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- Dumanski, Jan P., et al.
(author)
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Immune cells lacking Y chromosome show dysregulation of autosomal gene expression
- 2021
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In: Cellular and Molecular Life Sciences (CMLS). - : Springer. - 1420-682X .- 1420-9071. ; 78:8, s. 4019-4033
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Journal article (peer-reviewed)abstract
- Epidemiological investigations show that mosaic loss of chromosome Y (LOY) in leukocytes is associated with earlier mortality and morbidity from many diseases in men. LOY is the most common acquired mutation and is associated with aberrant clonal expansion of cells, yet it remains unclear whether this mosaicism exerts a direct physiological effect. We studied DNA and RNA from leukocytes in sorted- and single-cells in vivo and in vitro. DNA analyses of sorted cells showed that men diagnosed with Alzheimer’s disease was primarily affected with LOY in NK cells whereas prostate cancer patients more frequently displayed LOY in CD4 + T cells and granulocytes. Moreover, bulk and single-cell RNA sequencing in leukocytes allowed scoring of LOY from mRNA data and confirmed considerable variation in the rate of LOY across individuals and cell types. LOY-associated transcriptional effect (LATE) was observed in ~ 500 autosomal genes showing dysregulation in leukocytes with LOY. The fraction of LATE genes within specific cell types was substantially larger than the fraction of LATE genes shared between different subsets of leukocytes, suggesting that LOY might have pleiotropic effects. LATE genes are involved in immune functions but also encode proteins with roles in other diverse biological processes. Our findings highlight a surprisingly broad role for chromosome Y, challenging the view of it as a “genetic wasteland”, and support the hypothesis that altered immune function in leukocytes could be a mechanism linking LOY to increased risk for disease.
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| 2. |
- Jacobsson, Josefin A., et al.
(author)
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Major gender difference in association of FTO gene variant among severely obese children with obesity and obesity related phenotypes.
- 2008
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In: Biochemical and Biophysical Research Communications - BBRC. - : Elsevier BV. - 0006-291X .- 1090-2104. ; 368:3, s. 476-482
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Journal article (peer-reviewed)abstract
- Recent studies have shown that SNPs in the FTO gene predispose to childhood and adult obesity. In this study, we examined the association between variants in FTO and KIAA1005, a gene that maps closely to FTO, and obesity, as well as obesity related traits among 450 well characterised severely obese children and 512 normal weight controls. FTO showed significant association with several obesity related traits while SNPs in KIAA1005 did not. When stratified by gender, the FTO variant rs9939609 showed association with obesity and BMI among girls (P=0.006 and 0.004, respectively) but not among boys. Gender differences were also found in the associations of the FTO rs9939609 with obesity related traits such as insulin sensitivity and plasma glucose. This study suggests that FTO may have an important role for gender specific development of severe obesity and insulin resistance in children.
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| 3. |
- Jacobsson, J. A., et al.
(author)
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Novel genetic variant in FTO influences insulin levels and insulin resistance in severely obese children and adolescents.
- 2008
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In: International Journal of Obesity. - : Springer Science and Business Media LLC. - 0307-0565 .- 1476-5497. ; 32:11, s. 1730-1735
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Journal article (peer-reviewed)abstract
- BACKGROUND The global prevalence of obesity and overweight is increasing rapidly among adults as well as among children and adolescents. Recent genome-wide association studies have provided strong support for association between variants in the FTO gene and obesity. We sequenced regions of the FTO gene to identify novel variants that are associated with obesity and related metabolic traits. RESULTS We screened exons 3 and 4 including exon-intron boundaries in FTO in 48 obese children and adolescents and identified three novel single nucleotide polymorphism in the fourth intronic region, (c.896+37A>G, c.896+117C>G and c.896+223A>G). We further genotyped c.896+223A>G in 962 subjects, 450 well-characterized obese children and adolescents and 512 adolescents with normal weight. Evidence for differences in genotype frequencies were not detected for the c.896+223A>G variant between extremely obese children and adolescents and normal weight adolescents (P=0.406, OR=1.154 (0.768-1.736)). Obese subjects with the GG genotype, however, had 30% increased fasting serum insulin levels (P=0.017) and increased degree of insulin resistance (P=0.025). There were in addition no differences in body mass index (BMI) or BMI standard deviation score (SDS) levels among the obese subjects according to genotype and the associations with insulin levels and insulin resistance remained significant when adjusting for BMI SDS. CONCLUSION These findings suggest that this novel variant in FTO is affecting metabolic phenotypes such as insulin resistance, which are not mediated through differences in BMI levels.
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