914 DIABETES, VOL. 48, APRIL 1999 914 Brief Genetics Report Intermediate Expansions of a GAA Repeat in the Frataxin Gene Are Not Associated With Type 2 Diabetes or Altered Glucose-Induced -Cell Function in Danish Caucasians Louise T. Dalgaard, Torben Hansen, Søren A. Urhammer, Jesper O. Clausen, Hans Eiberg, and Oluf Pedersen A variable expansion of a GAA repeat is present in the first intron of the frataxin gene, also termed FRDA1 o r X25. Long repeat lengths (>66 repeats) are present in patients with Friedreich’s ataxia, while an intermediate expansion (10–66 repeats) has recently been reported to be highly associated with type 2 diabetes. Using a polymerase chain reaction–based assay, we found that 32.4% (95%CI 29.9–34.9) of 636 Danish Caucasian type 2 diabetic patients were carriers of an intermediate expansion, whereas the frequency was 30.4% ( 26.4–34.4) among 224 matched glucose-tolerant control subjects ( P = 0.6). In the control subjects, the values of serum insulin and C-peptide responses during an oral glucose tolerance test were similar between the 69 car- riers and 155 noncarriers. Furthermore, we investi- gated a possible relationship between expansions of the FRDA1 gene and glucose-induced -cell function in 338 young Caucasians (33.7% [30.1–37.3] carriers) and in 215 glucose-tolerant subjects (31.0% [26.6–35.4] carriers) with a type 2 diabetic parent. In neither pop- ulation did the carriers differ from noncarriers accord- ing to values of fasting plasma glucose, serum insulin, or C-peptide, acute serum insulin, or C-peptide responses after intravenous glucose. In conclusion, intermediate expansion of the frataxin trinucleotide repeat is not associated with type 2 diabetes or altered glucose-induced insulin secretion in Danish Cau- casians. Diabetes 48:914–917, 1999 L ong expansions of a GAA trinucleotide (ranging from 66 to >1,700 repeats) in the first intron of the frataxin gene, FR DA1 or X25, which has been located to chromosome 9q13–21.1, are responsible for the spin- ocerebellar degenerative disease Friedreich’s ataxia (FRDA) (1), whereas the normal range of repeats is from 7 to 36 (2). Frataxin is a mitochondrial pro tein involved in cellular iron metabolism (3). The expression pattern is wide, but the gene is predominantly expressed in tissues with a high metabolic rate. Frataxin mRNA levels are greatly reduced in FRDA patients, pre- sumably leading to reduced function of the respiratory chain (4). The clinical picture of FRDA patients is very heterogeneous, with a strong correlation between the expansion length and the severity of the disease (5). FRDA is often accompanied by type 2 diabetes and cardiomyopathy, and the incidence of bo th dis- eases increases with increasing mean allele length. This makes it imaginable that minor expansions o f this triplet repeat could lead to smaller reductions in frataxin mRNA, thus contributing to the development of -cell dysfunctio n. Recently, it has been demonstrated that intermediate expansions (defined as >9 repeats and <66) are asso ciated with type 2 diabetes in both an American and a German population (6). The objective of the present study was to examine whether intermediate expan- sions of the F R DA1 gene were associated with type 2 diabetes or altered -cell function and insulin sensitivity. Association studies were performed in 636 Danish Cau- casian type 2 diabetic patients recruited from the outpatient clinic at the Steno Diabetes Center and 224 age-matched, unrelated, and glucose-tolerant Danish Caucasian control subjects recruited through the Danish Central Population Register and living in the same area o f Co penhagen as the type 2 diabetic patients. Diabetes was diagnosed by World Health Organization criteria. All control subjects underwent a stan- dard 2-h 75-g oral glucose tolerance test (OGTT) (five blood samplings for analysis) with measurements of plasma glucose, serum insulin, and serum C-peptide during the test. For fur- ther studies of an effect of intermediary expansions on glu- cose metabolism, two populations were investigated: 1) a pop- ulation-based sample of 338 unrelated Danish Caucasians aged 18–32 years who underwent a tolbutamide-modified intravenous glucose tolerance test (IVGTT) for measurement of acute serum insulin and C-peptide responses and the From the Steno Diabetes Center (L.T.D., T.H., S.A.U., O.P.); the Center of Pre- ventive Medicine (J.O.C.), Glostrup University Hospital; and the University Institute of Medical Biochemistry and Genetics (H.E.), Department of Med- ical Genetics, University of Copenhagen, Copenhagen, Denmark. Address correspondence and reprint requests to Louise T. Dalgaard, MSci, Steno Diabetes Center, Niels Steensens Vej 2, DK-2820 Gentofte, Copenhagen, Denmark. Received for publication 8 June 1998 and accepted in revised form 31 August 1998. J.O.C. is currently employed by Eli Lilly. FRDA, Friedreich’s ataxia; IVGTT, intravenous glucose tolerance test; OGTT, oral glucose tolerance test; PCR, polymerase chain reaction.