AN ASSOCIATION BETWEEN NIDDM AND A GAA TRINUCLEOTIDE REPEAT POLYMORPHISM IN THE X25 FRATAXIN (FRIEDREICHS ATAXIA) GENE/

Friedreich's ataxia is the most common hereditary ataxia and is freque ntly associated with disturbances of glucose metabolism. This autosoma l recessive disease is caused by the decreased expression of a mitocho ndrial protein, frataxin, encoded by the X25 gene. Homozygous expansio n of a GAA repeat in the first intron of X25 inhibits frataxin express ion and is associated with clinical disease. we evaluated whether hete rozygous expansions of the triplet repeat in the frataxin gene X25 may be associated with NIDDM in two genetically distinct populations-one in Germany (n = 358) and the other in the U.S. (n = 292)-using a polym erase chain reaction-based assay. Intermediate expansions (10-36 repea ts), which are longer than normal but not sufficient for the appearanc e of the ataxia phenotype, were found in 24.7 and 27.3% of these two N IDDM cohorts compared with 7.6 and 6.3% of the matched control subject s (both P < 0.001), The odds ratios were 3.36 (95% CI 1.72-6.55) for t he German group and 4.01 (2.08-7.74) for the U.S. group. Therefore, we conclude that the X25/frataxin GAA repeat polymorphism is associated with NIDDM in a frequency higher than any other mutation heretofore de scribed. Further studies are needed to elucidate the possible role of frataxin in the pathogenesis of NIDDM.