Oral Presentation Australian and New Zealand Obesity Society Annual Scientific Conference 2026

One syndrome, distinct genomes: how sex shapes metabolic syndrome genetics and its downstream cancer risk (143937)

Kelsie Bouttle 1 2 3 , Dylan Glubb 1 3 , Jackson Thorp 1 4 5 , Oak Pollett 2 3 , Nathan Ingold 1 2 3 , Tracy O'Mara 1 2 3
  1. University of Queensland, Brisbane, Australia
  2. Queensland University of Technology, Brisbane, Qld, Australia
  3. Cancer Genetic Susceptibility Lab, QIMR Berghofer, Brisbane, Australia
  4. The Translational Neurogenomics Laboratory, QIMR Berghofer, Brisbane, Australia
  5. Department of Psychiatry, University of Oxford, Oxford, United Kingdom

Metabolic syndrome (MetS), characterised by co-occurring adiposity, dyslipidaemia, glycaemic dysfunction and elevated blood pressure, is associated with several cancers. However, key questions remain: is the genetic architecture of MetS sexually dimorphic, and does this translate into differences in cancer risk?

We used genomic structural equation modelling to derive a higher-order MetS factor from seven metabolic traits, integrating summary statistics representing approximately six million trait observations, and generated female-, male- and combined-sex GWAS. We tested whether the genetic architecture of MetS was equivalent across sexes using genome-wide, regional and variant-level analyses A suite of genetic analyses then evaluated associations between sex-stratified MetS and ten cancers and identified the metabolic components underlying these relationships.

Female and male MetS were strongly correlated but genetically non-equivalent, with type 2 diabetes more tightly coupled to adiposity in females and to lipid metabolism in males. Regional and variant-level analyses identified focal divergence, including sex-differentiated signals near LEPR and VIRMA. Genetic analysis revealed distinct cancer profiles: female MetS was associated most strongly with renal and endometrial cancer, whereas male MetS was associated with renal, oesophageal, colorectal and lung cancer and inversely with prostate cancer. Complementary methods identified adiposity as the primary driver of the MetS–endometrial cancer association. For renal cancer, these methods identified an independent relationship with diastolic blood pressure in females, and with diastolic blood pressure, waist circumference and triglycerides in males.

Taken together, these finding indicated MetS differs between sexes, and this is reflected in distinct downstream cancer profiles. Adiposity is the dominant driver of the MetS–endometrial cancer association. Ongoing analyses will determine whether renal and other MetS-associated cancers are attributable to specific components or broader, interrelated metabolic dysfunction.