The vast majority of patients with Nijmegen Breakage Syndrome (NBS) are of Slavic origin and carry a deleterious deletion (c.657del5; rs587776650) in the NBN gene on chromosome 8q21. This mutation is essentially confined to Slavic populations and may thus be considered a Slavic founder mutation. Notably, not a single parenthood of a homozygous c.657del5 carrier has been reported to date, while heterozygous carriers do reproduce but have an increased cancer risk. These observations seem to conflict with the considerable carrier frequency of c.657del5 of 0.5% to 1% as observed in different Slavic populations because deleterious mutations would be eliminated quite rapidly by purifying selection. Therefore, we propose that heterozygous c.657del5 carriers have increased reproductive success, i.e., that the mutation confers heterozygote advantage. In fact, in our cohort study of the reproductive history of 24 NBS pedigrees from the Czech Republic, we observed that female carriers gave birth to more children on average than female non-carriers, while no such reproductive differences were observed for males. We also estimate that c.657del5 likely occurred less than 300 generations ago, thus supporting the view that the original mutation predated the historic split and subsequent spread of the 'Slavic people'. We surmise that the higher fertility of female c.657del5 carriers reflects a lower miscarriage rate in these women, thereby reflecting the role of the NBN gene product, nibrin, in the repair of DNA double strand breaks and their processing in immune gene rearrangements, telomere maintenance, and meiotic recombination, akin to the previously described role of the DNA repair genes BRCA1 and BRCA2.
- MeSH
- detekce genetických nosičů MeSH
- dospělí MeSH
- efekt zakladatele * MeSH
- haplotypy MeSH
- jaderné proteiny genetika MeSH
- kohortové studie MeSH
- lidé středního věku MeSH
- lidé MeSH
- mutace * MeSH
- oprava DNA MeSH
- poškození DNA MeSH
- proteiny buněčného cyklu genetika MeSH
- rozmnožování genetika MeSH
- syndrom Nijmegen breakage etnologie genetika MeSH
- Check Tag
- dospělí MeSH
- lidé středního věku MeSH
- lidé MeSH
- mužské pohlaví MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- Geografické názvy
- Česká republika MeSH
- Slovenská republika MeSH
AIMS: Statins have antiinflammatory effects and are known to decrease risk of cardiovascular events and to reduce serum levels of C-reactive protein (CRP), a widely studied biomarker and potential mediator of inflammation and heart disease. However, it is unclear whether statins can block pro-inflammatory effects of human CRP independent of their ability to reduce serum levels of human CRP. Here, we investigated whether rosuvastatin could block pro-inflammatory effects of human CRP without reducing circulating levels of human CRP. METHODS AND RESULTS: We studied the antiinflammatory effects of rosuvastatin in spontaneously hypertensive rats (SHR) transgenically expressing human CRP (CRP-transgenic SHR) and in nontransgenic SHR lacking human CRP (nontransgenic SHR). The CRP-transgenic SHR is characterized by increased serum levels of human CRP and inflammation. In the CRP-transgenic strain, we found that rosuvastatin treatment decreased circulating levels of inflammatory response markers IL6 and TNFα without decreasing circulating levels of human CRP. In contrast, in the nontransgenic strain lacking human CRP, rosuvastatin treatment had little or no effect on IL6 and TNFα levels. Rosuvastatin also reduced cardiac inflammation and oxidative tissue damage, reduced epididymal fat mass, and improved adipose tissue lipolysis much more in the CRP-transgenic strain than in the nontransgenic strain. CONCLUSION: Rosuvastatin can protect against pro-inflammatory effects of human CRP in a manner that is not dependent on achieving a reduction in circulating levels of human CRP.
- MeSH
- antiflogistika farmakologie MeSH
- C-reaktivní protein genetika metabolismus MeSH
- fluorbenzeny farmakologie MeSH
- interleukin-6 krev MeSH
- játra účinky léků metabolismus MeSH
- kardiomyocyty účinky léků imunologie metabolismus MeSH
- krysa rodu rattus MeSH
- lidé MeSH
- mediátory zánětu krev MeSH
- modely nemocí na zvířatech MeSH
- oxidační stres účinky léků MeSH
- potkani inbrední SHR MeSH
- potkani transgenní MeSH
- pyrimidiny farmakologie MeSH
- regulace genové exprese MeSH
- sulfonamidy farmakologie MeSH
- TNF-alfa krev MeSH
- zánět krev genetika imunologie prevence a kontrola MeSH
- zvířata MeSH
- Check Tag
- krysa rodu rattus MeSH
- lidé MeSH
- mužské pohlaví MeSH
- zvířata MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH