SMIM1 absence is associated with reduced energy expenditure and excess weight

Luca Stefanucci; Camous Moslemi; Ana R Tomé; Samuel Virtue; Guillaume Bidault; Nicholas S Gleadall; Laura P E Watson; Jing E Kwa; Frances Burden; Samantha Farrow; Ji Chen; Urmo Võsa; Keith Burling; Lindsay Walker; John Ord; Peter Barker; James Warner; Amy Frary; Karola Renhstrom; Sofie E Ashford; Jo Piper; Gail Biggs; Wendy N Erber; Gary J Hoffman; Nadia Schoenmakers; Christian Erikstrup; Klaus Rieneck; Morten H Dziegiel; Henrik Ullum; Vian Azzu; Michele Vacca; Hugo Javier Aparicio; Qin Hui; Kelly Cho; Yan V Sun; Peter W Wilson; Omer A Bayraktar; Antonio Vidal-Puig; Sisse R Ostrowski; William J Astle; Martin L Olsson; Jill R Storry; Ole B Pedersen; Willem H Ouwehand; Krishna Chatterjee; Dragana Vuckovic; Mattia Frontini; DBDS Genetic Consortium; Allan  Linneberg; Lisette Kogelman; Thomas Folkmann Hansen

doi:10.1016/j.medj.2024.05.015

SMIM1 absence is associated with reduced energy expenditure and excess weight

Luca Stefanucci, Camous Moslemi, Ana R Tomé, Samuel Virtue, Guillaume Bidault, Nicholas S Gleadall, Laura P E Watson, Jing E Kwa, Frances Burden, Samantha Farrow, Ji Chen, Urmo Võsa, Keith Burling, Lindsay Walker, John Ord, Peter Barker, James Warner, Amy Frary, Karola Renhstrom, Sofie E AshfordJo Piper, Gail Biggs, Wendy N Erber, Gary J Hoffman, Nadia Schoenmakers, Christian Erikstrup, Klaus Rieneck, Morten H Dziegiel, Henrik Ullum, Vian Azzu, Michele Vacca, Hugo Javier Aparicio, Qin Hui, Kelly Cho, Yan V Sun, Peter W Wilson, Omer A Bayraktar, Antonio Vidal-Puig, Sisse R Ostrowski, William J Astle, Martin L Olsson, Jill R Storry, Ole B Pedersen, Willem H Ouwehand, Krishna Chatterjee, Dragana Vuckovic, Mattia Frontini, DBDS Genetic Consortium, Allan Linneberg (Medlem af forfattergruppering), Lisette Kogelman (Medlem af forfattergruppering), Thomas Folkmann Hansen (Medlem af forfattergruppering)

2 Citationer (Scopus)

Abstract

BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.

METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.

FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.

CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.

FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

Originalsprog	Engelsk
Tidsskrift	Med (New York, N.Y.)
Vol/bind	5
Udgave nummer	9
Sider (fra-til)	1083-1095.e6
ISSN	2666-6340
DOI	https://doi.org/10.1016/j.medj.2024.05.015
Status	Udgivet - 13 sep. 2024

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10.1016/j.medj.2024.05.015

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Stefanucci, L., Moslemi, C., Tomé, A. R., Virtue, S., Bidault, G., Gleadall, N. S., Watson, L. P. E., Kwa, J. E., Burden, F., Farrow, S., Chen, J., Võsa, U., Burling, K., Walker, L., Ord, J., Barker, P., Warner, J., Frary, A., Renhstrom, K., ... Hansen, T. F. (2024). SMIM1 absence is associated with reduced energy expenditure and excess weight. Med (New York, N.Y.), 5(9), 1083-1095.e6. https://doi.org/10.1016/j.medj.2024.05.015

Stefanucci, L, Moslemi, C, Tomé, AR, Virtue, S, Bidault, G, Gleadall, NS, Watson, LPE, Kwa, JE, Burden, F, Farrow, S, Chen, J, Võsa, U, Burling, K, Walker, L, Ord, J, Barker, P, Warner, J, Frary, A, Renhstrom, K, Ashford, SE, Piper, J, Biggs, G, Erber, WN, Hoffman, GJ, Schoenmakers, N, Erikstrup, C, Rieneck, K , Dziegiel, MH, Ullum, H, Azzu, V, Vacca, M, Aparicio, HJ, Hui, Q, Cho, K, Sun, YV, Wilson, PW, Bayraktar, OA, Vidal-Puig, A, Ostrowski, SR, Astle, WJ, Olsson, ML, Storry, JR, Pedersen, OB, Ouwehand, WH, Chatterjee, K, Vuckovic, D, Frontini, M, DBDS Genetic Consortium, Linneberg, A , Kogelman, L & Hansen, TF 2024, 'SMIM1 absence is associated with reduced energy expenditure and excess weight', Med (New York, N.Y.), bind 5, nr. 9, s. 1083-1095.e6. https://doi.org/10.1016/j.medj.2024.05.015

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title = "SMIM1 absence is associated with reduced energy expenditure and excess weight",

abstract = "BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.",

keywords = "blood groups, BMI, dyslipidemia, metabolism, obesity, population genetics, SMIM1, Translation to patients, Vel, weight, Leptin/blood, Loss of Function Mutation, Adiponectin/genetics, Humans, Middle Aged, Energy Metabolism/genetics, Membrane Proteins/genetics, Male, Case-Control Studies, Thyroid Hormones/blood, Obesity/genetics, Overweight/genetics, Adult, Female",

author = "Luca Stefanucci and Camous Moslemi and Tom{\'e}, {Ana R} and Samuel Virtue and Guillaume Bidault and Gleadall, {Nicholas S} and Watson, {Laura P E} and Kwa, {Jing E} and Frances Burden and Samantha Farrow and Ji Chen and Urmo V{\~o}sa and Keith Burling and Lindsay Walker and John Ord and Peter Barker and James Warner and Amy Frary and Karola Renhstrom and Ashford, {Sofie E} and Jo Piper and Gail Biggs and Erber, {Wendy N} and Hoffman, {Gary J} and Nadia Schoenmakers and Christian Erikstrup and Klaus Rieneck and Dziegiel, {Morten H} and Henrik Ullum and Vian Azzu and Michele Vacca and Aparicio, {Hugo Javier} and Qin Hui and Kelly Cho and Sun, {Yan V} and Wilson, {Peter W} and Bayraktar, {Omer A} and Antonio Vidal-Puig and Ostrowski, {Sisse R} and Astle, {William J} and Olsson, {Martin L} and Storry, {Jill R} and Pedersen, {Ole B} and Ouwehand, {Willem H} and Krishna Chatterjee and Dragana Vuckovic and Mattia Frontini and {DBDS Genetic Consortium} and Allan Linneberg and Lisette Kogelman and Hansen, {Thomas Folkmann}",

year = "2024",

month = sep,

day = "13",

doi = "10.1016/j.medj.2024.05.015",

language = "English",

volume = "5",

pages = "1083--1095.e6",

journal = "Med (New York, N.Y.)",

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publisher = "Cell Press",

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T1 - SMIM1 absence is associated with reduced energy expenditure and excess weight

AU - Stefanucci, Luca

AU - Moslemi, Camous

AU - Tomé, Ana R

AU - Virtue, Samuel

AU - Bidault, Guillaume

AU - Gleadall, Nicholas S

AU - Watson, Laura P E

AU - Kwa, Jing E

AU - Burden, Frances

AU - Farrow, Samantha

AU - Chen, Ji

AU - Võsa, Urmo

AU - Burling, Keith

AU - Walker, Lindsay

AU - Ord, John

AU - Barker, Peter

AU - Warner, James

AU - Frary, Amy

AU - Renhstrom, Karola

AU - Ashford, Sofie E

AU - Piper, Jo

AU - Biggs, Gail

AU - Erber, Wendy N

AU - Hoffman, Gary J

AU - Schoenmakers, Nadia

AU - Erikstrup, Christian

AU - Rieneck, Klaus

AU - Dziegiel, Morten H

AU - Ullum, Henrik

AU - Azzu, Vian

AU - Vacca, Michele

AU - Aparicio, Hugo Javier

AU - Hui, Qin

AU - Cho, Kelly

AU - Sun, Yan V

AU - Wilson, Peter W

AU - Bayraktar, Omer A

AU - Vidal-Puig, Antonio

AU - Ostrowski, Sisse R

AU - Astle, William J

AU - Olsson, Martin L

AU - Storry, Jill R

AU - Pedersen, Ole B

AU - Ouwehand, Willem H

AU - Chatterjee, Krishna

AU - Vuckovic, Dragana

AU - Frontini, Mattia

AU - DBDS Genetic Consortium

A2 - Linneberg, Allan

A2 - Kogelman, Lisette

A2 - Hansen, Thomas Folkmann

PY - 2024/9/13

Y1 - 2024/9/13

N2 - BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

AB - BACKGROUND: Obesity rates have nearly tripled in the past 50 years, and by 2030 more than 1 billion individuals worldwide are projected to be obese. This creates a significant economic strain due to the associated non-communicable diseases. The root cause is an energy expenditure imbalance, owing to an interplay of lifestyle, environmental, and genetic factors. Obesity has a polygenic genetic architecture; however, single genetic variants with large effect size are etiological in a minority of cases. These variants allowed the discovery of novel genes and biology relevant to weight regulation and ultimately led to the development of novel specific treatments.METHODS: We used a case-control approach to determine metabolic differences between individuals homozygous for a loss-of-function genetic variant in the small integral membrane protein 1 (SMIM1) and the general population, leveraging data from five cohorts. Metabolic characterization of SMIM1-/- individuals was performed using plasma biochemistry, calorimetric chamber, and DXA scan.FINDINGS: We found that individuals homozygous for a loss-of-function genetic variant in SMIM1 gene, underlying the blood group Vel, display excess body weight, dyslipidemia, altered leptin to adiponectin ratio, increased liver enzymes, and lower thyroid hormone levels. This was accompanied by a reduction in resting energy expenditure.CONCLUSION: This research identified a novel genetic predisposition to being overweight or obese. It highlights the need to investigate the genetic causes of obesity to select the most appropriate treatment given the large cost disparity between them.FUNDING: This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.

KW - blood groups

KW - BMI

KW - dyslipidemia

KW - metabolism

KW - obesity

KW - population genetics

KW - SMIM1

KW - Translation to patients

KW - Vel

KW - weight

KW - Leptin/blood

KW - Loss of Function Mutation

KW - Adiponectin/genetics

KW - Humans

KW - Middle Aged

KW - Energy Metabolism/genetics

KW - Membrane Proteins/genetics

KW - Male

KW - Case-Control Studies

KW - Thyroid Hormones/blood

KW - Obesity/genetics

KW - Overweight/genetics

KW - Adult

KW - Female

UR - http://www.scopus.com/inward/record.url?scp=85198207889&partnerID=8YFLogxK

U2 - 10.1016/j.medj.2024.05.015

DO - 10.1016/j.medj.2024.05.015

M3 - Journal article

C2 - 38906141

SN - 2666-6340

VL - 5

SP - 1083-1095.e6

JO - Med (New York, N.Y.)

JF - Med (New York, N.Y.)

IS - 9

ER -

SMIM1 absence is associated with reduced energy expenditure and excess weight

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