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Circulating sex hormone binding globulin: An integrating biomarker for an adverse cardio-metabolic profile in obese pregnant women.

ABSTRACT: Sex hormone-binding globulin (SHBG) negatively associates with pre-gestational body mass index (BMI) and gestational weight gain. The link with other cardio-metabolic risk factors in pregnant women is poorly understood. Our aim was to study the association of SHBG levels with common cardio-metabolic risk parameters in pregnant woman. Serum SHBG was quantified in 291 Caucasian pregnant women (142 with normal weight, 42 with pregestational obesity, 50 with gestational obesity and 57 with pregestational plus gestational obesity) with uncomplicated pregnancies and parturition. Cardio-metabolic [C-reactive protein (CRP), blood pressure (BP), glycosylated hemoglobin (HbAc1), glucose, C-peptide, insulin, triglycerides and high molecular weight (HMW) adiponectin], and endocrine [testosterone and estradiol] parameters were also assessed. SHBG was negatively correlated with BMI, but also with CRP, BP, HbAc1, pre and post-load glucose, C-peptide, HOMA-IR, triglycerides; and positively with HMW adiponectin (all p<0.01 to p<0.0001). These associations were more robust in women with pregestational plus gestational obesity, who had lower SHBG, in comparison to normal-weight women (p<0.0001). In multivariate analyses in women with pregestational plus gestational obesity SHBG showed independent associations with CRP (? = -0.352, p = 0.03, R2 = 8.0%), DBP (? = -0.353, p = 0.03, R2 = 7.0%) and SBP (? = -0.333, p = 0.04, R2 = 6.0%) independently of BMI and metabolic and endocrine parameters. SHBG is decreased in pregnant women with pregestational plus gestational obesity in association with common cardio-metabolic parameters. SHBG could represent an integrating biomarker for an adverse cardio-metabolic profile in pregnant women with pregestational plus gestational obesity.

SUBMITTER: Xargay-Torrent S

PROVIDER: S-EPMC6188865 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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Circulating sex hormone binding globulin: An integrating biomarker for an adverse cardio-metabolic profile in obese pregnant women.

Xargay-Torrent Sílvia S Carreras-Badosa Gemma G Borrat-Padrosa Sara S Prats-Puig Anna A Soriano Pilar P Álvarez-Castaño Elena E Ferri Mª Jose MJ De Zegher Francis F Ibáñez Lourdes L López-Bermejo Abel A Bassols Judit J

PloS one 20181015 10

Sex hormone-binding globulin (SHBG) negatively associates with pre-gestational body mass index (BMI) and gestational weight gain. The link with other cardio-metabolic risk factors in pregnant women is poorly understood. Our aim was to study the association of SHBG levels with common cardio-metabolic risk parameters in pregnant woman. Serum SHBG was quantified in 291 Caucasian pregnant women (142 with normal weight, 42 with pregestational obesity, 50 with gestational obesity and 57 with pregestat ...[more]

PMID: 30321217

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Project description:Background and Purpose- Circulating levels of SHBG (sex hormone-binding globulin) have been inversely linked to obesity, diabetes mellitus, and other cardiometabolic disorders. It remains uncertain whether low SHBG is prospectively predictive of stroke risk, particularly in women. We investigated whether SHBG is associated with risk of incident ischemic stroke (IS) among women in the WHI (Women's Health Initiative). Methods- From an observational cohort of 161 808 postmenopausal women enrolled in the WHI at 40 sites across the United States from 1993 to 1998, we identified 13 192 participants free of prevalent stroke at baseline who were included in an ancillary study that measured serum SHBG. We used Cox proportional hazards regression, stratified by SHBG measurement assay, to assess IS risk across quintiles of SHBG (Q1-Q5), adjusting first for demographic variables (model 1), additionally for body mass index, hypertension, alcohol use, and smoking status (model 2), and for physical activity and reproductive risk factors (model 3). In sensitivity analyses, potential mediators (diabetes mellitus status, levels of estradiol, testosterone, and CRP [C-reactive protein]) were included. Results- Of 13 192 participants (mean age, 62.5 years; 67.4% non-Hispanic white, 18.5% black, 7.6% Hispanic, and 5.0% Asian), after following for an average of 11.6 years, 768 IS events were adjudicated. Compared with the highest quintile of SHBG levels (referent), women in the lowest SHBG quintile had a higher risk of IS in all 3 multivariable models (model 1: hazard ratio, 1.88 [95% CI, 1.47-2.41]; model 2: hazard ratio, 1.69 [95% CI, 1.30-2.20]; model 3: hazard ratio, 1.61 [95% CI, 1.19-2.19]; trend tests P<0.05 for all models). Including potential mediators such as diabetes mellitus, estradiol, and testosterone in the models attenuated but did not eliminate significant inverse associations between SHBG and IS. Conclusions- In this prospective cohort of postmenopausal women, there was a statistically significant inverse association between serum SHBG levels and IS risk, which supports the notion that SHBG could be used as a risk stratification tool for predicting IS in women.

Project description:Sex hormone-binding globulin (SHBG) is a glycoprotein responsible for the transport and biologic availability of sex steroid hormones, primarily testosterone and estradiol. SHBG has been associated with chronic diseases including type 2 diabetes (T2D) and with hormone-sensitive cancers such as breast and prostate cancer. We performed a genome-wide association study (GWAS) meta-analysis of 21,791 individuals from 10 epidemiologic studies and validated these findings in 7,046 individuals in an additional six studies. We identified twelve genomic regions (SNPs) associated with circulating SHBG concentrations. Loci near the identified SNPs included SHBG (rs12150660, 17p13.1, p = 1.8 × 10(-106)), PRMT6 (rs17496332, 1p13.3, p = 1.4 × 10(-11)), GCKR (rs780093, 2p23.3, p = 2.2 × 10(-16)), ZBTB10 (rs440837, 8q21.13, p = 3.4 × 10(-09)), JMJD1C (rs7910927, 10q21.3, p = 6.1 × 10(-35)), SLCO1B1 (rs4149056, 12p12.1, p = 1.9 × 10(-08)), NR2F2 (rs8023580, 15q26.2, p = 8.3 × 10(-12)), ZNF652 (rs2411984, 17q21.32, p = 3.5 × 10(-14)), TDGF3 (rs1573036, Xq22.3, p = 4.1 × 10(-14)), LHCGR (rs10454142, 2p16.3, p = 1.3 × 10(-07)), BAIAP2L1 (rs3779195, 7q21.3, p = 2.7 × 10(-08)), and UGT2B15 (rs293428, 4q13.2, p = 5.5 × 10(-06)). These genes encompass multiple biologic pathways, including hepatic function, lipid metabolism, carbohydrate metabolism and T2D, androgen and estrogen receptor function, epigenetic effects, and the biology of sex steroid hormone-responsive cancers including breast and prostate cancer. We found evidence of sex-differentiated genetic influences on SHBG. In a sex-specific GWAS, the loci 4q13.2-UGT2B15 was significant in men only (men p = 2.5 × 10(-08), women p = 0.66, heterogeneity p = 0.003). Additionally, three loci showed strong sex-differentiated effects: 17p13.1-SHBG and Xq22.3-TDGF3 were stronger in men, whereas 8q21.12-ZBTB10 was stronger in women. Conditional analyses identified additional signals at the SHBG gene that together almost double the proportion of variance explained at the locus. Using an independent study of 1,129 individuals, all SNPs identified in the overall or sex-differentiated or conditional analyses explained ~15.6% and ~8.4% of the genetic variation of SHBG concentrations in men and women, respectively. The evidence for sex-differentiated effects and allelic heterogeneity highlight the importance of considering these features when estimating complex trait variance.

Project description:Background/objectivesAdiponectin concentrations are low in obese pregnant women. Restoring normal adiponectin concentrations by infusion in obese pregnant mice prevents placental dysfunction, foetal overgrowth and metabolic syndrome in the offspring. We hypothesised that normalising maternal adiponectin in obese late pregnant dams prevents cardiac dysfunction in the adult offspring.Subjects/methodsPregnant female mice with diet-induced obesity were infused with adiponectin (0.62 μg g-1 day-1, n = 24) or saline (n = 22) over days 14.5-18.5 of pregnancy (term = day 19.5). Control dams ate standard chow and received saline (n = 22). Offspring were studied at 3 and 6 months of age.ResultsMaternal obesity impaired ventricular diastolic function, increased cardiomyocyte cross-sectional area and upregulated cardiac brain natriuretic peptide (Nppb) and α-skeletal actin (Acta1) gene expression in adult male offspring, compared to control offspring. In adult female offspring, maternal obesity increased Nppb expression, decreased end-diastolic volume and caused age-dependent diastolic dysfunction but not cardiomyocyte hypertrophy. Maternal obesity also activated cardiac Akt and mechanistic target of rapamycin (mTOR) signalling in male, but not in female, offspring and inhibited cardiac extracellular signal-regulated kinase 1/2 (ERK1/2) in both sexes. Normalising maternal circulating adiponectin concentrations by infusing obese dams with adiponectin prevented offspring diastolic dysfunction and ventricular dilation and normalised cardiac Akt-mTOR signalling irrespective of sex. Maternal adiponectin infusion also reduced cardiac Nppb expression and increased ERK1/2 signalling in offspring of obese dams. Adiponectin infusion did not prevent cardiomyocyte hypertrophy but reduced ventricular wall thickness in male offspring and increased collagen content in female offspring of obese dams, compared to controls.ConclusionsLow maternal adiponectin levels in obese mice in late pregnancy are mechanistically linked to in utero programming of cardiac dysfunction in their offspring. Interventions enhancing endogenous adiponectin secretion or signalling in obese pregnant women could prevent the development of cardiac dysfunction in their children.

Dataset Information

Circulating sex hormone binding globulin: An integrating biomarker for an adverse cardio-metabolic profile in obese pregnant women.

Publications

Circulating sex hormone binding globulin: An integrating biomarker for an adverse cardio-metabolic profile in obese pregnant women.

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