Determinants of the Development of Diabetes (Maturity-Onset Diabetes of the Young-3) in Carriers of HNF-1α Mutations
Evidence for parent-of-origin effect
- Tomasz Klupa, MD123,
- James H. Warram, MD, SCD1,
- Anthony Antonellis, BS1,
- Marcus Pezzolesi, BS1,
- Moonsuk Nam, MD12,
- Maciej T. Malecki, MD, PHD123,
- Alessandro Doria, MD, PHD12,
- Stephen S. Rich, PHD4 and
- Andrzej S. Krolewski, MD, PHD12
- 1Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts
- 2Department of Medicine, Harvard Medical School, Boston, Massachusetts
- 3Department of Metabolic Diseases, Medical College, Jagiellonian University, Krakow, Poland
- 4Wake Forest University School of Medicine, Winston-Salem, North Carolina
OBJECTIVE—To determine the distribution of the age at onset of diabetes (maturity-onset diabetes of the young-3 [MODY3]) and to identify determinants of the onset of diabetes in carriers of HNF-1α mutations.
RESEARCH DESIGN 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-1α.
RESULTS—HNF-1α 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-1α accounts for diabetes in a small proportion of families with a dominant pattern of inheritance. Age at onset of diabetes in MODY3 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).
- HNF-1α, hepatocyte nuclear factor 1α
- IA2, insulinoma-associated antigen 2
- MODY, maturity-onset diabetes of the young
- OGTT, oral glucose tolerance test
- WHO, World Health Organization
Address correspondence and reprint requests to Andrzej S. Krolewski, Section on Genetics & Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail:.
Received for publication 8 May 2002 and accepted in revised form 3 August 2002.
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