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Association between a polygenic lipodystrophy genetic risk score and diabetes risk in the high prevalence Maltese population

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Abstract

Background

Type 2 diabetes (T2DM) is genetically heterogenous, driven by beta cell dysfunction and insulin resistance. Insulin resistance drives the development of cardiometabolic complications and is typically associated with obesity. A group of common variants at eleven loci are associated with insulin resistance and risk of both type 2 diabetes and coronary artery disease. These variants describe a polygenic correlate of lipodystrophy, with a high metabolic disease risk despite a low BMI.

Objectives

In this cross-sectional study, we sought to investigate the association of a polygenic risk score composed of eleven lipodystrophy variants with anthropometric, glycaemic and metabolic traits in an island population characterised by a high prevalence of both obesity and type 2 diabetes.

Methods

814 unrelated adults (n = 477 controls and n = 337 T2DM cases) of Maltese-Caucasian ethnicity were genotyped and associations with phenotypes explored.

Results

A higher polygenic lipodystrophy risk score was correlated with lower adiposity indices (lower waist circumference and body mass index measurements) and higher HOMA-IR, atherogenic dyslipidaemia and visceral fat dysfunction as assessed by the visceral adiposity index in the DM group. In crude and covariate-adjusted models, individuals in the top quartile of polygenic risk had a higher T2DM risk relative to individuals in the first quartile of the risk score distribution.

Conclusion

This study consolidates the association between polygenic lipodystrophy risk alleles, metabolic syndrome parameters and T2DM risk particularly in normal-weight individuals. Our findings demonstrate that polygenic lipodystrophy risk alleles drive insulin resistance and diabetes risk independent of an increased BMI.

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Data availability

The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.

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Funding

This work was supported by institutional funds from the Faculty of Medicine and Surgery, University of Malta.

Author information

Authors and Affiliations

  1. Department of Pathology, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta

    Maria Zammit

  2. Department of Medicine, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta

    Rachel Agius, Stephen Fava & Josanne Vassallo

  3. Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta

    Maria Zammit

  4. Department of Anatomy, Faculty of Medicine and Surgery, University of Malta, Msida, MSD2080, Malta

    Nikolai Paul Pace

  5. Centre for Molecular Medicine and Biobanking, Faculty of Medicine and Surgery, University of Malta, Room 325, Msida, MSD2080, Malta

    Nikolai Paul Pace

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  1. Maria Zammit
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Contributions

NPP, SF, JV and RA collected data. RA, MZ and NPP performed the analyses. NPP and MZ drafted the manuscript. SF and JV reviewed the manuscript. All authors contributed to study conception and design and have read and approved the submitted manuscript.

Corresponding author

Correspondence to Nikolai Paul Pace.

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Conflicts of interest

The authors declare that they have no conflict of interest.

Ethical standard statement

This study was approved by the institutional ethics review board of the University of Malta (FRECMDS_1819_049), and the study protocol was in compliance with the Declaration of Helsinki.

Informed consent

All subjects gave written informed consent for their participation in the study and for genetic analysis.

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Communicated by Fabrizio Barbetti.

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Zammit, M., Agius, R., Fava, S. et al. Association between a polygenic lipodystrophy genetic risk score and diabetes risk in the high prevalence Maltese population. Acta Diabetol 61, 555–564 (2024). https://doi.org/10.1007/s00592-023-02230-9

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