Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition

Kerrin S. Small; Marijana Todorčević; Mete Civelek; Julia S. El-Sayed Moustafa; Xiao Wang; Michelle M. Simon; Juan Fernandez-Tajes; Anubha Mahajan; Momoko Horikoshi; Alison Hugill; Craig A. Glastonbury; Lydia Quaye; Matt J. Neville; Siddharth Sethi; Marianne Yon; Calvin Pan; Nam Che; Ana Viñuela; Pei Chien Tsai; Abhishek Nag; Alfonso Buil; Gudmar Thorleifsson; Avanthi Raghavan; Qiurong Ding; Andrew P. Morris; Jordana T. Bell; Unnur Thorsteinsdottir; Kari Stefansson; Markku Laakso; Ingrid Dahlman; Peter Arner; Anna L. Gloyn; Kiran Musunuru; Aldons J. Lusis; Roger D. Cox; Fredrik Karpe; Mark I. McCarthy

doi:10.1038/s41588-018-0088-x

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition

Kerrin S. Small, Marijana Todorčević, Mete Civelek, Julia S. El-Sayed Moustafa, Xiao Wang, Michelle M. Simon, Juan Fernandez-Tajes, Anubha Mahajan, Momoko Horikoshi, Alison Hugill, Craig A. Glastonbury, Lydia Quaye, Matt J. Neville, Siddharth Sethi, Marianne Yon, Calvin Pan, Nam Che, Ana Viñuela, Pei Chien Tsai, Abhishek NagAlfonso Buil, Gudmar Thorleifsson, Avanthi Raghavan, Qiurong Ding, Andrew P. Morris, Jordana T. Bell, Unnur Thorsteinsdottir, Kari Stefansson, Markku Laakso, Ingrid Dahlman, Peter Arner, Anna L. Gloyn, Kiran Musunuru, Aldons J. Lusis, Roger D. Cox, Fredrik Karpe, Mark I. McCarthy

Research output: Contribution to journal › Article › peer-review

82 Citations (Scopus)

Abstract

Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

Original language	English
Pages (from-to)	572-580
Number of pages	9
Journal	Nature Genetics
Volume	50
Issue number	4
DOIs	https://doi.org/10.1038/s41588-018-0088-x
Publication status	Published - 1 Apr 2018

Bibliographical note

Funding Information:
This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC_U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161.

Funding Information:
This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC-U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for highperformance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161.

Publisher Copyright:
© 2018 The Author(s).

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10.1038/s41588-018-0088-x

Cite this

Small, K. S., Todorčević, M., Civelek, M., El-Sayed Moustafa, J. S., Wang, X., Simon, M. M., Fernandez-Tajes, J., Mahajan, A., Horikoshi, M., Hugill, A., Glastonbury, C. A., Quaye, L., Neville, M. J., Sethi, S., Yon, M., Pan, C., Che, N., Viñuela, A., Tsai, P. C., ... McCarthy, M. I. (2018). Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition. Nature Genetics, 50(4), 572-580. https://doi.org/10.1038/s41588-018-0088-x

@article{0d23cbe2cfce4bdd88bf9891dd48afd3,

title = "Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition",

abstract = "Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.",

author = "Small, {Kerrin S.} and Marijana Todor{\v c}evi{\'c} and Mete Civelek and {El-Sayed Moustafa}, {Julia S.} and Xiao Wang and Simon, {Michelle M.} and Juan Fernandez-Tajes and Anubha Mahajan and Momoko Horikoshi and Alison Hugill and Glastonbury, {Craig A.} and Lydia Quaye and Neville, {Matt J.} and Siddharth Sethi and Marianne Yon and Calvin Pan and Nam Che and Ana Vi{\~n}uela and Tsai, {Pei Chien} and Abhishek Nag and Alfonso Buil and Gudmar Thorleifsson and Avanthi Raghavan and Qiurong Ding and Morris, {Andrew P.} and Bell, {Jordana T.} and Unnur Thorsteinsdottir and Kari Stefansson and Markku Laakso and Ingrid Dahlman and Peter Arner and Gloyn, {Anna L.} and Kiran Musunuru and Lusis, {Aldons J.} and Cox, {Roger D.} and Fredrik Karpe and McCarthy, {Mark I.}",

note = "Funding Information: This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC_U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas{\textquoteright} NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161. Funding Information: This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC-U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for highperformance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161. Publisher Copyright: {\textcopyright} 2018 The Author(s).",

year = "2018",

month = apr,

day = "1",

doi = "10.1038/s41588-018-0088-x",

language = "English",

volume = "50",

pages = "572--580",

journal = "Nature Genetics",

issn = "1061-4036",

publisher = "Nature Publishing Group",

number = "4",

}

Small, KS, Todorčević, M, Civelek, M, El-Sayed Moustafa, JS, Wang, X, Simon, MM, Fernandez-Tajes, J, Mahajan, A, Horikoshi, M, Hugill, A, Glastonbury, CA, Quaye, L, Neville, MJ, Sethi, S, Yon, M, Pan, C, Che, N, Viñuela, A, Tsai, PC, Nag, A, Buil, A, Thorleifsson, G, Raghavan, A, Ding, Q, Morris, AP, Bell, JT, Thorsteinsdottir, U , Stefansson, K, Laakso, M, Dahlman, I, Arner, P, Gloyn, AL, Musunuru, K, Lusis, AJ, Cox, RD, Karpe, F & McCarthy, MI 2018, 'Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition', Nature Genetics, vol. 50, no. 4, pp. 572-580. https://doi.org/10.1038/s41588-018-0088-x

TY - JOUR

T1 - Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition

AU - Small, Kerrin S.

AU - Todorčević, Marijana

AU - Civelek, Mete

AU - El-Sayed Moustafa, Julia S.

AU - Wang, Xiao

AU - Simon, Michelle M.

AU - Fernandez-Tajes, Juan

AU - Mahajan, Anubha

AU - Horikoshi, Momoko

AU - Hugill, Alison

AU - Glastonbury, Craig A.

AU - Quaye, Lydia

AU - Neville, Matt J.

AU - Sethi, Siddharth

AU - Yon, Marianne

AU - Pan, Calvin

AU - Che, Nam

AU - Viñuela, Ana

AU - Tsai, Pei Chien

AU - Nag, Abhishek

AU - Buil, Alfonso

AU - Thorleifsson, Gudmar

AU - Raghavan, Avanthi

AU - Ding, Qiurong

AU - Morris, Andrew P.

AU - Bell, Jordana T.

AU - Thorsteinsdottir, Unnur

AU - Stefansson, Kari

AU - Laakso, Markku

AU - Dahlman, Ingrid

AU - Arner, Peter

AU - Gloyn, Anna L.

AU - Musunuru, Kiran

AU - Lusis, Aldons J.

AU - Cox, Roger D.

AU - Karpe, Fredrik

AU - McCarthy, Mark I.

N1 - Funding Information: This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC_U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for high-performance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas’ NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161. Funding Information: This study was supported by MRC grant MR/J010642/1 to K.S.S., R.D.C., F.K. and M.I.M. K.S.S. is supported by an MRC New Investigator Award (MR/L01999X/1). M.I.M. is a Wellcome Senior Investigator and is supported by Wellcome (090532, 106130, 098381, 203141), NIDDK (U01-DK105535) and the MRC (MR/L020149/1). F.K. is supported by the British Heart Foundation (RG/17/1/32663). M.C. is supported by NIH Award R00 HL121172. A.L.G. is a Wellcome Senior Fellow in Basic Biomedical Science (095101/Z/10/Z and 200837/Z/16/Z). K.M. is supported by NIH award R01-DK099571, and A.J.L. is supported by NIH award NIH P01HL28481. R.D.C. is supported by MRC MC-U142661184. J.F. was a Marie Curie Fellow. M.L. is supported by Academy of Finland grants 77299 and 124243, the Finnish Heart Foundation, the Finnish Diabetes Foundation, and Commission of the European Community HEALTH-F2-2007-201681. A.V. and A.B. were supported by the European Union Framework Programme 7 grant EuroBATS (259749). Some computations were performed at the Vital-IT center for highperformance computing of the Swiss Institute of Bioinformatics (SIB; http://www.vital-it. ch/). The TwinsUK study was funded by Wellcome and European Community's Seventh Framework Programme (FP7/2007-2013). The TwinsUK study also receives support from the National Institute for Health Research (NIHR)-funded BioResource, Clinical Research Facility and Biomedical Research Centre based at Guy's and St Thomas' NHS Foundation Trust in partnership with King's College London. We acknowledge excellent technical support for animal husbandry (Mary Lyon Centre), genotyping, histology and pathology. We thank the volunteers from the Oxford Biobank, NIHR Oxford Biomedical Research Centre, for their participation. The Oxford Biobank (http://www. oxfordbiobank.org.uk) is also part of the NIHR National Bioresource, which supported the recalling process of the volunteers. GERA data came from a grant, the Resource for Genetic Epidemiology Research in Adult Health and Aging (RC2 AG033067; C. Schaefer and N. Risch, principal investigators), awarded to the Kaiser Permanente Research Program on Genes, Environment, and Health (RPGEH) and the UCSF Institute for Human Genetics. The RPGEH was supported by grants from the Robert Wood Johnson Foundation, the Wayne and Gladys Valley Foundation, and the Ellison Medical Foundation. This research utilized data from the UK Biobank Resource under application 9161. Publisher Copyright: © 2018 The Author(s).

PY - 2018/4/1

Y1 - 2018/4/1

N2 - Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

AB - Individual risk of type 2 diabetes (T2D) is modified by perturbations to the mass, distribution and function of adipose tissue. To investigate the mechanisms underlying these associations, we explored the molecular, cellular and whole-body effects of T2D-associated alleles near KLF14. We show that KLF14 diabetes-risk alleles act in adipose tissue to reduce KLF14 expression and modulate, in trans, the expression of 385 genes. We demonstrate, in human cellular studies, that reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and in mice, that adipose tissue-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that carriers of the KLF14 T2D risk allele shift body fat from gynoid stores to abdominal stores and display a marked increase in adipocyte cell size, and that these effects on fat distribution, and the T2D association, are female specific. The metabolic risk associated with variation at this imprinted locus depends on the sex both of the subject and of the parent from whom the risk allele derives.

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U2 - 10.1038/s41588-018-0088-x

DO - 10.1038/s41588-018-0088-x

M3 - Article

C2 - 29632379

AN - SCOPUS:85045303087

SN - 1061-4036

VL - 50

SP - 572

EP - 580

JO - Nature Genetics

JF - Nature Genetics

IS - 4

ER -

Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition

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