT gene are associated with an adverse lipoprotein profile partially mediated by body mass index
Human Molecular Genetics, vol. 32, pp. 1741–1752
Abstract
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 (<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 < 36 are associated with metabolite levels, possibly mediated through reduced BMI. We pooled data from three European cohorts (n = 10 228) 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-similar to those of higher risk of coronary artery disease and type 2 diabetes-and 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.
Authors 12
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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University Hospital Bonn · German Center for Neurodegenerative Diseases
Affiliation as printed
Department of Neurology, Bonn University Hospital , Bonn 53175 , Germany
Population Health Sciences, German Center for Neurodegenerative Diseases (DZNE) , Bonn 53175 , Germany
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Amsterdam University Medical Centers
Affiliation as printed
Department of Neurology, Amsterdam UMC , Amsterdam 1080 HZ , The Netherlands
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Leiden University Medical Center · Metabolon (United States)
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
Metabolon, Inc. , Morrisville, NC 27560 , USA
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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Amsterdam Neuroscience · Amsterdam Public Health · Amsterdam UMC Location Vrije Universiteit Amsterdam
Affiliation as printed
Amsterdam Neuroscience, Complex Trait Genetics , Amsterdam 1081 HV , The Netherlands
Amsterdam Neuroscience, Mood, Anxiety, Psychosis, Sleep & Stress Program , Amsterdam 1081 HZ , The Netherlands
Amsterdam Public Health, Mental Health Program , Amsterdam 1081 HZ , The Netherlands
Department of Psychiatry, Amsterdam UMC Location Vrije Universiteit Amsterdam , Amsterdam 1081 HZ , The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Internal Medicine, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Cardiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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Ko Willems van Dijk Aachen Department of Human Genetics Department of Internal Medicine Division of Endocrinology Einthoven Laboratory for Experimental Vascular Medicine Division of Endocrinology Division of Endocrinology, Leiden University Medical Center
Leiden University · Leiden University Medical Center
Affiliation as printed
Department of Human Genetics, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
Department of Internal Medicine , Division of Endocrinology, , Leiden 2300 RC , The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
Leiden University Medical Center , Division of Endocrinology, , Leiden 2300 RC , The Netherlands
Department of Internal Medicine, Division of Endocrinology, Leiden University Medical Center, Leiden 2300 RC, The Netherlands
Einthoven Laboratory for Experimental Vascular Medicine, Leiden University Medical Center, Leiden 2300 RC, The Netherlands
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Dennis Owen Mook-Kanamori Aachen Department of Clinical Epidemiology Department of Public Health and Primary Care
Leiden University Medical Center
Affiliation as printed
Department of Clinical Epidemiology, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
Department of Public Health and Primary Care, Leiden University Medical Center , Leiden 2300 RC , The Netherlands
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