Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors

Lotta, Luca A.; Wittemans, Laura B. L.; Zuber, Verena; Stewart, Isobel D.; Sharp, Stephen J.; Luan, Jian’an; Day, Felix R.; Li, Chen; Bowker, Nicholas; Cai, Lina; Rolfe, Emanuella De Lucia; Khaw, Kay‐Tee; Perry, John; O’Rahilly, Stephen; Scott, Robert A.; Savage, David B.; Burgess, Stephen; Wareham, Nicholas J.; Langenberg, Claudia

doi:10.1001/jama.2018.19329

Cited by 178 publications

(170 citation statements)

References 41 publications

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“…Obesity traits were causally related to higher risk of T2D, in keeping with previous studies (6)(7)(8)(9)(10)(11)19,64). We could not detect a sex difference in risk of T2D from higher WHR or WHRadjBMI.…”

Section: Diabetessupporting

confidence: 89%

“…Even though some observational studies have suggested that WHR may be a stronger predictor of T2D risk in women than in men (18,19), studies investigating the effect on T2D risk from genetic predisposition to higher WHRadjBMI have not found evidence of sexual heterogeneity (6,9,11). In contrast, we found that BMI conferred a higher T2D risk in women than in men.…”

Section: Diabetescontrasting

confidence: 85%

“…Previous studies have found causal relationships between higher BMI and WHR adjusted for BMI (WHRadjBMI) and type 2 diabetes (T2D) and coronary artery disease (CAD), using a limited number of previously known obesity-associated SNPs (6)(7)(8)(9)(10)(11). However, sex-specific relationships are largely unexplored as is the the role that obesity traits play in the leading causes of death beyond these cardiometabolic diseases.…”

Section: Introductionmentioning

confidence: 99%

“…It has been suggested that fat distribution related traits might be more strongly associated with cardiometabolic outcomes in women, although many previous studies are inconclusive (15)(16)(17)(18)(19). Only a few studies have investigated sex differences in the effect of genetic risk for obesityrelated traits on disease risk (6,9,11) and have mostly been restricted to waist-related traits and T2D and CAD, using a limited number of analyses and/or SNPs, but without finding evidence of differences in disease risk between men and women (6,9,11).…”

Section: Introductionmentioning

confidence: 99%

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Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

Censin

Bovijn

Ferreira³

et al. 2019

Preprint

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Obesity traits are causally implicated with risk of cardiometabolic diseases. It remains unclear whether there are similar causal effects of obesity traits on other non-communicable diseases. Also, it is largely unexplored whether there are any sex-specific differences in the causal effects of obesity traits on cardiometabolic diseases and other leading causes of death.We constructed sex-specific genetic risk scores (GRS) for three obesity traits; body mass index (BMI), waist-hip ratio (WHR), and WHR adjusted for BMI, including 565, 324, and 337 genetic variants, respectively. These GRSs were then used as instrumental variables to assess associations between the obesity traits and leading causes of mortality in the UK Biobank using Mendelian randomization. We also investigated associations with potential mediators, including smoking, glycemic and blood pressure traits. Sex-differences were subsequently assessed by Cochran's Q-test (Phet).A Mendelian randomization analysis of 228,466 women and 195,041 men showed that obesity causes coronary artery disease, stroke (particularly ischemic), chronic obstructive pulmonary disease, lung cancer, type 2 and 1 diabetes mellitus, non-alcoholic fatty liver disease, chronic liver disease, and acute and chronic renal failure. Higher BMI led to higher risk of type 2 diabetes in women than in men (Phet=1.4×10 -5 ). Waist-hip-ratio led to a higher risk of chronic obstructive pulmonary disease (Phet=3.7×10 -6 ) and higher risk of chronic renal failure (Phet=1.0×10 -4 ) in men than women.Obesity traits have an etiological role in the majority of the leading global causes of death. Sex differences exist in the effects of obesity traits on risk of type 2 diabetes, chronic obstructive pulmonary disease, and renal failure, which may have downstream implications for public health. 4 Author summaryObesity is increasing globally and has been linked to major causes of death, such as diabetes and heart disease. Still, the causal effects of obesity on other leading causes of death is relatively unexplored. It is also unclear if any such effects differ between men and women.Mendelian randomization is a method that explores causal relationships between traits using genetic data. Using Mendelian randomization, we investigated the effects of obesity traits on leading causes of death and assessed if any such effects differ between men and women.

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Section: Diabetessupporting

confidence: 89%

Section: Diabetescontrasting

confidence: 85%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

Censin

Bovijn

Ferreira³

et al. 2019

Preprint

View full text Add to dashboard Cite

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“…Consistent with these findings, MIR196A1 miRNA levels are lower in endometrial tumors compared with healthy endometrial tissue [42]. There may also be a link between MIR196A1 and the endometrial cancer risk factors of obesity and insulinemia [43,44]: MIR196A1 miRNA is upregulated in gluteofemoral fat, which is associated with lower risk of diabetes [45]; and forced expression of the mouse homologue of MIR196A1 has been found to make mice resistant to obesity and prevent them from developing insulin resistance [46].…”

Section: Discussionmentioning

confidence: 64%

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

O’Mara

Spurdle

Glubb

2019

Preprint

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The identification of target genes at genome-wide association study (GWAS) loci is a major obstacle for GWAS follow-up. To identify candidate target genes at the 16 known endometrial cancer GWAS risk loci, we performed HiChIP chromatin looping analysis of endometrial cell lines. To enrich for enhancer-promoter interactions, a mechanism through which GWAS variation may target genes, we captured loops associated with H3K27Ac histone, characteristic of promoters and enhancers. Analysis of HiChIP loops contacting promoters revealed enrichment for endometrial cancer GWAS heritability and intersection with endometrial cancer risk variation identified 103 HiChIP target genes at 13 risk loci. Expression of four HiChIP target genes (SNX11, SRP14, HOXB2 and BCL11A) was associated with risk variation, providing further evidence for their regulation. Network analysis functionally prioritized a set of proteins that interact with those encoded by HiChIP target genes, and this set was enriched for pan-cancer and endometrial cancer drivers. Lastly, HiChIP target genes and prioritized interacting proteins were over-represented in pathways related to endometrial cancer development. In summary, we have generated the first global chromatin looping data from endometrial cells, enabling analysis of all known endometrial cancer risk loci and identifying biologically relevant candidate target genes.

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Obesity Management in Adults

Elmaleh-Sachs,

Schwartz,

Bramante

et al. 2023

JAMA

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ImportanceObesity affects approximately 42% of US adults and is associated with increased rates of type 2 diabetes, hypertension, cardiovascular disease, sleep disorders, osteoarthritis, and premature death.ObservationsA body mass index (BMI) of 25 or greater is commonly used to define overweight, and a BMI of 30 or greater to define obesity, with lower thresholds for Asian populations (BMI ≥25-27.5), although use of BMI alone is not recommended to determine individual risk. Individuals with obesity have higher rates of incident cardiovascular disease. In men with a BMI of 30 to 39, cardiovascular event rates are 20.21 per 1000 person-years compared with 13.72 per 1000 person-years in men with a normal BMI. In women with a BMI of 30 to 39.9, cardiovascular event rates are 9.97 per 1000 person-years compared with 6.37 per 1000 person-years in women with a normal BMI. Among people with obesity, 5% to 10% weight loss improves systolic blood pressure by about 3 mm Hg for those with hypertension, and may decrease hemoglobin A1c by 0.6% to 1% for those with type 2 diabetes. Evidence-based obesity treatment includes interventions addressing 5 major categories: behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures. Comprehensive obesity care plans combine appropriate interventions for individual patients. Multicomponent behavioral interventions, ideally consisting of at least 14 sessions in 6 months to promote lifestyle changes, including components such as weight self-monitoring, dietary and physical activity counseling, and problem solving, often produce 5% to 10% weight loss, although weight regain occurs in 25% or more of participants at 2-year follow-up. Effective nutritional approaches focus on reducing total caloric intake and dietary strategies based on patient preferences. Physical activity without calorie reduction typically causes less weight loss (2-3 kg) but is important for weight-loss maintenance. Commonly prescribed medications such as antidepressants (eg, mirtazapine, amitriptyline) and antihyperglycemics such as glyburide or insulin cause weight gain, and clinicians should review and consider alternatives. Antiobesity medications are recommended for nonpregnant patients with obesity or overweight and weight-related comorbidities in conjunction with lifestyle modifications. Six medications are currently approved by the US Food and Drug Administration for long-term use: glucagon-like peptide receptor 1 (GLP-1) agonists (semaglutide and liraglutide only), tirzepatide (a glucose-dependent insulinotropic polypeptide/GLP-1 agonist), phentermine-topiramate, naltrexone-bupropion, and orlistat. Of these, tirzepatide has the greatest effect, with mean weight loss of 21% at 72 weeks. Endoscopic procedures (ie, intragastric balloon and endoscopic sleeve gastroplasty) can attain 10% to 13% weight loss at 6 months. Weight loss from metabolic and bariatric surgeries (ie, laparoscopic sleeve gastrectomy and Roux-en-Y gastric bypass) ranges from 25% to 30% at 12 months. Maintaining long-term weight loss is difficult, and clinical guidelines support the use of long-term antiobesity medications when weight maintenance is inadequate with lifestyle interventions alone.Conclusion and RelevanceObesity affects approximately 42% of adults in the US. Behavioral interventions can attain approximately 5% to 10% weight loss, GLP-1 agonists and glucose-dependent insulinotropic polypeptide/GLP-1 receptor agonists can attain approximately 8% to 21% weight loss, and bariatric surgery can attain approximately 25% to 30% weight loss. Comprehensive, evidence-based obesity treatment combines behavioral interventions, nutrition, physical activity, pharmacotherapy, and metabolic/bariatric procedures as appropriate for individual patients.

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Association of Genetic Variants Related to Gluteofemoral vs Abdominal Fat Distribution With Type 2 Diabetes, Coronary Disease, and Cardiovascular Risk Factors

Cited by 178 publications

References 41 publications

Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

Causal relevance of obesity on the leading causes of death in women and men: A Mendelian randomization study

Analysis of promoter-associated chromatin interactions reveals biologically relevant candidate target genes at endometrial cancer risk loci

Obesity Management in Adults

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