Type 2 diabetes (T2D) in youth is associated with a pro-atherogenic lipid profile characterized by high triglycerides (TG), high low-density lipoprotein cholesterol (LDL-c), and low high-density lipoprotein cholesterol (HDL-c). Genome wide association studies (GWAS) in adults have discovered more than 100 variants associated with lipid traits, but the association of genetic variants to dyslipidemia in youth with T2D remains unknown. Therefore, we genotyped 206,928 variants and imputed 17,642,824 variants in 1,076 youth with T2D from the Treatment Options for type 2 diabetes in Adolescents and Youth (TODAY) and SEARCH for Diabetes in Youth (SEARCH) as part of ProDiGY, a collaboration with type 2 diabetes Genetic Exploration by Next-generation sequencing in multi-Ethnic Samples (T2D-GENES). Using a linear mixed model, we performed association testing for TG, LDL-c and HDL-c adjusted for age, sex, body mass index (BMI) Z-score, HbA1c, and genetic relationship matrix within each sub-study followed by meta-analyses for each lipid trait. We identified a novel variant between a deletion on chromosome 3 (3:67817380_AT/A_Deletion:RP11-81N13.1) that was associated with TG levels at genome wide level of significance (P-value=2.26×10-8, β=0.21±0.09). We also identified a genome-wide significant variant rs247617 (P-value=5.12×10-9, β=2.52±0.43) between HERFUD1 and CETP for association with HDL-c. This variant has been previously reported to be associated with HDL-c in adults in the Global Lipids Genetics Consortium (GLGC). We did not find any genome-wide significant variants in the LDL-c analysis.
In summary, our genetic analyses of lipid traits in youth with T2D identified one novel and one previously known locus. Further multi-phenotype analysis may uncover additional loci associated with lipid traits in youth with T2D.
L. Chen: None. S. Srinivasan: None. N. Santoro: None. J. Todd: None. J. Divers: None. A.S. Shah: None. S. Gidding: Research Support; Self; Color Genomics. B.K. Burke: None. M.W. Haymond: Advisory Panel; Self; Daiichi Sankyo Company, Limited, Zealand Pharma A/S. Stock/Shareholder; Self; Xeris Pharmaceuticals, Inc. Other Relationship; Self; AstraZeneca. L. Lange: None. S.M. Marcovina: None. A. Chait: Consultant; Self; MedImmune. J. Flannick: Consultant; Self; Decibel Therapeutics. S. Caprio: None. J.C. Florez: None.
National Institutes of Health