Genetic Modifiers of the Age at Diagnosis of Diabetes (MODY3) in Carriers of Hepatocyte Nuclear Factor-1α Mutations Map to Chromosomes 5p15, 9q22, and 14q24 Sung-Hoon Kim 1 2 , Xiaowei Ma 1 2 , Tomasz Klupa 1 2 , Christine Powers 1 , Marcus Pezzolesi 1 , James H. Warram 1 , Stephen S. Rich 3 , Andrzej S. Krolewski 1 2 and Alessandro Doria 1 2 1 Research Division, Joslin Diabetes Center, Boston, Massachusetts 2 Department of Medicine, Harvard Medical School, Boston, Massachusetts 3 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{at}joslin.harvard.edu Abstract Mutations in hepatocyte nuclear factor (HNF)-1α (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-1α 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. 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 Footnotes Current affiliation for S.-H.K.: Division of Endocrinology, Samsung Cheil Hospital and Women’s Healthcare Center, Sungkyunkwan University School of Medicine, Seoul, Korea. Accepted May 12, 2003. Received February 7, 2003. DIABETES