title: Metabolic factors and genetic risk mediate familial type 2 diabetes risk in the Framingham Heart Study.
abstract: OBJECTIVE
  Type 2 diabetes mellitus in parents is a strong determinant of diabetes risk in their offspring. We hypothesise that offspring diabetes risk associated with parental diabetes is mediated by metabolic risk factors.
  
  
  METHODS
  We studied initially non-diabetic participants of the Framingham Offspring Study. Metabolic risk was estimated using beta cell corrected insulin response (CIR), HOMA-IR or a count of metabolic syndrome components (metabolic syndrome score [MSS]). Dietary risk and physical activity were estimated using questionnaire responses. Genetic risk score (GRS) was estimated as the count of 62 type 2 diabetes risk alleles. The outcome of incident diabetes in offspring was examined across levels of parental diabetes exposure, accounting for sibling correlation and adjusting for age, sex and putative mediators. The proportion mediated was estimated by comparing regression coefficients for parental diabetes with (β adj) and without (β unadj) adjustments for CIR, HOMA-IR, MSS and GRS (percentage mediated = 1 - β adj / β unadj).
  
  
  RESULTS
  Metabolic factors mediated 11% of offspring diabetes risk associated with parental diabetes, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.96. GRS mediated 9% of risk, corresponding to a reduction in OR per diabetic parent from 2.13 to 1.99.
  
  
  CONCLUSIONS
  Metabolic risk factors partially mediated offspring type 2 diabetes risk conferred by parental diabetes to a similar magnitude as genetic risk. However, a substantial proportion of offspring diabetes risk associated with parental diabetes remains unexplained by metabolic factors, genetic risk, diet and physical activity, suggesting that important familial influences on diabetes risk remain undiscovered.
authors.affiliation: Division of General Internal Medicine, Department of Medicine, Harvard Medical School and Massachusetts General Hospital, 50 Staniford Street, 9th Floor, Boston, MA, 02114, USA.
authors.forename: Sridharan
authors.initials: S
authors.lastname: Raghavan
authors.forename: Bianca
authors.initials: B
authors.lastname: Porneala
authors.forename: Nicola
authors.initials: N
authors.lastname: McKeown
authors.forename: Caroline S
authors.initials: CS
authors.lastname: Fox
authors.forename: Josée
authors.initials: J
authors.lastname: Dupuis
authors.forename: James B
authors.initials: JB
authors.lastname: Meigs
mesh_terms: D000328:Adult; D000368:Aged; D003924:Diabetes Mellitus, Type 2 / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D005260:Female; D020022:Genetic Predisposition to Disease; D006801:Humans; D015994:Incidence; D007333:Insulin Resistance / Q000502:physiology*; D008019:Life Style; D008297:Male; D024821:Metabolic Syndrome / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism*; D008875:Middle Aged; D012306:Risk