Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations

Rull, Kristiina; Nagirnaja, Liina; Ulander, Veli-Matti; Kelgo, Piret; Margus, Tõnu; Kaare, Milja; Aittomäki, Kristiina; Laan, Maris

doi:10.1210/jc.2008-1101

Cited by 38 publications

(55 citation statements)

References 36 publications

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“…1). Moreover, high heterozygosity in non-Africans suggests that balancing selection accompanied ancient human migrations (Rull et al 2008). Taken together, this is consistent with the concept that genotypic (thus, phenotypic) variability improves the persistence of a population in a given habitat (Forsman 2014), providing more flexible reproductive features, such as endocrine adaptation to the new environmental conditions (Cornelius et al 2013) reasonably encountered out from Africa.…”

Section: Population Genetics Of Gonadotropins and Gonadotropin Receptsupporting

confidence: 81%

“…The human genome carries eight CGB genes contiguous with the LHB gene on chromosome 19; subsequently, frame-shift mutations and nucleotide insertions resulted in 24 additional codons for CGB. The LHB/CGB gene cluster spans about 40 kbp and carries several SNPs; especially, polymorphic variants of the CGB5 were associated with recurrent spontaneous abortions in Chinese and Caucasian women (Rull et al 2008, Sun & Ji 2014.…”

Section: Polymorphisms Of the Lhcgr Gene And Lhb/cgb Gene Clustermentioning

confidence: 99%

“…Protective effect from recurrent miscarriage was associated with some SNPs located in both the CGB5 and CGB8 genes, which encode the major fraction of R178 L Casarini and others CGB-mRNA transcripts (Rull et al 2008) reflecting their importance in physiological adaptation to pregnancy. The genomic region embedding the CGB2, CGB5, and CGB8 promoter genes is featured by high heterozygosity and increased frequencies of the derived alleles in nonAfrican populations (Fig.…”

Section: Population Genetics Of Gonadotropins and Gonadotropin Receptmentioning

confidence: 99%

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Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success

Casarini¹,

Santi²,

Marino³

2015

Reproduction

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Gonadotropins and their receptors' genes carry several single-nucleotide polymorphisms resulting in endocrine genotypes modulating reproductive parameters, diseases, and lifespan leading to important implications for reproductive success and potential relevance during human evolution. Here we illustrate common genotypes of the gonadotropins and gonadotropin receptors' genes and their clinical implications in phenotypes relevant for reproduction such as ovarian cycle length, age of menopause, testosterone levels, polycystic ovary syndrome, and cancer. We then discuss their possible role in human reproduction and adaptation to the environment. Gonadotropins and their receptors' variants are differently distributed among human populations. Some hints suggest that they may be the result of natural selection that occurred in ancient times, increasing the individual chance of successful mating, pregnancy, and effective post-natal parental cares. The gender-related differences in the regulation of the reproductive endocrine systems imply that many of these genotypes may lead to sex-dependent effects, increasing the chance of mating and reproductive success in one sex at the expenses of the other sex. Also, we suggest that sexual conflicts within the FSH and LH-choriogonadotropin receptor genes contributed to maintain genotypes linked to subfertility among humans. Because the distribution of polymorphic markers results in a defined geographical pattern due to human migrations rather than natural selection, these polymorphisms may have had only a weak impact on reproductive success. On the contrary, such genotypes could acquire relevant consequences in the modern, developed societies in which parenthood attempts often occur at a later age, during a short, suboptimal reproductive window, making clinical fertility treatments necessary.Reproduction (2015) 150 R175-R184

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Section: Population Genetics Of Gonadotropins and Gonadotropin Receptsupporting

confidence: 81%

Section: Polymorphisms Of the Lhcgr Gene And Lhb/cgb Gene Clustermentioning

confidence: 99%

Section: Population Genetics Of Gonadotropins and Gonadotropin Receptmentioning

confidence: 99%

See 1 more Smart Citation

Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success

Casarini¹,

Santi²,

Marino³

2015

Reproduction

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“…Previous studies have confirmed that carriage of certain variances in the promoter region of CGB5 seems to protect against RSA [5]. According to the results of metaanalysis across data from three populations (Estonians, Finns, and Danes), a modest but significant effect of the CGB5 promoter variants rs59079581 (−155 G/C, OR= 0.64; 95 % CI, 0.44-0.94) and rs377204493 (−142 T/A, OR=0.66; 95 % CI, 0.45-0.94) in reducing the risk for RM has been established in Northern European population [15].…”

Section: Discussionmentioning

confidence: 81%

“…Because cytokines, hormones, and angiogenic mediators have their important roles in implantation and gestation, the polymorphisms in these genes have been intensively studied [4]. A resequencing study using samples from Estonia and Finland indicated a possible role of the chorionic gonadotropin β-subunit gene (CGBs) polymorphisms in RSA [5]. CGB genes encode the receptor-binding and hormonespecific subunit of human chorionic gonadotrophin (hCG), which is an indispensable placental hormone in human pregnancy [6].…”

Section: Introductionmentioning

confidence: 99%

Association of rs7260002 of chorionic gonadotrophin β5 with idiopathic recurrent spontaneous abortion in Chinese population

Sun

2014

J Assist Reprod Genet

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Purpose Low levels of serum hCG during the first trimester is regarded as a predictor of miscarriage. This study was designed to examine whether variance in chorionic gonadotrophin β5 (Cgb5) gene confers risk to recurrent spontaneous abortions (RSA) in Chinese women. Methods We recruited a total of 454 RSA subjects and 460 controls from our medical center between the years 2010 to 2013. rs7260002, which resides in the promoter region of Cgb5, was genotyped through direct sequencing. Results The carriers with the minor allele of rs7260002 had reduced risk of RSA (P=0.018; P adjusted=0.032; OR: 0.76; 95 % CI: 0.61-0.96). Genotype frequency was further analyzed under additive, recessive, and dominant models. Significant differences between the RSA subjects and controls were detected under additive and recessive models (P additive= 0.040; P recessive=0.010). Conclusions The current study identified a protective allele of the Cgb5 gene against RSA. Functional studies are required to elucidate the effect of the identified SNP on CGB expression and HCG hormone activity.

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Evolution of the Chorionic Gonadotropin β Genes in Primates

Laan

2009

Encyclopedia of Life Sciences

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Several genes associated with reproduction have been duplicated during primate evolution and evolved under positive selection. Chorionic gonadotropin hormone (HCG) produced by trophoblast cells has emerged in primates and assists maternal physiology to establish pregnancy. CGB gene, coding for the HCG β subunit has evolved through a duplication of the ancestral lutenizing hormone β ( LHB ) gene 55–35 million years ago. Only a few sequence changes in the duplicate locus were required to result in a novel CGB gene with different tissue‐specificity and function. Evolution of the LHB / CGB genomic region has been accompanied by active genome dynamics either as series of additional duplications in Old World monkeys and apes, or as functional modifications of genes in New World monkeys. Duplicated, highly homologous genes with diverged functions are maintained through a balance between selective pressures targeted to their specific functions and evolution in consort facilitated by interlocus gene conversion. Key Concepts Several genes associated with female and male reproduction have been shown to be duplicated during primate evolution and evolve under positive selection. Chorionic gonadotropin hormone (HCG) produced by the trophoblast cells has emerged in primates and acts as a key hormone to assist maternal physiology to establish pregnancy. Primate‐specific CGB gene, coding for the β subunit of HCG has emerged through a duplication of the ancestral lutenizing hormone β ( LHB ) gene approximately 55–35 million years ago. Only a few sequence changes in the duplicate locus were required to result in a novel CGB gene with different tissue‐specificity, expression pattern and function. Evolution of the LHB / CGB genomic region in primates has been accompanied by active genome dynamics either as a series of additional duplications in the lineage to OWM and apes, or as functional modifications of the gene loci in NWM. Comparison of the human and chimpanzee LHB/CGB gene clusters identified large species‐specific parallel rearrangement events, resulting in lineage‐specific number of CGB gene copies (five versus six genes in chimpanzee compared to human). Duplicated genes tend to evolve in consort facilitated by active interlocus gene conversion increasing and preserving sequence similarity among the gene copies. Intraspecies gene conversion events have led to a higher human–chimpanzee divergence between duplicated LHB/CGB genes compared to the available data for unique genomic regions. Duplicated, highly homologous genes with diverged functions are maintained through balancing interlocus gene conversion activity with selective pressure targeting their specific functions.

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Chorionic Gonadotropin β-Gene Variants Are Associated with Recurrent Miscarriage in Two European Populations

Abstract: The findings encourage studying the functional effect of the identified variants on CGB expression and HCG hormone activity to elucidate further the role of CGB variation in RM.

Cited by 38 publications

References 36 publications

Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success

Impact of gene polymorphisms of gonadotropins and their receptors on human reproductive success

Association of rs7260002 of chorionic gonadotrophin β5 with idiopathic recurrent spontaneous abortion in Chinese population

Evolution of the Chorionic Gonadotropin β Genes in Primates

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