Apolipoprotein E (
            <i>ApoE</i>
            ) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?

Jasieńska, Grażyna; Ellison, Peter T.; Galbarczyk, Andrzej; Jasieński, Michał; Kalemba-Drożdż, Małgorzata; Kapiszewska, Maria; Nenko, Ilona; Thune, Inger; Ziomkiewicz, Anna

doi:10.1098/rspb.2014.2395

Cited by 56 publications

(46 citation statements)

References 73 publications

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“…Our observations on APOE ε4 and fertility extends findings from rural Ecuador, where APOE ε4 carrying women had more offspring [31]· Moreover, young regularly menstruating women with APOE ε4 in rural and urban Poland have higher levels of progesterone in the luteal phase, suggesting a higher fecundability [32]. However, the findings from these two studies are based on relatively small samples.…”

Section: Discussionsupporting

confidence: 79%

Effect of APOE ε4 allele on survival and fertility in an adverse environment

et al. 2017

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BackgroundThe apolipoprotein-ε4 allele (APOE-ε4) is strongly associated with detrimental outcomes in affluent populations including atherosclerotic disease, Alzheimer’s disease, and reduced lifespan. Despite these detrimental outcomes, population frequencies of APOE-ε4 are high. We hypothesize that the high frequency of APOE-ε4 was maintained because of beneficial effects during evolution when infectious pathogens were more prevalent and a major cause of mortality. We examined a rural Ghanaian population with a high pathogen exposure for selective advantages of APOE-ε4, to survival and or fertility.Methods and findingsThis rural Ghanaian population (n = 4311) has high levels of mortality from widespread infectious diseases which are the main cause of death. We examined whether APOE-ε4 was associated with survival (total follow-up time was 30,262 years) and fertility after stratifying by exposure to high or low pathogen levels. Households drawing water from open wells and rivers were classified as exposed to high pathogen levels while low pathogen exposure was classified as those drawing water from borehole wells. We found a non-significant, but positive survival benefit, i.e. the hazard ratio per APOE-ε4 allele was 0.80 (95% confidence interval: 0.69 to 1.05), adjusted for sex, tribe, and socioeconomic status. Among women aged 40 years and older (n = 842), APOE-ε4 was not associated with the lifetime number of children. However, APOE-ε4 was associated with higher fertility in women exposed to high pathogen levels. Compared with women not carrying an APOE-ε4 allele, those carrying one APOE-ε4 allele had on average one more child and those carrying two APOE-ε4 alleles had 3.5 more children (p = 0.018).ConclusionsContrary to affluent modern-day populations, APOE-ε4 did not carry a survival disadvantage in this rural Ghanaian population. Moreover, APOE-ε4 promotes fertility in highly infectious environments. Our findings suggest that APOE-ε4 may be considered as evolutionarily adaptive. Its adverse associations in affluent modern populations with later onset diseases of aging further characterize APOE-ε4 as an example of antagonistic pleiotropy.

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Section: Discussionsupporting

confidence: 79%

Effect of APOE ε4 allele on survival and fertility in an adverse environment

et al. 2017

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“…The persistence of APOE4 in modern populations, despite its later costs to lifespan and brain aging, may be due to benefits to young ages. APOE4 women have higher luteal phase blood progesterone (Jasienska et al, 2015), which may enhance fertility. Moreover, APOE4 may be adaptive in immunity by higher cytokine responses (Finch and Morgan, 2007) and in pathogen resistance (Azevedo et al 2014; Finch and Martin, 2015; Rougeron et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

Cacciottolo

Christensen

Moser

et al. 2016

Neurobiology of Aging

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The APOE4 allele confers greater risk of Alzheimer’s Disease (AD) for women than men, in conjunction with greater clinical deficits per unit of AD neuropathology (plaques, tangles). Cerebral microbleeds, which contribute to cognitive dysfunctions during AD, also show APOE4 excess, but sex-APOE allele interactions are not described. We report that elderly men diagnosed for mild cognitive impairment (MCI) and AD showed a higher risk of cerebral cortex microbleeds with APOE4 allele dose effect in two clinical cohorts (ADNI and KIDS). Sex-APOE interactions were further analyzed in EFAD mice carrying human APOE alleles and familial AD genes. At 7 months, E4FAD mice had cerebral cortex microbleeds with female excess, in contrast to humans. Cerebral amyloid angiopathy (CAA), plaques, and soluble Aβ also showed female excess. Both the cerebral microbleeds and CAA increased in proportion to individual Aβ load. In humans, the opposite sex bias of APOE4 allele for microbleeds vs the plaques and tangles is the first example of organ-specific, sex-linked APOE allele effects, and further shows AD as a uniquely human condition.

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“…In a study involving a population with modern reproductive patterns, however, the APOE e4 allele, a recognized risk allele for Alzheimer's disease and cardiovascular disease which prevents the attainment of advanced age 37 , was found to be associated with reduced fertility 40 , showing a negative pleiotropic action on both survival and fertility in modern populations. A more recent study has suggested that it may predispose to higher fertility 41 .…”

Section: Rejuvenation Researchmentioning

confidence: 98%

Genetic Basis of the Relationship Between Reproduction and Longevity: A Study on Common Variants of Three Genes in Steroid Hormone Metabolism—CYP17, HSD17B1, and COMT

Scarabino

Scacchi

Pinto

et al. 2015

Rejuvenation Research

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Evolutionary theories of aging predict an antagonistic relationship between fertility and life span in humans, but the genetic basis of this phenomenon is not clear. The variation of three genes in steroid hormone metabolism--CYP17 (rs743572), HSD17B1 (rs 605059), and COMT (rs4680)--was examined to elucidate the genetic basis of the relationship between fertility and life span. A sample of 277 individuals (mean age, 82.9 years) was recruited in 2000. On the basis of mortality data collected in 2009, the sample was divided into two groups of subjects surviving to over 90 years (long-lived) or not (controls). Fertility data (number of children) were collected in the same sample. The HSD17B1 AA genotype was found to be significantly associated (p = 0.0085) with longevity only in the females (estimated odds ratio = 3.77). Because the HSD17B1 AA genotype was also associated with a higher number of children (5.3 ± 2.1) than the other genotypes (p = 0.006), we may infer that HSD17B1 genotypes could exert a positive pleiotropic action on longevity and fertility. CYP17 and COMT gene variation did not influence either life span or fertility. We then searched the literature for genes studied in relation to both reproduction and aging. A review of the studies showed a pleiotropic action for six out of 16 genes and revealed that genes may exert positive, or negative, or antagonistic pleiotropic actions. These potential actions may be modified by such environmental factors such as changing reproductive behaviors, which seem to be able to mitigate or enhance a gene's phenotypic effects.

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Apolipoprotein E ( ApoE ) polymorphism is related to differences in potential fertility in women: a case of antagonistic pleiotropy?

Cited by 56 publications

References 73 publications

Effect of APOE ε4 allele on survival and fertility in an adverse environment

Effect of APOE ε4 allele on survival and fertility in an adverse environment

The APOE4 allele shows opposite sex bias in microbleeds and Alzheimer's disease of humans and mice

Genetic Basis of the Relationship Between Reproduction and Longevity: A Study on Common Variants of Three Genes in Steroid Hormone Metabolism—CYP17, HSD17B1, and COMT

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