| 1. |
- Larsson, Susanna C., et al.
(författare)
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Alcohol Consumption and Cardiovascular Disease A Mendelian Randomization Study
- 2020
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Ingår i: Circulation. - : LIPPINCOTT WILLIAMS & WILKINS. - 2574-8300. ; 13:3, s. 121-127
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Tidskriftsartikel (refereegranskat)abstract
- Background: The causal role of alcohol consumption for cardiovascular disease remains unclear. We used Mendelian randomization (MR) to predict the effect of alcohol consumption on 8 cardiovascular diseases. Methods: Up to 94 single-nucleotide polymorphisms were used as instrumental variables for alcohol consumption. Genetic association estimates for cardiovascular diseases were obtained from large-scale consortia and UK Biobank. Analyses were conducted using the inverse variance-weighted, weighted median, MR-PRESSO, MR-Egger, and multivariable MR methods. Results: Genetically predicted alcohol consumption was consistently associated with stroke and peripheral artery disease across the different analyses. The odds ratios (ORs) per 1-SD increase of log-transformed alcoholic drinks per week were 1.27 ([95% CI, 1.12-1.45]P=2.87x10(-4)) for stroke and 3.05 ([95% CI, 1.92-4.85]P=2.30x10(-6)) for peripheral artery disease in the inverse variance-weighted analysis. There was some evidence for positive associations of genetically predicted alcohol consumption with coronary artery disease (OR, 1.16 [95% CI, 1.00-1.36];P=0.052), atrial fibrillation (OR, 1.17 [95% CI, 1.00-1.37];P=0.050), and abdominal aortic aneurysm (OR, 2.60 [95% CI, 1.15-5.89];P=0.022) in the inverse variance-weighted analysis. These associations were somewhat attenuated in multivariable MR analysis adjusted for smoking initiation. There was no evidence of associations of genetically predicted alcohol consumption with heart failure (OR, 1.00 [95% CI, 0.68-1.47];P=0.996), venous thromboembolism (OR, 1.04 [95% CI, 0.77-1.39];P=0.810), and aortic valve stenosis (OR, 1.03 [95% CI, 0.56-1.90];P=0.926). Conclusions: This study provides evidence of a causal relationship between higher alcohol consumption and increased risk of stroke and peripheral artery disease. The causal role of alcohol consumption for other cardiovascular diseases requires further research.
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| 2. |
- Larsson, Susanna C., et al.
(författare)
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Association of Genetic Variants Related to Serum Calcium Levels With Coronary Artery Disease and Myocardial Infarction
- 2017
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Ingår i: Journal of the American Medical Association (JAMA). - : AMER MEDICAL ASSOC. - 0098-7484 .- 1538-3598. ; 318:4, s. 371-380
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Tidskriftsartikel (refereegranskat)abstract
- IMPORTANCE Serum calcium has been associated with cardiovascular disease in observational studies and evidence from randomized clinical trials indicates that calcium supplementation, which raises serum calcium levels, may increase the risk of cardiovascular events, particularly myocardial infarction.OBJECTIVE To evaluate the potential causal association between genetic variants related to elevated serum calcium levels and risk of coronary artery disease (CAD) and myocardial infarction using mendelian randomization.DESIGN, SETTING, AND PARTICIPANTS The analyses were performed using summary statistics obtained for single-nucleotide polymorphisms (SNPs) identified from a genome-wide association meta-analysis of serum calcium levels (N = up to 61 079 individuals) and from the Coronary Artery Disease Genome-wide Replication and Meta-analysis Plus the Coronary Artery Disease Genetics (CardiogramplusC4D) consortium's 1000 genomes-based genome-wide association meta-analysis (N = up to 184 305 individuals) that included cases (individuals with CAD andmyocardial infarction) and noncases, with baseline data collected from 1948 and populations derived from across the globe. The association of each SNP with CAD andmyocardial infarction was weighted by its association with serum calcium, and estimates were combined using an inverse-variance weighted meta-analysis.EXPOSURES Genetic risk score based on genetic variants related to elevated serum calcium levels.MAIN OUTCOMES AND MEASURES Co-primary outcomes were the odds of CAD and myocardial infarction.RESULTS Among the mendelian randomized analytic sample of 184 305 individuals (60 801 CAD cases [approximately 70% with myocardial infarction] and 123 504 noncases), the 6 SNPs related to serum calcium levels and without pleiotropic associations with potential confounders were estimated to explain about 0.8% of the variation in serum calcium levels. In the inverse-variance weighted meta-analysis (combining the estimates of the 6 SNPs), the odds ratios per 0.5-mg/dL increase (about 1 SD) in genetically predicted serum calcium levels were 1.25 (95% CI, 1.08-1.45; P = .003) for CAD and 1.24 (95% CI, 1.05-1.46; P = .009) for myocardial infarction.CONCLUSIONS AND RELEVANCE A genetic predisposition to higher serum calcium levels was associated with increased risk of CAD andmyocardial infarction. Whether the risk of CAD associated with lifelong genetic exposure to increased serum calcium levels can be translated to a risk associated with short-term to medium-term calcium supplementation is unknown.
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| 3. |
- Larsson, Susanna C, et al.
(författare)
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Circulating Serum 25-Hydroxyvitamin D Levels and Bone Mineral Density : Mendelian Randomization Study
- 2018
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Ingår i: Journal of Bone and Mineral Research. - : Wiley. - 0884-0431 .- 1523-4681. ; 33:5, s. 840-844
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Tidskriftsartikel (refereegranskat)abstract
- There is considerable discussion of the importance for increased serum 25‐hydroxyvitamin D (S‐25OHD) concentration associated with adequacy for bone health. Accordingly, whether long‐term high S‐25OHD concentration in general positively affects bone mineral density (BMD) is uncertain. We used a Mendelian randomization design to determine the association between genetically increased S‐25OHD concentrations and BMD. Five single‐nucleotide polymorphisms (SNPs) in or near genes encoding enzymes and carrier proteins involved in vitamin D synthesis or metabolism were used as instrumental variables to genetically predict 1 standard deviation increase in S‐25OHD concentration. Summary statistics data for the associations of the S‐25OHD‐associated SNPs with dual‐energy X‐ray absorptiometry (DXA)‐derived femoral neck and lumbar spine BMD were obtained from the Genetic Factors for Osteoporosis (GEFOS) Consortium (32,965 individuals) and ultrasound‐derived heel estimated BMD from the UK Biobank (142,487 individuals). None of the SNPs were associated with BMD at Bonferroni‐corrected significance level, but there was a suggestive association between rs6013897 near CYP24A1 and femoral neck BMD (p = 0.01). In Mendelian randomization analysis, genetically predicted 1 standard deviation increment of S‐25OHD was not associated with higher femoral neck BMD (SD change in BMD 0.02; 95% confidence interval [CI] –0.03 to 0.07; p = 0.37), lumbar spine BMD (SD change in BMD 0.02; 95% CI –0.04 to 0.08; p = 0.49), or estimated BMD (g/cm2 change in BMD –0.03; 95% CI –0.05 to –0.01; p = 0.02). This study does not support a causal association between long‐term elevated S‐25OHD concentrations and higher BMD in generally healthy populations. These results suggest that more emphasis should be placed on the development of evidence‐based cut‐off points for vitamin D inadequacy rather than a general recommendation to increase S‐25OHD.
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| 4. |
- Larsson, Susanna C, et al.
(författare)
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Genetic association between adiposity and gout : a Mendelian randomization study
- 2018
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Ingår i: Rheumatology. - : OXFORD UNIV PRESS. - 1462-0324 .- 1462-0332. ; 57:12, s. 2145-2148
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Tidskriftsartikel (refereegranskat)abstract
- Objective: To investigate whether overall obesity (as measured by BMI) and abdominal obesity (as measured by waist-to-hip ratio adjusted for BMI) are associated with gout risk and serum urate concentrations using Mendelian randomization.Methods: Single nucleotide polymorphisms associated with BMI (n = 97) and waist-to-hip ratio adjusted for BMI (n = 49) were analysed for association with gout risk in 2115 gout cases and 67 259 controls, and with serum urate concentrations in 110 347 individuals from the Global Urate Genetics Consortium.Results: Genetically higher BMI, but not waist-to-hip ratio adjusted for BMI, was positively associated with risk of gout and serum urate concentrations. Each standard deviation (about 4.6 kg/m(2)) increase in genetically predicted BMI was associated with an odds ratio of gout of 2.24 (95% CI 1.70, 2.95; P = 8.4 x 10(-9)) and with a 0.30 mg/dl (95% CI 0.25, 0.35; P = 1.6 x 10(-36)) increase in serum urate concentrations.Conclusion: These findings provide support that overall obesity may be a risk factor for gout and is associated with higher serum urate concentrations.
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| 5. |
- Larsson, Susanna C., et al.
(författare)
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Genetic predisposition to smoking in relation to 14 cardiovascular diseases
- 2020
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Ingår i: European Heart Journal. - : Oxford University Press. - 0195-668X .- 1522-9645. ; 41:35, s. 3304-3310
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Tidskriftsartikel (refereegranskat)abstract
- AIMS: The aim of this study was to use Mendelian randomization (MR) to determine the causality of the association between smoking and 14 different cardiovascular diseases (CVDs).METHODS AND RESULTS: Our primary genetic instrument comprised 361 single-nucleotide polymorphisms (SNPs) associated with smoking initiation (ever smoked regularly) at genome-wide significance. Data on the associations between the SNPs and 14 CVDs were obtained from the UK Biobank study (N = 367 643 individuals), CARDIoGRAMplusC4D consortium (N = 184 305 individuals), Atrial Fibrillation Consortium (2017 dataset; N = 154 432 individuals), and Million Veteran Program (MVP; N = 190 266 individuals). The main analyses were conducted using the random-effects inverse-variance weighted method and complemented with multivariable MR analyses and the weighted median and MR-Egger approaches. Genetic predisposition to smoking initiation was most strongly and consistently associated with higher odds of coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension. Genetic predisposition to smoking initiation was additionally associated with higher odds of deep vein thrombosis and pulmonary embolism in the UK Biobank but not with venous thromboembolism in the MVP. There was limited evidence of causal associations of smoking initiation with atrial fibrillation, aortic valve stenosis, thoracic aortic aneurysm, and intracerebral and subarachnoid haemorrhage.CONCLUSION: This MR study supports a causal association between smoking and a broad range of CVDs, in particular, coronary artery disease, heart failure, abdominal aortic aneurysm, ischaemic stroke, transient ischaemic attack, peripheral arterial disease, and arterial hypertension.
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| 6. |
- Larsson, Susanna C., et al.
(författare)
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Genetically predicted plasma phospholipid arachidonic acid concentrations and 10 site-specific cancers in UK biobank and genetic consortia participants : A mendelian randomization study
- 2021
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Ingår i: Clinical Nutrition. - : Elsevier. - 0261-5614 .- 1532-1983. ; 40:5, s. 3332-3337
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND & AIMS: Arachidonic acid (AA) is metabolized by cyclooxygenases and lipoxygenases to pro-inflammatory eicosanoids, which according to experimental research modulate tumor cell proliferation, differentiation, and apoptosis. We employed the Mendelian randomization design to test the hypothesis that higher plasma phospholipid AA concentrations are associated with increased risk of 10 site-specific cancers.METHODS: Two genetic variants associated with plasma phospholipid concentrations of AA (rs174547 in FADS1 [P = 3.0 × 10-971] and rs16966952 in PDXDC1 [P = 2.4 × 10-10]) in the Cohorts for Heart and Aging Research in Genomic Epidemiology Consortium were used as genetic instruments. The associations of those variants with cancer were taken from the UK Biobank (n = 367,643), FinnGen consortium (n = 135,638), International Lung Cancer Consortium (n = 27,209), Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254), Breast Cancer Association Consortium (n = 228,951), Ovarian Cancer Association Consortium (n = 66,450), and BioBank Japan (n = 212,453).RESULTS: Higher genetically predicted plasma phospholipid AA concentrations were associated with increased risk of colorectal and lung cancer. Results were consistent across data sources and variants. The combined odds ratios per standard deviation increase of AA concentrations were 1.08 (95% CI 1.05-1.11; P = 6.3 × 10-8) for colorectal cancer and 1.07 (95%CI 1.05-1.10; P = 3.5 × 10-7) for lung cancer. Genetically predicted AA concentrations had a suggestive positive association with esophageal cancer (odds ratio 1.09; 95% CI 1.02-1.17; P = 0.016) but were not associated with cancers of the stomach, pancreas, bladder, prostate, breast, uterus, or ovary.CONCLUSION: These results indicate that AA may be implicated in the development of colorectal and lung cancer and possibly esophageal cancer. Treatments with plasma AA-lowering properties should be evaluated for clinical benefit.
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| 7. |
- Larsson, Susanna C., et al.
(författare)
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Genetically proxied milk consumption and risk of colorectal, bladder, breast, and prostate cancer : a two-sample Mendelian randomization study
- 2020
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Ingår i: BMC Medicine. - : Springer Science and Business Media LLC. - 1741-7015. ; 18:1
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Observational studies have shown that milk consumption is inversely associated with colorectal, bladder, and breast cancer risk, but positively associated with prostate cancer. However, whether the associations reflect causality remains debatable. We investigated the potential causal associations of milk consumption with the risk of colorectal, bladder, breast, and prostate cancer using a genetic variant near the LCT gene as proxy for milk consumption.METHODS: We obtained genetic association estimates for cancer from the UK Biobank (n = 367,643 women and men), FinnGen consortium (n = 135,638 women and men), Breast Cancer Association Consortium (n = 228,951 women), and Prostate Cancer Association Group to Investigate Cancer Associated Alterations in the Genome consortium (n = 140,254 men). Milk consumption was proxied by a genetic variant (rs4988235 or rs182549) upstream of the gene encoding lactase, which catalyzes the breakdown of lactose.RESULTS: Genetically proxied milk consumption was associated with a reduced risk of colorectal cancer. The odds ratio (OR) for each additional milk intake increasing allele was 0.95 (95% confidence interval [CI] 0.91-0.99; P = 0.009). There was no overall association of genetically predicted milk consumption with bladder (OR 0.99; 95% CI 0.94-1.05; P = 0.836), breast (OR 1.01; 95% CI 1.00-1.02; P = 0.113), and prostate cancer (OR 1.01; 95% CI 0.99-1.02; P = 0.389), but a positive association with prostate cancer was observed in the FinnGen consortium (OR 1.07; 95% CI 1.01-1.13; P = 0.026).CONCLUSIONS: Our findings strengthen the evidence for a protective role of milk consumption on colorectal cancer risk. There was no or limited evidence that milk consumption affects the risk of bladder, breast, and prostate cancer.
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| 8. |
- Larsson, Susanna C., et al.
(författare)
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Genome-wide association and Mendelian randomization study of fibroblast growth factor 21 reveals causal associations with hyperlipidemia and possibly NASH
- 2022
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Ingår i: Metabolism. - : Elsevier. - 0026-0495 .- 1532-8600. ; 137
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Tidskriftsartikel (refereegranskat)abstract
- Background: Fibroblast growth factor 21 (FGF21) is a hepatokine that produces metabolic benefits, such as improvements of lipid profile. We performed a genome-wide association study (GWAS) to identify genetic variants associated with circulating FGF21 and investigated the causal effects of FGF21 on pertinent outcomes using Mendelian randomization (MR).Methods: We conducted a GWAS testing similar to 7.8 million DNA sequence variants with circulating FGF21 in a discovery cohort of 6259 Swedish adults with replication in 4483 Swedish women. We then performed two-sample MR analyses of genetically predicted circulating FGF21 in relation to alcohol and nutrient intake, cardiovascular and metabolic biomarkers and diseases, and liver function biomarkers using publicly available GWAS summary statistics data.Results: Our GWAS identified multiple single-nucleotide polymorphisms with genome-wide significant associations (P < 5 x 10(-8)) with circulating FGF21 on chromosomes 2 and 19 in or near the GCKR and FGF21 genes, respectively. The strongest signal at the FGF21 locus (rs2548957, beta = 0.181, P < 2.18 x 10(-42)) displayed in twosample MR analyses robust associations with lower alcohol intake, lower circulating low-density lipoprotein cholesterol, apolipoprotein B, C-reactive protein, gamma-glutamyl transferase, and galectin-3 concentrations, and higher circulating insulin-like growth factor-I and alkaline phosphatase concentrations after correcting for multiple testing (P < 0.0018) whereas associations with fat mass, type 2 diabetes, and cardiovascular disease were largely null.Conclusions: We identified robust associations of certain genetic variants in or near the GCKR and FGF21 genes with circulating FGF21 concentrations. Furthermore, our results support a strong causal effect of FGF21 on improved lipid profile, reduced alcohol consumption and C-reactive protein concentrations, and liver function biomarkers including fibrosis. We found largely null or weak positive associations with fat mass, diabetes, and cardiovascular disease as well as higher insulin-like growth factor-I concentrations, which could indicate a compensatory increase to regulate the above FGF21 resistant states in humans.
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| 9. |
- Larsson, Susanna C., et al.
(författare)
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Genome-Wide Association and Two-Sample Mendelian Randomization Analyses of Plasma Ghrelin and Gastrointestinal Cancer Risk
- 2023
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Ingår i: Cancer Epidemiology, Biomarkers and Prevention. - : American Association For Cancer Research (AACR). - 1055-9965 .- 1538-7755. ; 32:12, s. 1771-1776
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Tidskriftsartikel (refereegranskat)abstract
- BACKGROUND: Observational studies have suggested that the gut hormone ghrelin is an early marker of future risk of developing gastrointestinal cancer. However, whether ghrelin is a causal risk factor remains unclear. We conducted a genome-wide association study (GWAS) of plasma ghrelin and used Mendelian randomization (MR) to investigate the possible causal association between ghrelin and gastrointestinal cancer risk.METHODS: Genetic variants associated with plasma ghrelin were identified in a GWAS comprising 10 742 Swedish adults in the discovery (N=6259) and replication (N=4483) cohorts. The association between ghrelin and gastrointestinal cancer was examined through a two-sample MR analysis using the identified genetic variants as instruments and GWAS data from the UK Biobank, FinnGen, and a colorectal cancer consortium.RESULTS: GWAS found associations between multiple genetic variants within ±200 kb of the GHRL gene and plasma ghrelin. A two-sample MR analysis revealed that genetically predicted higher plasma ghrelin levels were associated with a lower risk of gastrointestinal cancer in UK Biobank and in a meta-analysis of the two studies. The combined odds ratio per approximate doubling of genetically predicted plasma ghrelin was 0.91 (95% confidence interval, 0.85-0.99; P=0.02). Colocalization analysis revealed limited evidence of shared causal variants for plasma ghrelin and gastrointestinal cancer at the GHRL locus (posterior probability H4=24.5%); however, this analysis was likely underpowered.CONCLUSIONS: Our study provides evidence in support of a possible causal association between higher plasma ghrelin levels and a reduced risk of gastrointestinal cancer.IMPACT: Elevated plasma ghrelin levels might reduce the risk of gastrointestinal cancer.
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| 10. |
- Larsson, Susanna C., et al.
(författare)
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IGF-1 and cardiometabolic diseases : a Mendelian randomisation study
- 2020
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Ingår i: Diabetologia. - : Springer Nature. - 0012-186X .- 1432-0428. ; 63:9, s. 1775-1782
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Tidskriftsartikel (refereegranskat)abstract
- Aims/hypothesis Abnormal serum IGF-1 levels are associated with an increased risk of type 2 diabetes and cardiovascular disease. However, the causal role of IGF-1 levels within the normal range in cardiometabolic disease remains unclear. We employed Mendelian randomisation to explore the associations between genetically predicted serum IGF-1 levels and cardiometabolic diseases. Methods Serum IGF-1 levels were predicted using 416 SNPs associated with IGF-1 levels among 358,072 individuals in UK Biobank. Genetic association estimates for the outcomes were obtained from consortia of type 2 diabetes (74,124 cases, 824,006 controls), coronary artery disease (60,801 cases, 123,504 controls), heart failure (47,309 cases, 930,014 controls), atrial fibrillation (65,446 cases, 522,744 controls), and ischaemic stroke (60,341 cases, 454,450 controls). Results Genetic predisposition to elevated serum IGF-1 levels was associated with higher risk of type 2 diabetes and coronary artery disease. The OR (95% CI) per SD increment in IGF-1 level was 1.14 (1.05, 1.24) for type 2 diabetes and 1.09 (1.02, 1.16) for coronary artery disease. The association between IGF-1 and coronary artery disease was attenuated after adjustment for type 2 diabetes (OR 1.06 [95% CI 1.00, 1.13]), suggesting that the association may be partly mediated via type 2 diabetes. There was limited evidence of associations between IGF-1 levels and heart failure, atrial fibrillation and ischaemic stroke. Conclusions/interpretation This study found evidence that increased IGF-1 levels may be causally associated with higher risk of type 2 diabetes.
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