Journal
DIABETES CARE
Volume 45, Issue 3, Pages 674-683Publisher
AMER DIABETES ASSOC
DOI: 10.2337/dc21-1395
Keywords
-
Categories
Funding
- National Institutes of Health (NIH) [N01-AG-1-2100, HHSN271201200022C]
- Intramural Research Program, Hjartavernd (the Icelandic Heart Association)
- Althingi (the Icelandic Parliament)
- Icelandic Centre for Research [184845-051]
- National Heart, Lung, and Blood Institute (NHLB)
- Department of Health and Human Services [HHSN268201700001I, HHSN268201700002I, HHSN268201700003I, HHSN268201700004I, HHSN268201700005I, R01HL087641, R01HL059367, R01HL086694]
- National Human Genome Research Institute (NHGRI) [U01HG004402]
- NIH [HHSN268200625226C, UL1RR025005]
- National Institutes of Health Roadmap for Medical Research
- Andrea and Charles Bronfman Philanthropies
- NHLBI [X01HL134588, R01HL142302, HHSN268201500001I, N01-HC-25195, R01 HL151855, N02-HL-64278]
- NHGRI [U01HG007417, R56HG010297]
- NIH NIDDK [R01DK127139, R56DK126930, K23DK107908, R01DK 110113, R01DK107786, R03DK118305]
- Ministry of Health, Welfare and Sport of the Netherlands
- National Institute for Public Health and the Environment
- Affymetrix, Inc. [N02-HL-6-4278]
- NIDDK [DK078616, U01 DK0 78616, UM1 DK078616, K23DK114551]
- NIGMS [T32GM074905]
- NIH NBLBI [HL054457, HL054464, HL054481, HL087660, HL119443]
- NIA [N01-AG-6-2101, N01-AG-6-2103, N01-AG-6-2106, R01-AG028050]
- National Institute of Nursing Research [R01-NR012459]
- Intramural Research Program of the NIH, NIA
- American Diabetes Association Innovative and Clinical Translational Award [1-19-ICTS-068]
- NHGRI, grant FAIN [U01HG011723]
- NIDDK Pathway [K99DK127196]
- Doris Duke Charitable Foundation [2020096]
- NHLBI in collaboration
- MESA investigators
- MESA [75N92020D00001, HHSN268201500003I, N01-HC-95159, 75N920 20D00005, N01-HC-95160, 75N92020D00002, N01-HC-95161, 75N92020D00003, N01-HC-95 162]
- National Center for Advancing Translational Sciences [UL1-TR-000040, UL1TR-001079, UL1-TR-001420]
- National Center for Advancing Translational Sciences, Clinical and Translational Science Institute CTSI [UL1TR001881]
- NIDDK Diabetes Research Center [DK063491]
- Centre National de G~enotypage (Paris, France)
- Jean-Francois Deleuze
- Board of Directors of the Leiden University Medical Center
- Leiden University, Research Profile Area Vascular and Regenerative Medicine
- Dutch Science Organization [916.14.023]
- Netherlands Heart Foundation [2001 D 032]
- Seventh Framework Program of the European commission [223004]
- Netherlands Genomics Initiative [050-060-810]
- Erasmus MC and Erasmus University Rotterdam
- Netherlands Organisation for Scientific Research (NWO)
- Netherlands Organisation for Health Research and Development (ZonMW)
- Research Institute for Diseases in the Elderly (RIDE)
- Netherlands Genomics Initiative
- Ministry of Education
- Culture and Science
- Ministry of Health
- Welfare and Sports
- European Commission (DG XII)
- Municipality of Rotterdam
- Bristol-Myers Squibb
- The MESA [75N92020D00006, N01-HC-95163, 75N 92020D00004, N01-HC-95164, 75N92020D0 0007, N01-HC-95165, N01-HC-95166, N01-HC95167, N01-HC-95168, N01-HC-95169]
Ask authors/readers for more resources
This study finds that the genetic basis of type 2 diabetes (T2D) is closely related to the clinical characteristics and outcomes of patients.
OBJECTIVE Type 2 diabetes (T2D) has heterogeneous patient clinical characteristics and outcomes. In previous work, we investigated the genetic basis of this heterogeneity by clustering 94 T2D genetic loci using their associations with 47 diabetes-related traits and identified five clusters, termed beta-cell, proinsulin, obesity, lipodystrophy, and liver/lipid. The relationship between these clusters and individual-level metabolic disease outcomes has not been assessed. RESEARCH DESIGN AND METHODS Here we constructed individual-level partitioned polygenic scores (pPS) for these five clusters in 12 studies from the Cohorts for Heart and Aging Research in Genomic Epidemiology (CHARGE) consortium and the UK Biobank (n = 454,193) and tested for cross-sectional association with T2D-related outcomes, including blood pressure, renal function, insulin use, age at T2D diagnosis, and coronary artery disease (CAD). RESULTS Despite all clusters containing T2D risk-increasing alleles, they had differential associations with metabolic outcomes. Increased obesity and lipodystrophy cluster pPS, which had opposite directions of association with measures of adiposity, were both significantly associated with increased blood pressure and hypertension. The lipodystrophy and liver/lipid cluster pPS were each associated with CAD, with increasing and decreasing effects, respectively. An increased liver/lipid cluster pPS was also significantly associated with reduced renal function. The liver/lipid cluster includes known loci linked to liver lipid metabolism (e.g., GCKR, PNPLA3, and TM6SF2), and these findings suggest that cardiovascular disease risk and renal function may be impacted by these loci through their shared disease pathway. CONCLUSIONS Our findings support that genetically driven pathways leading to T2D also predispose differentially to clinical outcomes.
Authors
I am an author on this paper
Click your name to claim this paper and add it to your profile.
Reviews
Recommended
No Data Available
Share Paper
