By studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS)... Show moreBy studying the loci that contribute to human longevity, we aim to identify mechanisms that contribute to healthy aging. To identify such loci, we performed a genome-wide association study (GWAS) comparing 403 unrelated nonagenarians from long-living families included in the Leiden Longevity Study (LLS) and 1670 younger population controls. The strongest candidate SNPs from this GWAS have been analyzed in a meta-analysis of nonagenarian cases from the Rotterdam Study, Leiden 85-plus study, and Danish 1905 cohort. Only one of the 62 prioritized SNPs from the GWAS analysis (P < 1 x 10(-4)) showed genome-wide significance with survival into old age in the meta-analysis of 4149 nonagenarian cases and 7582 younger controls [OR = 0.71 (95% CI 0.65-0.77), P = 3.39 x 10(-17)]. This SNP, rs2075650, is located in TOMM40 at chromosome 19q13.32 close to the apolipoprotein E (APOE) gene. Although there was only moderate linkage disequilibrium between rs2075650 and the ApoE epsilon 4 defining SNP rs429358, we could not find an APOE-independent effect of rs2075650 on longevity, either in cross-sectional or in longitudinal analyses. As expected, rs429358 associated with metabolic phenotypes in the offspring of the nonagenarian cases from the LLS and their partners. In addition, we observed a novel association between this locus and serum levels of IGF-1 in women (P = 0.005). In conclusion, the major locus determining familial longevity up to high age as detected by GWAS was marked by rs2075650, which tags the deleterious effects of the ApoE epsilon 4 allele. No other major longevity locus was found. Show less
Boef, A.G.C.; May, L.; Bodegom, D. van; Kuningas, M.; Eriksson, U.K.; Westendorp, R.G.J. 2011
Interleukin-10 (IL-10) production is under tight genetic control in populations living in affluent environments. However, little is known about the role of IL10 genetics on cytokine production in... Show moreInterleukin-10 (IL-10) production is under tight genetic control in populations living in affluent environments. However, little is known about the role of IL10 genetics on cytokine production in populations living in environments with high infectious pressure. We have previously reported that, in a rural Ghanaian population, the most common IL10 haplotype associates with a pro-inflammatory response. Here, we aim to replicate these findings in an independent sample of the same population 2 years later. IL-10 and tumour necrosis factor-α (TNF-α) protein concentrations were determined in whole-blood samples ex vivo stimulated with lipopolysaccharide and zymosan in 2006 (n=615) and 2008 (n=647). The association between IL10 single nucleotide polymorphisms and Z-scores of IL-10 and TNF-α levels was analysed in each population subset. The most common IL10 haplotype was associated with a significantly lower IL-10 production and nonsignificantly increased TNF-α levels. The correlation between repeated cytokine assays, based on 111 individuals with measurements in both 2006 and 2008, was r=0.53 (P<0.001) for IL-10 and r=0.36 (P<0.001) for TNF-α. The replication of our previously found effect of variation in the IL10 gene on IL-10 production and the correlation between repeated cytokine stimulation assays provide evidence that IL10 genetics have an important role in regulating the host response under high infectious pressure.Genes and Immunity advance online publication, 11 August 2011; doi:10.1038/gene.2011.57. Show less
Bodegom, D. van; Rozing, M.; May, L.; Kuningas, M.; Thomese, F.; Meij, H.; Westendorp, R. 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 co-evolved 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. Copyright (C) 2009 S. Karger AG, Basel Show less
May, L.; Bodegom, D. van; Frolich, M.; Lieshout, L. van; Slagboom, P.E.; Westendorp, R.G.J.; Kuningas, M. 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 (P=0.0005). 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. European Journal of Human Genetics (2010) 18, 490-495; doi:10.1038/ejhg.2009.182; published online 21 October 2009 Show less
Kuningas, M.; Bodegom, D. van; May, L.; Meij, J.J.; Slagboom, P.E.; Westendorp, R.G.J. 2010
Various studies in mice have found support for the hypothesis that heterozygous carriers of cystic fibrosis transmembrane conductance regulator (CFTR) mutations have an increased resistance to... Show moreVarious studies in mice have found support for the hypothesis that heterozygous carriers of cystic fibrosis 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 influence on survival and on body composition in the population at large. With a sliding-window haplotype analysis, we identified a set of six common haplotypes that influenced survival probabilities (global p = 6.00 x 10(-05)). Individual haplotype analyses revealed two haplotypes of specific interest. One of these haplotypes was enriched (p = 0.003), whereas the other was depleted (p = 0.041) among people of old age (> or = 65 years) compared to young study participants (< or = 5 years). In addition, children (n = 474) carrying the latter haplotype had lower body weight (p (trend) = 0.020) and height (p (trend) = 0.010) compared to non-carriers. For all these analyses, similar associations for heterozygous and homozygous CFTR haplotype carriers were observed, revealing an additive effect of haplotype alleles. In conclusion, we identified common haplotypes in the CFTR gene that influence survival and body composition in the population at large with no evidence for heterozygote advantage. Show less
Kuningas, M.; Bodegom, D. van; May, L.; Meij, J.J.; Slagboom, P.E.; Westendorp, R.G.J. 2010
Pentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we... Show morePentraxin 3 (PTX3) plays an important role in innate immune responses and in female fertility, as discovered with studies in mice. However, the role of PTX3 in human fertility is unknown. Here, we report on a population-based study from a rural area of Upper East Ghana (n = 4346). We studied the association between the number of children given birth by women during their lifetime and ex vivo, lipopolysaccharide (LPS)-induced PTX3 production (n = 362). In addition, we studied the association of genetic variation in the PTX3 gene with PTX3 production (n = 617) and with female fertility (n = 1999). We found that ex vivo LPS-induced PTX3 production was associated with fertility (P = 0.040). Furthermore, we identified genetic variants in the PTX3 gene that influence PTX3 production, and also fertility. The strongest associations were observed for the rs6788044 single-nucleotide polymorphism (SNP). We found that carriers of this SNP had higher PTX3 production capacity (P = 0.003) and higher fertility (P = 0.043). The results reported here provide the first evidence, based on protein production and analysis of polymorphisms, that the long pentraxin PTX3 plays a role in female fertility in humans. Show less
The lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between... Show moreThe lifespan of an organism is determined by a complex network of environmental-, genetic- and stochastic factors. Each of these components contributes to the wide variability in lifespan between and within species. In recent years, it has been shown that 20-30 % of human lifespan is under genetic control. Furthermore, a number of longevity candidate genes have been identified. The majority of candidate genes have emerged from studies with model organisms, but also from the biology of human ageing. The objective of this thesis was to test the impact of the most prominent longevity candidate genes on the prevalence of age-related diseases and lifespan in humans. All studies presented in this thesis were performed within the Leiden 85-plus Study, which is a population-based prospective study of the oldest old. The results revealed that genetic variations in most of the candidate genes influence metabolism, prevalence of age-related diseases, cognitive functioning and lifespan. Therefore, the approach of analyzing the most prominent longevity candidate genes in humans, contributes to the identification of biological mechanisms that influence the prevalence of disease in old age and lifespan. Show less
