Genetic basis of early onset and progression of type 2 diabetes in South Asians

South Asians develop type 2 diabetes (T2D) early in life and often with normal body mass index (BMI). However, reasons for this are poorly understood because genetic research is largely focused on European ancestry groups. We used recently derived multi-ancestry partitioned polygenic scores (pPSs) to elucidate underlying etiological pathways British Pakistani and British Bangladeshi individuals with T2D (n = 11,678) and gestational diabetes mellitus (GDM) (n = 1,965) in the Genes & Health study (n = 50,556). Beta cell 2 (insulin deficiency) and Lipodystrophy 1 (unfavorable fat distribution) pPSs were most strongly associated with T2D, GDM and younger age at T2D diagnosis. Individuals at high genetic risk of both insulin deficiency and lipodystrophy were diagnosed with T2D 8.2 years earlier with BMI 3 kg m<sup>-</sup><sup>2</sup> lower compared to those at low genetic risk. The insulin deficiency pPS was associated with poorer HbA1c response to SGLT2 inhibitors. Insulin deficiency and lipodystrophy pPSs were associated with faster progression to insulin dependence and microvascular complications. South Asians had a greater genetic burden from both of these pPSs than white Europeans in the UK Biobank. In conclusion, genetic predisposition to insulin deficiency and lipodystrophy in British Pakistani and British Bangladeshi individuals is associated with earlier onset of T2D, faster progression to complications, insulin dependence and poorer response to medication.

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Nature Medicine
Published
2024-11-26
DOI
https://doi.org/10.1038/s41591-024-03317-8
Citations
31
Primary Topic
Genetic Associations and Epidemiology
Type
article
Field-Weighted Citation Impact
17.06

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article

Genetic basis of early onset and progression of type 2 diabetes in South Asians

Daniel G. MacArthur, Chris Griffiths, Daniel Shiloh Malawsky, Gerome D. Breen et al.
31 citations
Nature Medicine
Genetic Associations and Epidemiology
17.06
article

Genetic basis of early onset and progression of type 2 diabetes in South Asians

Daniel G. MacArthur, Chris Griffiths, Daniel Shiloh Malawsky, Gerome D. Breen, David Collier, Klaudia Walter, Rohini Mathur, John McDermott, Benjamin M. Jacobs, Mohammed Bodrul Mazid, David A. van Heel, Julia Zöllner, Teng Heng, Stuart Rison, Kamrul Islam, Vladimir Ovchinnikov, Caroline Winckley, Margherita Bigossi, Michael A. Simpson, Richard C. Trembath, Dan Mason, Sam Hodgson, Caroline E Morton, Ayat Salman, Faiza Durrani, Cath Lavery, Charles Curtis, Sabina Yasmin, Shapna Hussain, Miriam Samuel, Saeed Bidi, Omar Asgar, John Solly, Fabíola Eto, Claudia Langenberg, Alice Williamson, S. M. Wood, Qin Qin Huang, Elizabeth Owor, Marie Spreckley, Sarah Finer, Asma Qureshi, Moneeza K. Siddiqui, Daniel Stow, Hilary C. Martin, Joanne E. Harvey, William G. Newman, Shabana Chaudhary, Matt Hurles, Ariadna González‐del Angel, Ceri Durham, Nishat Safa, Grainne Colligan, Panos Deloukas, John Wright, Joseph Gafton, Sang Hyuck Lee, Sidra Malik, Iaroslav Popov, James Broster, Michael D. Taylor, Ahsan Khan, Shaheen Akhtar, Raymond Chung, Samina Ashraf, Eamonn Maher, Vivek Iyer, Jessry Russell, Karen Tricker, Karen A. Hunt, Jan Whalley, Mehru Raza, Georgios Kalantzis, Ishevanhu Zengeya
article en
31 citations

Abstract

South Asians develop type 2 diabetes (T2D) early in life and often with normal body mass index (BMI). However, reasons for this are poorly understood because genetic research is largely focused on European ancestry groups. We used recently derived multi-ancestry partitioned polygenic scores (pPSs) to elucidate underlying etiological pathways British Pakistani and British Bangladeshi individuals with T2D (n = 11,678) and gestational diabetes mellitus (GDM) (n = 1,965) in the Genes & Health study (n = 50,556). Beta cell 2 (insulin deficiency) and Lipodystrophy 1 (unfavorable fat distribution) pPSs were most strongly associated with T2D, GDM and younger age at T2D diagnosis. Individuals at high genetic risk of both insulin deficiency and lipodystrophy were diagnosed with T2D 8.2 years earlier with BMI 3 kg m<sup>-</sup><sup>2</sup> lower compared to those at low genetic risk. The insulin deficiency pPS was associated with poorer HbA1c response to SGLT2 inhibitors. Insulin deficiency and lipodystrophy pPSs were associated with faster progression to insulin dependence and microvascular complications. South Asians had a greater genetic burden from both of these pPSs than white Europeans in the UK Biobank. In conclusion, genetic predisposition to insulin deficiency and lipodystrophy in British Pakistani and British Bangladeshi individuals is associated with earlier onset of T2D, faster progression to complications, insulin dependence and poorer response to medication.

Nature MedicineVol. 31(1)
Garvan Institute of Medical Research (AU), Queen Mary University of London (GB), Aston University (GB), King's College London (GB), Action for ME (GB), London Borough Of Lewisham (GB), Wellcome Sanger Institute (GB), University of Manchester (GB), William Harvey Research Institute (GB), NIHR Research Delivery Network (GB), Bradford Teaching Hospitals NHS Foundation Trust (GB), University College London (GB)
Bristol-Myers Squibb, Pfizer, AstraZeneca, GlaxoSmithKline, Alnylam Pharmaceuticals, Queen Mary University of London, Broad Institute, Barts Charity, Maze Therapeutics, National Institute for Health and Care Research, King's College London, Public Health England, Novo Nordisk, Aston University, Barts Health NHS Trust, Medical Research Council, Engineering and Physical Sciences Research Council, Economic and Social Research Council
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Genetic Associations and Epidemiology
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