Parental transmission of type 2 diabetes: the Framingham Offspring Study.
Study of parental transmission of diabetes provides insight into the relative contributions of underlying maternal and paternal influences. We estimated risk for type 2 diabetes and milder degrees of glucose intolerance associated with parental diabetes among subjects of the population-based Framingham Offspring Study, in which participants are primarily Caucasian and at relatively low risk for diabetes and for which both parental and offspring phenotypes were ascertained by direct examination. Parental diabetes, assessed over 40 years of biennial follow-up, was defined by use of hypoglycemic drug therapy or a casual plasma glucose level > or = 11.1 mmol/l at any examination. Offspring glucose tolerance, assessed over 20 years of quadrennial follow-up, was defined by fasting plasma glucose levels > or = 7.8 mmol/l at any two examinations, use of hypoglycemic drug therapy at any examination, or with a 75-g oral glucose tolerance test (1980 World Health Organization criteria) at the most recent examination. We calculated odds ratios (ORs) and 95% CIs for offspring glucose tolerance status using generalized estimating equations to account for differential correlations within and between families. The 2,527 offspring came from 1,303 nuclear families, of which 77.6% had two or more siblings per family and in which the prevalence of parental diabetes was 24.6%. The mean offspring age was 54 years (range 26-82), 53% were women, 8.6% had diabetes, 11.4% had impaired glucose tolerance, 76.3% had no parental diabetes, 10.5% had maternal diabetes, 11.5% had paternal diabetes, and 1.7% had bilineal diabetes. Relative to individuals without parental diabetes, the age-adjusted ORs (95% CI) for offspring type 2 diabetes or abnormal glucose tolerance (fasting plasma glucose > or = 6.1 mmol/l or 2-h postchallenge glucose tolerance > or = 7.8 mmol/l) among individuals with maternal diabetes were 3.4 (2.3-4.9) and 2.7 (2.0-3.7), respectively; among individuals with paternal diabetes were 3.5 (2.3-5.2) and 1.7 (1.2-2.4), respectively; and among individuals with bilineal diabetes were 6.1 (2.9-13.0) and 5.2 (2.6-10.5), respectively. Although maternal and paternal diabetes conferred equivalent risk for offspring type 2 diabetes, offspring with maternal diabetes were slightly more likely to have abnormal glucose tolerance compared with those with paternal diabetes (OR 1.6, 95% CI 1.1-2.4). Offspring with maternal diabetes and an age of onset of <50 years had marked increased risk for both type 2 diabetes (9.7, 4.3-22.0) and abnormal glucose tolerance (9.0, 4.2-19.7). We conclude that risk ratios for offspring type 2 diabetes are consistent with a simple additive risk model, where risk when both parents are affected equals the sum of risk when either parent is affected. For maternal diabetes to confer excess risk for mild but not overt glucose intolerance, offspring of diabetic fathers may transit abnormal to impaired glucose tolerance relatively quickly, or diabetic mothers may transmit risk for a mild slowly progressive form of abnormal glucose tolerance in addition to overt diabetes. Very high risk for abnormal glucose homeostasis among offspring with young age-of-onset maternal diabetes is consistent with hypotheses that perinatal exposures increase diabetes risk. Given equivalent risk ratios for type 2 diabetes, fathers may transmit unique paternal genetic factors of similar strength to maternal environmental factors.
Meigs
J B
JB
Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston 02114, USA. jmeigs@partners.org
Cupples
L A
LA
Wilson
P W
PW
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001786:Blood Glucose / Q000032:analysis; D015331:Cohort Studies; D003924:Diabetes Mellitus, Type 2 / Q000097:blood / Q000175:diagnosis / Q000188:drug therapy / Q000453:epidemiology / Q000235:genetics*; D005220:Fathers; D005260:Female; D020022:Genetic Predisposition to Disease; D005951:Glucose Tolerance Test; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use; D007333:Insulin Resistance / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009035:Mothers; D016017:Odds Ratio; D015995:Prevalence; D016032:Randomized Controlled Trials as Topic
D001786:Blood Glucose; D007004:Hypoglycemic Agents