Adiposity significantly modifies genetic risk for dyslipidemia

Area of Science:

• Genetics
• Metabolic Diseases
• Cardiovascular Health

Background:

• Genome-wide association studies (GWAS) identify genetic loci for plasma lipids, but explain <12% of trait variation.
• Adiposity (body mass index - BMI) significantly influences plasma triglycerides (TGs) and HDL cholesterol (HDLc).
• Unexplained heritability in lipid traits may stem from gene-environment interactions.

Purpose of the Study:

• Investigate interactions between genetic risk scores (GRS) for TGs and HDLc and adiposity (BMI) in extreme BMI cohorts.
• Identify specific genes and pathways involved in these interactions.
• Examine sexual dimorphism in GRS-adiposity interactions for HDLc.

Main Methods:

• Applied weighted GRS for plasma TGs and HDLc in two large cohorts stratified by BMI (obese vs. lean).
• Performed interaction analyses between GRS and BMI status for TG and HDLc.
• Investigated GRS-adiposity interactions for LDL cholesterol.
• Assessed sexual dimorphism in GRS-HDLc interactions within obese and lean groups.

Main Results:

• Both BMI and GRS strongly associated with TG and HDLc.
• Significant interactions between obese/lean status and GRS observed for TG (P=2.87×10⁻⁴) and HDLc (P=1.05×10⁻³).
• Interactions for TG involved SNPs in APOA5, GCKR, LPL; for HDLc, SNPs in CETP, GALNT2, LIPG, PLTP.
• No significant interaction for LDL cholesterol GRS × adiposity.
• Sexual dimorphism in GRSHDLc interaction evident in obese (P=0.016) but not lean subjects.

Conclusions:

• Gene-environment interactions, particularly between GRS for TGs/HDLc and BMI, contribute to lipid trait variation and missing heritability.
• Specific genes (e.g., APOA5, CETP) are implicated in these BMI-dependent lipid associations.
• Understanding these interactions provides biological insight into genetic associations and may inform personalized medicine approaches for dyslipidemia.