Dataset Information

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

ABSTRACT: Objective:This study investigated the prospective associations of circulating levels of sex hormone-binding globulin (SHBG) levels with cardiometabolic biomarkers and risk of gestational diabetes (GDM) during pregnancy. It also examines the longitudinal trajectory of SHBG in women with and without GDM. Methods:We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human Development Fetal Growth Studies-Singleton Cohort. The cohort enrolled non-obese and obese women aged 18-40 years with a singleton pregnancy between 8 and 13 weeks of gestation from 2009 to 2013. GDM was ascertained via medical records review. Blood samples were drawn four times at gestational weeks 10-14, 15-26, 23-31, and 33-39. The prospective associations between SHBG levels and cardiometabolic biomarkers were examined using the Spearman partial correlation among the controls. The longitudinal trajectories of SHBG levels were examined among the cases and the controls. Meta-analysis of prospective studies were performed to examine the association between SHBG levels and GDM risk. Results:SHBG levels at gestational weeks 10-14 were significantly inversely associated with fasting insulin (r?=?-0.17, P?=?0.01) and insulin resistance as measured by HOMA-IR (r?=?-0.17, P?=?0.01) at gestational week 15-26. SHBG at gestational weeks 10-14 and 15-26 was lower in cases than controls (mean ± standard deviation: (204.0?±?97.6) vs. (220.9?±?102.5) nmol/L, P?=?0.16 and (305.6?±?124.3) vs. (322.7?±?105.1) nmol/L, P?=?0.14, respectively), yet the differences were not significant. In the meta-analysis, SHBG was 41.5?nmol/L (95% confidence interval: 23.9, 59.1, P?

SUBMITTER: Li MY

PROVIDER: S-EPMC7357819 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

Li Meng-Ying MY Rawal Shristi S Hinkle Stefanie N SN Zhu Ye-Yi YY Tekola-Ayele Fasil F Tsai Michael Y MY Liu Si-Min SM Zhang Cui-Lin CL

Maternal-fetal medicine (Wolters Kluwer Health, Inc.) 20200124 1

<h4>Objective</h4>This study investigated the prospective associations of circulating levels of sex hormone-binding globulin (SHBG) levels with cardiometabolic biomarkers and risk of gestational diabetes (GDM) during pregnancy. It also examines the longitudinal trajectory of SHBG in women with and without GDM.<h4>Methods</h4>We conducted a nested case-control study of 107 incident GDM cases and 214 matched controls within the Eunice Kennedy Shriver National Institute of Child Health and Human De ...[more]

PMID: 32776014

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Project description:This study aims to investigate the relationship between single nucleotide polymorphisms (SNPs) of sex hormone binding globulin (SHBG) and type 2 diabetes mellitus (T2DM) in an Uighur population. One hundred and fourteen T2DM male patients (with a history of diabetes or diagnosed as diabetic by the oral glucose tolerance test) and 173 healthy males from the Uighur ethnic group were included in the study to test the following SNPs of SHBG: rs727428, rs1799941, rs6259, rs6257, rs858521, rs858518, rs3760213, and rs11078701. The body mass index (BMI), blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, HOMA-IR, testosterone, and SHBG levels of enrolled individuals were measured. We used the t-test or rank sum test and Chi-square test to analyze the difference and compare numeration data, respectively, between the case and control groups. Comparisons among multiple groups were carried out using analysis of variance, and the correlation between variables was determined by nonparametric Spearman rank correlation analysis; multivariate logistic regression analysis was used to assess the risk of abnormal glucose in the two groups. There was a significant difference (P < 0.05) in BMI, blood pressure, and waist circumference, and lipid, glucose, HbA1c, insulin, and HOMA-IR levels between the case and control groups. The risk factors for diabetes included testosterone (P = 0.042) and SHBG (P = 0.001). The distribution of rs858521 (P = 0.001), rs1799941 (2.3%, P = 0.032), rs6259 (2.5%, P = 0.040), and rs727428 (3.4%, P = 0.016) was significantly different between the case and control groups (P < 0.05). In the control group, there was linkage disequilibrium (LD) between rs727428 and rs6259, while in the case group LD was found among rs858518, rs3760213, rs1799941, and rs6257. The frequency of rs858518-rs3760213-rs1799941-rs6257 haplotype TCGC was significantly different between the two groups (P = 0.033). Both testosterone and SHBGwere found to be risk factors of diabetes in the Uighur population, and SNPs of SHBG may contribute to T2DM.

Project description:BackgroundCirculating sex hormone-binding globulin levels are inversely associated with insulin resistance, but whether these levels can predict the risk of developing type 2 diabetes is uncertain.MethodsWe performed a nested case-control study of postmenopausal women in the Women's Health Study who were not using hormone therapy (359 with newly diagnosed type 2 diabetes and 359 controls). Plasma levels of sex hormone-binding globulin were measured; two polymorphisms of the gene encoding sex hormone-binding globulin, SHBG, that were robustly associated with the protein levels were genotyped and applied in mendelian randomization analyses. We then conducted a replication study in an independent cohort of men from the Physicians' Health Study II (170 with newly diagnosed type 2 diabetes and 170 controls).ResultsAmong women, higher plasma levels of sex hormone-binding globulin were prospectively associated with a lower risk of type 2 diabetes: multivariable odds ratios were 1.00 for the first (lowest) quartile of plasma levels, 0.16 (95% confidence interval [CI], 0.08 to 0.33) for the second quartile, 0.04 (95% CI, 0.01 to 0.12) for the third quartile, and 0.09 (95% CI, 0.03 to 0.21) for the fourth (highest) quartile (P<0.001 for trend). These prospective associations were replicated among men (odds ratio for the highest quartile of plasma levels vs. the lowest quartile, 0.10; 95% CI, 0.03 to 0.36; P<0.001 for trend). As compared with homozygotes of the respective wild-type allele, carriers of a variant allele of the SHBG single-nucleotide polymorphism (SNP) rs6259 had 10% higher sex hormone-binding globulin levels (P=0.005), and carriers of an rs6257 variant had 10% lower plasma levels (P=0.004); variants of both SNPs were also associated with a risk of type 2 diabetes in directions corresponding to their associated sex hormone-binding globulin levels. In mendelian randomization analyses, the predicted odds ratio of type 2 diabetes per standard-deviation increase in the plasma level of sex hormone-binding globulin was 0.28 (95% CI, 0.13 to 0.58) among women and 0.29 (95% CI, 0.15 to 0.58) among men, a finding that suggests that sex hormone-binding globulin may have a causal role in the risk of type 2 diabetes.ConclusionsLow circulating levels of sex hormone-binding globulin are a strong predictor of the risk of type 2 diabetes in women and men. The clinical usefulness of both SHBG genotypes and plasma levels in stratification and intervention for the risk of type 2 diabetes warrants further examination.

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.

Dataset Information

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

Publications

Sex Hormone-binding Globulin, Cardiometabolic Biomarkers, and Gestational Diabetes: A Longitudinal Study and Meta-analysis.

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