Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D
Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,3...
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Elsevier
2025-01-01
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| Series: | Journal of Lipid Research |
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| Online Access: | http://www.sciencedirect.com/science/article/pii/S0022227524002074 |
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| author | Lihua Wang Siyu Wang Jason A. Anema Vaha A. Moghaddam Yanli Lu Shiow Lin E. Warwick Daw Allison L. Kuipers Iva Miljkovic Michael Brent Gary J. Patti Bharat Thygarajan Joseph M. Zmuda Michael A. Province Ping An |
| author_facet | Lihua Wang Siyu Wang Jason A. Anema Vaha A. Moghaddam Yanli Lu Shiow Lin E. Warwick Daw Allison L. Kuipers Iva Miljkovic Michael Brent Gary J. Patti Bharat Thygarajan Joseph M. Zmuda Michael A. Province Ping An |
| author_sort | Lihua Wang |
| collection | DOAJ |
| description | Triglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P = 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds = 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p = 7e-5)/ADIPOQ (P = 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P = 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance. |
| format | Article |
| id | doaj-art-1ff1f421f24742b3ae61246fa204dca1 |
| institution | Kabale University |
| issn | 0022-2275 |
| language | English |
| publishDate | 2025-01-01 |
| publisher | Elsevier |
| record_format | Article |
| series | Journal of Lipid Research |
| spelling | doaj-art-1ff1f421f24742b3ae61246fa204dca12025-01-30T05:12:36ZengElsevierJournal of Lipid Research0022-22752025-01-01661100702Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2DLihua Wang0Siyu Wang1Jason A. Anema2Vaha A. Moghaddam3Yanli Lu4Shiow Lin5E. Warwick Daw6Allison L. Kuipers7Iva Miljkovic8Michael Brent9Gary J. Patti10Bharat Thygarajan11Joseph M. Zmuda12Michael A. Province13Ping An14Division of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USA; For correspondence: Lihua WangDivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADepartment of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USADepartment of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USADivision of Computation & Data Sciences, Washington University School of Medicine, St. Louis, MO, USADepartment of Chemistry, Washington University School of Medicine, St. Louis, MO, USADepartment of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USADepartment of Epidemiology, University of Pittsburgh, Pittsburgh, PA, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USADivision of Statistical Genomics, Washington University School of Medicine, St. Louis, MO, USATriglyceride (TG)/HDL-C ratio (THR) is a surrogate predictor of hyperinsulinemia. To identify novel genetic loci for THR change over time (ΔTHR), we conducted genome-wide association study (GWAS) and genome-wide linkage scan (GWLS) among nondiabetic Europeans from the Long Life Family Study (n = 1,384). Subjects with diabetes or on dyslipidemia medications were excluded. ΔTHR was derived using growth curve modeling and adjusted for age, sex, field centers, and principal components. GWAS used a linear mixed model accounting for familial relatedness. GWLS employed haplotype-based identity-by-descent estimation with 0.5 cM average spacing. Heritability of ΔTHR was moderate (46%). Our GWAS identified a significant locus at the LPL (P = 1.58e-9) for ΔTHR; this locus has been reported before influencing baseline THR levels. Our GWLS found significant linkage with a logarithm of the odds exceeding 3 on 3q28 (logarithm of the odds = 4.1). Using a subset of 25 linkage-enriched families, we assessed sequence elements under 3q28 and identified two novel variants (EIF4A2 [eukaryotic translation initiation factor 4A2]/ADIPOQ-rs114108468, p = 5e-6, minor allele frequency = 1.8%; TPRG1-rs16864075, p = 3e-6, minor allele frequency = 8%; accounted for ∼28% and ∼29% of the linkage, respectively). While the former variant was associated with EIF4A2 (p = 7e-5)/ADIPOQ (P = 3.49e-2) transcriptional levels, the latter variant was not associated with TPRG1 (P = 0.23) transcriptional levels. Replication in the Framingham Heart Study Offspring Cohort observed modest effect of these loci on ΔTHR. Our approach discovered two novel gene variants EIF4A2/ADIPOQ-rs114108468 and TPRG1-rs16864075 on 3q28 for ΔTHR among subjects without diabetes. Our findings provided novel insights into the molecular regulation of insulin resistance.http://www.sciencedirect.com/science/article/pii/S0022227524002074insulin resistanceaginggenome-wide linkage scanGWASmultiomics analyses |
| spellingShingle | Lihua Wang Siyu Wang Jason A. Anema Vaha A. Moghaddam Yanli Lu Shiow Lin E. Warwick Daw Allison L. Kuipers Iva Miljkovic Michael Brent Gary J. Patti Bharat Thygarajan Joseph M. Zmuda Michael A. Province Ping An Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D Journal of Lipid Research insulin resistance aging genome-wide linkage scan GWAS multiomics analyses |
| title | Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D |
| title_full | Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D |
| title_fullStr | Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D |
| title_full_unstemmed | Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D |
| title_short | Novel loci for triglyceride/HDL-C ratio longitudinal change among subjects without T2D |
| title_sort | novel loci for triglyceride hdl c ratio longitudinal change among subjects without t2d |
| topic | insulin resistance aging genome-wide linkage scan GWAS multiomics analyses |
| url | http://www.sciencedirect.com/science/article/pii/S0022227524002074 |
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