SMIM1 absence is associated with reduced energy expenditure and excess weight.
BMI
SMIM1
Translation to patients
Vel
blood groups
dyslipidemia
metabolism
obesity
population genetics
weight
Journal
Med (New York, N.Y.)
ISSN: 2666-6340
Titre abrégé: Med
Pays: United States
ID NLM: 101769215
Informations de publication
Date de publication:
17 Jun 2024
17 Jun 2024
Historique:
received:
07
08
2023
revised:
06
12
2023
accepted:
29
05
2024
medline:
22
6
2024
pubmed:
22
6
2024
entrez:
21
6
2024
Statut:
aheadofprint
Résumé
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. 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 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. 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. This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
Sections du résumé
BACKGROUND
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
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
FINDINGS
RESULTS
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
CONCLUSIONS
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
BACKGROUND
This work was funded by the National Institute of Health Research, British Heart Foundation, and NHS Blood and Transplant.
Identifiants
pubmed: 38906141
pii: S2666-6340(24)00219-8
doi: 10.1016/j.medj.2024.05.015
pii:
doi:
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Investigateurs
Karina Banasik
(K)
Jakob Bay
(J)
Jens Kjærgaard Boldsen
(JK)
Thorsten Brodersen
(T)
Søren Brunak
(S)
Kristoffer Burgdorf
(K)
Mona Ameri Chalmer
(MA)
Maria Didriksen
(M)
Khoa Manh Dinh
(KM)
Joseph Dowsett
(J)
Christian Erikstrup
(C)
Bjarke Feenstra
(B)
Frank Geller
(F)
Daniel Gudbjartsson
(D)
Thomas Folkmann Hansen
(TF)
Lotte Hindhede
(L)
Henrik Hjalgrim
(H)
Rikke Louise Jacobsen
(RL)
Gregor Jemec
(G)
Bitten Aagaard Jensen
(BA)
Katrine Kaspersen
(K)
Bertram Dalskov Kjerulff
(BD)
Lisette Kogelman
(L)
Margit Anita Hørup Larsen
(MA)
Ioannis Louloudis
(I)
Agnete Lundgaard
(A)
None Susan
Christina Mikkelsen
(C)
Ioanna Nissen
(I)
Mette Nyegaard
(M)
Sisse Rye Ostrowski
(SR)
Ole Birger Pedersen
(OB)
Alexander Pil Henriksen
(AP)
Palle Duun Rohde
(PD)
Klaus Rostgaard
(K)
Michael Schwinn
(M)
Kari Stefansson
(K)
Hreinn Stefánsson
(H)
Erik Sørensen
(E)
Unnur Þorsteinsdóttir
(U)
Lise Wegner Thørner
(LW)
Mie Topholm Bruun
(MT)
Henrik Ullum
(H)
Thomas Werge
(T)
David Westergaard
(D)
Ji Chen
(J)
Cassandra N Spracklen
(CN)
Gaëlle Marenne
(G)
Arushi Varshney
(A)
Laura J Corbin
(LJ)
Jian'an Luan
(J)
Sara M Willems
(SM)
Ying Wu
(Y)
Xiaoshuai Zhang
(X)
Momoko Horikoshi
(M)
Thibaud S Boutin
(TS)
Reedik Mägi
(R)
Johannes Waage
(J)
Ruifang Li-Gao
(R)
Kei Hang Katie Chan
(KH)
Jie Yao
(J)
Mila D Anasanti
(MD)
Audrey Y Chu
(AY)
Annique Claringbould
(A)
Jani Heikkinen
(J)
Jaeyoung Hong
(J)
Jouke-Jan Hottenga
(JJ)
Shaofeng Huo
(S)
Marika A Kaakinen
(MA)
Tin Louie
(T)
Winfried März
(W)
Hortensia Moreno-Macias
(H)
Anne Ndungu
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Sarah C Nelson
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Ilja M Nolte
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Kari E North
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Chelsea K Raulerson
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Debashree Ray
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Rebecca Rohde
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Denis Rybin
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Claudia Schurmann
(C)
Xueling Sim
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Loz Southam
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Isobel D Stewart
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Carol A Wang
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Peitao Wu
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Weihua Zhang
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Tarunveer S Ahluwalia
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Emil V R Appel
(EVR)
Lawrence F Bielak
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Johanna Kuusisto
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Kristi Läll
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Kelvin Lam
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Deborah A Lawlor
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Nanette R Lee
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Jaana Lindström
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Allan Linneberg
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Jianjun Liu
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Carlos Lorenzo
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Tatsuaki Matsubara
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Fumihiko Matsuda
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Geltrude Mingrone
(G)
Simon Mooijaart
(S)
Sanghoon Moon
(S)
Toru Nabika
(T)
Girish N Nadkarni
(GN)
Jerry L Nadler
(JL)
Mari Nelis
(M)
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Jill M Norris
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(JV)
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(JC)
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(DI)
Yii-Der Ida Chen
(YD)
Ching-Yu Cheng
(CY)
Francis S Collins
(FS)
Adolfo Correa
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H Janaka de Silva
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George Dedoussis
(G)
Sölve Elmståhl
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Michele K Evans
(MK)
Ele Ferrannini
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Luigi Ferrucci
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Paul W Franks
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(B)
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(MO)
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(X)
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Torben Hansen
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Caroline Hayward
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(SR)
Bernardo L Horta
(BL)
Wei Huang
(W)
Erik Ingelsson
(E)
Pankow S James
(PS)
Marjo-Ritta Jarvelin
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Jost B Jonas
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Mika Kivimaki
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Lars Lind
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Cecilia Lindgren
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(A)
Dennis O Mook-Kanamori
(DO)
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Inger Njølstad
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Ken K Ong
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Sandosh Padmanabhan
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Nicholette D Palmer
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Harold Snieder
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Tamar Sofer
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Thorkild I A Sørensen
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Tim D Spector
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Alice Stanton
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Claire J Steves
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Michael Stumvoll
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Liang Sun
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Yasuharu Tabara
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E Shyong Tai
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Nicholas J Timpson
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Anke Tönjes
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Jaakko Tuomilehto
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Matti Uusitupa
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Pim van der Harst
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Cornelia van Duijn
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Veronique Vitart
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Peter Vollenweider
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Lynne E Wagenknecht
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Mark Walker
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Ya X Wang
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Nick J Wareham
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Ananda R Wickremasinghe
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Jer-Yuarn Wu
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Anny H Xiang
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Loïc Yengo
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Mitsuhiro Yokota
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Eleftheria Zeggini
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Wei Zheng
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Alan B Zonderman
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Jerome I Rotter
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Anna L Gloyn
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James B Meigs
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Inês Barroso
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Informations de copyright
Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.
Déclaration de conflit d'intérêts
Declaration of interests J.S. is the deputy CEO and 50% owner of BLUsang AB. He holds patents on Vel genotyping (inventors: Jill Storry, Magnus Jöud, Björn Nilsson, and Martin L. Olsson). J.S. has received speaker fees, royalties, and honoraria from the following companies: Grifols Diagnostic Solutions, QuidelOrtho Inc., and Biorad Laboratories. J.S. receives an honorarium for Section Editor work, Vox Sanguinis from John Wiley & Sons Ltd. J.S. is Vice President of the International Society of Blood Transfusion and married to Professor M.L.O. M.L.O. is CEO and 50% owner of BLUsang AB. M.L.O. holds patents on Vel genotyping (inventors: Jill Storry, Magnus Jöud, Björn Nilsson, and Martin L. Olsson). M.L.O. received speaker fees, royalties, and honoraria from the following companies: Grifols Diagnostic Solutions, QuidelOrtho Inc., and Biorad Laboratories. M.L.O. is married to Adjunct Professor J.S. W.N.E. is chair of the International Council for Standardization in Haematology. W.N.E. works as advisor for Scorpio Labs and is on the editorial board of the Journal of Clinical Pathology. W.H.O. is chair of the Blood Transfusion Genomics Consortium. W.H.O. is in receipt of an educational/research grant from Thermo Fisher Scientific. N.G. offers scientific consulting services to Thermo Fisher Scientific.