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

Acta Diabetol. 2024 May;61(5):555-564. doi: 10.1007/s00592-023-02230-9. Epub 2024 Jan 27.

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.

Keywords: Genetics; Insulin resistance; Lean; Polygenic lipodystrophy; Type 2 diabetes.

MeSH terms

  • Adult
  • Aged
  • Body Mass Index
  • Cross-Sectional Studies
  • Diabetes Mellitus, Type 2* / epidemiology
  • Diabetes Mellitus, Type 2* / genetics
  • Female
  • Genetic Risk Score*
  • Humans
  • Insulin Resistance / genetics
  • Lipodystrophy* / epidemiology
  • Lipodystrophy* / genetics
  • Male
  • Malta / epidemiology
  • Middle Aged
  • Obesity / complications
  • Obesity / epidemiology
  • Obesity / genetics
  • Prevalence