Clinical risk factors, DNA variants, and the development of type 2 diabetes
Open accessAbstract
BACKGROUND: Type 2 diabetes mellitus is thought to develop from an interaction between environmental and genetic factors. We examined whether clinical or genetic factors or both could predict progression to diabetes in two prospective cohorts. METHODS: We genotyped 16 single-nucleotide polymorphisms (SNPs) and examined clinical factors in 16,061 Swedish and 2770 Finnish subjects. Type 2 diabetes developed in 2201 (11.7%) of these subjects during a median follow-up period of 23.5 years. We also studied the effect of genetic variants on changes in insulin secretion and action over time. RESULTS: Strong predictors of diabetes were a family history of the disease, an increased body-mass index, elevated liver-enzyme levels, current smoking status, and reduced measures of insulin secretion and action. Variants in 11 genes (TCF7L2, PPARG, FTO, KCNJ11, NOTCH2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, and HHEX) were significantly associated with the risk of type 2 diabetes independently of clinical risk factors; variants in 8 of these genes were associated with impaired beta-cell function. The addition of specific genetic information to clinical factors slightly improved the prediction of future diabetes, with a slight increase in the area under the receiver-operating-characteristic curve from 0.74 to 0.75; however, the magnitude of the increase was significant (P=1.0x10(-4)). The discriminative power of genetic risk factors improved with an increasing duration of follow-up, whereas that of clinical risk factors decreased. CONCLUSIONS: As compared with clinical risk factors alone, common genetic variants associated with the risk of diabetes had a small effect on the ability to predict the future development of type 2 diabetes. The value of genetic factors increased with an increasing duration of follow-up.
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In prospective studies, decreases in the disposition index, the product of insulin secretion and SI, are a strong predictor of diabetes onset and worsening of metabolic function pre- and postdiagnosis.
“In prospective studies, decreases in the disposition index, the product of insulin secretion and SI, are a strong predictor of diabetes onset and worsening of metabolic function pre- and postdiagnosis (53).”
From Sleep Restriction for 1 Week Reduces Insulin Sensitivity in Healthy Men (2010) · cites this paper as [53]
The Measurements section defines the disposition index as insulin secretion adjusted for insulin sensitivity (CIR × ISI), and Clinical Factors Predicting Incidence of Diabetes calls it a strong predictor of future diabetes. The cited passages do not establish that decreases in the index predict worsening metabolic function both before and after diagnosis; the reported longitudinal analysis concerns subjects who did not have diabetes. (LLM, conf=0.88)
Experimental — accuracy not yet measuredTogether these genes do not explain much of the genetic basis of type 2 diabetes; genotype risk scores only slightly improve prediction compared to common clinical risk factors.
“Together these genes do not appear to explain much of the genetic basis of the disease with the use of genotype risk scores only slightly improving prediction of subsequent diabetes compared to common clinical risk factors22,23.”
From Pathophysiology and treatment of type 2 diabetes: perspectives on the past, present, and future (2014) · cites this paper as [23]
The relative risks associated with elevated amino acids were comparable to or higher than those associated with higher age, fasting glucose, or body mass index in prior population-based studies.
“Indeed, the relative risks associated with elevated amino acids were comparable to, or higher than, those associated with higher age, fasting glucose, or body mass index in prior population-based studies28.”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [28]
Known diabetes polymorphisms add modestly to risk assessment, being associated with 5% to 37% increases in relative risk.
“There has been interest in genetic risk prediction, but the known diabetes polymorphisms add modestly to risk assessment27,28. For instance, known polymorphisms are only associated with 5% to 37% increases in the relative risk of diabetes”
From Metabolite profiles and the risk of developing diabetes (2011) · cites this paper as [28]
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Risk assessment tools for identifying individuals at risk of developing type 2 diabetes
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Gene-Lifestyle Interaction and Type 2 Diabetes: The EPIC InterAct Case-Cohort Study
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Self-citationThe Spectrum of Achalasia: Lessons From Studies of Pathophysiology and High-Resolution Manometry
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Therapeutic opportunities for pancreatic β-cell ER stress in diabetes mellitus
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Beneficial modulation of the gut microbiota
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Phenotypes of prediabetes and stratification of cardiometabolic risk
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Induced pluripotent stem cells: at the heart of cardiovascular precision medicine
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Review of methods for detecting glycemic disorders
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Gut microbiota and diet in patients with different glucose tolerance
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Self-citationRelationship between gut microbiota, probiotics, and type 2 diabetes mellitus
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Genetic risk prediction in complex disease
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Genetics of type 2 diabetes: pathophysiologic and clinical relevance
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“Accordingly, monitoring the insulin secretory capacity of pancreatic b cells best predicts future diabetes (Lyssenko et al., 2008).”
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Biomarkers for the Prediction of Type 2 Diabetes and Cardiovascular Disease
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Self-citationGenetic Screening for the Risk of Type 2 Diabetes
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Development and Evaluation of a Genetic Risk Score for Obesity
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Genetics of type 2 diabetes: the GWAS era and future perspectives [Review]
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Type 2 Diabetes Genetics: Beyond GWAS
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The emerging genetics of type 2 diabetes
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- Authors
- Lyssenko, V., Jonsson, A., Almgren, P., Pulizzi, N., Isomaa, B., Tuomi, T., Berglund, G., Altshuler, D., Nilsson, P., & Groop, L.
- Affiliations
- Lund University (SE)
- University of Helsinki (FI)
- Broad Institute (US)
- Venue
- New England Journal of Medicine
- Publisher
- Massachusetts Medical Society
- Published
- 2008-11-20
- Volume
- 359
- Issue
- 21
- Pages
- 2220-2232
- ISSN
- 0028-4793 (ISSN-L)
- 1533-4406
- OpenAlex
- W2165796078
- Cited by
- 938
- References
- 30
- Citations by year
- 2026: 10 · 2025: 12 · 2024: 19 · 2023: 25 · 2022: 36 · 2021: 33 · 2020: 29 · 2019: 33 · 2018: 34 · 2017: 37 · 2016: 55 · 2015: 54 · 2014: 76 · 2013: 90 · 2012: 106
- FWCI
- 55.04
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- New England Journal of Medicine (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- Funders
- Vetenskapsrådet
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Diabetes and associated disorders
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Nutrition, Genetics, and Disease
- Keywords
- type 2 diabetes, genetic risk factors, single nucleotide polymorphisms, clinical risk factors, diabetes prediction, TCF7L2, PPARγ, FTO, KCNJ11, Notch2, WFS1, CDKAL1, IGF2BP2, SLC30A8, JAZF1, HHEX, beta-cell function, insulin secretion, insulin action, family history (medicine), body mass index, smoking, liver enzymes, gene-environment interaction
- MeSH terms
- Insulin Secretion, Adult, Transaminases, Blood Glucose, Blood Pressure, Diabetes Mellitus, Type 2, Female, Finland, Follow-Up Studies, Genotype, Humans, Insulin, Male, Middle Aged, Proteins, Risk Factors, ROC Curve, Smoking, Sweden, Body Mass Index, Logistic Models, Odds Ratio, Genetic Predisposition to Disease, Polymorphism, Single Nucleotide
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