Gender-specific effects in physiology, pathophyiology and longevity

Child Health And Human Development

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Abstract

Since the early1960s when Mary Lyon advanced the elegant concept of random X-inactivation in (46,XX) female cells as a form of sex chromosome dosage compensation, the 2nd X chromosome was considered totally inert. Given the view that each sex had only one functional X chromosome, it was assumed until very recently that the only genetic difference between sexes derived from Y chromosome, testis determining genes. Thus, phenotypic differences between the sexes were attributed to differential exposure to gonadal secretions, e.g., estrogen in females and androgen in males. While many sex differences are clearly due to differential exposure to sex steroids, some important distinctions, in particular the greater longevity of women, are not adequately explained by sex steroid effects. Moreover, it was was difficult to reconcile the view that only one X chromosome was actually functional in normal females with the fact that there is a distinct phenotype in girls with monosomy for the X chromosome, or Turner syndrome (TS). Indeed, the study of TS has shown that the 2nd X chromosome is essential for normal female development.[unreadable] We now know that 20% of genes on the 2nd X chromosome are transcribed. Two types of X-linked genes escape inactivation. Pseudoautosomal X-chromosome genes have Y chromosome homologues and essentially behave like autosomal genes, with expression from both X chromosomes in females and from X- and Y-chromosomes in males. For example, haplo-insufficiency for a pseudoautosomal gene known as SHOX causes short stature and skeletal defects in TS. The second type of gene escaping X-inactivation is unique to the X and has no Y-allele. The expression of such genes from both X chromosomes in females may contribute to female-specific reproductive processes such as oocyte survival, and some sex specific aspects of brain development. Genomic imprinting may also regulate X-chromosome gene expression contributing to male-female differences and to the TS phenotype. Genomic imprinting involves the selective expression of certain genes determined by their parental origin, often associated with DNA methylation of imprinted, or silenced, alleles. Genomic imprinting of X-linked genes causes different gene expression in males and females, since normal women are mosaic for maternally and paternally inherited active X chromosomes (XM and XP), while men are monosomic for XM. Genes imprinted (silenced) on XM would still be expressed in females from 50% of cells, but not expressed in males. The study of girls and women with TS provides a unique opportunity to elucidate X-chromosome gene dosage effects and to improve our understanding of this relatively common genetic disorder which affects approximately 1/2000 females. This research will improve our ability to care for girls and women with TS and enhance our understanding of disease processes such as the increased susceptibility to autoimmune disease in women and increased risk for coronary disease in men.[unreadable] X-chromosome, genomic imprinting and longevity [unreadable] Women enjoy greater longevity than men mainly due to their lower risk, across all age groups, for ischemic heart disease. The key advantage women have in this regard is their salutary, gynoid fat distribution, meaning adipose tissue preferentially concentrated subcutaneously in the hips and thighs. In contrast, normal men tend to concentrate fat in the abdominal area, especially intraperitoneal visceral fat, which has many adverse metabolic effects, including an atherogenic lipid profile and elevated mediators of inflammation- all independently associated with increased cardiovascular risk. Parental imprinting of X-linked genes involved in regional fat distribution and lipid metabolism may have favorable effects in women. For example, an X chromosome gene that prevents intra-abdominal fat deposition could be imprinted, or silenced on XM but active from XP. Since men only receive XM, they would be disadvantaged compared normal women who, because of random X inactivation, express the XP allele in about 50% of their cells. To test the hypothesis that X-chromosome genomic imprinting contributes to the regional fat and metabolic differences between normal women and men, we these factors in groups of women that were monosomic for XM vs. XP.[unreadable] The XM and XP groups had similar BMI and total body fat, but women with a single maternally inherited X-chromosome had 2-fold greater abdominal and specifically intra-abdominal, or visceral fat. This was associated with a distinctly atherogenic lipid profile compared to the paternal X group. The male-type fat distribution and lipid profile in XM women supports the view that differential X-chromosome gene dosage, determined by genomic imprinting, contributes to the excess mortality from ischemic heart disease in 46,XY men. [unreadable] Because of the different parental origins of the X chromosome in males and females, genomic imprinting is predictably associated with differential effects depending on the sex of the offspring (not so in autosomal imprinting). Thus, X-linked imprinting is not expected to regulate traits that are not sexually dimorphic C such as renal or cardiac development. We proved this prediction in a recent study showing equal prevalence of renal and cardiovascular defects in XM vs. XP groups with TS. Somatic size, in contrast, is sexually dimorphic with men typically considerably larger than women, and we have provided evidence that this is related to X chromosome origin.[unreadable] [unreadable] Congenital cardiovascular disease may be the most serious medical problem in monosomy X or TS. Pioneering the use of high resolution magnetic resonance angiography (MRA) in this syndrome, we demonstrated cardiovascular anomalies in 50% of study subjects, in contrast to the previously accepted 20-30% prevalence based on echocardiographic studies. Whereas congenital heart defects in TS were thought limited to left-sided, outflow tract defects, MRA revealed a high prevalence of major venous malformations, including partial anomalous pulmonary venous return and persistent left superior vena cava affecting over 20% of the study population. The most common anomaly defined in our study was a distinctive aortic deformation affecting 50% of women with TS, termed elongated transverse arch of the aorta (ETA). We recently reported the first prospective measure of the incidence of aortic dissection in TS and proposed new guidelines to identify high risk patients. We evaluated aortic diameters and other parameters in a large group of asymptomatic, unselected women with TS and followed these women followed for an average of 3 years. We recorded three cases of aortic dissection among 158 patients during this time. This translates to an incidence of 618 cases per 100,000 TS years, compared to 6 per 100,000 non-TS women year. The women who dissected were in their 40s and had aortic diameters ranging from 3.7-4.8 cm. They were under cardiologist care in their home area, but at less than 5 cm were not considered candidates for prophylactic intervention. We found that aortic diameter/body surface area ((Aortic Size Index, ASI) provided the highest correlation and greatest accuracy in identifying those at risk for dissection. In summary, 25% of the women with absolute ascending aortic diameter >3.5 cm and 33% of the women with ASI > 2.5 cm/m2 experienced aortic dissection within 3 years of follow-up. Thus, for screening purposes, we use ASI 95th percentile 2 cm/m2 for the ascending aorta. This method takes into account the considerable size variation of these patients and identifies about 30% of women with TS that require close monitoring. If the ASI 2.5 cm/m2, the patient shhould be evaluated for prophylactic intervention.