Abstract
BackgroundA role for sex hormone-binding globulin (SHBG) in determining the pregnancy outcome was evidenced by the rise in SHBG levels during pregnancy linked with favorable pregnancy, while reduction in SHBG levels and hyperandrogenemia were linked with poor pregnancy outcome. Since SHBG production is genetically determined, this study investigated the association of SHBG polymorphisms with the susceptibility to recurrent pregnancy loss (RPL).MethodsRetrospective case-control study, involving 308 women with RPL, and 310 control women RPL, defined as ≥3 consecutive miscarriages, and with the same partner, was the main outcome measure. SHBG genotyping was done by allelic exclusion method (real-time PCR).ResultsOf the seven tested SHBG SNP, lower MAF of rs6257 was seen in RPL cases than in control women, which was linked with lower risk of RPL, after controlling for key covariates. At the genotype level, significantly higher frequencies of heterozygous rs858521 and rs6259, and homozygous rs858521 genotype carriers, and reduced frequency of heterozygous rs6257 and homozygous rs6257 and rs6259 genotype carriers were seen in RPL cases vs. control women, respectively. Univariate regression analysis confirmed the positive association of rs858521 and rs6259 with RPL. Multivariate regression analysis confirmed the positive association of rs858521 heterozygote and homozygote genotypes with RPL; only heterozygous rs6259 remained associated with RPL. Haploview analysis demonstrated marked linkage disequilibrium among 6 of the 7 tested SHBG SNP. Of the possible 6-locus haplotypes, 12 were common, and were included in subsequent analysis. Within these haplotypes, only increased frequency of CCGTGA haplotypes was seen in RPL cases, thus conferring RPL susceptibility.ConclusionsSpecific SHBG variants, and SHBG haplotypes are associated with altered risk of RPL, suggesting role for SHBG as RPL candidate gene.
Highlights
A role for sex hormone-binding globulin (SHBG) in determining the pregnancy outcome was evidenced by the rise in SHBG levels during pregnancy linked with favorable pregnancy, while reduction in SHBG levels and hyperandrogenemia were linked with poor pregnancy outcome
Univariate regression analysis confirmed the positive association of rs858521 [P = 0.01; odds ratio (OR) = 1.72 (1.13–2.60)] and rs6259 [P = 0.03; OR = 15.75 (1.29–192.46)] with recurrent pregnancy loss (RPL) (Table 4)
Multivariate regression analysis confirmed the positive association of rs858521 heterozygote [P = 0.007; aOR =1.80 (1.17–2.77)] and homozygote [P = 0.05; aOR = 1.60 (1.00–2.58)] genotypes with RPL
Summary
A role for sex hormone-binding globulin (SHBG) in determining the pregnancy outcome was evidenced by the rise in SHBG levels during pregnancy linked with favorable pregnancy, while reduction in SHBG levels and hyperandrogenemia were linked with poor pregnancy outcome. Several studies documented the association of hyperandrogenemia with RPL [2, 9], often with inconclusive findings. This was attributed to the wide variation in androgen levels, the time of sampling (i.e. within 7 days of the cycle), and the testosterone pool examined. The latter was attributed to the lipophilic nature of steroid sex hormones, in which circulating androgens and estrogens bind albumin and sex hormone binding globulin (SHBG), resulting in limited amounts of non-bound sex hormones, and reduced bioavailability [9, 10]. Accurate assessment of biochemical hyperandrogenemia requires measurement of either free testosterone, or free androgen index, which require determination of the serum levels SHBG, a 373-amino acid glycoprotein produced mainly by the liver, and binding the testosterone, dihydrotestosterone, and estradiol [11, 12], limiting their target tissue availability [12]
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