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; MAGIC

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, MAGIC

Research output: Contribution to journal › Journal article › Research › peer-review

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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.

Original language	English
Journal	Med
Volume	5
Issue number	9
Pages (from-to)	1083-1095.e6
Number of pages	19
ISSN	2666-6359
DOIs	https://doi.org/10.1016/j.medj.2024.05.015
Publication status	Published - 2024

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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., ... MAGIC (2024). SMIM1 absence is associated with reduced energy expenditure and excess weight. Med, 5(9), 1083-1095.e6. https://doi.org/10.1016/j.medj.2024.05.015

SMIM1 absence is associated with reduced energy expenditure and excess weight. / Stefanucci, Luca; Moslemi, Camous; Tomé, Ana R.; Virtue, Samuel; Bidault, Guillaume; Gleadall, Nicholas S.; Watson, Laura P. E.; Kwa, Jing E.; Burden, Frances; Farrow, Samantha; Chen, Ji; Võsa, Urmo; Burling, Keith; Walker, Lindsay; Ord, John; Barker, Peter; Warner, James; Frary, Amy; Renhstrom, Karola; Ashford, Sofie E.; Piper, Jo; Biggs, Gail; Erber, Wendy N.; Hoffman, Gary J.; Schoenmakers, Nadia; Erikstrup, Christian; Rieneck, Klaus; Dziegiel, Morten H.; Ullum, Henrik; Azzu, Vian; Vacca, Michele; Aparicio, Hugo Javier; Hui, Qin; Cho, Kelly; Sun, Yan V.; Wilson, Peter W.; Bayraktar, Omer A.; Vidal-Puig, Antonio; Ostrowski, Sisse R.; Astle, William J.; Olsson, Martin L.; Storry, Jill R.; Pedersen, Ole B.; Ouwehand, Willem H.; Chatterjee, Krishna; Vuckovic, Dragana; Frontini, Mattia; DBDS Genetic Consortium; MAGIC.

In: Med, Vol. 5, No. 9, 2024, p. 1083-1095.e6.

Research output: Contribution to journal › Journal article › Research › peer-review

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 & MAGIC 2024, 'SMIM1 absence is associated with reduced energy expenditure and excess weight', Med, vol. 5, no. 9, pp. 1083-1095.e6. https://doi.org/10.1016/j.medj.2024.05.015

Stefanucci, Luca ; Moslemi, Camous ; Tomé, Ana R. ; Virtue, Samuel ; Bidault, Guillaume ; Gleadall, Nicholas S. ; Watson, Laura P. E. ; Kwa, Jing E. ; Burden, Frances ; Farrow, Samantha ; Chen, Ji ; Võsa, Urmo ; Burling, Keith ; Walker, Lindsay ; Ord, John ; Barker, Peter ; Warner, James ; Frary, Amy ; Renhstrom, Karola ; Ashford, Sofie E. ; Piper, Jo ; Biggs, Gail ; Erber, Wendy N. ; Hoffman, Gary J. ; Schoenmakers, Nadia ; Erikstrup, Christian ; Rieneck, Klaus ; Dziegiel, Morten H. ; Ullum, Henrik ; Azzu, Vian ; Vacca, Michele ; Aparicio, Hugo Javier ; Hui, Qin ; Cho, Kelly ; Sun, Yan V. ; Wilson, Peter W. ; Bayraktar, Omer A. ; Vidal-Puig, Antonio ; Ostrowski, Sisse R. ; Astle, William J. ; Olsson, Martin L. ; Storry, Jill R. ; Pedersen, Ole B. ; Ouwehand, Willem H. ; Chatterjee, Krishna ; Vuckovic, Dragana ; Frontini, Mattia ; DBDS Genetic Consortium ; MAGIC. / SMIM1 absence is associated with reduced energy expenditure and excess weight. In: Med. 2024 ; Vol. 5, No. 9. pp. 1083-1095.e6.

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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.",

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 MAGIC",

year = "2024",

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

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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

AU - MAGIC

PY - 2024

Y1 - 2024

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.

U2 - 10.1016/j.medj.2024.05.015

DO - 10.1016/j.medj.2024.05.015

M3 - Journal article

C2 - 38906141

VL - 5

SP - 1083-1095.e6

JO - Med

JF - Med

SN - 2666-6359

IS - 9

ER -