PMID- 30565958 OWN - NLM STAT- MEDLINE DCOM- 20191203 LR - 20200608 IS - 1524-4636 (Electronic) IS - 1079-5642 (Print) IS - 1079-5642 (Linking) VI - 39 IP - 1 DP - 2019 Jan TI - Gene-Based Elevated Triglycerides and Type 2 Diabetes Mellitus Risk in the Women's Genome Health Study. PG - 97-106 LID - 10.1161/ATVBAHA.118.311562 [doi] AB - Objective- Higher triglyceride (TG) is a risk factor for incident type 2 diabetes mellitus (T2DM), but paradoxically, genetic susceptibility for higher TG has been associated with lower T2DM risk. There is also evidence that the genetic association may be modified by baseline TG. Whether such associations can be replicated and the interaction is selective for certain TG-rich lipoprotein particles remains to be explored. Approach and Results- Cox regression involving TG, TG-rich lipoprotein particles, and genetic determinants of TG was performed among 15 813 participants with baseline fasting status in the WGHS (Women's Genome Health Study), including 1453 T2DM incident cases during a mean 18.6 (SD=5.3) years of follow-up. A weighted, 40-single-nucleotide polymorphism TG genetic risk score was inversely associated with incident T2DM (hazard ratio [95% CI], 0.66 [0.58-0.75]/10-TG risk alleles; P<0.0001) with adjustment for baseline body mass index, HDL (high-density lipoprotein) cholesterol, and TG. TG-associated risk was higher among individuals in the low compared with the high 40-single-nucleotide polymorphism TG genetic risk score tertile (hazard ratio [95% CI], 1.98 [1.83-2.14] versus 1.68 [1.58-1.80] per mmol/L; P(interaction)=0.0007). In TG-adjusted analysis, large and medium but not small TG-rich lipoprotein particles were associated with higher T2DM incidence for successively lower 40-single-nucleotide polymorphism TG genetic risk score tertiles, P(interaction)=0.013, 0.012, and 0.620 across tertiles, respectively. Conclusions- Our results confirm the previous observations of the paradoxical associations of TG with T2DM while focusing attention on the larger TG-rich lipoprotein particle subfractions, suggesting their importance in clinical profiling of T2DM risk. FAU - Ahmad, Shafqat AU - Ahmad S AD - From the Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (S.A., F.B.H.). AD - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.A., S.M., P.M.R., D.I.C.). AD - Department of Medical Sciences, Molecular Epidemiology, Uppsala University, Sweden (S.A.). FAU - Mora, Samia AU - Mora S AD - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.A., S.M., P.M.R., D.I.C.). AD - Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.M., P.M.R.). AD - Center for Lipid Metabolomics, Harvard Medical School, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.M., P.M.R.). FAU - Ridker, Paul M AU - Ridker PM AD - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.A., S.M., P.M.R., D.I.C.). AD - Cardiovascular Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.M., P.M.R.). AD - Center for Lipid Metabolomics, Harvard Medical School, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.M., P.M.R.). FAU - Hu, Frank B AU - Hu FB AD - From the Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA (S.A., F.B.H.). AD - Channing Division of Network Medicine, Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (F.B.H.). FAU - Chasman, Daniel I AU - Chasman DI AD - Division of Preventive Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, MA (S.A., S.M., P.M.R., D.I.C.). LA - eng GR - R01 HL043851/HL/NHLBI NIH HHS/United States GR - R21 NS104398/NS/NINDS NIH HHS/United States GR - K08 HL094375/HL/NHLBI NIH HHS/United States GR - UM1 CA182913/CA/NCI NIH HHS/United States GR - R01 CA047988/CA/NCI NIH HHS/United States GR - U01 CA182913/CA/NCI NIH HHS/United States GR - R01 HL134811/HL/NHLBI NIH HHS/United States GR - R01 EY021900/EY/NEI NIH HHS/United States GR - R01 DK112940/DK/NIDDK NIH HHS/United States GR - R01 HL080467/HL/NHLBI NIH HHS/United States GR - K24 HL136852/HL/NHLBI NIH HHS/United States GR - R21 NS092963/NS/NINDS NIH HHS/United States PT - Journal Article PT - Research Support, N.I.H., Extramural PT - Research Support, Non-U.S. Gov't PL - United States TA - Arterioscler Thromb Vasc Biol JT - Arteriosclerosis, thrombosis, and vascular biology JID - 9505803 RN - 0 (Lipoproteins) RN - 0 (Triglycerides) RN - 0 (lipoprotein triglyceride) SB - IM MH - Aged MH - Diabetes Mellitus, Type 2/blood/etiology/*genetics MH - Female MH - Humans MH - Lipoproteins/blood MH - Middle Aged MH - *Polymorphism, Single Nucleotide MH - Proportional Hazards Models MH - Risk MH - Triglycerides/*blood MH - Women's Health PMC - PMC6377260 MID - NIHMS1512616 OTO - NOTNLM OT - diabetes mellitus, type 2 OT - genetic predisposition OT - lipid metabolism OT - lipoproteins, VLDL OT - triglycerides COIS- Disclosures: Samia Mora received research grant support from Atherotech Diagnostics for research outside the current work, served as a consultant to Quest Diagnostics, and has a patent application regarding the use of an NMR biomarker (not related to lipoproteins) in relation to colorectal cancer risk. All other coauthors have no conflict of interests. EDAT- 2018/12/20 06:00 MHDA- 2019/12/04 06:00 PMCR- 2020/01/01 CRDT- 2018/12/20 06:00 PHST- 2018/12/20 06:00 [pubmed] PHST- 2019/12/04 06:00 [medline] PHST- 2018/12/20 06:00 [entrez] PHST- 2020/01/01 00:00 [pmc-release] AID - 10.1161/ATVBAHA.118.311562 [doi] PST - ppublish SO - Arterioscler Thromb Vasc Biol. 2019 Jan;39(1):97-106. doi: 10.1161/ATVBAHA.118.311562.