Determinants of the development of diabetes (maturity-onset diabetes of the young-3) in carriers of HNF-1 a mutations. Evidence for parent-of-origin effect

Abstract

INTRODUCTION. To determine the distribution of the age at onset of diabetes (maturity-onset diabetes of the young-3 [MODY 3]and to identify determinants of the onset of diabetes in carriers of HNF-1a mutations.
MATERIAL AND METHODS. Extended families (n = 104) with type 2 diabetes inherited in a dominant pattern were recruited and screened for diabetes-causing mutations in HNF-1a.
RESULTS. HNF-1a mutations cosegregated with diabetes in only 13 families, all with a mean age at onset < 35 years. Insulin secretion was diminished or absent in mutation carriers (n = 101), and diabetes developed in 65% by age 25 years and in 100% by age 50 years. If the mutation was inherited from the mother, diabetes onset was very young in those exposed to diabetes in utero; 57 ± 8% were affected by age 15 years as compared with 0,0% in those not exposed (p < 7 × 10–6). By age 25 years, the difference was reduced (85 ± 6 and 55 ± 12%, respectively; P = 0.02). If the mutation was inherited from the father, diabetes developed in 52 ± 8% by age 25 years. Age at diagnosis was shown to be highly heritable (h2 = 0.47, P = 0.003). When parent of origin was included in the analyses, the magnitude of genetic contribution increased markedly (h2 = 0.91).
CONCLUSIONS. Mutations in HNF-1a accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY 3 families varied widely and was influenced by familial factors (including modifying genes) and parent of origin (whether a mutation carrier was exposed to diabetes in utero).