IDDM2 and the Polymorphism of the Human Tyrosine Hydroxylase: DISCUSSION

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This report uses the microsatellite repeats (TCAT)n on chromosome 11 to investigate the tyrosine hydroxylase gene as IDDM2, the second major candidate gene for susceptibility to type-1 diabetes. No significant association was found either at the allele level or at the genotype level. This data is in contrast with findings in previous association studies that detected a significant association of hTH with type-1 diabetes in Caucasians. The data reported here for African Americans was consistent with findings reported by Field and coworker in a family study that failed to demonstrate significant evidence of linkage between type-1 diabetes and hTH, either by lod score or affected sibling pair linkage analysis. No association was found with hTH in another study that used restriction fragment polymorphism. The exact localization of the IDDM2 and the depiction of its effect on the expression of hTH, INS, and IGF2 may prove to be important in understanding the biological mechanisms that lead to the onset of type-1 diabetes and its complications. The study of microsatellite sequences has shown that they may have a function in recombination, in the generation of nucleosome positioning signals, and more subtle effects on expression. Previous studies have shown that hTH tetranucleotide repeat acts as a transcriptional enhancer in vitro. Moreover, these repeated sequences interact specifically and with high affinity with nuclear proteins.

It is also interesting to mention that previous studies have shown that microsatellite allelic variations have a quantitative silencing effect on TH gene expression. Two specific proteins—ZNF191, a zinc finger protein, and HBP1, an HMG box transcriptional factor—which bind the TCAT motif of TH, were cloned. Allelic variation of hTH microsatellite repeat correlates with quantitative and qualitative changes in the binding by ZNF191. Based on this data and despite the absence of significant association of the TCAT repeat in this study of African Americans with type-1 diabetes, these sequences may still contribute indirectly to the control of expression of disease.
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We conclude that no apparent hTH polymorphism seems to be associated with type-1 diabetes in African Americans. This data shifts the focus from the hTH gene to the generic insulin gene as having a major role in IDDM2.

In the absence of a clear indication of where the IDDM2 specifically resides, the refinement of this candidate gene will require additional analyses with a larger and diverse sample size to allow for stratification of the data and removal of the strong genetic effect oflDDMl.
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