Common CFTR gene variants influence body composition and survival in rural Ghana

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 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

Selection for Genetic Variation Inducing Pro-Inflammatory Responses under Adverse Environmental Conditions in a Ghanaian Population

Background: Chronic inflammation is involved in the pathogenesis of chronic age-associated, degenerative diseases. Proinflammatory host responses that are deleterious later in life may originate from evolutionary selection for genetic variation mediating resistance to infectious diseases under adverse environmental conditions. Methodology/Principal Findings: In the Upper-East region of Ghana where infection has remained the leading cause of death, we studied the effect on survival of genetic variations at the IL10 gene locus that have been associated with chronic diseases. Here we show that an IL10 haplotype that associated with a pro-inflammatory innate immune response, characterised by low IL-10 (p = 0.028) and high TNF-a levels (p = 1.3961023), was enriched among Ghanaian elders (p = 2.4661026). Furthermore, in an environment where the source of drinking water (wells/rivers vs. boreholes) influences mortality risks (HR 1.28, 95% CI [1.09–1.50]), we observed that carriers of the pro-inflammatory haplotype have a survival advantage when drinking from wells/rivers but a disadvantage when drinking from boreholes (pinteraction = 0.013). Resequencing the IL10 gene region did not uncover any additional common variants in the pro-inflammatory haplotype to those SNPs that were initially genotyped. Conclusions/Significance: Altogether, these data lend strong arguments for the selection of pro-inflammatory host responses to overcome fatal infection and promote survival in adverse environments

Loote reesusstaatuse mitteinvasiivne diagnostika – prenataalse diagnostika uus võimalus Eestis

Rasedusaegne reesuskonflikt on üks tähtsamaid loote ja vastsündinu hemolüütilise haiguse tekkepõhjuseid. Reesuskonflikt tekib, kui reesusnegatiivne naine kannab reesuspositiivset loodet. Loote reesusstaatuse määramine, mille kõige täpsemaks meetodiks on invasiivne geneetiline sünnieelne diagnostika (SeD), võimaldab teostada õigeaegset reesuskonflikti profülaktikat ja ravi. Eesti Arst 2005; 84 (12): 853–85

Impact of genetic variations in the WRN gene on age related pathologies and mortality.Mech

Abstract Mutations in the WRN gene lead to the Werner syndrome (WS), which resembles premature aging. Here, we hypothesize that genetic variations in the WRN gene may also influence aging-trajectories in the population at large. To test this hypothesis, we assessed the impact of the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene on the occurrence of cardiovascular pathologies, on cognitive performance and on the risks of all-cause, cardiovascular and cancer mortalities in the population-based Leiden 85-plus Study. This prospective follow-up study includes 1245 participants aged 85 years and older, with a total follow-up of 5164 person-years. At baseline the risks of myocardial infarction, myocardial ischemia, intermittent claudication, arterial surgery and stroke dependent on the i1-C/T, L1074F and C1367R polymorphisms, did not vary between the different genotypes. Also no differences in cognitive functioning were observed, except for attention, where carriers of the 1367R allele performed worse compared to the 1367C homozygotes (94.2 (4.35) versus 84.8 (1.84), p = 0.04). Mortality risks, calculated separately for all SNPs, were similar between the different genotype carriers of the i1-C/T, L1074F and C1367R polymorphisms, showing no evidence of altered survival. In conclusion, the i1-C/T, L1074F and C1367R polymorphisms in the WRN gene do not influence the aging-trajectories and survival in the population at large.

Runs of homozygosity do not influence survival to old age

Runs of homozygosity (ROH) are extended tracts of adjacent homozygous single nucleotide polymorphisms (SNPs) that are more common in unrelated individuals than previously thought. It has been proposed that estimating ROH on a genome-wide level, by making use of the genome-wide single nucleotide polymorphism (SNP) data, will enable to indentify recessive variants underlying complex traits. Here, we examined ROH larger than 1.5 Mb individually and in combination for association with survival in 5974 participants of the Rotterdam Study. In addition, we assessed the role of overall homozygosity, expressed as a percentage of the autosomal genome that is in ROH longer than 1.5 Mb, on survival during a mean follow-up period of 12 years. None of these measures of homozygosity was associated with survival to old age

Variants of the IL-10 gene associate with muscle strength in elderly from rural Africa: A candidate gene study

Recently, it has been shown that the capacity of the innate immune system to produce cytokines relates to skeletal muscle mass and strength in older persons. The interleukin-10 (IL-10) gene regulates the production capacities of IL-10 and tumour necrosis factor-α (TNF-α). In rural Ghana, IL-10 gene variants associated with different production capacities of IL-10 and TNF-α are enriched compared with Caucasian populations. In this setting, we explored the association between these gene variants and muscle strength. Among 554 Ghanaians aged 50 years and older, we determined 20 single nucleotide polymorphisms in the IL-10 gene, production capacities of IL-10 and TNF-α in whole blood upon stimulation with lipopolysaccharide (LPS) and handgrip strength as a proxy for skeletal muscle strength. We distinguished pro-inflammatory haplotypes associated with low IL-10 production capacity and anti-inflammatory haplotypes with high IL-10 production capacity. We found that distinct haplotypes of the IL-10 gene associated with handgrip strength. A pro-inflammatory haplotype with a population frequency of 43.2% was associated with higher handgrip strength (P = 0.015). An anti-inflammatory haplotype with a population frequency of 7.9% was associated with lower handgrip strength (P = 0.006). In conclusion, variants of the IL-10 gene contributing to a pro-inflammatory cytokine response associate with higher muscle strength, whereas those with anti-inflammatory response associate with lower muscle strength. Future research needs to elucidate whether these effects of variation in the IL-10 gene are exerted directly through its role in the repair of muscle tissue or indirectly through its role in the defence against infectious diseases

The effect of common genetic variation in 11β-hydroxysteroid dehydrogenase type 1 on hypothalamic-pituitary-adrenal axis activity and incident depression

Background: Accumulating evidence suggests that hyperactivity of the hypothalamic-pituitary-adrenal axis (HPA axis) is involved in depression. 11β-Hydroxysteroid dehydrogenase type 1 (11β-HSD1) converts inert cortisone to active cortisol and is implicated in HPA axis regulation in animal studies. The aim of our study was to identify polymorphisms in 11β-HSD1 gene (HSD11B1) with consistent associations with increased HPA axis activity and relate those polymorphisms to depression. Methods: Twelve single-nucleotide polymorphisms (SNPs), including 11 tagging SNPs, were selected using the HapMap database and genotyped in 4228 participants of the population-based Rotterdam Study. The outcome measures were salivary cortisol levels after awakening, 30 min later, at 1700 h, at bedtime, and plasma levels of androstenedione (in women only). SNPs that were significantly associated with cortisol as well as androstenedione levels were also related to incident depression. Results: rs11119328 was associated with higher cortisol saliva samples collected at bedtime as well as higher androstenedione levels (P value after correction for multiple testing: 0.01 and 0.04, respectively). Carriers of this polymorphism had an increased risk of an incident depression (hazard ratio 1.28, 95% confidence interval 1.03-1.59). Two other SNPs, which were in high linkage disequilibrium with rs11119328, were related to higher cortisol levels but not with androstenedione levels. Conclusions: We identified one SNP, which was associated with increased salivary cortisol levels at nadir as well as higher androstenedione levels. Moreover, this SNP was also associated with a higher risk of an incident depression. This suggests that 11β-HSD1 is implicated in human HPA axis regulation and susceptibility to depression. Copyrigh

Adverse environmental conditions influence age-related innate immune responsiveness

BACKGROUND-: The innate immune system plays an important role in the recognition and induction of protective responses against infectious pathogens, whilst there is increasing evidence for a role in mediating chronic inflammatory diseases at older age. Despite indications that environmental conditions can influence the senescence process of the adaptive immune system, it is not known whether the same holds true for the innate immune system. Therefore we studied whether age-related innate immune responses are similar or differ between populations living under very diverse environmental conditions. METHODS-: We compared cross-sectional age-related changes in ex vivo innate cytokine responses in a population living under affluent conditions in the Netherlands (age 20–68 years old, n = 304) and a population living under adverse environmental conditions in Ghana (age 23–95 years old, n = 562). RESULTS-: We found a significant decrease in LPS-induced Interleukin (IL)-10 and Tumor Necrosis Factor (TNF) production with age in the Dutch population. In Ghana a similar age-related decline in IL-10 responses to LPS, as well as to zymosan, or LPS plus zymosan, was observed. TNF production, however, did not show an age-associated decline, but increased significantly with age in response to co-stimulation with LPS and zymosan. CONCLUSION-: We conclude that the decline in innate cytokine responses is an intrinsic ageing phenomenon, while pathogen exposure and/or selective survival drive pro-inflammatory responses under adverse living conditions

The relationship between fertility and lifespan in humans

Evolutionary theories of aging predict a trade-off between fertility and lifespan, where increased lifespan comes at the cost of reduced fertility. Support for this prediction has been obtained from various sources. However, which genes underlie this relationship is unknown. To assess it, we first analyzed the association of fertility with age at menarche and menopause, and with mortality in 3,575 married female participants of the Rotterdam Study. In addition, we conducted a candidate gene study where 1,664 single nucleotide polymorphisms (SNPs) in 25 candidate genes were analyzed in relation to number of children as a measure of fertility. SNPs that associated with fertility were analyzed for association with mortality. We observed no associations between fertility and age at menarche (p = 0.38) and menopause (p = 0.07). In contrast, fertility was associated with mortality. Women with two to three children had significantly lower mortality (hazard ratio (HR), 0.82; 95% confidence interval (95% CI), 0.69–0.97) compared to women with no children. No such benefit was observed for women with four or more children, who had a similar mortality risk (HR, 0.93; 95% CI, 0.76–1.13) as women with no children. The analysis of candidate genes revealed four genes that influence fertility after correction for multiple testing: CGB/LHB gene cluster (p = 0.0036), FSHR (p = 0.023), FST (p = 0.023), and INHBA (p = 0.021). However, none of the independent SNPs in these genes predicted mortality. In conclusion, women who bear two to three children live longer than those who bear none or many children, but this relationship was not mediated by the candidate genes analyzed in this study