| 1. |
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| 2. |
- Ahmad, Shafqat, et al.
(författare)
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Gene × physical activity interactions in obesity: combined analysis of 111,421 individuals of European ancestry. : combined analysis of 111,421 individuals of European ancestry
- 2013
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Ingår i: PLoS Genetics. - : Public Library of Science (PLoS). - 1553-7404. ; 9:7, s. 1003607-1003607
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Tidskriftsartikel (refereegranskat)abstract
- Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS × physical activity interaction effect estimate (Pinteraction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, Pinteraction = 0.014 vs. n = 71,611, Pinteraction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (Pinteraction = 0.003) and the SEC16B rs10913469 (Pinteraction = 0.025) variants showed evidence of SNP × physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
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| 3. |
- Ahmad, Shafqat, et al.
(författare)
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Gene x physical activity interactions in obesity : combined analysis of 111,421 individuals of European ancestry
- 2013
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Ingår i: PLOS Genetics. - : Public Library of Science. - 1553-7390 .- 1553-7404. ; 9:7, s. e1003607-
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Tidskriftsartikel (refereegranskat)abstract
- Numerous obesity loci have been identified using genome-wide association studies. A UK study indicated that physical activity may attenuate the cumulative effect of 12 of these loci, but replication studies are lacking. Therefore, we tested whether the aggregate effect of these loci is diminished in adults of European ancestry reporting high levels of physical activity. Twelve obesity-susceptibility loci were genotyped or imputed in 111,421 participants. A genetic risk score (GRS) was calculated by summing the BMI-associated alleles of each genetic variant. Physical activity was assessed using self-administered questionnaires. Multiplicative interactions between the GRS and physical activity on BMI were tested in linear and logistic regression models in each cohort, with adjustment for age, age(2), sex, study center (for multicenter studies), and the marginal terms for physical activity and the GRS. These results were combined using meta-analysis weighted by cohort sample size. The meta-analysis yielded a statistically significant GRS x physical activity interaction effect estimate (P-interaction = 0.015). However, a statistically significant interaction effect was only apparent in North American cohorts (n = 39,810, P-interaction = 0.014 vs. n = 71,611, P-interaction = 0.275 for Europeans). In secondary analyses, both the FTO rs1121980 (P-interaction = 0.003) and the SEC16B rs10913469 (P-interaction = 0.025) variants showed evidence of SNP x physical activity interactions. This meta-analysis of 111,421 individuals provides further support for an interaction between physical activity and a GRS in obesity disposition, although these findings hinge on the inclusion of cohorts from North America, indicating that these results are either population-specific or non-causal.
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| 4. |
- Atabaki Pasdar, Naeimeh, et al.
(författare)
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Predicting and elucidating the etiology of fatty liver disease: A machine learning modeling and validation study in the IMI DIRECT cohorts
- 2020
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Ingår i: PLoS Medicine. - San Francisco : Public Library of Science (PLoS). - 1549-1676 .- 1549-1277. ; 17:6, s. 1003149-1003149
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Non-alcoholic fatty liver disease (NAFLD) is highly prevalent and causes serious health complications in individuals with and without type 2 diabetes (T2D). Early diagnosis of NAFLD is important, as this can help prevent irreversible damage to the liver and, ultimately, hepatocellular carcinomas. We sought to expand etiological understanding and develop a diagnostic tool for NAFLD using machine learning. METHODS AND FINDINGS: We utilized the baseline data from IMI DIRECT, a multicenter prospective cohort study of 3,029 European-ancestry adults recently diagnosed with T2D (n = 795) or at high risk of developing the disease (n = 2,234). Multi-omics (genetic, transcriptomic, proteomic, and metabolomic) and clinical (liver enzymes and other serological biomarkers, anthropometry, measures of beta-cell function, insulin sensitivity, and lifestyle) data comprised the key input variables. The models were trained on MRI-image-derived liver fat content (
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| 5. |
- Atabaki-Pasdar, Naeimeh, et al.
(författare)
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Statistical power considerations in genotype-based recall randomized controlled trials
- 2016
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Ingår i: Scientific Reports. - : Springer Science and Business Media LLC. - 2045-2322. ; 6
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Tidskriftsartikel (refereegranskat)abstract
- Randomized controlled trials (RCT) are often underpowered for validating gene-treatment interactions. Using published data from the Diabetes Prevention Program (DPP), we examined power in conventional and genotype-based recall (GBR) trials. We calculated sample size and statistical power for gene-metformin interactions (vs. placebo) using incidence rates, gene-drug interaction effect estimates and allele frequencies reported in the DPP for the rs8065082 SLC47A1 variant, a metformin transported encoding locus. We then calculated statistical power for interactions between genetic risk scores (GRS), metformin treatment and intensive lifestyle intervention (ILI) given a range of sampling frames, clinical trial sample sizes, interaction effect estimates, and allele frequencies; outcomes were type 2 diabetes incidence (time-to-event) and change in small LDL particles (continuous outcome). Thereafter, we compared two recruitment frameworks: GBR (participants recruited from the extremes of a GRS distribution) and conventional sampling (participants recruited without explicit emphasis on genetic characteristics). We further examined the influence of outcome measurement error on statistical power. Under most simulated scenarios, GBR trials have substantially higher power to observe gene-drug and gene-lifestyle interactions than same-sized conventional RCTs. GBR trials are becoming popular for validation of gene-treatment interactions; our analyses illustrate the strengths and weaknesses of this design.
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| 6. |
- Bizzotto, Roberto, et al.
(författare)
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Processes Underlying Glycemic Deterioration in Type 2 Diabetes : An IMI DIRECT Study
- 2021
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Ingår i: Diabetes Care. - : American Diabetes Association. - 1935-5548 .- 0149-5992. ; 44:2, s. 511-518
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Tidskriftsartikel (refereegranskat)abstract
- OBJECTIVE: We investigated the processes underlying glycemic deterioration in type 2 diabetes (T2D). RESEARCH DESIGN AND METHODS: A total of 732 recently diagnosed patients with T2D from the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) study were extensively phenotyped over 3 years, including measures of insulin sensitivity (OGIS), β-cell glucose sensitivity (GS), and insulin clearance (CLIm) from mixed meal tests, liver enzymes, lipid profiles, and baseline regional fat from MRI. The associations between the longitudinal metabolic patterns and HbA1c deterioration, adjusted for changes in BMI and in diabetes medications, were assessed via stepwise multivariable linear and logistic regression. RESULTS: Faster HbA1c progression was independently associated with faster deterioration of OGIS and GS and increasing CLIm; visceral or liver fat, HDL-cholesterol, and triglycerides had further independent, though weaker, roles (R2 = 0.38). A subgroup of patients with a markedly higher progression rate (fast progressors) was clearly distinguishable considering these variables only (discrimination capacity from area under the receiver operating characteristic = 0.94). The proportion of fast progressors was reduced from 56% to 8-10% in subgroups in which only one trait among OGIS, GS, and CLIm was relatively stable (odds ratios 0.07-0.09). T2D polygenic risk score and baseline pancreatic fat, glucagon-like peptide 1, glucagon, diet, and physical activity did not show an independent role. CONCLUSIONS: Deteriorating insulin sensitivity and β-cell function, increasing insulin clearance, high visceral or liver fat, and worsening of the lipid profile are the crucial factors mediating glycemic deterioration of patients with T2D in the initial phase of the disease. Stabilization of a single trait among insulin sensitivity, β-cell function, and insulin clearance may be relevant to prevent progression.
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| 7. |
- Chen, Yan, et al.
(författare)
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The combined effects of FADS gene variation and dietary fats in obesity-related traits in a population from the far north of Sweden : the GLACIER Study
- 2019
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Ingår i: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 43:4, s. 808-820
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Tidskriftsartikel (refereegranskat)abstract
- Background: Recent analyses in Greenlandic Inuit identified six genetic polymorphisms (rs74771917, rs3168072, rs12577276, rs7115739, rs174602 and rs174570) in the fatty acid desaturase gene cluster (FADS1-FADS2-FADS3) that are associated with multiple metabolic and anthropometric traits. Our objectives were to systematically assess whether dietary polyunsaturated fatty acid (PUFA) intake modifies the associations between genetic variants in the FADS gene cluster and cardiometabolic traits, and to functionally annotate top-ranking candidates to estimate their regulatory potential. Methods: Data analyses consisted of the following: interaction analyses between the 6 candidate genetic variants and dietary PUFA intake; gene-centric joint analyses to detect interaction signals in the FADS region; haplotype-centric joint tests across 30 haplotype blocks in the FADS region to refine interaction signals; and functional annotation of top-ranking loci from the previous steps. These analyses were undertaken in Swedish adults from the GLACIER Study (N = 5,160); data on genetic variation and eight cardiometabolic traits were used. Results: Interactions were observed between rs174570 and n-6 PUFA intake on fasting glucose (Pint = 0.005) and between rs174602 and n-3 PUFA intake on total cholesterol (Pint = 0.001). Gene-centric analyses demonstrated a statistically significant interaction effect for FADS and n-3 PUFA on triglycerides (Pint = 0.005) considering genetic main effects as random. Haplotype analyses revealed three blocks (Pint < 0.011) that could drive the interaction between FADS and n-3 PUFA on triglycerides; functional annotation of these regions showed that each block harbours a number of highly functional regulatory variants; FADS2 rs5792235 demonstrated the highest functionality score. Conclusions: The association between FADS variants and triglycerides may be modified by PUFA intake. The intronic FADS2 rs5792235 variant is a potential causal variant in the region, having the highest regulatory potential. However, our results suggest that multiple haplotypes may harbour functional variants in a region, rather than a single causal variant.
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| 8. |
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| 9. |
- Koivula, Robert W., et al.
(författare)
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Discovery of biomarkers for glycaemic deterioration before and after the onset of type 2 diabetes : descriptive characteristics of the epidemiological studies within the IMI DIRECT Consortium
- 2019
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Ingår i: Diabetologia. - : Springer. - 0012-186X .- 1432-0428. ; 62:9, s. 1601-1615
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Here, we describe the characteristics of the Innovative Medicines Initiative (IMI) Diabetes Research on Patient Stratification (DIRECT) epidemiological cohorts at baseline and follow-up examinations (18, 36 and 48 months of follow-up).Methods: From a sampling frame of 24,682 adults of European ancestry enrolled in population-based cohorts across Europe, participants at varying risk of glycaemic deterioration were identified using a risk prediction algorithm (based on age, BMI, waist circumference, use of antihypertensive medication, smoking status and parental history of type 2 diabetes) and enrolled into a prospective cohort study (n = 2127) (cohort 1, prediabetes risk). We also recruited people from clinical registries with type 2 diabetes diagnosed 6-24 months previously (n = 789) into a second cohort study (cohort 2, diabetes). Follow-up examinations took place at similar to 18 months (both cohorts) and at similar to 48 months (cohort 1) or similar to 36 months (cohort 2) after baseline examinations. The cohorts were studied in parallel using matched protocols across seven clinical centres in northern Europe.Results: Using ADA 2011 glycaemic categories, 33% (n = 693) of cohort 1 (prediabetes risk) had normal glucose regulation and 67% (n = 1419) had impaired glucose regulation. Seventy-six per cent of participants in cohort 1 was male. Cohort 1 participants had the following characteristics (mean +/- SD) at baseline: age 62 (6.2) years; BMI 27.9 (4.0) kg/m(2); fasting glucose 5.7 (0.6) mmol/l; 2 h glucose 5.9 (1.6) mmol/l. At the final follow-up examination the participants' clinical characteristics were as follows: fasting glucose 6.0 (0.6) mmol/l; 2 h OGTT glucose 6.5 (2.0) mmol/l. In cohort 2 (diabetes), 66% (n = 517) were treated by lifestyle modification and 34% (n = 272) were treated with metformin plus lifestyle modification at enrolment. Fifty-eight per cent of participants in cohort 2 was male. Cohort 2 participants had the following characteristics at baseline: age 62 (8.1) years; BMI 30.5 (5.0) kg/m(2); fasting glucose 7.2 (1.4) mmol/l; 2 h glucose 8.6 (2.8) mmol/l. At the final follow-up examination, the participants' clinical characteristics were as follows: fasting glucose 7.9 (2.0) mmol/l; 2 h mixed-meal tolerance test glucose 9.9 (3.4) mmol/l.Conclusions/interpretation: The IMI DIRECT cohorts are intensely characterised, with a wide-variety of metabolically relevant measures assessed prospectively. We anticipate that the cohorts, made available through managed access, will provide a powerful resource for biomarker discovery, multivariate aetiological analyses and reclassification of patients for the prevention and treatment of type 2 diabetes.
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| 10. |
- Koivula, Robert W., et al.
(författare)
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The role of physical activity in metabolic homeostasis before and after the onset of type 2 diabetes : an IMI DIRECT study
- 2020
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:4, s. 744-756
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: It is well established that physical activity, abdominal ectopic fat and glycaemic regulation are related but the underlying structure of these relationships is unclear. The previously proposed twin-cycle hypothesis (TC) provides a mechanistic basis for impairment in glycaemic control through the interactions of substrate availability, substrate metabolism and abdominal ectopic fat accumulation. Here, we hypothesise that the effect of physical activity in glucose regulation is mediated by the twin-cycle. We aimed to examine this notion in the Innovative Medicines Initiative Diabetes Research on Patient Stratification (IMI DIRECT) Consortium cohorts comprised of participants with normal or impaired glucose regulation (cohort 1: N ≤ 920) or with recently diagnosed type 2 diabetes (cohort 2: N ≤ 435). Methods: We defined a structural equation model that describes the TC and fitted this within the IMI DIRECT dataset. A second model, twin-cycle plus physical activity (TC-PA), to assess the extent to which the effects of physical activity in glycaemic regulation are mediated by components in the twin-cycle, was also fitted. Beta cell function, insulin sensitivity and glycaemic control were modelled from frequently sampled 75 g OGTTs (fsOGTTs) and mixed-meal tolerance tests (MMTTs) in participants without and with diabetes, respectively. Abdominal fat distribution was assessed using MRI, and physical activity through wrist-worn triaxial accelerometry. Results are presented as standardised beta coefficients, SE and p values, respectively. Results: The TC and TC-PA models showed better fit than null models (TC: χ2 = 242, p = 0.004 and χ2 = 63, p = 0.001 in cohort 1 and 2, respectively; TC-PA: χ2 = 180, p = 0.041 and χ2 = 60, p = 0.008 in cohort 1 and 2, respectively). The association of physical activity with glycaemic control was primarily mediated by variables in the liver fat cycle. Conclusions/interpretation: These analyses partially support the mechanisms proposed in the twin-cycle model and highlight mechanistic pathways through which insulin sensitivity and liver fat mediate the association between physical activity and glycaemic control.
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| 11. |
- Kurbasic, Azra, et al.
(författare)
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A general method for linkage disequilibrium correction for multipoint linkage and association.
- 2008
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Ingår i: Genetic Epidemiology. - : Wiley. - 0741-0395 .- 1098-2272. ; 32:7, s. 647-657
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Tidskriftsartikel (refereegranskat)abstract
- Lately, many different methods of linkage, association or joint analysis for family data have been invented and refined. Common to most of those is that they require a map of markers that are in linkage equilibrium. However, at the present day, high-density single nucleotide polymorphisms (SNPs) maps are both more inexpensive to create and they have lower genotyping error. When marker data is incomplete, the crucial and computationally most demanding moment in the analysis is to calculate the inheritance distribution at a certain position on the chromosome. Recently, different ways of adjusting traditional methods of linkage analysis to denser maps of SNPs in linkage disequilibrium (LD) have been proposed. We describe a hidden Markov model which generalizes the Lander-Green algorithm. It combines Markov chain for inheritance vectors with a Markov chain modelling founder haplotypes and in this way takes account for LD between SNPs. It can be applied to association, linkage or combined association and linkage analysis, general phenotypes and arbitrary score functions. We also define a joint likelihood for linkage and association that extends an idea of Kong and Cox (1997 Am. J. Hum. Genet. 61: 1179-1188) for pure linkage analysis. Genet. Epidemiol. 2008. (c) 2008 Wiley-Liss, Inc.
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| 12. |
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| 13. |
- Kurbasic, Azra, et al.
(författare)
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Gene-Lifestyle Interactions in Complex Diseases : Design and Description of the GLACIER and VIKING Studies
- 2014
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Ingår i: Current nutrition reports. - : Springer Science and Business Media LLC. - 2161-3311. ; 3:4, s. 400-411
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Tidskriftsartikel (refereegranskat)abstract
- Most complex diseases have well-established genetic and non-genetic risk factors. In some instances, these risk factors are likely to interact, whereby their joint effects convey a level of risk that is either significantly more or less than the sum of these risks. Characterizing these gene-environment interactions may help elucidate the biology of complex diseases, as well as to guide strategies for their targeted prevention. In most cases, the detection of gene-environment interactions will require sample sizes in excess of those needed to detect the marginal effects of the genetic and environmental risk factors. Although many consortia have been formed, comprising multiple diverse cohorts to detect gene-environment interactions, few robust examples of such interactions have been discovered. This may be because combining data across studies, usually through meta-analysis of summary data from the contributing cohorts, is often a statistically inefficient approach for the detection of gene-environment interactions. Ideally, single, very large and well-genotyped prospective cohorts, with validated measures of environmental risk factor and disease outcomes should be used to study interactions. The presence of strong founder effects within those cohorts might further strengthen the capacity to detect novel genetic effects and gene-environment interactions. Access to accurate genealogical data would also aid in studying the diploid nature of the human genome, such as genomic imprinting (parent-of-origin effects). Here we describe two studies from northern Sweden (the GLACIER and VIKING studies) that fulfill these characteristics.
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| 14. |
- Kurbasic, Azra, et al.
(författare)
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Maternal Hypertensive Disorders of Pregnancy and Offspring Risk of Hypertension : A Population-Based Cohort and Sibling Study
- 2019
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Ingår i: American Journal of Hypertension. - : Oxford University Press. - 0895-7061 .- 1941-7225. ; 32:4, s. 331-334
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Women with a history of hypertensive disorders of pregnancy (HDP) are at increased risk of hypertension, cardiovascular disease, and type 2 diabetes. Offspring from pregnancies complicated by HDP also have worse cardiometabolic status in childhood and young adulthood, but the offspring risk of clinical hypertension in adulthood is largely unknown.METHODS: We studied 13,893 first-born adult offspring (49.4% female) who attended a structured population-based primary care visit (The Västerbotten Health Survey) at age 40 years in Sweden between 1994 and 2013. Data on maternal HDP were collected from a population-based birth register. We investigated the association between maternal HDP and the risk of adult offspring hypertension and worse cardiometabolic risk factor status utilizing multivariable poisson and linear regression models. We also conducted a sibling comparison, which inherently accounted for familial factors shared by siblings (N = 135).RESULTS: Offspring participants of women with HDP (N = 383, 2.8%) had increased relative risk of hypertension (1.67, 95% confidence interval: 1.38, 2.01) and also higher mean body mass index, systolic blood pressure, diastolic blood pressure, and worse 2-hour 75 g oral glucose tolerance test result at age 40 years. No difference was observed for serum cholesterol. Point estimates for the cardiometabolic risk factors were attenuated in the sibling analyses.CONCLUSION: Offspring born to mothers with a history of HDP are on an adverse cardiometabolic trajectory and should be considered as concomitant targets for primordial prevention of hypertension in the maternal post-pregnancy period.
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| 15. |
- Kurbasic, Azra, et al.
(författare)
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On computation of p-values in parametric linkage analysis
- 2004
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Ingår i: Human Heredity. - : S. Karger AG. - 1423-0062 .- 0001-5652. ; 57:4, s. 207-219
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Tidskriftsartikel (refereegranskat)abstract
- Parametric linkage analysis is usually used to find chromosomal regions linked to a disease (phenotype) that is described with a specific genetic model. This is done by investigating the relations between the disease and genetic markers, that is, well-characterized loci of known position with a clear Mendelian mode of inheritance. Assume we have found an interesting region on a chromosome that we suspect is linked to the disease. Then we want to test the hypothesis of no linkage versus the alternative one of linkage. As a measure we use the maximal lod score Z(max). It is well known that the maximal lod score has asymptotically a (2 ln 10)(-1) x (1/2 chi(2)(0) + 1/2 chi(2)(1)) distribution under the null hypothesis of no linkage when only one point ( one marker) on the chromosome is studied. In this paper, we show, both by simulations and theoretical arguments, that the null hypothesis distribution of Z(max) has no simple form when more than one marker is used ( multipoint analysis). In fact, the distribution of Z(max) depends on the number of families, their structure, the assumed genetic model, marker denseness, and marker informativity. This means that a constant critical limit of Z(max) leads to tests associated with different significance levels. Because of the above-mentioned problems, from the statistical point of view the maximal lod score should be supplemented by a p-value when results are reported. Copyright (C) 2004 S. Karger AG, Basel.
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| 16. |
- Kurbasic, Azra, et al.
(författare)
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Relative risks and effective number of meioses: A unified approach for general genetic models and phenotypes
- 2006
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Ingår i: Annals of Human Genetics. - : Wiley. - 1469-1809 .- 0003-4800. ; 70:6, s. 907-922
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Tidskriftsartikel (refereegranskat)abstract
- Many common diseases are known to have genetic components, but since they are non-Mendelian, i.e. a large number of genetic factors affect the phenotype, these components are difficult to localize. These traits are often called complex and analysis of siblings is a valuable tool for mapping them. It has been shown that the power of the affected relative pairs method to detect linkage of a disease susceptibility locus depends on the locus contribution to increased risk of relatives compared with population prevalence Risch, 1990a,b). In this paper we generalize calculation of relative risk to arbitrary phenotypes and genetic models, but also show that the relative risk can be split into the relative risk at the main locus and the relative risk due to interaction between the main locus and loci at other chromosomes. We demonstrate how the main locus contribution to the relative risk is related to probabilities of allele sharing identical by descent at the main locus, as well as power to detect linkage. To this end we use the effective number of meioses, introduced by Hossjer (2005a) as a convenient tool. Relative risks and effective number of meioses are computed for several genetic models with binary or quantitative phenotypes, with or without polygenic effects.
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| 17. |
- Kurbasic, Azra
(författare)
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Topics in Human Gene Mapping
- 2007
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Doktorsavhandling (övrigt vetenskapligt/konstnärligt)abstract
- This thesis is interdisciplinary between Mathematical Statistics, Genetics, and Medicine. It mainly consists of topics in mathematical modelling of the correlation of inheritance of genes and disease in a family, a method called linkage analysis. It is organized as follows. First, a short introduction with the relevant background is given and then four papers are included. The first paper discusses hypothesis testing of linkage of a disease gene to a certain position on the chromosome. The focus is on the choice of lod scores and its relation to p-values. The second paper is a result of collaboration with the research groups in Lund and Denmark in the effort to localize the gene responsible for a malignant melanoma. Here, the theory presented in the first paper is used. The third paper concerns modelling of complex diseases, i.e. diseases governed by genetic contribution from at least two loci. We have studied the contribution of a particular locus to increased risk of relatives compared with population prevalence. Relative risk is modelled as the product of the relative risk at the main locus and the relative risk due to genetic contribution from other loci and shared environmental effects. Additionally, we show how this relative risk is related to probabilities of allele sharing identical by descent at the main locus and the power to detect linkage. The last paper contributes to the development of the algorithms used in the linkage and family based association analysis. One of the most demanding issues in these analyses is how to calculate the inheritance distribution at a certain position on the chromosome. The well established algorithms are based on the assumption that the markers used in the studies are in linkage equilibrium (LE). However, today's marker data have markers in linkage disequilibrium (LD). We develop a novel hidden Markov model algorithm for association and linkage analysis when markers are in LD.
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| 18. |
- Obura, Morgan, et al.
(författare)
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Post-load glucose subgroups and associated metabolic traits in individuals with type 2 diabetes : An IMI-DIRECT study
- 2020
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Ingår i: PLoS ONE. - : Public Library of Science (PLoS). - 1932-6203. ; 15:11
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Tidskriftsartikel (refereegranskat)abstract
- AIM: Subclasses of different glycaemic disturbances could explain the variation in characteristics of individuals with type 2 diabetes (T2D). We aimed to examine the association between subgroups based on their glucose curves during a five-point mixed-meal tolerance test (MMT) and metabolic traits at baseline and glycaemic deterioration in individuals with T2D. METHODS: The study included 787 individuals with newly diagnosed T2D from the Diabetes Research on Patient Stratification (IMI-DIRECT) Study. Latent class trajectory analysis (LCTA) was used to identify distinct glucose curve subgroups during a five-point MMT. Using general linear models, these subgroups were associated with metabolic traits at baseline and after 18 months of follow up, adjusted for potential confounders. RESULTS: At baseline, we identified three glucose curve subgroups, labelled in order of increasing glucose peak levels as subgroup 1-3. Individuals in subgroup 2 and 3 were more likely to have higher levels of HbA1c, triglycerides and BMI at baseline, compared to those in subgroup 1. At 18 months (n = 651), the beta coefficients (95% CI) for change in HbA1c (mmol/mol) increased across subgroups with 0.37 (-0.18-1.92) for subgroup 2 and 1.88 (-0.08-3.85) for subgroup 3, relative to subgroup 1. The same trend was observed for change in levels of triglycerides and fasting glucose. CONCLUSIONS: Different glycaemic profiles with different metabolic traits and different degrees of subsequent glycaemic deterioration can be identified using data from a frequently sampled mixed-meal tolerance test in individuals with T2D. Subgroups with the highest peaks had greater metabolic risk.
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| 19. |
- Poveda, Alaitz, et al.
(författare)
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Environment-wide association study (EWAS) on cardiometabolic traits: A systematic assessment of the association of lifestyle variables on a longitudinal setting
- 2021
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Annan publikation (övrigt vetenskapligt/konstnärligt)abstract
- The present study aims to assess the over-time association of ∼300 lifestyle exposures with nine cardiometabolic traits with the ultimate aim of identifying exposures/exposure groups that could inform lifestyle interventions aiming at controlling cardiometabolic diseases. The analyses were undertaken in a longitudinal sample comprising >31000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test association with 10-year change of the cardiometabolic traits. ‘Physical activity’ and ‘General Health’ were the exposure categories containing the highest number of ‘tentative signals’ in analyses assessing the average association of lifestyle variables, while ‘Tobacco use’ was the top-category for the 10-year change association analyses. Thirteen modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to four main groups: i) Smoking, ii) Diet (secoisolariciresinol intake and brewed coffee), iii) Leisure time physical activity and iv) a group of variables more specific to the Swedish lifestyle (snuff status, hunting/fishing during leisure time and boiled coffee). Interestingly, sweet drinks, fish intake and salt content, all lifestyle exposures frequently mentioned in public health recommendations were not broadly associated with the analysed cardiometabolic traits.
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| 20. |
- Poveda, Alaitz, et al.
(författare)
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Exposome-wide ranking of modifiable risk factors for cardiometabolic disease traits
- 2022
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Ingår i: Scientific Reports. - : Nature Publishing Group. - 2045-2322. ; 12:1
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Tidskriftsartikel (refereegranskat)abstract
- The present study assessed the temporal associations of ~ 300 lifestyle exposures with nine cardiometabolic traits to identify exposures/exposure groups that might inform lifestyle interventions for the reduction of cardiometabolic disease risk. The analyses were undertaken in a longitudinal sample comprising > 31,000 adults living in northern Sweden. Linear mixed models were used to assess the average associations of lifestyle exposures and linear regression models were used to test associations with 10-year change in the cardiometabolic traits. ‘Physical activity’ and ‘General Health’ were the exposure categories containing the highest number of ‘tentative signals’ in analyses assessing the average association of lifestyle variables, while ‘Tobacco use’ was the top category for the 10-year change association analyses. Eleven modifiable variables showed a consistent average association among the majority of cardiometabolic traits. These variables belonged to the domains: (i) Smoking, (ii) Beverage (filtered coffee), (iii) physical activity, (iv) alcohol intake, and (v) specific variables related to Nordic lifestyle (hunting/fishing during leisure time and boiled coffee consumption). We used an agnostic, data-driven approach to assess a wide range of established and novel risk factors for cardiometabolic disease. Our findings highlight key variables, along with their respective effect estimates, that might be prioritised for subsequent prediction models and lifestyle interventions.
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| 21. |
- Poveda, Alaitz, et al.
(författare)
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The heritable basis of gene–environment interactions in cardiometabolic traits
- 2017
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Ingår i: Diabetologia. - : Springer Science and Business Media LLC. - 0012-186X .- 1432-0428. ; 60:3, s. 442-452
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis: Little is known about the heritable basis of gene–environment interactions in humans. We therefore screened multiple cardiometabolic traits to assess the probability that they are influenced by genotype–environment interactions. Methods: Fourteen established environmental risk exposures and 11 cardiometabolic traits were analysed in the VIKING study, a cohort of 16,430 Swedish adults from 1682 extended pedigrees with available detailed genealogical, phenotypic and demographic information, using a maximum likelihood variance decomposition method in Sequential Oligogenic Linkage Analysis Routines software. Results: All cardiometabolic traits had statistically significant heritability estimates, with narrow-sense heritabilities (h2) ranging from 24% to 47%. Genotype–environment interactions were detected for age and sex (for the majority of traits), physical activity (for triacylglycerols, 2 h glucose and diastolic BP), smoking (for weight), alcohol intake (for weight, BMI and 2 h glucose) and diet pattern (for weight, BMI, glycaemic traits and systolic BP). Genotype–age interactions for weight and systolic BP, genotype–sex interactions for BMI and triacylglycerols and genotype–alcohol intake interactions for weight remained significant after multiple test correction. Conclusions/interpretation: Age, sex and alcohol intake are likely to be major modifiers of genetic effects for a range of cardiometabolic traits. This information may prove valuable for studies that seek to identify specific loci that modify the effects of lifestyle in cardiometabolic disease.
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| 22. |
- Siddiqui, Faiza, et al.
(författare)
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Changes in dietary intake following a culturally adapted lifestyle intervention among Iraqi immigrants to Sweden at high risk of type 2 diabetes : a randomised trial
- 2017
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Ingår i: Public Health Nutrition. - 1368-9800. ; 20:15, s. 2827-2838
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate the effectiveness of a culturally adapted lifestyle intervention for changing dietary intake, particularly energy, fat and fibre intakes, in the intervention group (IG) compared with the control group (CG). Design: Randomised controlled trial. Setting: IG (n 50) and CG (n 46). The IG was offered seven group sessions, including one cooking class, over a period of 4 months. The participants filled out 4 d food diaries at the start, mid and end of the study. Subjects: Iraqi-born residents of Malmö, Sweden, at increased risk for developing diabetes. Results: At baseline, participants’ fat intake was high (40 % of total energy intake (E%)). The predefined study goals of obtaining <30 E% from fat and ≥15 g fibre/4184 kJ (1000 kcal) were met by very few individuals. In the IG v. the CG, the proportion of individuals obtaining <40 E% from fat (48·4 v. 34·6 %, P=0·65), <10 E% from saturated fat (32·3 v. 11·5 %, P=0·14) and ≥10 g fibre/4184 kJ (45·2 v. 26·9 %, P=0·46) appeared to be higher at the last visit, although the differences were statistically non-significant. A trend towards decreased mean daily intakes of total energy (P=0·03), carbohydrate (P=0·06), sucrose (P=0·02) and fat (P=0·02) was observed within the IG. Differences in changes over time between the groups did not reach statistical significance. Conclusions: Although no significant differences were observed in the two groups, our data indicate that this culturally adapted programme has the potential to modify dietary intake in Middle Eastern immigrants. The high fat intake in this group should be addressed.
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| 23. |
- Siddiqui, Faiza, et al.
(författare)
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Effects of a culturally adapted lifestyle intervention on cardio-metabolic outcomes: a randomized controlled trial in Iraqi immigrants to Sweden at high risk for Type 2 diabetes
- 2017
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Ingår i: Metabolism: Clinical and Experimental. - : Elsevier BV. - 0026-0495 .- 1532-8600. ; 66, s. 1-13
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Tidskriftsartikel (refereegranskat)abstract
- Background andAims Middle-Eastern immigrants constitute a growing proportion of the Swedish population and are at high risk for Type 2 diabetes. This calls for a more proactive preventive approach for dealing with diabetes risk in this target group. The aim was to test the effect of a culturally adapted lifestyle intervention programme on changes in lifestyle habits and cardio-metabolic outcomes comparing an intervention group with a control group receiving usual care. Methods Citizens of Malmö, Sweden born in Iraq and at high risk for Type 2 diabetes (n=636) were invited. Participation rate was 15.1%. In all, 96 participants were randomized to the intervention group (n=50) or to the control group (n=46). The intervention group was offered seven group sessions addressing healthy diet and physical activity including one cooking class. Changes in body weight, physical activity levels and cardio-metabolic outcomes were evaluated using linear mixed-effects models. Results The mean follow-up time was 3.9 and 3.5months in the intervention and control groups, respectively. The drop-out rate from baseline to the last visit was 30.0% in the intervention group (n=15) and 30.4% in the control group (n=14). The mean insulin sensitivity index increased significantly at follow-up in the intervention group compared to the control group (10.9% per month, p=0.005). The intervention group also reached a significant reduction in body weight (0.4% per month, p=0.004), body mass index (0.4% per month, p=0.004) and LDL-cholesterol (2.1% per month, p=0.036) compared to the control group. In total, 14.3% in the intervention group reached the goal to lose ≥5% of body weight versus none in the control group. Conclusions This culturally adapted lifestyle intervention programme shows a beneficial effect on insulin action, body weight reduction, as well as LDL-cholesterol reduction, in Middle-Eastern immigrants. The programme adapted to resources in primary health care provides tools for improved primary prevention and reduced cardio-metabolic risk in this high-risk group for Type 2 diabetes. © 2016 The Authors
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| 24. |
- Siddiqui, Faiza, et al.
(författare)
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Physical Activity in a Randomized Culturally Adapted Lifestyle Intervention
- 2018
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Ingår i: American Journal of Preventive Medicine. - : Elsevier BV. - 0749-3797. ; 55:2, s. 187-196
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Tidskriftsartikel (refereegranskat)abstract
- Introduction: Middle Eastern immigrants exhibit high levels of physical inactivity and are at an increased risk for Type 2 diabetes. The primary aim of this study was to examine the changes in objectively assessed physical activity levels following a culturally adapted lifestyle intervention program. The secondary aim was to examine the association between objectively assessed physical activity and insulin sensitivity. Participants: Iraqi immigrants residing in Malmo, Sweden, exhibiting one or more risk factors for Type 2 diabetes. Intervention: The intervention group (n=50) was offered a culturally adapted lifestyle intervention comprising seven group sessions including a cooking class. The control group (n=46) received usual care. Main outcome measures: Raw accelerometry data were processed by validated procedures and daily mean physical activity intensity, vector magnitude high-pass filtered (VM-HPF), was inferred. Further inferences into the number of hours/day spent in sedentary (VM-HPF <48 milli-Gs [mGs] where G=9.8 m/sec(2)) and light- (48- <163 mGs); moderate- (163- <420 mGs); and vigorous-intensity (>= 420 mGs) activities were also calculated (year of analysis was 2016-2017). Results: No difference was observed between the two groups in terms of change over time in VM-HPF. There was a significant increase in the number of hours/day spent in light intensity physical activity in the intervention group compared with the control group (beta=0.023, 95% CI=0.001, 0.045, p=0.037). The intervention group also increased the time spent in sedentary activities, with the highest VM-HPF (36- < 48 mGs) within the sedentary behavior (B=0.022, 95% CI=0.002, 0.042, p=0.03). Higher VM-HPF was significantly associated with a higher insulin sensitivity index (beta=0.014, 95% CI=0.0004, 0.025, p=0.007). Conclusions: The findings favor the culturally adapted intervention approach for addressing low physical activity levels among Middle Eastern immigrants. Replacing sedentary time with light-intensity activities could be an achievable goal and will have potential beneficial effects for diabetes prevention among this sedentary group of immigrants. Trial registration: This study was registered at www.clinicaltrials.gov NCT01420198. Am J Prev Med 2018;55(2):187-196. (C) 2018 American Journal of Preventive Medicine. Published by Elsevier Inc. All rights reserved.
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| 25. |
- Varga, Tibor V., et al.
(författare)
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Novel genetic loci associated with long-term deterioration in blood lipid concentrations and coronary artery disease in European adults
- 2017
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Ingår i: International Journal of Epidemiology. - : Oxford University Press (OUP). - 0300-5771 .- 1464-3685. ; 46:4, s. 1211-1222
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Tidskriftsartikel (refereegranskat)abstract
- Background: Cross-sectional genome-wide association studies have identified hundreds of loci associated with blood lipids and related cardiovascular traits, but few genetic association studies have focused on long-term changes in blood lipids.Methods: Participants from the GLACIER Study (N-max = 3492) were genotyped with the MetaboChip array, from which 29 387 SNPs (single nucleotide polymorphisms;replication, fine-mapping regions and wildcard SNPs for lipid traits) were extracted for association tests with 10-year change in total cholesterol (Delta TC) and triglycerides (Delta TG). Four additional prospective cohort studies (MDC, PIVUS, ULSAM, MRC Ely; N-max = 8263 participants) were used for replication. We conducted an in silico look-up for association with coronary artery disease (CAD) in the Coronary ARtery DIsease Genome-wide Replication and Meta-analysis (CARDIoGRAMplusC4D) Consortium (N similar to 190 000) and functional annotation for the top ranking variants.Results: In total, 956 variants were associated (P < 0.01) with either Delta TC or Delta TG in GLACIER. In GLACIER, chr19:50121999 at APOE was associated with Delta TG and multiple SNPs in the APOA1/A4/C3/A5 region at genome-wide significance (P < 5 x 10(-8)), whereas variants in four loci, DOCK7, BRE, SYNE1 and KCNIP1, reached study-wide significance (P < 1.7 x 10(-6)). The rs7412 variant at APOE was associated with DTC in GLACIER (P < 1.7 x 10(-6)). In pooled analyses of all cohorts, 139 SNPs at six and five loci were associated with Delta TC and for Delta TG, respectively (P < 10(-3)). Of these, a variant at CAPN3 (P = 1.2 x 10(-4)), multiple variants at HPR (P-min = 1.5 x 10(-6)) and a variant at SIX5 (P = 1.9 x 10(-4)) showed evidence for association with CAD.Conclusions: We identified seven novel genomic regions associated with long-term changes in blood lipids, of which three also raise CAD risk.
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| 26. |
- Wesolowska-Andersen, A., et al.
(författare)
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Four groups of type 2 diabetes contribute to the etiological and clinical heterogeneity in newly diagnosed individuals: An IMI DIRECT study
- 2022
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Ingår i: Cell Reports Medicine. - : Elsevier BV. - 2666-3791. ; 3:1
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Tidskriftsartikel (refereegranskat)abstract
- The presentation and underlying pathophysiology of type 2 diabetes (T2D) is complex and heterogeneous. Recent studies attempted to stratify T2D into distinct subgroups using data-driven approaches, but their clinical utility may be limited if categorical representations of complex phenotypes are suboptimal. We apply a soft-clustering (archetype) method to characterize newly diagnosed T2D based on 32 clinical variables. We assign quantitative clustering scores for individuals and investigate the associations with glycemic deterioration, genetic risk scores, circulating omics biomarkers, and phenotypic stability over 36 months. Four archetype profiles represent dysfunction patterns across combinations of T2D etiological processes and correlate with multiple circulating biomarkers. One archetype associated with obesity, insulin resistance, dyslipidemia, and impaired β cell glucose sensitivity corresponds with the fastest disease progression and highest demand for anti-diabetic treatment. We demonstrate that clinical heterogeneity in T2D can be mapped to heterogeneity in individual etiological processes, providing a potential route to personalized treatments. © 2021 The Authors
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