Various studies in mice have found support for the hypothesis that heterozygous carriers of cystic Wbrosis transmembrane conductance regulator (CFTR) mutations have an increased resistance to fatal... Show moreVarious studies in mice have found support for the hypothesis that heterozygous carriers of cystic Wbrosis transmembrane conductance regulator (CFTR) mutations have an increased resistance to fatal infection compared to both homozygous mutation carriers and non-carriers, while in humans such evidence is scarce. In this study, we assessed the CFTR heterozygotes survival advantage hypothesis in a contemporary rural population that lives under adverse environmental conditions in the Upper-East region of Ghana. We genotyped 30 SNPs throughout the CFTR gene in 4,230 participants and tested their inXuence on survival and on body composition in the population at large. With a sliding-window haplotype analysis, we identi- Wed a set of six common haplotypes that inXuenced survival probabilities (global p = 6.00 £ 10¡05). Individual haplotype analyses revealed two haplotypes of speciWc interest. One of these haplotypes was enriched (p = 0.003), whereas the other was depleted (p = 0.041) among people of old age (¸65 years) compared to young study participants (·5 years). In addition, children (n = 474) carrying the latter haplotype had lower body weight (ptrend = 0.020) and height (ptrend = 0.010) compared to non-carriers. For all these analyses, similar associations for heterozygous and homozygous CFTR haplotype carriers were observed, revealing an additive eVect of haplotype alleles. In conclusion, we identiWed common haplotypes in the CFTR gene that inXuence survival and body composition in the population at large with no evidence for heterozygote advantage. Show less
Bodegom, David van; Rozing, Maarten; May, Linda; Kuningas, Maris; Thomese, Fleur; Meij, Hans; Westendorp, Rudi 2010
In a recent issue of this journal, Herndon [1] discussed the grandmother hypothesis and its implications for studies on cognitive ageing. According to this hypothesis, the long post-reproductive... Show moreIn a recent issue of this journal, Herndon [1] discussed the grandmother hypothesis and its implications for studies on cognitive ageing. According to this hypothesis, the long post-reproductive life span in human females is an adaptive mechanism that evolved to maximize female fitness by investing resources in the care of their grandchildren rather than by continuing to reproduce themselves. From this, Herndon deduces that special cognitive robustness to be maintained until after the age of menopause must have coevolved because grandmothers can only exert the beneficial effect if their cognitive abilities remain intact. He therefore pleas to compare cognitive ageing in humans with other primates, especially chimpanzees, because they lack a long post-reproductive life span and would therefore not have evolved this cognitive robustness. Here, we question the important role of grandmothers in our evolutionary past, first because of the different family structures during this time and second because of the low number of females that actually lived to experience a post-reproductive lifespan. We also show that in a population that reflects our evolutionary past, grandmothers do not have an important role for child survival. Finally, we react on the implications for the study of cognitive ageing as put forward by Herndon. Show less
May, Linda; Bodegom, David van; Frolich, Marijke; Lieshout, Lisette van; Slagboom, P Eline; Westendorp, Rudi GJ and Kuningas, Maris 2010
Toll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and... Show moreToll-like receptors (TLRs) are involved in the induction of an adequate immune response on infection. We hypothesized that genetic variation in TLR4 and TLR2 genes could influence this response and lead to variability in cytokine production and survival. We tested this hypothesis in 4292 participants who were followed up for all-cause mortality for 6 years and live under adverse environmental conditions in the Upper-East region of Ghana, where malaria is endemic. In 605 participants, tumor necrosis factor-a and interleukin-10 (IL10) production, after stimulation with lipopolysaccharide and zymosan, was measured. In addition, 34 single-nucleotide polymorphisms (SNPs) in TLR4 and 12 SNPs in TLR2 were genotyped and tested for association with cytokine production, malaria infection and mortality. In this comprehensive gene-wide approach, we identified novel SNPs in the TLR4 gene that influence cytokine production. From the analyzed SNPs, rs7860896 associated the strongest with IL10 production (P¼0.0005). None of the SNPs in this study associated with malaria or overall mortality risks. In conclusion, we demonstrate that genetic variation within the TLR4 gene influences cytokine production capacity, but in an endemic area does not influence the susceptibility to malaria infection or mortality. Show less
