Genetic Modifiers of the Age at Diagnosis of Diabetes ( MODY 3 ) in Carriers of Hepatocyte Nuclear Factor-1 Mutations Map to Chromosomes 5 p 15 , 9 q 22 , and 14 q 24

Mutations in hepatocyte nuclear factor (HNF)-1 (MODY3) account for the largest proportion of maturity-onset diabetes of the young (MODY) cases in the U.S. This form of diabetes is characterized by impaired insulin secretion in response to glucose, but wide variability exists in the severity of hyperglycemia and in the age at which it becomes clinically manifest. We have previously shown that the age at onset of diabetes in MODY3 families is influenced by familial factors (including modifying genes) and exposure to diabetes in utero. To identify genes influencing the onset of MODY3, we conducted a genome scan in 13 extended MODY families in which diabetes segregates with an HNF-1 mutation. Linkage with age at onset of diabetes was assessed by genetic variance component analysis using SOLAR. The locus with the strongest evidence of linkage was on chromosome 14q24 (D14S588; logarithm of odds [LOD] 2.58, P 0.0004). This location overlaps with IDDM11 and includes SEL1L, a negative regulator of the Notch pathway that may control islet development. Linkage evidence also supported loci on 5p15 (D5S817; LOD 2.44, P 0.0004) and 9q22 (D9S910; LOD 2.02, P 0.0018). The latter matches a region linked to 2-h insulin levels in Pima Indians. Less strong linkage evidence was observed at three other regions: chromosomes 3p24 (LOD 1.44), 7q21 (1.20), and 16q23 (1.51). Our data are consistent with the existence of multiple loci that contribute to the expression of the MODY3 phenotype. Identification of these genes will offer new insights into the pathophysiology of MODY that may, in turn, increase our understanding of the cellular events underlying more common forms of diabetes. Diabetes 52:2182–2186, 2003 Maturity-onset diabetes of the young (MODY) is a form of familial diabetes characterized by an early age of onset and an autosomal dominant pattern of inheritance (1). Six MODY genes have been identified to date (2–8). One MODY locus corresponds to the enzyme glucokinase, which is an essential component of the -cell glucose sensor (2,3). The other five MODY genes are transcription factors (hepatocyte nuclear factor [HNF]-1 , HNF-4 , HNF-1 , insulin promoter factor 1 (IPF1), and NEUROD1) that are involved in islet cell differentiation and metabolism as well as insulin secretion (4–8). Most MODY cases in the U.S. are attributable to mutations in HNF-1 (9). This form of diabetes, also known as MODY3, is characterized by impaired insulin secretion in response to glucose (10,11). While HNF-1 mutations are highly penetrant, there is wide variability in the severity of the disease. There is also wide variation in the age at which MODY becomes clinically manifest. Indeed, only 50–60% of HNF-1 mutation carriers develop diabetes before age 25 years (the traditional criterion for a MODY diagnosis) (9). Such variability does not appear to be related to the type (truncated versus missense) or to the domain localization of the HNF-1 mutations (9). In a large panel of HNF-1 mutation carriers, we found that inheritance of the mutation from the mother and exposure to maternal diabetes in utero are associated with an early onset of MODY (9). In addition, we found the age of diabetes onset to be highly heritable (h 0.47), and when the parent-of-origin of the HNF-1 mutation was taken into account, the heritability was even greater, with familial (presumably genetic) factors accounting for 91% of the residual variability (9). Thus, the clinical manifestation of MODY3 appears to be more complex than previously thought, being influenced by both modifying genes that are inherited independently of HNF-1 as well as environmental factors. Similar phenotypic complexity has been proposed for other “simple” Mendelian disorders such as Gaucher disease (12). To identify loci that influence MODY3 onset, we conducted a genome screen of 13 extended families in which diabetes segregates with an HNF-1 mutation. The clinical characteristics of these families have been previously From the Research Division, Joslin Diabetes Center, Boston, Massachusetts; the Department of Medicine, Harvard Medical School, Boston, Massachusetts; and the Department of Public Health Sciences, Wake Forest University School of Medicine, Winston-Salem, North Carolina. Address correspondence and reprint requests to Alessandro Doria, MD, PhD, Section on Genetics and Epidemiology, Joslin Diabetes Center, One Joslin Place, Boston, MA 02215. E-mail: alessandro.doria@joslin.harvard. edu. Current affiliation for S. -H.K. : Division of Endocrinology, Samsung Cheil Hospital and Women’s Healthcare Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Received for publication 7 February 2003 and accepted in revised form 12 May 2003. HNF, hepatocyte nuclear factor; IGT, impaired glucose tolerance; LOD, logarithm of odds; MODY, maturity-onset diabetes of the young; Ngn3, neurogenin 3; OGTT, oral glucose tolerance test; WHO, World Health Organization. © 2003 by the American Diabetes Association.