Sex Differences In Association Research Articles

Acute pharmacodynamic responses to sitagliptin: Drug-induced increase in early insulin secretion in oral glucose tolerance test.

DPP4 inhibitors are widely prescribed as treatments for type 2 diabetes. Because drug responses vary among individuals, we initiated investigations to identify genetic variants associated with the magnitude of drug responses. Sitagliptin (100 mg) was administered to 47 healthy volunteers. Several endpoints were measured to assess clinically relevant responses - including the effect of sitagliptin on glucose and insulin levels during an oral glucose tolerance test (OGTT). This pilot study confirmed that sitagliptin (100 mg) decreased the area under the curve for glucose during an OGTT (p = 0.0003). Furthermore, sitagliptin promoted insulin secretion during the early portion of the OGTT as reflected by an increase in the ratio of plasma insulin at 30 min divided by plasma insulin at 60 min (T30:T60) from mean ± SEM 0.87 ± 0.05 to 1.62 ± 0.36 mU/L (p = 0.04). The magnitude of sitagliptin's effect on insulin secretion (as judged by the increase in the T30:T60 ratio for insulin) was correlated with the magnitude of sitagliptin-induced increase in the area under the curve for intact plasma GLP1 levels during the first hour of the OGTT. This study confirmed previously reported sex differences in glucose and insulin levels during an OGTT. Specifically, females exhibited higher levels of glucose and insulin at the 90-180 min time points. However, we did not detect significant sex-associated differences in the magnitude of sitagliptin-induced changes in T30:T60 ratios for either glucose or insulin. In conclusion, T30:T60 ratios for insulin and glucose during an OGTT provide useful indices to assess pharmacodynamic responses to DPP4 inhibitors.

Echocardiographic characterization of age- and sex-associated differences in cardiac function and morphometry in nonhuman primates.

Aging per se is a major risk factor for cardiovascular diseases and is associated with progressive changes in cardiac structure and function. Rodent models are commonly used to study cardiac aging, but do not closely mirror differences as they occur in humans. Therefore, we performed a 2D echocardiographic study in non-human primates (NHP) to establish age- and sex-associated differences in cardiac function and morphometry in this animal model. M mode and 2D echocardiography and Doppler analyses were performed cross-sectionally in 38 healthy rhesus monkeys (20 females and 18 males), both young (age 7-12years; n = 20) and old (age 19-30years; n = 18). The diameters of the cardiac chambers did not differ significantly by age group, but males had larger left ventricular diameters (2.43 vs 2.06cm in diastole and 1.91 vs 1.49cm in systole, p = 0.0004 and p = 0.0001, respectively) and left atrial diameter (1.981 vs 1.732cm; p = 0.0101). Left ventricular mass/body surface area did not vary significantly with age and sex. Ejection fraction did not differ by age and females presented a higher ejection fraction than males (54.0 vs 50.8%, p = 0.0237). Diastolic function, defined by early to late mitral peak flow velocity ratio (E/A), was significantly lower in old rhesus monkeys (2.31 vs 1.43, p = 0.0020) and was lower in females compared to males (1.595 vs 2.230, p = 0.0406). Right ventricular function, evaluated by measuring the Tricuspid Annular Plane Systolic Excursion, did not differ by age or sex, and Right Ventricular Free Wall Longitudinal Strain, did not differ with age but was lower in males than in females (-22.21 vs -17.95%, p = 0.0059). This is the first echocardiographic study to evaluate age- and sex-associated changes of cardiac morphometry and function in young and old NHP. The findings of this work will provide a reference to examine the effect of age and sex on cardiac diseases in NHP.

Incongruence between Cardiorespiratory Fitness and Subjective Reports of Physical Activity in Multiple Sclerosis: A Focus on Sex Differences.

The link between moderate- to vigorous-intensity physical activity (MVPA) and cardiorespiratory fitness in individuals with multiple sclerosis (MS) remains unclear. This study examined the relationship between self-reported MVPA and objectively assessed cardiorespiratory fitness, emphasizing sex differences. 107 adults with MS (77 females), aged (mean ± standard deviation) 47.2 ± 10.2 years, were recruited from a local MS clinic. Fitness was measured as maximal oxygen uptake (V̇O2max) during a graded maximal exercise test using a recumbent stepper. MVPA (24-hour recall) was estimated as the duration of activities ≥ 3 MET (metabolic equivalent of task). MET-minutes were calculated by multiplying MET by duration. We explored sex differences in self-reported MVPA, cardiorespiratory fitness, and disability; examined sex differences in associations between these variables; and investigated whether MET-minutes of MVPA predicted V̇O2max in females and males. Mean V̇O2max was 24.79 mL·kg-1·min-1, indicating poor cardiorespiratory fitness levels, despite high levels of self-reported MVPA (mean = 412.5 MET-minutes). Fifty-three percent of males and 40% of females had V̇O2max levels below the 20th age- and sex-standardized population percentile, indicating poor cardiorespiratory fitness. There were statistically significant associations between MVPA and V̇O2max (Rho = 0.27, p = .01), as well as disability and V̇O2max (Rho = -0.35, p = .02), in females but not males. A regression model using sex, age, body mass, disability, and MVPA to estimate V̇O2max was valid in predicting V̇O2max values that were statistically equivalent to those measured in the laboratory in females but not males. However, the inclusion of MVPA did not add to the predictive value of this equation. Despite reporting high levels of MVPA, people with MS had poor cardiorespiratory fitness. MVPA, fitness, and disability were associated in females only, indicating that sex differences should be considered in fitness appraisal. Self-reported MVPA did not predict fitness, suggesting 24-hour recall may not be representative of true activity or fitness levels in persons with MS. Future work should examine sex differences in associations between MVPA and fitness using objective measures such as accelerometry.

Sex-associated differences in cardiac ageing: Clinical aspects and molecular mechanisms.

Despite the extensive clinical and scientific advances in prevention, diagnostics and treatment, cardiovascular diseases (CVD) remain the leading cause of morbidity and mortality worldwide for people aged 65 and over. Of all ageing-related diseases, CVD are responsible for almost one-third of deaths in the elderly, being above all cancers combined. Age is an independent and unavoidable risk factor contributing to the impairment of heart and blood vessels. As the average age of the population in industrialized countries has doubled in the last century, and almost a fifth of the world's population is predicted to be over 65 in the next decade, we can assume that the burden of CVD will fall primarily on the elderly. Evidence from basic and clinical science has shown that sex significantly influences the onset and severity of CVD. In women, CVD usually develop later than in men and with atypical symptomatology. After menopause, however, the incidence and severity of CVD increase in women, reaching equality in both sexes. Although intrinsic sexual dimorphism in cardiovascular ageing may contribute to the sex differences in CVD progression, the molecular mechanisms associated with cardiovascular ageing and their clinical value are not known in detail. In this review, we discuss the scientific knowledge available, focusing on structural, hormonal, genetic/epigenetic and inflammatory pathways, seeking to transfer these findings to the cardiovascular clinic in terms of prevention, diagnosis, prognosis and management of these pathologies and proposing possible validation of target specifics.

Peripheral Blood Cells From Older Adults Exhibit Sex-Associated Differences in Mitochondrial Function.

Blood-based mitochondrial bioenergetic profiling is a feasible, economical, and minimally invasive approach that can be used to examine mitochondrial function and energy metabolism in human subjects. In this study, we use 2 complementary respirometric techniques to evaluate mitochondrial bioenergetics in both intact and permeabilized peripheral blood mononuclear cells (PBMCs) and platelets to examine sex dimorphism in mitochondrial function among older adults. Employing equal numbers of PBMCs and platelets to assess mitochondrial bioenergetics, we observe significantly higher respiration rates in female compared to male participants. Mitochondrial bioenergetic differences remain significant after controlling for independent parameters including demographic parameters (age, years of education), and cognitive parameters (mPACC5, COGDX). Our study illustrates that circulating blood cells, immune cells in particular, have distinctly different mitochondrial bioenergetic profiles between females and males. These differences should be taken into account as blood-based bioenergetic profiling is now commonly used to understand the role of mitochondrial bioenergetics in human health and aging.

Parental status and markers of brain and cellular age: A 3D convolutional network and classification study

Recent research shows prominent effects of pregnancy and the parenthood transition on structural brain characteristics in humans. Here, we present a comprehensive study of how parental status and number of children born/fathered links to markers of brain and cellular ageing in 36,323 UK Biobank participants (age range 44.57–82.06 years; 52% female). To assess global effects of parenting on the brain, we trained a 3D convolutional neural network on T1-weighted magnetic resonance images, and estimated brain age in a held-out test set. To investigate regional specificity, we extracted cortical and subcortical volumes using FreeSurfer, and ran hierarchical clustering to group regional volumes based on covariance. Leukocyte telomere length (LTL) derived from DNA was used as a marker of cellular ageing. We employed linear regression models to assess relationships between number of children, brain age, regional brain volumes, and LTL, and included interaction terms to probe sex differences in associations. Lastly, we used the brain measures and LTL as features in binary classification models, to determine if markers of brain and cellular ageing could predict parental status. The results showed associations between a greater number of children born/fathered and younger brain age in both females and males, with stronger effects observed in females. Volume-based analyses showed maternal effects in striatal and limbic regions, which were not evident in fathers. We found no evidence for associations between number of children and LTL. Classification of parental status showed an Area under the ROC Curve (AUC) of 0.57 for the brain age model, while the models using regional brain volumes and LTL as predictors showed AUCs of 0.52. Our findings align with previous population-based studies of middle- and older-aged parents, revealing subtle but significant associations between parental experience and neuroimaging-based surrogate markers of brain health. The findings further corroborate results from longitudinal cohort studies following parents across pregnancy and postpartum, potentially indicating that the parenthood transition is associated with long-term influences on brain health.

Exploring the sex-associated differences in molars fused roots

BackgroundHuman sexual dimorphism is associated with many biological characteristics, including dental variables. ObjectivesTo investigate if molars fused roots present sex-associated differences. MethodsPanoramic radiographs were used to investigate the frequency and distribution of permanent molars fused roots. Only patients with all first and second permanent molars were included. Third molars were not investigated. Any molar with roots fused apical to the usual furcal position were considered molar fused roots. Comparisons between males and females were performed using chi-square or Fisher’s and Mann-Whitney tests and the established alpha was 5% (p<0.05). Sex-differential liability models were also proposed. ResultsA total of 84 males and 86 females were included and 1360 molars were analyzed. Among them, 46 (26.06%) present at least one molar with fused root. Second maxillary molars were the most affected teeth. There was an association between sex and molars with fused roots. Females had a 3.4 higher chance to present fused roots than males (OR=3.4, CI 95% 1.6–6.8; p=0.0008). The female: male ratio of molars with fused roots was 2.5:1. The number of molars with fused roots ranged from 1 to 6 per patient, and the mean number of Females presented more molars with fused roots (mean = 1.01; standard deviation = 1.52) than males (mean = 0.31; standard deviation = 0.85) (p<0.05). ConclusionsMolar fused root of permanent teeth presents sex-associated differences, in which females are more affected than males. Our results support sex-differential liability models for molars fused roots.

Sex- and species-associated differences in complement-mediated immunity in humans and rhesus macaques.

The complement system can be viewed as a "moderator" of innate immunity, "instructor" of humoral immunity, and "regulator" of adaptive immunity. While sex is known to affect humoral and cellular immune systems, its impact on complement in humans and rhesus macaques, a commonly used non-human primate model system, has not been well studied. To address this knowledge gap, we analyzed serum samples from 90 humans and 72 rhesus macaques for the abundance and activity of the complement system components. While sequences of cascade proteins were highly conserved, dramatically different levels were observed between species. Whereas the low levels detected in rhesus samples raised questions about the suitability of the test for use with macaque samples, differences in levels of complement proteins were observed in male and female humans. Levels of total and antibody-dependent deposition of C1q and C3b on a glycosylated antigen differed between humans and rhesus, suggesting differential recognition of glycans and balance between classical and alternative activation pathways. Functional differences in complement-mediated lysis of antibody-sensitized cells were observed in multiple assays and showed that human females frequently exhibited higher lytic activity than human males or rhesus macaques, which typically did not exhibit such sex-associated differences. Other differences between species and sexes were observed in more narrow contexts-for only certain antibodies, antigens, or assays. Collectively, these results expand knowledge of sex-associated differences in the complement system in humans, identifying differences absent from rhesus macaques.IMPORTANCEThe complement system is a critical part of host defense to many bacterial, fungal, and viral infections. In parallel, rich epidemiological, clinical, and biomedical research evidence demonstrates that sex is an important biological variable in immunity, and many sex-specific differences in immune system are intimately tied with disease outcomes. This study focuses on the intersection of these two factors to define the impact of sex on complement pathway components and activities. This work expands our knowledge of sex-associated differences in the complement system in humans and also identifies the differences that appear to be absent in rhesus macaques, a popular non-human primate model. Whereas differences between species suggest potential limitations in the ability of macaque model to recapitulate human biology, knowledge of sex-based differences in humans has the potential to inform clinical research and practice.

Sex Differences under Vitamin D Supplementation in an Animal Model of Progressive Multiple Sclerosis.

A central role for vitamin D (VD) in immune modulation has recently been recognized linking VD insufficiency to autoimmune disorders that commonly exhibit sex-associated differences. Similar to other autoimmune diseases, there is a higher incidence of multiple sclerosis (MS) in women, but a poorer prognosis in men, often characterized by a more rapid progression. Although sex hormones are most likely involved, this phenomenon is still poorly understood. Oxidative stress, modulated by VD serum levels as well as sex hormones, may act as a contributing factor to demyelination and axonal damage in both MS and the corresponding preclinical models. In this study, we analyzed sex-associated differences and VD effects utilizing an animal model that recapitulates histopathological features of the progressive MS phase (PMS). In contrast to relapsing-remitting MS (RRMS), PMS has been poorly investigated in this context. Male (n = 50) and female (n = 46) Dark Agouti rats received either VD (400 IU per week; VD+) or standard rodent food without extra VD (VD-) from weaning onwards. Myelination, microglial activation, apoptotic cell death and neuronal viability were assessed using immunohistochemical markers in brain tissue. Additionally, we also used two different histological markers against oxidized lipids along with colorimetric methods to measure protective polyphenols (PP) and total antioxidative capacity (TAC) in serum. Neurofilament light chain serum levels (sNfL) were analyzed using single-molecule array (SIMOA) analysis. We found significant differences between female and male animals. Female rats exhibited a better TAC and higher amounts of PP. Additionally, females showed higher myelin preservation, lower microglial activation and better neuronal survival while showing more apoptotic cells than male rats. We even found a delay in reaching the peak of the disease in females. Overall, both sexes benefitted from VD supplementation, represented by significantly less cortical, neuroaxonal and oxidative damage. Unexpectedly, male rats had an even higher overall benefit, most likely due to differences in oxidative capacity and defense systems.

Sex difference in association between suicide attempts and lipid profile in first-episode and drug naive patients with major depressive disorder

BackgroundThe relationship between suicide attempts and lipid profiles in patients with major depressive disorder (MDD) remains uncertain. The purpose of this study was to investigate sex differences in the relationship between suicide attempts and plasma lipid profiles in a large sample of first-episode and drug naive (FEDN) MDD patients. MethodsWe recruited 1718 FEDN MDD patients and gathered demographic, clinical, and blood lipid data. The Hamilton Depression Rating Scale, Hamilton Anxiety Rating Scale and the Positive and Negative Syndrome Scale were used to assess the symptoms of patients. ResultsThere was no significant difference in the prevalence of suicide attempts between male and female MDD patients. The suicide attempt group had higher levels of depression, anxiety, psychotic symptoms, total cholesterol (TC), and low-density lipoprotein cholesterol (LDL-C), but lower levels of high-density lipoprotein cholesterol (HDL-C) levels than the non-suicide attempt group. Binary logistic regression showed that TC levels were significantly correlated with suicidal attempts in both male and female patients. Correlation analysis revealed that the levels of TC, HDL-C and LDL-C were significantly associated with the number of suicide attempts in both male and female patients. Further multiple linear regression revealed that TC levels were significantly associated with the number of suicide attempts in male patients only. ConclusionsLipid biomarkers, particularly high TC levels, are associated with suicide attempts in both male and female MDD patients. However, there is gender difference in association between lipid biomarkers, especially TC levels, and the number of suicide attempts in MDD patients.

Subcutaneous Alfaxalone-XylazineBuprenorphine for Surgical Anesthesia and Echocardiographic Evaluation of Mice (Mus musculus).

Alfaxalone is a commonly used injectable anesthetic in dogs and cats due to its minimal cardiovascular side effects. Data for its use in mice are limited and demonstrate strain- and sex-associated differences in dose-response relationships. We performed a dose-comparison study of alfaxalone-xylazine-buprenorphine (AXB) in Crl: CFW (SW) mice. Subcutaneous injection of 50 mg/kg alfaxalone-10 mg/kg xylazine-0.1 mg/kg buprenorphine HCl consistently achieved a surgical plane of anesthesia (loss of toe pinch) for 48.6 ± 4.7 and 60.8 ± 9.6 min in females and males, respectively. The same dose and route of AXB induced a surgical plane of anesthesia in C57Bl/6NCrl (females: 42.3 ± 11.2 min; males: 51.6 ± 12.3 min), NCr-Foxn1nu (females: 76.8 ± 32.5 min; males: 80.0 ± 1.2 min), and NOD. Cg-Prkdc SCID Il2rg tm1Wjl /SzJCr (females: 56.0 ± 37.2 min and males: 61.2 ± 10.2 min) mice. We found no significant difference in the duration of the surgical plane of anesthesia between males and females within the mouse strains Crl: CFW (SW), C57Bl/6NCrl, NCr-Foxn1nu, and NOD. Cg-PrkdcSCID Il2rgtm1Wjl /SzJCr. We next performed an echocardiography study (n = 5 per group) of Crl: CFW (SW) mice ( n = 5 per group) to compare subcutaneous AXB anesthesia with that produced by intraperitoneal injection of 100 mg/kg ketamine and 10 mg/kg xylazine (KX). AXB induced significantly less bradycardia (295.4 ± 29 bpm) than KX (185.8 ± 38.9 bpm) did, with no significant differences in cardiac output, ejection fraction, end-diastolic volume, end-systolic volume, or fractional shortening. These results suggest that subcutaneous administration of AXB is a viable alternative to KX for inducing a surgical plane of anesthesia in Crl: CFW (SW), C57Bl/6NCrl, NCr-Foxn1nu, and NOD. Cg-PrkdcSCID Il2rgtm1Wjl /SzJCr mice, regardless of sex. AXB may also be a better injectable anesthetic option as compared with KX for avoiding adverse cardiac effects in mice.

Heterogeneity of gut microbiome compositions in the third decade of life in Japanese women: insights from a comparative analysis.

The reasons for sex-associated gut microbiota differences have not been determined, and although sex hormones, diet, and other factors are considered to contribute to them, many of these factors are age related. To shed light on this complex interplay, our study aimed to investigate and compare the gut microbial compositions of males and females across a broad range of ages, aiming to identify sex-associated disparities and potential causal factors. Our study encompassed a comprehensive analysis of gut microbiota data obtained from 444 Japanese individuals, ranging from newborns to centenarians, sourced from the DNA Data Bank of Japan. We categorized the subjects into 13 distinct age groups and examined their relative microbial abundances, as well as alpha and beta diversities, in relation to sex and age. No difference was observed between gut microbiota relative abundances or alpha diversities between men and women at any age. However, the study showed that the heterogeneity of gut microbiota among women in their 20s was greater than in men. To confirm the general occurrence of this difference, we conducted additional analyses using seven datasets: three from Japan and four from other countries. Interestingly, this variance was particularly noticeable within Japanese women. We also showed a potential link between the observed heterogeneity and dietary fiber intake. It is hoped this study will provide clues that aid in the identification of factors responsible for sex-associated differences in gut microbiota compositions.

Sexual dimorphisms in longitudinal associations of the blood lipidome with cognitive decline in Alzheimer’s disease

AbstractBackgroundLate‐onset Alzheimer’s disease (AD) is the leading cause of dementia with neither cure nor a clearly understood disease trajectory. Previous studies have shown cross‐sectional and longitudinal associations of the blood lipidome and AD. We previously reported on significant sex differences in the associations of lipids with AD biomarkers and it has been suggested that such sex differences may result in distinct trajectories of AD progression. We performed an association study of sex‐stratified longitudinal lipidomics data with cognitive function to further characterize sexual dimorphisms in lipidomic manifestations of AD.MethodWe used a subset of the Alzheimer’s Disease Neuroimaging Initiative (ADNI) dataset: 1349 individuals (745 males and 604 females) with blood samples and clinical data collected at 10 time points with intervals of 6 to12 months (4145 samples total). We analyzed 749 lipid species measured by quantitative LC‐MS lipidomics profiling (Baker Heart and Diabetes Institute, Melbourne, Australia). We calculated linear mixed models (LMMs) and generalized additive mixed models (GAMMs) to analyze time‐resolved associations between lipids and two composite cognitive scores (ADNI memory and executive function) while adjusting for age, sex (pooled analysis only), BMI, HDL‐C, total cholesterol, copies of APOE ε4, years of education as well as significant medication effects.ResultWe observed a significant difference in lipid concentrations between males and females in line with previous studies, however, these differences were not fully consistent across diagnostic groups. In longitudinal association analyses, we found a substantial fraction of lipid species to have significant sex‐specific associations with cognitive function, which were not observed in the pooled analysis. These lipids were distributed across several lipid classes with enrichment in phosphatidylcholines (PC), phosphatidylethanolamines (PE) and triglycerides (TG). Comparisons between LMMs and GAMMs further indicated that some lipids might have a nonlinear relationship with cognitive trajectories.ConclusionOur results suggest that there are substantial sex differences in longitudinal associations of the blood lipidome with cognitive decline resulting in complex and partially nonlinear relationships. The highlighted lipid pathways can serve as a starting point to better characterize sex‐specific molecular changes linked to cognitive decline in AD.

Sex-associated differences in frequencies and prognostic impact of recurrent genetic alterations in adult acute myeloid leukemia (Alliance, AMLCG)

Clinical outcome of patients with acute myeloid leukemia (AML) is associated with demographic and genetic features. Although the associations of acquired genetic alterations with patients’ sex have been recently analyzed, their impact on outcome of female and male patients has not yet been comprehensively assessed. We performed mutational profiling, cytogenetic and outcome analyses in 1726 adults with AML (749 female and 977 male) treated on frontline Alliance for Clinical Trials in Oncology protocols. A validation cohort comprised 465 women and 489 men treated on frontline protocols of the German AML Cooperative Group. Compared with men, women more often had normal karyotype, FLT3-ITD, DNMT3A, NPM1 and WT1 mutations and less often complex karyotype, ASXL1, SRSF2, U2AF1, RUNX1, or KIT mutations. More women were in the 2022 European LeukemiaNet intermediate-risk group and more men in adverse-risk group. We found sex differences in co-occurring mutation patterns and prognostic impact of select genetic alterations. The mutation-associated splicing events and gene-expression profiles also differed between sexes. In patients aged <60 years, SF3B1 mutations were male-specific adverse outcome prognosticators. We conclude that sex differences in AML-associated genetic alterations and mutation-specific differential splicing events highlight the importance of patients’ sex in analyses of AML biology and prognostication.

Sex differences in the clinical profile of individuals with prediabetes and type 2 diabetes mellitus in the general population - results from the Gutenberg Health Study

Abstract Introduction The rising prevalence of type 2 diabetes mellitus (T2DM) and concomitant diseases accompany mounting evidence of clinically significant sex differences. T2DM is more frequently diagnosed at lower ages in men, differences in biology and lifestyle affect risk and complications differently in both sexes, and risk for vascular disease was shown to be higher in women. Also, in prediabetes, sex differences were detected, but only a few studies exist. Purpose To investigate the sex-related prevalence of prediabetes and T2DM in the general population, the clinical profile regarding asymptomatic organ damage (AOD) and prevalent cardiovascular disease (CVD), and its influence on CVD risk prediction and mortality. Methods The Gutenberg Health Study sample (15,010 subjects, 35-74 years) was stratified regarding sex and glucose state. Euglycemia, prediabetes, and T2DM were categorized based on clinical information and HbA1c level. CVD included the prevalence of coronary artery disease, myocardial infarction, stroke or transient ischemic attack, heart failure, atrial fibrillation, and peripheral artery disease. AOD was assessed in individuals without prevalent CVD as an indicator of early, subclinical CVD according to current guidelines and included left ventricular mass index, carotid intima-media thickness and plaque, ankle-brachial index, and renal function. Ten years of CVD risk prediction was assessed using the Framingham score. Clinical outcome was assessed by structured follow-up. Results Overall, 14,870 individuals were included in the present analysis, 7,352 women and 7,518 men. Among them, 4,784 (65.1%) women and 4,642 (61.7%) men revealed euglycemia, 2,065 (28.1%) women and 2,063 (27.4%) men had prediabetes, and in 503 (6.8%) women and 813 (10.8%) men T2DM was present. Except for obesity, cardiovascular risk factors were more prevalent in prediabetic and diabetic men than in women. Female sex was associated with a reduced risk for AOD (prevalence ratio (PR) 0.92, 95% confidence interval (CI) 0.89 to 0.94, P&amp;lt;0.0001) and CVD (PR 0.65, 95%CI 0.59 to 0.71, P&amp;lt;0.0001). The 10-year risk for CVD was about doubled in men compared to women in euglycemia (women 6.8±6.2% vs. men 14.9±11.3%), prediabetes (women 11.6±7.8% vs. men 21.6±12.6%) and T2DM (women 24.7±12.9% vs. men 42.6±17.9%). Regarding all-cause mortality, female sex was favorable (hazard ratio 0.58, 95%CI 0.51 to 0.66, P&amp;lt;0.0001). Conclusions In the general population, euglycemia and prediabetes were more prevalent in women, T2DM was more prevalent in men. Distinct differences were found in risk between both sexes, with a more favorable profile in women. Particularly the high prevalence of the primarily unrecognized prediabetes in the general population highlights the necessity for prevention and early detection. Investigating sex-associated differences may help to elucidate the pathophysiology and improve prevention and treatment by more individualized therapy concepts.

Abstract 13490: Sex Differences in the Association of Multi-Ethnic Genome-Wide Blood Pressure Polygenic Risk Score With Population Systolic Blood Pressure Trajectories

Introduction: Sex differences in the systolic blood pressure (SBP) trajectories have been described previously. However, the contribution of underlying genetic architecture to the sex associated differences in SBP trajectories has not been assessed. Methods: Multiancestry sex-specific SBP polygenic risk scores (SBP-PRS), accumulating 1.1 million variants each, were calculated in the participants of the ARIC, JHS, CARDIA, CHS, MESA, FHS, and JHS who underwent whole genome sequencing under the TransOmics for Precision Medicine Program. Based on the SBP-PRS, the cohort was stratified into low (&lt;20 th centile), intermediate (20 th -80 th centile), and high (&gt;80 th centile) genetic risk of SBP. For individuals on antihypertensive medications, SBP measurements were corrected by adding 15 mmHg. Multivariable adjusted restricted cubic splines were used to depict the non-linear relationship of SBP with age in each sex separately. Bootstrapping using 1000 samples was used to estimate the age and 95% CIs at which the sex-specific SBP trajectories crossed over in each SBP-PRS group. Results: In this study of 21,542 individuals (median age: 56 years; 56.0% females; 35.8% non-White individuals), the non-linear association of SBP with age varied by sex (P interaction : &lt;0.001) and SBP-PRS groups (P interaction : 0.05). On stratifying by SBP-PRS, females had a higher age-related increase in SBP compared with males across the groups (p&lt;0.001 in low, intermediate, and high SBP-PRS groups). The age at which the SBP in females surpassed that of males progressively decreased with increasing genetic risk of SBP [low: 66.7 (66.4-67.0) years, intermediate: 64.3 (64.1-64.6) years, high: 55.8 (54.4-57.1) years; p: &lt;0.001]. In the high SBP-PRS group, the sex-associated differences in SBP trajectories were modest with females and males having nearly similar SBP values in old age. Conclusion: The underlying genetic architecture may contribute to sex difference of SBP trajectories.

Abstract 13489: Sex Differences in the Association of Multi-Ethnic Genome-Wide Systolic Blood Pressure Polygenic Risk Score With Hypertension

Introduction: Hypertension affects about half the US adult population with a higher prevalence in males. This study examines the contribution of the genetic architecture to the sex-associated differences in hypertension in a multi-ethnic US population. Methods: Multi-ancestry genome-wide association studies for systolic blood pressure (SBP) were conducted for each sex separately in the UK BioBank. Sex-specific SBP polygenic risk scores (SBP-PRS), comprising 1.1 million variants each, were generated from these GWASs. Sex-specific SBP-PRS was calculated in participants who underwent whole genome sequencing in the All of Us project. Based on the SBP-PRS, the cohort was stratified into low (&lt;2.5 th centile), low-intermediate (2.5 th -20 th centile), intermediate (20 th -80 th centile), high-intermediate (80 th -97.5 th centile), and high (&gt;97.5 th centile) genetic risk of SBP. Hypertension was defined as a BP ≥130/80 mmHg or anti-hypertensive use. Logistic regression models were used to assess the sex-stratified association of SBP-PRS with hypertension. Results: The All of Us cohort had 212,669 individuals [median age: 54 (38, 65) years] comprising 127,679 (60.0%) females and 97,600 (45.9%) non-White individuals (20.6% Black, 3.3% Asian, and 19.1% Hispanic). Hypertension was reported in 118,984 (55.9%) in the overall population and in 53,307 (62.7%) males and 65,677 (51.4%) females. Females [OR adj : 1.29 (1.27-1.30)] had higher odds of developing hypertension per SD increase in SBP PRS compared with males [OR adj : 1.22 (1.20-1.23)]. (P interaction :2.5x10 -6 ) On stratification by SBP-PRS, females in the high-risk group and the low-risk group had higher odds of developing hypertension [OR adj : 1.81 (1.68-1.95) vs. 1.61 (1.46-1.74)] and lower odds of hypertension [OR adj : 0.52 (0.48-0.56) vs. 0.65 (0.60-0.71)], respectively compared with males. Conclusion: The contributions of the genetic underpinnings to the development of hypertension vary by sex.

Sex differences in risk factors for incident peripheral artery disease hospitalisation or death: Cohort study of UK Biobank participants.

Women with peripheral artery disease (PAD) often have atypical symptoms, late hospital presentations, and worse prognosis. Risk factor identification and management are important. We assessed sex differences in associations of risk factors with PAD. 500,207 UK Biobank participants (54.5% women, mean age 56.5 years) without prior hospitalisation of PAD at baseline were included. Examined risk factors included blood pressure, smoking, diabetes, lipids, adiposity, history of stroke or myocardial infarction (MI), socioeconomic status, kidney function, C-reactive protein, and alcohol consumption. Poisson and Cox regressions were used to estimate sex-specific incidence of PAD hospitalisation or death, hazard ratios (HRs), and women-to-men ratios of HRs (RHR) with confidence intervals (CIs). Over a median of 12.6 years, 2658 women and 5002 men had a documented PAD. Age-adjusted incidence rates were higher in men. Most risk factors were associated with a higher risk of PAD in both sexes. Compared with men, women who were smokers or had a history of stroke or MI had a greater excess risk of PAD (relative to those who never smoked or had no history of stroke or MI): RHR 1.18 (95%CI 1.04, 1.34), 1.26 (1.02, 1.55), and 1.50 (1.25, 1.81), respectively. Higher high-density lipoprotein cholesterol (HDL-C) was more strongly associated with a lower risk of PAD in women than men, RHR 0.81 (0.68, 0.96). Compared to HDL-C at 40 to 60 mg/dL, the lowest level of HDL-C (≤40 mg/dL) was related to greater excess risk in women, RHR 1.20 (1.02, 1.41), whereas the highest level of HDL-C (>80 mg/dL) was associated with lower risk of PAD in women, but higher risk in men, RHR 0.50 (0.38, 0.65). While the incidence of PAD was higher in men, smoking and a history of stroke or MI were more strongly associated with a higher risk of PAD in women than men. HDL-C was more strongly associated with a lower risk of PAD in women than men.

Sex differences in the association between dynapenic abdominal obesity and onset of disability in activities of daily living among adults aged ≥50years: A prospective analysis of the Irish Longitudinal Study on Ageing.

Sex differences in the longitudinal relationship between dynapenic abdominal obesity, i.e., impairment in muscle strength and high waist circumference, and disability in activities of daily living have not been investigated to date. Therefore, we aimed to examine sex differences in the longitudinal association between dynapenic abdominal obesity at baseline and the onset of disability in activities of daily living during a four-year follow-up period among Irish adults aged ≥50years. Data from Wave 1 (2009-2011) and Wave 3 (2014-2015) of the Irish Longitudinal Study on Ageing survey were analyzed. Dynapenia was defined as handgrip strength of <26kg for men and <16kg for women. Abdominal obesity was defined as waist circumference of >88cm for women and >102cm for men. Dynapenic abdominal obesity was defined as having both dynapenia and abdominal obesity. Disability was defined as having difficulty with at least one of six activities of daily living (dressing, walking, bathing, eating, getting in or out of bed, using the toilet). Multivariable logistic regression was conducted to assess associations. Data on 4471 individuals aged ≥50years and free of disability at baseline were analyzed [mean (SD) age 62.3 (8.6) years; 48.3% males]. In the overall sample, compared to no dynapenia and no abdominal obesity, dynapenic abdominal obesity was associated with 2.15 (95%CI=1.17-3.93) times higher odds for incident disability at 4-year follow-up. This association was significant among men (OR=3.78; 95%CI=1.70-8.38) but not among women (OR=1.34; 95%CI=0.60-2.98). Interventions to prevent or address dynapenic abdominal obesity may aid in the prevention of disability, especially among men.

Multiple urinary peptides display distinct sex-specific distribution.

Previous studies have established the association of sex with gene and protein expression. This study investigated the association of sex with the abundance of endogenous urinary peptides, using capillary electrophoresis-coupled to mass spectrometry (CE-MS) datasets from 2008 healthy individuals and patients with type II diabetes, divided in one discovery and two validation cohorts. Statistical analysis using the Mann-Whitney test, adjusted for multiple testing, revealed 143 sex-associated peptides in the discovery cohort. Of these, 90 peptides were associated with sex in at least one of the validation cohorts and showed agreement in their regulation trends across all cohorts. The 90 sex-associated peptides were fragments of 29 parental proteins. Comparison with previously published transcriptomics data demonstrated that the genes encoding 16 of these parental proteins had sex-biased expression. The 143 sex-associated peptides were combined into a support vector machine-based classifier that could discriminate males from females in two independent sets of healthy individuals and patients with type II diabetes, with an AUC of 89% and 81%, respectively. Collectively, the urinary peptidome contains multiple sex-associated differences, which may enable a better understanding of sex-biased molecular mechanisms and the development of more accurate diagnostic, prognostic, or predictive classifiers for each individual sex.