Haplotype construction of the FRDA gene and evaluation of its role in type II diabetes

A GAA-repeat in the X25 gene is causing Friedreich's ataxia (FRDA), a common neurodegenerative disease and >20% of FRDA patients develop type II diabetes (T2D). Linkage has previously been detected between T2D and chromosome 9p13-q21, the region that harbours the X25 gene, but association studies of this gene in T2D have been contradicting. Here, we examined whether genetic variation in the X25 gene is associated with risk for T2D. The GAA-repeat and 18 single nucleotide polymorphisms (SNPs) covering the X2S gene were genotyped in 220 trios in which the affected offspring had abnormal glucose tolerance. Any nominally significant findings were examined in an independent sample consisting of 523 individuals with T2D and 326 healthy controls. Previously reported results were analysed together with our data using a meta-analysis approach. There was no association between the GAA-repeat and T2D susceptibility in our study, which was supported by the meta-analysis including all previous publications. One SNP (rs2498429), 8.2 kb downstream of X25, was nominally associated with T2D in the trios (P= 0.02) and showed a trend of association in the same direction in the case-controls (P=0.08; combined permuted P=0.01). Further analysis showed that the nine-marker haplotype containing the rare allele of rs2498429 was nominally associated with T2D in the trios (P<0.01) as well as in the case-controls (P=0.03). In conclusions, this study excludes a role of genetic variation within the X25 gene, but instead suggests that genetic variation downstream the X25 gene, may increase risk for T2D.