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 (Lead / Corresponding author), 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 (Lead / Corresponding author)

Population Health and Genomics

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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	15
Journal	Nature Genetics
Volume	50
Issue number	4
Early online date	9 Apr 2018
DOIs	https://doi.org/10.1038/s41588-018-0088-x
Publication status	Published - Apr 2018

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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

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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 Pei-Chien Tsai 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.}",

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

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pages = "572–580",

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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, P-C, 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.

PY - 2018/4

Y1 - 2018/4

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

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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