Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition
| العنوان: | Regulatory variants at KLF14 influence type 2 diabetes risk via a female-specific effect on adipocyte size and body composition |
|---|---|
| المؤلفون: | Kiran Musunuru, Aldons J. Lusis, Juan Fernández-Tajes, Michelle Simon, Lydia Quaye, Peter Arner, Jordana T. Bell, Momoko Horikoshi, Avanthi Raghavan, Andrew P. Morris, Ana Viñuela, Xiao Wang, Nam Che, Ingrid Dahlman, Qiurong Ding, Mete Civelek, Matt J. Neville, Fredrik Karpe, Siddharth Sethi, Unnur Thorsteinsdottir, Calvin Pan, Kerrin S. Small, Gudmar Thorleifsson, Pei-Chien Tsai, Mark I. McCarthy, Markku Laakso, Marianne Yon, Alison Hugill, Anubha Mahajan, Anna L. Gloyn, Marijana Todorčević, Kari Stefansson, Roger D. Cox, Julia S. El-Sayed Moustafa, Alfonso Buil, Abhishek Nag, Craig A. Glastonbury |
| المصدر: | Small, K S, Marijana, M, Civelek, M, El-Sayed Moustafa, J S, Wang, X, Simon, M M, Tajes, J F, Mahajan, A, Horikoshi, M, Hugill, A, Glastonbury, C A, Quaye, L, Neville, M J, Sethi, S, Yon, M, Pan, C, Che, N, Vinuela, A, Tsai, P-C, Nag, A, Buil, A, Thorleifsson, G, Raghavan, A, Ding, Q, Morris, A P, Bell, J T, Thorsteinsdottir, U, Stefansson, K, Laakso, M, Dahlman, I, Arner, P, Gloyn, A L, Musunuru, K, Lusis, A J, Cox, R D, Karpe, F & 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, vol. 50, pp. 572–580 . https://doi.org/10.1038/s41588-018-0088-xTest Nature Genetics 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, Nag, A, Buil, A, Thorleifsson, G, Raghavan, A, Ding, Q, Morris, A P, Bell, J T, Thorsteinsdottir, U, Stefansson, K, Laakso, M, Dahlman, I, Arner, P, Gloyn, A L, Musunuru, K, Lusis, A J, Cox, R D, Karpe, F & 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, vol. 50, no. 4, pp. 572-580 . https://doi.org/10.1038/s41588-018-0088-xTest |
| بيانات النشر: | Springer Science and Business Media LLC, 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | Male, 0301 basic medicine, medicine.medical_specialty, Kruppel-Like Transcription Factors, Gene Expression, Adipose tissue, KLF14, Type 2 diabetes, Biology, Genomic Imprinting, Mice, 03 medical and health sciences, chemistry.chemical_compound, Insulin resistance, Risk Factors, Internal medicine, Adipocyte, Adipocytes, Genetics, medicine, Animals, Body Fat Distribution, Humans, Allele, Alleles, Cell Size, Mice, Knockout, Sp Transcription Factors, Body Composition/genetics, Sp Transcription Factors/genetics, Sex Characteristics, Lipogenesis, medicine.disease, Mice, Inbred C57BL, Enhancer Elements, Genetic, Phenotype, 030104 developmental biology, Endocrinology, Lipogenesis/genetics, Diabetes Mellitus, Type 2, chemistry, Kruppel-Like Transcription Factors/deficiency, Body Composition, Diabetes Mellitus, Type 2/genetics, Female, Genomic imprinting, Adipocytes/pathology, Genome-Wide Association Study |
| الوصف: | Individual risk of type 2 diabetes (T2D) is modified by perturbations of adipose mass, distribution and function. To investigate mechanisms responsible, 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, expression of >400 genes. We demonstrate that, in human cellular studies, reduced KLF14 expression increases pre-adipocyte proliferation but disrupts lipogenesis, and, in mice, adipose-specific deletion of Klf14 partially recapitulates the human phenotype of insulin resistance, dyslipidemia and T2D. We show that KLF14 T2D risk-allele carriers shift body fat from gynoid to abdominal stores, and display a marked increase in adipocyte cell size: these effects on fat distribution, and the T2D-association, are female-specific. Metabolic risk associated with variation at this imprinted locus depends on both the sex of the subject, and of the parent from whom the risk-allele derives The replicated genome-wide significant T2D association signal at chr7q32.3 maps to a 45kb recombination interval, extending from 3kb to 48kb upstream of KLF141,2 (Figure 1a-c). In previous work based on microarray-derived RNA expression data, KLF14, which encodes an imprinted transcription factor, was exposed as the likely cis-effector gene for this locus in subcutaneous adipose tissue1 and revealed to be a trans-regulator of a programme of adipose tissue expression3. The KLF family of zinc-finger binding proteins have wide-ranging regulatory roles in biological processes such as proliferation, differentiation and growth4,5. However, little is known about KLF14, a single exon gene whose transcription is limited to the maternally inherited chromosome in embryonic, extra-embryonic, and adult tissue in humans and mice6. |
| وصف الملف: | application/pdf; application/vnd.openxmlformats-officedocument.wordprocessingml.document |
| تدمد: | 1546-1718 1061-4036 |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::be2a48142a73254b78b7f405200b5b31Test https://doi.org/10.1038/s41588-018-0088-xTest |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....be2a48142a73254b78b7f405200b5b31 |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 15461718 10614036 |
|---|