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Genetic variant near IRS1 is associated with type 2 diabetes, insulin resistance and hyperinsulinemia
Abstract
Genome-wide association studies have identified common variants that only partially explain the genetic risk for type 2 diabetes (T2D). Using genome-wide association data from 1,376 French individuals, we identified 16,360 SNPs nominally associated with T2D and studied these SNPs in an independent sample of 4,977 French individuals. We then selected the 28 best hits for replication in 7,698 Danish subjects and identified 4 SNPs showing strong association with T2D, one of which (rs2943641, P = 9.3 x 10(-12), OR = 1.19) was located adjacent to the insulin receptor substrate 1 gene (IRS1). Unlike previously reported T2D risk loci, which predominantly associate with impaired beta cell function, the C allele of rs2943641 was associated with insulin resistance and hyperinsulinemia in 14,358 French, Danish and Finnish participants from population-based cohorts; this allele was also associated with reduced basal levels of IRS1 protein and decreased insulin induction of IRS1-associated phosphatidylinositol-3-OH kinase activity in human skeletal muscle biopsies.
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“The failure to identify a qualitative or monogenic inheritance pattern and the findings from GWAS, MR, familial and twin studies, suggests that the heritability of PCOS is likely to be due to the combination of multiple genes with small effect size, as has been found with obesity and type 2 diabetes [79,80,94,95,96].”
From Polycystic Ovary Syndrome: An Evolutionary Adaptation to Lifestyle and the Environment (2022) · cites this paper as [94]
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Basile, K. J., Johnson, M. E., Xia, Q., & Grant, S. F. A. (2014) · International Journal of Endocrinology · doi:10.1155/2014/769671 · Cited by 78
New type 2 diabetes risk genes provide new insights in insulin secretion mechanisms
Schäfer, S., Machicao, F. E., Fritsche, A., Häring, H., & Kantartzis, K. (2011) · Diabetes Research and Clinical Practice · doi:10.1016/s0168-8227(11)70008-0 · Cited by 80
“In 2009 only one SNP, rs2943641, located adjacent to the insulin receptor substrate 1 gene (IRS1) was identified by GWA studies [84], but there were a lot of association studies indicating candidate gene variants.”
BackgroundInfluentialA MicroRNA Linking Human Positive Selection and Metabolic Disorders
Wang, L., Sinnott-Armstrong, N., Wagschal, A., Wark, A. R., Camporez, J. P., Perry, R. J., Ji, F., Sohn, Y., Oh, J. D., Wu, S., et al. (2020) · Cell · doi:10.1016/j.cell.2020.09.017 · Cited by 81
The Evolution and Refinement of Traditional Risk Factors for Cardiovascular Disease
deGoma, E. M., Knowles, J. W., Angeli, F., Budoff, M. J., & Rader, D. J. (2011) · Cardiology in Review · doi:10.1097/crd.0b013e318239b924 · Cited by 81
Ohshige, T., Iwata, M., Omori, S., Tanaka, Y., Hirose, H., Kaku, K., Maegawa, H., Watada, H., Kashiwagi, A., Kawamori, R., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0026911 · Cited by 75
Morton, N. M., Beltram, J., Carter, R. N., Michailidou, Z., Gorjanc, G., McFadden, C., Barrios-Llerena, M. E., Rodríguez‐Cuenca, S., Gibbins, M., Aird, R. E., et al. (2016) · Nature Medicine · doi:10.1038/nm.4115 · Cited by 78
Genetic Defects in Human Pericentrin Are Associated With Severe Insulin Resistance and Diabetes
Huang‐Doran, I., Bicknell, L. S., Finucane, F. M., Rocha, N., Porter, K. M., Tung, Y. C. L., Szekeres, F. L. M., Krook, A., Nolan, J. J., O’Driscoll, M., et al. (2011) · Diabetes · doi:10.2337/db10-1334 · Cited by 74
Technical Reproducibility of Genotyping SNP Arrays Used in Genome-Wide Association Studies
Hong, H., Xu, L., Liu, J., Jones, W. D., Su, Z., Ning, B., Perkins, R., Ge, W., Miclaus, K. J., Zhang, L., et al. (2012) · PLoS ONE · doi:10.1371/journal.pone.0044483 · Cited by 74
A Genome-Wide Association Study Confirms Previously Reported Loci for Type 2 Diabetes in Han Chinese
Cui, B., Zhu, X., Xu, M., Guo, T., Zhu, D., Chen, G., Li, X., Xu, L., Bi, Y., Chen, Y., et al. (2011) · PLoS ONE · doi:10.1371/journal.pone.0022353 · Cited by 72
“More recently, several genome-wide association studies (GWASs) have been completed in independent population samples derived from Caucasians and Japanese, and identified a host of novel susceptibility loci of T2D [8–19].”
BackgroundStančáková, A., & Laakso, M. (2016) · Endocrine development · doi:10.1159/000439418 · Cited by 72
Type 2 diabetes risk alleles near ADCY5, CDKAL1 and HHEX-IDE are associated with reduced birthweight
Galijatovic, E. A. A., Pilgaard, K. A., Pisinger, C. H., Harder, M. N., Grarup, N., Færch, K., Poulsen, P., Witte, D. R., Jørgensen, T., Vaag, A. A., et al. (2010) · Diabetologia · doi:10.1007/s00125-010-1790-0 · Cited by 74
Self-citationGenetic and inflammatory factors underlying gestational diabetes mellitus: a review
Ray, G. W., Zeng, Q., Kusi, P., Zhang, H., Shao, T., Yang, T., Wei, Y., Li, M., Che, X., & Guo, R. (2024) · Frontiers in Endocrinology · doi:10.3389/fendo.2024.1399694 · Cited by 82
“The IRS1 gene encodes the IRS1 protein, crucial for transmitting insulin signals and regulating glucose metabolism (73, 74).”
BackgroundThe Genetics of Obesity and the Metabolic Syndrome
Monda, K. L., North, K. E., Hunt, S. C., Rao, D. C., Province, M. A., & Kraja, A. T. (2010) · Endocrine Metabolic & Immune Disorders - Drug Targets · doi:10.2174/187153010791213100 · Cited by 68
Chen, L., Li, H., Qi, L., Loos, R. J. F., Qi, Q., Lu, L., Gan, W., & Xu, L. (2011) · PLoS ONE · doi:10.1371/journal.pone.0021464 · Cited by 66
“*Glucose-increasing alleles were determined based upon the recent GWAS results [2,6] The associations remained significant after Bonferroni correction for multiple tests, and the Bonferroni corrected cutoff P value is 0.”
InfluentialBork‐Jensen, J., Schéele, C., Christophersen, D. V., Nilsson, E., Friedrichsen, M. H., Fernandez‐Twinn, D. S., Grunnet, L. G., Litman, T., Holmstrøm, K., Vind, B. F., et al. (2014) · Diabetologia · doi:10.1007/s00125-014-3434-2 · Cited by 68
“Muscle biopsies The protein levels of INSR, IRS-1 and PIK3R1 were measured using western blotting as described in [2, 34].”
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Transferability and Fine Mapping of Type 2 Diabetes Loci in African Americans
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Is Genetic testing useful to predict type 2 diabetes?
Vassy, J. L., & Meigs, J. B. (2012) · Best Practice & Research Clinical Endocrinology & Metabolism · doi:10.1016/j.beem.2011.09.002 · Cited by 64
Pierce, B. L., Austin, M. A., & Ahsan, H. (2011) · Cancer Causes & Control · doi:10.1007/s10552-011-9760-5 · Cited by 60
“The relative risk measure is similar to the allele count but assigns weights to alleles based on previously reported effect sizes [12–23].”
BackgroundMethodInfluentialThe use of race, ethnicity and ancestry in human genetic research
Ali‐Khan, S. E., Krakowski, T., Tahir, R., & Daar, A. S. (2011) · The HUGO Journal · doi:10.1007/s11568-011-9154-5 · Cited by 62
High Levels of Genetic Diversity within Nilo-Saharan Populations: Implications for Human Adaptation
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Robiou-du-Pont, S., Bonnefond, A., Yengo, L., Vaillant, E., Lobbens, S., Durand, E., Weill, J., Lantieri, O., Balkau, B., Charpentier, G., et al. (2012) · International Journal of Obesity · doi:10.1038/ijo.2012.175 · Cited by 57
Self-citationPanagiotou, O. A., Εvangelou, Ε., & Ioannidis, J. P. A. (2010) · American Journal of Epidemiology · doi:10.1093/aje/kwq234 · Cited by 59
Yaturu, S. (2011) · Journal of Diabetes Mellitus · doi:10.4236/jdm.2011.14012 · Cited by 64
Segrè, A. V., Wei, N., MAGIC Investigators, Altshuler, D., & Florez, J. C. (2014) · Diabetes · doi:10.2337/db14-0703 · Cited by 57
Karaderi, T., Drong, A., & Lindgren, C. M. (2015) · Current Diabetes Reports · doi:10.1007/s11892-015-0648-8 · Cited by 57
Petrie, J. R., Pearson, E. R., & Sutherland, C. D. (2010) · Biochemical Pharmacology · doi:10.1016/j.bcp.2010.11.010 · Cited by 61
Genetics of Type 2 Diabetes in East Asian Populations
Cho, Y. S., Lee, J., Park, K. S., & Nho, C. W. (2012) · Current Diabetes Reports · doi:10.1007/s11892-012-0326-z · Cited by 57
The outliers become a stampede as immunometabolism reaches a tipping point
Nikolajczyk, B. S., Jagannathan‐Bogdan, M., & Denis, G. V. (2012) · Immunological Reviews · doi:10.1111/j.1600-065x.2012.01142.x · Cited by 55
“Although many genetic polymorphisms have been linked to obesity and ⁄or T2D (reviewed in 177) and some have obvious connections with metabolic regulation, such as insulin receptor substrate-1 (178), the functional outcome of most polymorphisms is untested.”
BackgroundType 2 diabetes risk variants and colorectal cancer risk: the Multiethnic Cohort and PAGE studies
Cheng, I. C., Caberto, C., Lum‐Jones, A., Seifried, A., Wilkens, L. R., Schumacher, F. R., Monroe, K. R., Lim, U., Tiirikainen, M., Kolonel, L. N., et al. (2011) · Gut · doi:10.1136/gut.2011.237727 · Cited by 55
Physiologic Characterization of Type 2 Diabetes–Related Loci
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Self-citation
Metadata
- Authors
- Rung, J., Cauchi, S., Albrechtsen, A., Shen, L., Rocheleau, G., Cavalcanti-Proença, C., Bacot, F., Balkau, B., Belisle, A., Borch-Johnsen, K., Charpentier, G., Dina, C., Durand, E., Elliott, P., Hadjadj, S., Järvelin, M.-R., Laitinen, J., Lauritzen, T., Marre, M., Mazur, A., Meyre, D., Montpetit, A., Pisinger, C., Posner, B., Poulsen, P., Pouta, A., Prentki, M., Ribel-Madsen, R., Ruokonen, A., Sandbaek, A., Serre, D., Tichet, J., Vaxillaire, M., Wojtaszewski, J. F. P., Vaag, A., Hansen, T., Polychronakos, C., Pedersen, O., Froguel, P., & Sladek, R.
- Affiliations
- McGill University and Génome Québec Innovation Centre (CA)
- Centre National de la Recherche Scientifique (FR)
- University of Copenhagen (DK)
- Université Paris-Sud (FR)
- Centre Hospitalier Sud Francilien (FR)
- Imperial College London (GB)
- Inserm (FR)
- Finnish Institute of Occupational Health (FI)
- Aarhus University (DK)
- Glostrup Hospital (DK)
- McGill University (CA)
- Centre Hospitalier de l’Université de Montréal (CA)
- University of Oulu (FI)
- Lund University (SE)
- University of Southern Denmark (DK)
- Corresponding author
- Pedersen, Oluf
- Froguel, Philippe
- Sladek, Robert
- ORCID
- Rung, Johan
- Cauchi, Stéphane
- Albrechtsen, Anders
- Rocheleau, Ghislain
- Balkau, Beverley
- Charpentier, Guillaume
- Durand, Emmanuelle
- Elliott, Paul
- Hadjadj, Samy
- Järvelin, Marjo-Riitta
- Laitinen, Jaana
- Lauritzen, Torsten
- Marre, Michel
- Meyre, David
- Pisinger, Charlotta
- Prentki, Marc
- Serre, David
- Vaxillaire, Martine
- Wojtaszewski, Jørgen F P
- Vaag, Allan
- Hansen, Torben
- Polychronakos, Constantin
- Pedersen, Oluf
- Froguel, Philippe
- Sladek, Robert
- Venue
- Nature Genetics
- Published
- 2009-09-06
- Volume
- 41
- Issue
- 10
- Pages
- 1110-1115
- ISSN
- 1061-4036 (ISSN-L)
- 1546-1718
- OpenAlex
- W2044518560
- Cited by
- 479
- References
- 43
- Citations by year
- 2026: 5 · 2025: 8 · 2024: 16 · 2023: 11 · 2022: 37 · 2021: 16 · 2020: 19 · 2019: 14 · 2018: 13 · 2017: 21 · 2016: 30 · 2015: 40 · 2014: 42 · 2013: 47 · 2012: 58
- FWCI
- 31.00
- Type
- journal article
- Language
- en
- Update notices
- erratum (2009-10-01)
- Open access
- closed
- Locations
- Nature Genetics (publishedVersion)
- PubMed (publishedVersion)
- Lund University Publications (Lund University) (submittedVersion)
- Research at the University of Copenhagen (University of Copenhagen) (submittedVersion)
- University of Southern Denmark Research Portal (University of Southern Denmark) (submittedVersion)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Associations and Epidemiology
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetic Mapping and Diversity in Plants and Animals
- Health Sciences › Medicine › Endocrinology, Diabetes and Metabolism › Diabetes, Cardiovascular Risks, and Lipoproteins
- Keywords
- type 2 diabetes, insulin resistance, hyperinsulinemia, IRS-1, genetic susceptibility, single nucleotide polymorphisms, insulin signaling, skeletal muscle, genetic susceptibility loci
- MeSH terms
- Adult, Alleles, Biopsy, Diabetes Mellitus, Type 2, Female, Humans, Hyperinsulinism, Insulin Resistance, Male, Middle Aged, Genome, Human, Muscle, Skeletal, Phosphatidylinositol 3-Kinases, Polymorphism, Single Nucleotide, White People, Genome-Wide Association Study, Insulin Receptor Substrate Proteins
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