The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases

Natri, Heini M.; García, Angela R.; Buetow, Kenneth H.; Trumble, Benjamin C.; Wilson, Melissa A.

doi:10.1016/j.tig.2019.04.008

Cited by 107 publications

(120 citation statements)

References 85 publications

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“…The 'pregnancy-compensation hypothesis' (70) suggests that women's immune system ramps up throughout adulthood to prepare for a sequence of pregnancies, as from an evolutionary perspective and before birth control, the majority of women would have been pregnant for many of their adult years. According to Natri and colleagues, problems may arise when the 'expected' pregnancies fail to occur; without a frequent push-back from pregnancy-related mechanisms, the immune system can become overly elevated and start releasing auto-antibodies that attack healthy cells (70). Positive effects of parity on the brain may thus reflect mechanisms related to immune factors rather than estrogen fluctuations involved in pregnancy (40).…”

Section: Discussionmentioning

confidence: 99%

Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease

A-M.

Barth

Kaufmann

et al. 2019

Preprint

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Estrogen exposure may influence women's risk of Alzheimer's disease, but little is known about how it affects normal brain aging. Recent findings from the UK Biobank demonstrate less evidence of brain aging in women with a history of multiple childbirths. Here, we investigated the link between brain aging, estrogen exposure, and APOE genotype beyond the effects of parity in 16,854 UK Biobank women. Machine learning was used to predict brain age based on neuroimaging-derived measures, and the difference between an individual's predicted and chronological age was used as an estimate of brain aging. Cumulative estrogen exposure was estimated using an index including age at menarche and menopause, BMI, time since menopause, and duration of hormone replacement therapy. Endogenous hormone exposure was approximated by reproductive span, while exogenous exposure was estimated by usage, onset, and duration of hormone replacement therapy and oral contraceptives. Higher cumulative, endogenous, and exogenous estrogen exposure were each linked to higher brain age relative to chronological age. Earlier onset of hormone replacement therapy, particularly before menopause, was associated with less evident brain aging in APOE e4 carriers only, while higher circulating estradiol levels during menopause were linked to more evident brain aging in carriers and less evident brain aging in non-carriers. The results indicate that estrogen exposure and parity may differentially relate to women's brain aging, and that APOE e4-specific associations between estrogen and brain aging may be of importance for optimizing hormone replacement therapy regimes in perimenopausal women. Women's health | Estrogens | Parity | Apolipoproteins E | Neuroimaging | Machine learningCorrespondence: a.m.g.d.lange@psykologi.uio.no claudia.barth@medisin.uio.no

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Section: Discussionmentioning

confidence: 99%

Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease

A-M.

Barth

Kaufmann

et al. 2019

Preprint

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“…Most women do not manifest X-linked disorders because (1) they are not homozygous for the pathogenic variant, and (2) their variant cells (those expressing the deleterious allele) receive sufficient gene product to carry out the essential metabolic function from the cells that transcribe the normal allele.…”

Section: Females Can Ameliorate the Effects Of Pathogenic Variantsmentioning

confidence: 99%

“…Sex differences in human disease are usually attributed to sex specific life experiences, and sex hormones that influence the function of susceptible genes throughout the genome. [1][2][3][4][5] Such factors do account for some dissimilarities. However, a major cause of sex-determined expression of disease has to do with differences in how males and females transcribe their gene-rich human X chromosomes, which is often underappreciated as a cause of sex differences in disease.…”

Section: Introductionmentioning

confidence: 99%

X-linked diseases: susceptible females

Migeon

2020

Genetics in Medicine

120

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The role of X-inactivation is often ignored as a prime cause of sex differences in disease. Yet, the way males and females express their X-linked genes has a major role in the dissimilar phenotypes that underlie many rare and common disorders, such as intellectual deficiency, epilepsy, congenital abnormalities, and diseases of the heart, blood, skin, muscle, and bones. Summarized here are many examples of the different presentations in males and females. Other data include reasons why women are often protected from the deleterious variants carried on their X chromosome, and the factors that render women susceptible in some instances.

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“…When further investigation revealed that the only known function or disease was related with the immune system, and there were no arguments to be assigned to another system, the genes were annotated as ISRG, e.g. CXorf21 [33], DOCK11 [34], GAB3 [35] (Additional file 3). All these were confirmed by the GO approach.…”

Section: Discussionmentioning

confidence: 99%

SeXY chromosomes and the immune system: reflections after a comparative study

et al. 2020

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Background: Sex bias in immune function has been contributed in part to a preponderance of immune systemrelated genes (ISRG) on the X-chromosome. We verified whether ISRG are more abundant on the X chromosome as compared to autosomal chromosomes and reflected on the impact of our findings. Methods: Consulting freely accessible databases, we performed a comparative study consisting of three complementary strategies. First, among coding X/Y-linked genes, the abundance of ISRG was compared to the abundance of genes dedicated to other systems. Genes were assigned considering three criteria: disease, tissue expression, and function (DEF approach). In addition, we carried out two genome-wide approaches to compare the contribution of sex and autosomal chromosomes to immune genes defined by an elevated expression in lymphatic tissues (LTEEG approach) or annotation to an immune system process, GO:0002376 (GO approach).Results: The X chromosome had less immune genes than the median of the autosomal chromosomes. Among Xlinked genes, ISRG ranked fourth after the reproductive and nervous systems and genes dedicated to development, proliferation and apoptosis. On the Y chromosome, ISRG ranked second, and at the pseudoautosomal region (PAR) first. According to studies on the expression of X-linked genes in a variety of (mostly non-lymphatic) tissues, almost two-thirds of ISRG are expressed without sex bias, and the remaining ISRG presented female and male bias with similar frequency. Various epigenetic controllers, X-linked MSL3 and Y-linked KDM5D and UTY, were preferentially expressed in leukocytes and deserve further attention for a possible role in sex biased expression or its neutralisation. Conclusions: The X chromosome is not enriched for ISRG, though particular X-linked genes may be responsible for sex differences in certain immune responses. So far, there is insufficient information on sex-biased expression of X/ Y-linked ISRG in leukocytes to draw general conclusions on the impact of X/Y-linked ISRG in immune function. More research on the regulation of the expression X-linked genes is required with attention to 1) female and male mechanisms that may either augment or diminish sex biased expression and 2) tissue-specific expression studies.

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The Pregnancy Pickle: Evolved Immune Compensation Due to Pregnancy Underlies Sex Differences in Human Diseases

Cited by 107 publications

References 85 publications

Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease

Women’s brain aging: effects of sex-hormone exposure, pregnancies, and genetic risk for Alzheimer’s disease

X-linked diseases: susceptible females

SeXY chromosomes and the immune system: reflections after a comparative study

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