it is possible that at least part of this effect may be due to a reduction in the malignant cell number of the primary tumor, with a corresponding reduction in the likelihood of tumor spread

, for example CpG islands overlapping with promoters of tumor-suppressor genes, which can lead to a silencing of such genes as observed for MLH1 and BRCA1. Agedependent effects on DNA methylation were also shown in a noncancer-context. These can be induced by either nonrandom mechanisms like responses to environmental changes or by stochastic errors in maintaining patterns of DNA methylation during cell proliferation. Thus, age- and/or sequencedependent changes in DNA methylation can 8321748 have an impact on the etiology of diseases or phenotypic variability. Melanin-concentrating hormone receptor 1 plays a significant role in regulation of energy balance, food intake and body weight in humans and rodents. To date, five human obesity association studies of SNPs in the MCHR1 protein-coding region of exon 1 were published and show inconsistent results or no association at all. In adolescent German study groups, association of the A allele of rs133072 and obesity was detected and supported by transmission disequilibrium. However, findings in other German and Danish, French and American study samples did not support the initial association. In the Danish sample and in a second, epidemiological German sample the frequency of the A allele of rs133072 was higher in nonobese vs. obese individuals, but not statistically significant. In a French Caucasian group comprising obese children and obese adults the G allele of rs133072 was associated with obesity/BMI compared to adult controls. Further, in Danish men a significant association of the rs133072 A allele with reduced abdominal obesity was found. In contrast, two other groups did not find association of SNPs rs133072 and rs133073 with obesity in a population-based cohort of British Caucasians aged 405 years and a Finnish study group aged between 500 years, respectively. Further, the missense SNP rs133072 does not show obvious functional relevance in vitro. These contrasting results suggest that SNP-dependent epigenetic variations may influence the association with obesity. The role of genotype-dependent DNA methylation in gene silencing/ expression has previously been shown for the respiratory chain component NDUFB6, a gene associated with the risk of type 2 Vitamin D2 diabetes mellitus, in human skeletal muscle. In the present study, we analyzed DNA methylation with respect to allelic status of SNPs rs133072 and rs133073 of the obesity candidate gene MCHR1. SNPs rs133072 and rs133073 are located in the first exon of MCHR1. They are in tight linkage and form two major haplotypes, GT and AC; in these, one allele of either SNP constitutes a potential methylation site. We analyzed DNA isolated from blood cells of 49 individuals and found differential, haplotype-specific methylation levels. This ASM at MCHR1 is age-dependent, which means the difference in methylation status between haplotypes is significant in young but abolished in old individuals. Interestingly, the methylation status of the GT haplotype decreases with increasing BMI, whereas the AC haplotype shows no association in methylation status with BMI. In a MCHR1 heterozygous lymphoblastoid cell line, which shows ASM, ASE could be abolished by treatment with the methylation inhibitor 5-aza-29-deoxycytidine. Results The MCHR1 CpG island The SNPs rs133072 and rs133073 form each a CpG, if allele G or C is present, respectively. Based on sequences of chimpanzee and rhesus macaque, these alleles represent the ancestral state. In the vicinity of these SNPs th

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