Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

Batton, Kyle A.; Austin, Christopher O.; Bruno, Katelyn A.; Burger, Charles D.; Shapiro, Brian P.; Fairweather, De Lisa

doi:10.1186/s13293-018-0176-8

Cited by 62 publications

(62 citation statements)

References 194 publications

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“…However, there was an enrichment of child-onset cases (95/268, 37.2%, p<0.0001 by Chi-square) in the APAH-CHD subclass. As has been reported previously for adult populations 24 , there was an overall 3.7:1 ratio of females to males, with a 9:1 ratio for PAH associated with autoimmune disease and 1:1.2 ratio for the portopulmonary subclass. The genetic ancestries included European (72%), Hispanic (12%), African (11%), East Asian (2.7%) and South Asian (1.1%), fairly equally distributed amongst PAH subclasses.…”

Section: Cohort Characteristicssupporting

confidence: 85%

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Zhu

Pauciulo

Welch

et al. 2019

Preprint

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Group 1 pulmonary arterial hypertension (PAH) is a rare disease with high mortality despite recent therapeutic advances. Pathogenic remodeling of pulmonary arterioles leads to increased pulmonary pressures, right ventricular hypertrophy and heart failure. Mutations in bone morphogenetic protein receptor type 2 and other risk genes predispose to disease, but the vast majority of non-familial cases remain genetically undefined. To identify new risk genes, we performed exome sequencing in a large cohort from the National Biological Sample and Data Repository for PAH. By statistical association of rare deleterious variants, we found tissue kallikrein 1 and gamma glutamyl carboxylase as new candidate risk genes for idiopathic PAH associated with a later age-of-onset and relatively moderate disease phenotype compared to bone morphogenetic receptor type 2. Both genes play important roles in vascular hemodynamics and inflammation but have not been implicated in PAH previously. These data suggest new genes, pathogenic mechanisms and therapeutic targets for this lethal vasculopathy.Word count: 154

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Section: Cohort Characteristicssupporting

confidence: 85%

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Zhu

Pauciulo

Welch

et al. 2019

Preprint

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“…Familial segregation has been reported in approximately 6-10% of all patients with PAH, wherein the disease segregates as a monogenic, autosomal dominant trait with incomplete penetrance, ranging from 14% in males to 42% in females 12 . PAH is observed much more frequently in females, with a ratio of occurrence in women to men ranging between 2:1 and 4:1, which reflects the distinctions across different patient populations and PAH subtypes 13 .…”

Section: [H1] Introductionmentioning

confidence: 99%

Molecular genetic framework underlying pulmonary arterial hypertension

et al. 2019

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| Pulmonary arterial hypertension (PAH) is a rare, progressive disorder typified by occlusion of the pulmonary arterioles owing to endothelial dysfunction and uncontrolled proliferation of pulmonary artery smooth muscle cells and fibroblasts. Vascular occlusion can lead to increased pressure in the pulmonary arteries, often resulting in right ventricular failure with shortness of breath and syncope. Since the identification of BMPR2, which encodes a receptor in the transforming growth factor-β superfamily, the development of highthroughput sequencing approaches to identify novel causal genes has substantially advanced our understanding of the molecular genetics of PAH. In the past 6 years, additional pathways involved in PAH susceptibility have been described through the identification of deleterious genetic variants in potassium channels (KCNK3 and ABCC8) and transcription factors (TBX4 and SOX17), among others. Although familial PAH most often has an autosomal dominant pattern of inheritance, cases of incomplete penetrance and evidence of genetic heterogeneity support a model of PAH as a Mendelian disorder with complex disease features. In this Review, we outline the latest advances in the detection of rare and common genetic variants underlying PAH susceptibility and disease progression. These findings have clinical implications on lung vascular function and can help to identify mechanistic pathways amenable to pharmacological intervention. P ag e | 2

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“…In the past two decades, data coming from various registries worldwide have confirmed the early observations of female preponderance of PAH made in the 1950s by Doctors Drexler and Wood [1,2]. The female-to-male (F:M) ratio in PAH ranges from 2:1 to 4:1, and even higher (4:1 to 9:1) in PAH associated with connective-tissue diseases (CTD) [3][4][5][6]. In elderly PAH patients, the gender bias disappears (F:M-1.2:1.0) [7], suggesting that female sex hormones are a risk factor for developing PAH.…”

Section: Introductionmentioning

confidence: 83%

“…For example, ERα signaling promotes T cell activation and proliferation and contributes to T cell-mediated autoimmune inflammation [202]. Women more frequently develop various autoimmune diseases (including systemic sclerosis, systemic lupus erythematosus, mixed connective tissue disease, and rheumatoid arthritis) that are associated with increased risk of PAH [5]. The autoimmune inflammation may have significant effects on EMet and E2 levels.…”

Section: Inflammation Immunity and Estradiol Metabolism In Pahmentioning

confidence: 99%

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

Tofovic

Jackson

2019

IJMS

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Pulmonary arterial hypertension (PAH) is a debilitating and progressive disease that predominantly develops in women. Over the past 15 years, cumulating evidence has pointed toward dysregulated metabolism of sex hormones in animal models and patients with PAH. 17β-estradiol (E2) is metabolized at positions C2, C4, and C16, which leads to the formation of metabolites with different biological/estrogenic activity. Since the first report that 2-methoxyestradiol, a major non-estrogenic metabolite of E2, attenuates the development and progression of experimental pulmonary hypertension (PH), it has become increasingly clear that E2, E2 precursors, and E2 metabolites exhibit both protective and detrimental effects in PH. Furthermore, both experimental and clinical data suggest that E2 has divergent effects in the pulmonary vasculature versus right ventricle (estrogen paradox in PAH). The estrogen paradox is of significant clinical relevance for understanding the development, progression, and prognosis of PAH. This review updates experimental and clinical findings and provides insights into: (1) the potential impacts that pathways of estradiol metabolism (EMet) may have in PAH; (2) the beneficial and adverse effects of estrogens and their precursors/metabolites in experimental PH and human PAH; (3) the co-morbidities and pathological conditions that may alter EMet and influence the development/progression of PAH; (4) the relevance of the intracrinology of sex hormones to vascular remodeling in PAH; and (5) the advantages/disadvantages of different approaches to modulate EMet in PAH. Finally, we propose the three-tier-estrogen effects in PAH concept, which may offer reconciliation of the opposing effects of E2 in PAH and may provide a better understanding of the complex mechanisms by which EMet affects the pulmonary circulation–right ventricular interaction in PAH.

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Sex differences in pulmonary arterial hypertension: role of infection and autoimmunity in the pathogenesis of disease

Cited by 62 publications

References 194 publications

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Novel risk genes and mechanisms implicated by exome sequencing of 2,572 individuals with pulmonary arterial hypertension

Molecular genetic framework underlying pulmonary arterial hypertension

Estradiol Metabolism: Crossroads in Pulmonary Arterial Hypertension

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