BackgroundHuntington disease (HD) is caused by a polyglutamine expansion of more than 35 units in the huntingtin protein. This expanded repeat length inversely correlates with the age-at-onset (AAO), however, additional genetic factors apart from the expanded CAG repeat size are thought to influence the course and the AAO in HD. Until now, among others, the gene encoding PCG-1α (PPARGC1A) was shown to modify the AAO in two independent, however small, populations. PGC-1α is involved in the induction of various mechanisms regulating mitochondrial biogenesis and oxidative stress defence. Furthermore, several studies have linked impairment of its function and/or its expression to HD pathogenesis. As the identification of distinct modifiers in association studies is largely dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNPs) in PPARGC1A in order to replicate the disease modifying effect in more than 800 European HD patients and to identify an association with AAO in HD.ResultsTwo SNPs, one in the promoter and one in the transcribed region of the gene, showed a significant effect on the AAO. While the minor allele of SNP rs7665116 (g.38570C), located in the transcribed gene region, was associated with a delay in disease onset, especially in HD patients with Italian ancestry, the minor allele of SNP rs2970870 (g.-1437C) in the promoter region leads to an earlier onset of HD in its homozygous state. Additionally, global testing of haplotype block 2, which covers the main part of the transcribed region of the gene, revealed an association between block 2 haplotypes and the disease onset.ConclusionTherefore, our results indicate opposing modifying influences of two SNPs within one gene on AAO and support the idea that PGC-1α dysfunction is involved in HD pathology.

Crohn's disease and ulcerative colitis, the two main types of inflammatory bowel disease (IBD), were reported to be associated with a variety of genetic polymorphisms. A subset of these polymorphisms was identified in both diseases and only three of them were found in primary sclerosing cholangitis (PSC). rs3197999 (Arg689Cys) located in the MST1 gene is one of the most convincingly replicated IBD/PSC-associated polymorphisms but its functional consequences have not been investigated, yet. We expressed both MST1 gene variants (Arg 689 (MSP wt ) and Cys 689 (MSP mut )) in a eukaryotic cell system and compared their stimulatory effects on macrophage-like THP-1 cells. Except for the rate of apoptosis that remained unchanged, MSP mut significantly increased the stimulatory effect of MSP (macrophage-stimulating protein) on chemotaxis and proliferation by THP-1 cells, indicating a gain of function associated with the Arg689Cys exchange. A broad set of evidence reported previously suggests that pro-inflammatory changes in macrophage function have a major role in the initiation of the inflammatory process in IBD and PSC. Therefore, the gain of function observed with rs3197999 in MST1 might provide a cellular mechanism for the consistent association of this polymorphism with an increased risk for IBD and PSC.

Background A polyglutamine repeat expansion of more than 36 units in the huntingtin protein is the only known cause of Huntington's disease (HD). The expanded repeat length is inversely correlated with the age at onset (AAO) but additional genetic factors apart from the expanded CAG repeat length can modify the course and AAO in HD. Until now, among others the gene encoding PCG-1α, a transcriptional coactivator in metabolic processes that seems to be defective in HD, could be identified to modify the AAO in two independent populations. Aim/method As the identification of distinct modifiers in association studies is generally dependent on the size of the observed population, we investigated nine different single nucleotide polymorphisms (SNP) in the PGC-1α gene for a disease modifying effect in more than 800 European HD patients. Results Two SNPs, one in the promotor and one in the transcribed region of the PGC-1α gene, showed a significant effect on the AAO. While the variant allele of SNP rs7665116 was associated with a delay in disease onset, the variant allele of SNP rs2970870 leads to an earlier onset of HD in its homozygous state. Conclusion Therefore, our results indicate opposing modifying influences of one gene to disease pathology and support the concept of a reduced PGC-1α expression due to mutant huntingtin as well as an altered functionality of PGC-1α towards target genes in HD pathogenesis.