title: Mendelian randomization studies do not support a role for raised circulating triglyceride levels influencing type 2 diabetes, glucose levels, or insulin resistance.
abstract: OBJECTIVE
  The causal nature of associations between circulating triglycerides, insulin resistance, and type 2 diabetes is unclear. We aimed to use Mendelian randomization to test the hypothesis that raised circulating triglyceride levels causally influence the risk of type 2 diabetes and raise normal fasting glucose levels and hepatic insulin resistance.
  
  
  METHODS
  We tested 10 common genetic variants robustly associated with circulating triglyceride levels against the type 2 diabetes status in 5,637 case and 6,860 control subjects and four continuous outcomes (reflecting glycemia and hepatic insulin resistance) in 8,271 nondiabetic individuals from four studies.
  
  
  RESULTS
  Individuals carrying greater numbers of triglyceride-raising alleles had increased circulating triglyceride levels (SD 0.59 [95% CI 0.52-0.65] difference between the 20% of individuals with the most alleles and the 20% with the fewest alleles). There was no evidence that the carriers of greater numbers of triglyceride-raising alleles were at increased risk of type 2 diabetes (per weighted allele odds ratio [OR] 0.99 [95% CI 0.97-1.01]; P = 0.26). In nondiabetic individuals, there was no evidence that carriers of greater numbers of triglyceride-raising alleles had increased fasting insulin levels (SD 0.00 per weighted allele [95% CI -0.01 to 0.02]; P = 0.72) or increased fasting glucose levels (0.00 [-0.01 to 0.01]; P = 0.88). Instrumental variable analyses confirmed that genetically raised circulating triglyceride levels were not associated with increased diabetes risk, fasting glucose, or fasting insulin and, for diabetes, showed a trend toward a protective association (OR per 1-SD increase in log(10) triglycerides: 0.61 [95% CI 0.45-0.83]; P = 0.002).
  
  
  CONCLUSIONS
  Genetically raised circulating triglyceride levels do not increase the risk of type 2 diabetes or raise fasting glucose or fasting insulin levels in nondiabetic individuals. One explanation for our results is that raised circulating triglycerides are predominantly secondary to the diabetes disease process rather than causal.
authors.affiliation: Genetics of Complex Traits, Institute of Biomedical and Clinical Sciences, Peninsula College of Medicine and Dentistry, University of Exeter, Exeter, UK.
authors.forename: N Maneka G
authors.initials: NM
authors.lastname: De Silva
authors.forename: Rachel M
authors.initials: RM
authors.lastname: Freathy
authors.forename: Tom M
authors.initials: TM
authors.lastname: Palmer
authors.forename: Louise A
authors.initials: LA
authors.lastname: Donnelly
authors.forename: Jian'an
authors.initials: J
authors.lastname: Luan
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.forename: Claudia
authors.initials: C
authors.lastname: Langenberg
authors.forename: Michael N
authors.initials: MN
authors.lastname: Weedon
authors.forename: Beverley
authors.initials: B
authors.lastname: Shields
authors.forename: Beatrice A
authors.initials: BA
authors.lastname: Knight
authors.forename: Kirsten J
authors.initials: KJ
authors.lastname: Ward
authors.forename: Manjinder S
authors.initials: MS
authors.lastname: Sandhu
authors.forename: Roger M
authors.initials: RM
authors.lastname: Harbord
authors.forename: Mark I
authors.initials: MI
authors.lastname: McCarthy
authors.forename: George Davey
authors.initials: GD
authors.lastname: Smith
authors.forename: Shah
authors.initials: S
authors.lastname: Ebrahim
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Hattersley
authors.forename: Nicholas
authors.initials: N
authors.lastname: Wareham
authors.forename: Debbie A
authors.initials: DA
authors.lastname: Lawlor
authors.forename: Andrew D
authors.initials: AD
authors.lastname: Morris
authors.forename: Colin N A
authors.initials: CN
authors.lastname: Palmer
authors.forename: Timothy M
authors.initials: TM
authors.lastname: Frayling
mesh_terms: D000368:Aged; D000483:Alleles; D001786:Blood Glucose / Q000235:genetics*; D016022:Case-Control Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood* / Q000235:genetics; D005260:Female; D014644:Genetic Variation; D005838:Genotype; D006801:Humans; D007328:Insulin / Q000235:genetics; D007333:Insulin Resistance / Q000235:genetics*; D008297:Male; D057182:Mendelian Randomization Analysis; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D014280:Triglycerides / Q000097:blood / Q000235:genetics*
chemical_list: D001786:Blood Glucose; D007328:Insulin; D014280:Triglycerides