Sex steroids, growth factors and mammographic density: a cross-sectional study of UK postmenopausal Caucasian and Afro-Caribbean women

INTRODUCTION: Sex steroids, insulin-like growth factors (IGFs) and prolactin are breast cancer risk factors but whether their effects are mediated through mammographic density, one of the strongest risk factors for breast cancer, is unknown. If such a hormonal basis of mammographic density exists, hormones may underlie ethnic differences in both mammographic density and breast cancer incidence rates. METHODS: In a cross-sectional study of 270 postmenopausal Caucasian and Afro-Caribbean women attending a population-based breast screening service in London, UK, we investigated whether plasma biomarkers (oestradiol, oestrone, sex hormone binding globulin (SHBG), testosterone, prolactin, leptin, IGF-I, IGF-II and IGF binding protein 3 (IGFBP3)) were related to and explained ethnic differences in mammographic percent density, dense area and nondense area, measured in Cumulus using the threshold method. RESULTS: Mean levels of oestrogens, leptin and IGF-I:IGFBP3 were higher whereas SHBG and IGF-II:IGFBP3 were lower in Afro-Caribbean women compared with Caucasian women after adjustment for higher mean body mass index (BMI) in the former group (by 3.2 kg/m(2) (95% confidence interval (CI): 1.8, 4.5)). Age-adjusted percent density was lower in Afro-Caribbean compared with Caucasian women by 5.4% (absolute difference), but was attenuated to 2.5% (95% CI: -0.2, 5.1) upon BMI adjustment. Despite ethnic differences in biomarkers and in percent density, strong ethnic-age-adjusted inverse associations of oestradiol, leptin and testosterone with percent density were completely attenuated upon adjustment for BMI. There were no associations of IGF-I, IGF-II or IGFBP3 with percent density or dense area. We found weak evidence that a twofold increase in prolactin and oestrone levels were associated, respectively, with an increase (by 1.7% (95% CI: -0.3, 3.7)) and a decrease (by 2.0% (95% CI: 0, 4.1)) in density after adjustment for BMI. CONCLUSIONS: These findings suggest that sex hormone and IGF levels are not associated with BMI-adjusted percent mammographic density in cross-sectional analyses of postmenopausal women and thus do not explain ethnic differences in density. Mammographic density may still, however, be influenced by much higher premenopausal hormone levels

Mammographic density and ageing:A collaborative pooled analysis of cross-sectional data from 22 countries worldwide

BACKGROUND: Mammographic density (MD) is one of the strongest breast cancer risk factors. Its age-related characteristics have been studied in women in western countries, but whether these associations apply to women worldwide is not known. METHODS AND FINDINGS: We examined cross-sectional differences in MD by age and menopausal status in over 11,000 breast-cancer-free women aged 35-85 years, from 40 ethnicity- and location-specific population groups across 22 countries in the International Consortium on Mammographic Density (ICMD). MD was read centrally using a quantitative method (Cumulus) and its square-root metrics were analysed using meta-analysis of group-level estimates and linear regression models of pooled data, adjusted for body mass index, reproductive factors, mammogram view, image type, and reader. In all, 4,534 women were premenopausal, and 6,481 postmenopausal, at the time of mammography. A large age-adjusted difference in percent MD (PD) between post- and premenopausal women was apparent (-0.46 cm [95% CI: -0.53, -0.39]) and appeared greater in women with lower breast cancer risk profiles; variation across population groups due to heterogeneity (I2) was 16.5%. Among premenopausal women, the √PD difference per 10-year increase in age was -0.24 cm (95% CI: -0.34, -0.14; I2 = 30%), reflecting a compositional change (lower dense area and higher non-dense area, with no difference in breast area). In postmenopausal women, the corresponding difference in √PD (-0.38 cm [95% CI: -0.44, -0.33]; I2 = 30%) was additionally driven by increasing breast area. The study is limited by different mammography systems and its cross-sectional rather than longitudinal nature. CONCLUSIONS: Declines in MD with increasing age are present premenopausally, continue postmenopausally, and are most pronounced over the menopausal transition. These effects were highly consistent across diverse groups of women worldwide, suggesting that they result from an intrinsic biological, likely hormonal, mechanism common to women. If cumulative breast density is a key determinant of breast cancer risk, younger ages may be the more critical periods for lifestyle modifications aimed at breast density and breast cancer risk reduction

Variants in RBP4 and AR genes modulate age at onset in familial amyloid polyneuropathy (FAP ATTRV30M)

Familial amyloid polyneuropathy (FAP) ATTRV30M is a neurodegenerative disorder due to point mutations in the transthyretin gene, with V30M being the commonest. FAP ATTRV30M shows a wide variation in age at onset (AO) between clusters, families and generations. Portuguese patients also show remarkable AO differences between genders. Genes found to be associated with FAP ATTRV30M pathways may act as AO modifiers. Our aim was to further explore the role of APCS and RBP4 genes and to study for the first time the involvement of sex-linked genetic modifiers - AR and HSD17B1 genes - in AO variation in Portuguese families. We collected DNA from a sample of 318 patients, currently under follow-up. A total of 18 tagging SNPs from APCS, RBP4, AR and HSD17B1 and 5 additional SNPs from APCS and RBP4 previously studied were genotyped. To account for nonindependency of AO between members of the same family, we used generalized estimating equations (GEEs). We found that APCS and RBP4 were associated with late AO. In addition, rs11187545 of the RBP4 was associated with an early AO. For the AR, in the male group three SNPs were associated with an early AO, whereas in the female group four were associated with both an early and later AO. These results strengthened the role of APCS and RBP4 genes and revealed for the first time the contribution of AR genes as an AO modifier in both males and females. These findings may have important implications in genetic counseling and for new therapeutic strategies

The genetic architecture of the human cerebral cortex

The cerebral cortex underlies our complex cognitive capabilities, yet little is known about the specific genetic loci that influence human cortical structure. To identify genetic variants that affect cortical structure, we conducted a genome-wide association meta-analysis of brain magnetic resonance imaging data from 51,665 individuals. We analyzed the surface area and average thickness of the whole cortex and 34 regions with known functional specializations. We identified 199 significant loci and found significant enrichment for loci influencing total surface area within regulatory elements that are active during prenatal cortical development, supporting the radial unit hypothesis. Loci that affect regional surface area cluster near genes in Wnt signaling pathways, which influence progenitor expansion and areal identity. Variation in cortical structure is genetically correlated with cognitive function, Parkinson's disease, insomnia, depression, neuroticism, and attention deficit hyperactivity disorder

A scoping review of survey research with gender minority adolescents and youth in low and middle-income countries

Background: Survey data that categorizes gender identity in binary terms and conflates sex and gender limits knowledge around the experience of gender minority populations, whose gender identity or expression does not align with the sex they were assigned at birth. In this review, we outline the existing survey research on the experience of a gender minority demographic for whom there is particularly limited data: adolescents and youth in low and middle-income countries (LMICs). Methods: This paper is a scoping review of peer-reviewed articles, published in English, that use survey data to examine the experience of gender minority adolescents and youth in LMICs. We conducted a search on two major databases using key terms related to gender identity, adolescence and youth, and country and region. This search yielded 385 articles. Following a team-conducted review, we retained 33 articles for the final analysis. Results: Our review shows that surveys with adolescents and youth in LMICs are increasingly including questions and taking sampling approaches that allow gender minority populations to be visible in survey data. Surveys that do so are largely focused in upper middle-income countries (n = 24), rather than lower middle-income or low-income countries, with South East Asia a notable sub-region of focus (n = 15). Sexual health, mental health, and violence are key topics of interest. Most of the surveys rely on some form of network-driven sampling focused on sexual and/or gender minorities (n = 22). The studies vary in how they ask about gender identity, both in terms of question formulation and the answer categories that are offered, as well as the extent to which they describe the questions in the article text. Conclusions: This review reveals a growing body of work that provides important insights into the experiences of gender minority adolescents and youth in LMICs. More studies could integrate these approaches, but it must be done in a way that is thoughtful about cultural and political context. Given the relatively nascent nature of such research, we encourage scholars to continue providing details on methodology, including around participant recruitment and the development of gender identity questions. This information would be valuable for researchers seeking to better include gender minorities and their experiences in survey research, but who might be daunted methodologically

A scoping review of survey research with gender minority adolescents and youth in low and middle-income countries

Background Survey data that categorizes gender identity in binary terms and conflates sex and gender limits knowledge around the experience of gender minority populations, whose gender identity or expression does not align with the sex they were assigned at birth. In this review, we outline the existing survey research on the experience of a gender minority demographic for whom there is particularly limited data: adolescents and youth in low and middle-income countries (LMICs). Methods This paper is a scoping review of peer-reviewed articles, published in English, that use survey data to examine the experience of gender minority adolescents and youth in LMICs. We conducted a search on two major databases using key terms related to gender identity, adolescence and youth, and country and region. This search yielded 385 articles. Following a team-conducted review, we retained 33 articles for the final analysis. Results Our review shows that surveys with adolescents and youth in LMICs are increasingly including questions and taking sampling approaches that allow gender minority populations to be visible in survey data. Surveys that do so are largely focused in upper middle-income countries (n = 24), rather than lower middle-income or low-income countries, with South East Asia a notable sub-region of focus (n = 15). Sexual health, mental health, and violence are key topics of interest. Most of the surveys rely on some form of network-driven sampling focused on sexual and/or gender minorities (n = 22). The studies vary in how they ask about gender identity, both in terms of question formulation and the answer categories that are offered, as well as the extent to which they describe the questions in the article text. Conclusions This review reveals a growing body of work that provides important insights into the experiences of gender minority adolescents and youth in LMICs. More studies could integrate these approaches, but it must be done in a way that is thoughtful about cultural and political context. Given the relatively nascent nature of such research, we encourage scholars to continue providing details on methodology, including around participant recruitment and the development of gender identity questions. This information would be valuable for researchers seeking to better include gender minorities and their experiences in survey research, but who might be daunted methodologically

CYP3A variation, premenopausal estrone levels, and breast cancer risk.

BACKGROUND: Epidemiological studies have provided strong evidence for a role of endogenous sex steroids in the etiology of breast cancer. Our aim was to identify common variants in genes involved in sex steroid synthesis or metabolism that are associated with hormone levels and the risk of breast cancer in premenopausal women. METHODS: We measured urinary levels of estrone glucuronide (E1G) using a protocol specifically developed to account for cyclic variation in hormone levels during the menstrual cycle in 729 healthy premenopausal women. We genotyped 642 single-nucleotide polymorphisms (SNPs) in these women; a single SNP, rs10273424, was further tested for association with the risk of breast cancer using data from 10 551 breast cancer case patients and 17 535 control subjects. All statistical tests were two-sided. RESULTS: rs10273424, which maps approximately 50 kb centromeric to the cytochrome P450 3A (CYP3A) gene cluster at chromosome 7q22.1, was associated with a 21.8% reduction in E1G levels (95% confidence interval [CI] = 27.8% to 15.3% reduction; P = 2.7 × 10(-9)) and a modest reduction in the risk of breast cancer in case patients who were diagnosed at or before age 50 years (odds ratio [OR] = 0.91, 95% CI = 0.83 to 0.99; P = .03) but not in those diagnosed after age 50 years (OR = 1.01, 95% CI = 0.93 to 1.10; P = .82). CONCLUSIONS: Genetic variation in noncoding sequences flanking the CYP3A locus contributes to variance in premenopausal E1G levels and is associated with the risk of breast cancer in younger patients. This association may have wider implications given that the most predominantly expressed CYP3A gene, CYP3A4, is responsible for metabolism of endogenous and exogenous hormones and hormonal agents used in the treatment of breast cancer

Landmark of the past in the Antequera megalithic landscape: a multi-disciplinary approach to the Matacabras rock art shelter

The background of this paper is the biographical relationship between the Menga dolmen and La Peña de los Enamorados mountain (a conspicuous and highly-recognisable natural formation), both part of the Antequera megalithic landscape. Our main aim is to provide a high-resolution characterisation of the Matacabras rock art shelter, located on the northern side of La Peña de los Enamorados. This is achieved through a photogrammetric topographic survey, a detailed assessment of the graphic motifs identified through the use of digital image processing and various types of physical and chemical analysis, a geochemical characterisation of pottery found on its surface, and 22 a comparative stylistic analysis of its motifs. Our study suggests that Matacabras (and the site of Piedras Blancas I, located just below it), played an important role in the genesis of Menga, which perhaps makes it the most important rock art location of Spanish Late Prehistory