Protein-truncating variants in BSN are associated with severe adult-onset obesity, type 2 diabetes and fatty liver disease

Publication: Nature Genetics

Yajie Zhao, Maria Chukanova, Katherine A. Kentistou, Zammy Fairhurst-Hunter, Anna Maria Siegert, Raina Y. Jia, Georgina K. C. Dowsett, Eugene J. Gardner, Katherine Lawler, Felix R. Day, Lena R. Kaisinger, Yi-Chun Loraine Tung, Brian Yee Hong Lam, Hsiao-Jou Cortina Chen, Quanli Wang, Jaime Berumen-Campos, Pablo Kuri-Morales, Roberto Tapia-Conyer, Jesus Alegre-Diaz, Inês Barroso, Jonathan Emberson, Jason M. Torres, Rory Collins, Danish Saleheen, Katherine R. Smith, Dirk S. Paul, Florian Merkle, I. Sadaf Farooqi, Nick J. Wareham, Slavé Petrovski, Stephen O’Rahilly, Ken K. Ong, Giles S. H. Yeo & John R. B. Perry

4 April 2024

Summary

A study has identified genetic variants in two genes that have some of the largest impacts on obesity risk discovered to date.

The discovery of rare variants in the genes BSN and APBA1 are some of the first obesity-related genes identified for which the increased risk of obesity is not observed until adulthood.

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Fetally-encoded GDF15 and maternal GDF15 sensitivity are major determinants of nausea and vomiting in human pregnancy

Publication: Nature

M. Fejzo, N. Rocha, I. Cimino, S. M. Lockhart, C. J. Petry, R. G. Kay, K. Burling, P. Barker, A. L. George, N. Yasara, A. Premawardhena, S. Gong, E. Cook, D. Rimmington, K. Rainbow, D. J. Withers, V. Cortessis, P. M. Mullin, K. W. MacGibbon, E. Jin, A. Kam, A. Campbell, O. Polasek, G. Tzoneva, F. M. Gribble, G. S. H. Yeo, B. Y. H. Lam, V. Saudek, I. A. Hughes, K. K. Ong, J. R. B. Perry, A. Sutton Cole, M. Baumgarten, P. Welsh, N. Sattar, G. C. S. Smith, D. S. Charnock-Jones, A. P. Coll, C. L. Meek, S. Mettananda, C. Hayward, N. Mancuso & S. O’Rahilly

Summary

13 December 2023

A Cambridge-led study supported by the NIHR Cambridge BRC has shown why many women experience nausea and vomiting during pregnancy – and why some women become so sick they need to be admitted to hospital. The culprit is a hormone produced by the fetus – a protein known as GDF15. But how sick the mother feels depends on a combination of how much of the hormone is produced by the fetus and how much exposure the mother had to this hormone before becoming pregnant. Read the full news story.

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Replacing device-measured sedentary time with physical activity is associated with lower risk of coronary heart disease regardless of genetic risk

Publication: Journal of Internal Medicine

Youngwon Kim, Haeyoon Jang, Mengyao Wang, Qiaoxin Shi, Tessa Strain, Stephen J Sharp, Shiu Lun Au Yeung, Shan Luo, Simon Griffin, Nicholas J. Wareham, Katrien Wijndaele, Soren Brage

23 August 2023

Summary

Excess sedentary time (ST) is recognized as an important modifiable risk factor for coronary heart disease (CHD). However, whether the associations of genetic susceptibility with CHD incidence can be modified by replacing wearable-device-measured ST with physical activity (PA) is unknown.

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Chromosomal deletions on 16p11.2 encompassing SH2B1 are associated with accelerated metabolic disease

Publication: Cell Reports Medicine

Ruth Hanssen, Chiara Auwerx, Maarja Jõeloo, Sadaf Farooqi, Alexandre Reymond, Katherine Lawler

15 August 2023


New approaches are needed to treat people whose obesity and type 2 diabetes (T2D) are driven by specific mechanisms. We investigate a deletion on chromosome 16p11.2 (breakpoint 2–3 [BP2–3]) encompassing SH2B1, a mediator of leptin and insulin signaling. Phenome-wide association scans in the UK (N = 502,399) and Estonian (N = 208,360) biobanks show that deletion carriers have increased body mass index (BMI; p = 1.3 × 10−10) and increased rates of T2D. Compared with BMI-matched controls, deletion carriers have an earlier onset of T2D, with poorer glycemic control despite higher medication usage. Cystatin C, a biomarker of kidney function, is significantly elevated in deletion carriers, suggesting increased risk of renal impairment. In a Mendelian randomization study, decreased SH2B1 expression increases T2D risk (p = 8.1 × 10−6). We conclude that people with 16p11.2 BP2–3 deletions have early, complex obesity and T2D and may benefit from therapies that enhance leptin and insulin signaling.

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Accelerated waning of the humoral response to COVID-19 vaccines in obesity

Publication: Nature Medicine

Agatha A. van der Klaauw, Emily C. Horner, Pehuén Pereyra-Gerber, Utkarsh Agrawal, William S. Foster, Sarah Spencer, Bensi Vergese, Miriam Smith, Elana Henning, Isobel D. Ramsay, Jack A. Smith, Stephane M. Guillaume, Hayley J. Sharpe, Iain M. Hay, Sam Thompson, Silvia Innocentin, Lucy H. Booth, Chris Robertson, Colin McCowan, Steven Kerr, Thomas E. Mulroney, Martin J. O’Reilly, Thevinya P. Gurugama, Lihinya P. Gurugama, Maria A. Rust, Alex Ferreira, Soraya Ebrahimi, Lourdes Ceron-Gutierrez, Jacopo Scotucci, Barbara Kronsteiner, Susanna J. Dunachie, Paul Klenerman, PITCH Consortium, Adrian J. Park, Francesco Rubino, Abigail A. Lamikanra, Hannah Stark, Nathalie Kingston, Lise Estcourt, Heli Harvala, David J. Roberts, Rainer Doffinger, Michelle A. Linterman, Nicholas J. Matheson, Aziz Sheikh, I. Sadaf Farooqi & James E. D. Thaventhiran

11 May 2023

Summary

Clinical trials have shown that COVID-19 vaccines are highly effective at reducing symptoms, hospitalisation and deaths caused by the virus, including for people with obesity. Previous studies have suggested that antibody levels may be lower in vaccinated people who have obesity and that they may remain at higher risk of severe disease than vaccinated people with normal weight. The reasons for this have, however, remained unclear. Read the news story.

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Fully automated closed-loop insulin delivery in adults with type 2 diabetes: an open-label, single-center, randomized crossover trial

Publication: Nature Medicine

Aideen B. Daly, Charlotte K. Boughton, Munachiso Nwokolo, Sara Hartnell, Malgorzata E. Wilinska, Alina Cezar, Mark L. Evans & Roman Hovorka

12 January 2023


Summary

Cambridge scientists have successfully trialled an artificial pancreas for use by patients living with type 2 diabetes. The device – powered by an algorithm developed at the University of Cambridge – doubled the amount of time patients were in the target range for glucose and halved the time spent experiencing high glucose levels. Read the full news story.

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Factors Associated with Significant Weight Loss in Hospitalised Patients with COVID-19: A Retrospective Cohort Study in a Large Teaching Hospital

Publication: Nutrients

Dimitra Zannidi, Pinal S. Patel, Eleni Leventea, Jessica Paciepnik,  Frances Dobson,  Caroline Heyes, Robert J. B. Goudie,  Linda M. Oude Griep,  Jacobus Preller, and Lynsey N. Spillman, 

8 October 2022


Summary

Previous research has shown that people hospitalised with COVID-19 are at risk of weight loss and malnutrition. This study looked at patients who experienced weight loss of 10% or more during their hospital admission to Cambridge University Hospitals NHS with COVID-19 during the first wave of the pandemic. Weight loss of 10% or more is considered a large amount to lose as it increases the chance of someone becoming more poorly and not surviving. Therefore, preventing weight loss may help patients to survive and recover. The study looked at risk factors for weight loss to help better recognise the patients that need more support to prevent weight loss. 

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Estimating dose-response relationships for vitamin D with coronary heart disease, stroke, and all-cause mortality: observational and Mendelian randomisation analyses

Publication: The Lancet Diabetes and Endocrinology

Nick Wareham, Nita Forouhi

27 October 2021


Summary

Randomised trials of vitamin D supplementation for cardiovascular disease and all-cause mortality have generally reported null findings. However, generalisability of results to individuals with low vitamin D status is unclear. Researcgers aimed to characterise dose-response relationships between 25-hydroxyvitamin D (25[OH]D) concentrations and risk of coronary heart disease, stroke, and all-cause mortality in observational and Mendelian randomisation frameworks.

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Placental uptake and metabolism of 25(OH)vitamin D determine its activity within the fetoplacental unit

Publication: Elife

Brogan Ashley, Claire Simner, Antigoni Manousopoulou, Carl Jenkinson, Felicity Hey, Jennifer M Frost, Faisal I Rezwan, Cory H White, Emma M Lofthouse, Emily Hyde, Laura DF Cooke, Sheila Barton, Pamela Mahon, Elizabeth M Curtis, Rebecca J Moon, Sarah R Crozier, Hazel M Inskip, Keith M Godfrey, John W Holloway, Cyrus Cooper, Kerry S Jones, Rohan M Lewis, Martin Hewison, Spiros DD Garbis, Miguel R Branco, Nicholas C Harvey, Jane K Cleal

8 March 2022


Summary

This is the first quantitative study demonstrating vitamin D transfer and metabolism by the human placenta, with widespread effects on the placenta itself.

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Distinct infant feeding type-specific plasma metabolites at age 3 months associate with body composition at 2 years

Publication: Clinical Nutrition

Inge A.L.P. van Beijsterveldt, Pernille Neve Myers, Stuart G. Snowden, Ken K. Ong, Susanne Brix, Anita C.S. Hokken-Koelega, Albert Koulman 

21 April 2022


Summary

Early life is a critical window for adiposity programming and metabolic profile may affect this programming. Researchers investigated if plasma metabolites at age 3 months were associated with fat mass, fat free mass and abdominal subcutaneous and visceral fat outcomes at age 2 years in a cohort of healthy infants and if these associations were different between infants receiving exclusive breastfeeding and those with exclusive formula feeding.

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