Recent studies show that different aspects of smoking behavior are associated with the α-5 subunit of the nicotinic acetylcholine receptor (CHRNA5) gene and the gene coding for brain-derived ...neurotrophic factor (BDNF). This raises the question whether the amount of cigarettes smoked per day has a different genetic background than smoking initiation and what other smoking phenotypes may be relevant. The aim of this study was to replicate these associations in a large population-based sample. We investigated the association with smoking initiation and the number of cigarettes used per day and additional smoking phenotypes in a population-based sample of 2166 participants of Dutch origin. Rs6265 in BDNF was not associated with smoking initiation. This single nucleotide polymorphism was associated with smoking cessation. Rs16969968 in CHRNA5 was associated with the amount of nicotine used and in particular smoking 25 cigarettes or more per day. Overall, the results confirm the involvement of the CHRNA5 gene in the amount of nicotine use and further suggest involvement of the BDNF gene in smoking behavior.
To study genetic loci influencing obesity in nuclear families with type 2 diabetes, we performed a genome‐wide screen with 325 microsatellite markers that had an average spacing of 11 cM and a mean ...heterozygosity of ∼75% covering all 22 autosomes. Genotype data were obtained from 562 individuals from 178 families from the Breda Study Cohort. These families were determined to have at least two members with type 2 diabetes. As a measure of obesity, the BMI of each diabetes patient was determined. The genotypes were analyzed using variance components (VCs) analysis implemented in GENEHUNTER 2 to determine quantitative trait loci influencing BMI. The VC analysis revealed two genomic regions showing VC logarithm of odds (LOD) scores ≥1.0 on chromosome 1 and chromosome 11. The regions of interest on both chromosomes were further investigated by fine‐mapping with additional markers, resulting in a VC LOD score of 1.5 on chromosome 1q and a VC LOD of 2.4 on chromosome 11q. The locus on chromosome 1 has been implicated previously in diabetes. The locus on chromosome 11 has been implicated previously in diabetes and obesity. Our study to determine linkage for BMI confirms the presence of quantitative trait loci influencing obesity in subjects with type 2 diabetes on chromosomes 1q31‐q42 and 11q14‐q24.
Immunodeficiency in association with centromere instability of chromosomes 1, 9, and 16 and facial anomalies (ICF syndrome) is a rare autosomal recessive disorder. ICF patients show marked ...hypomethylation of their DNA; undermethylation of classical satellites II and III is thought to be associated with the centromere instability. We used DNA from three consanguineous families with a total of four ICF patients and performed a total genome screen, to localize the ICF syndrome gene by homozygosity mapping. One chromosomal region (20q11-q13) was consistently found to be homozygous in ICF patients, whereas all healthy sibs showed a heterozygous pattern. Comparison of the regions of homozygosity in the four ICF patients localized the
ICF locus to a 9-cM region between the markers D20S477 and D20S850. Analysis of more families will be required, to refine the map location further. Isolation of the gene associated with the ICF syndrome not only will give insight into the etiology of the ICF syndrome but will also broaden our understanding of DNA methylation processes.
Cytosine-5 methylation within CpG dinucleotides is a potentially important mechanism of epigenetic influence on human traits and disease. In addition to influences of age and gender, genetic control ...of DNA methylation levels has recently been described. We used whole blood genomic DNA in a twin set (23 MZ twin-pairs and 23 DZ twin-pairs, N = 92) as well as healthy controls (N = 96) to investigate heritability and relationship with age and gender of selected DNA methylation profiles using readily commercially available GoldenGate bead array technology. Despite the inability to detect meaningful methylation differences in the majority of CpG loci due to tissue type and locus selection issues, we found replicable significant associations of DNA methylation with age and gender. We identified associations of genetically heritable single nucleotide polymorphisms with large differences in DNA methylation levels near the polymorphism (cis effects) as well as associations with much smaller differences in DNA methylation levels elsewhere in the human genome (trans effects). Our results demonstrate the feasibility of array-based approaches in studies of DNA methylation and highlight the vast differences between individual loci. The identification of CpG loci of which DNA methylation levels are under genetic control or are related to age or gender will facilitate further studies into the role of DNA methylation and disease.
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Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
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