Gestational diabetes mellitus (GDM) is supposed to have multifactorial causes, one of them may result from gene variations with the influence of some individual effects. Gestational diabetes mellitus (GDM) is supposed to have multifactorial causes; one of them may result from gene variations with the influence of some individual effects. For prediction, prevention and management of GDM, genetic risk scores were implemented. These scores were derived from several genes and their single nucleotide polymorphisms (functional polymorphisms) or haplotypes (Vrachnis et al., 2012).
This study is conducted on pregnant Egyptian women with GDM; we have investigated the probable associations of ACE (I/D), AGT (M235T), and ARNT-like protein-1 (G/A) genetic variations with the risk of GDM. Though the actual mechanism of GDM development through gestation is still unknown, it could be recognized by increasing insulin resistance caused by maternal adiposity superimposed by the effect of insulin-desensitizing placental products as prolactin, estrogen, and human placental lactogen (Khan et al., 2014).
In an insertion/deletion (I/D) polymorphism of ACE gene with intron 16, 287-base pair Alu repetitive sequence is a common occurring variant (Chmaisse et al., 2009). This result indicated that the DD genotype and D allele of ACE was significantly associated with an increased risk of GDM. This is, also, reported with a positive association in women of Brno and Indian population (Dostalova et al., 2006; Khan et al., 2013). In the same line, a study by Khan et al., (2013) in an Asian Indian population of pregnant women revealed that the relationship between polymorphism of ACE (ID+DD) and the risk for GDM development. Alternatively, the frequency of DD genotype showed no significant difference among GDM patients in a Saudi population, and D allele frequency had a non-significant statistical difference between GDM and controls (Saddick, 2015). Moreover, Dostalova et al., (2006) had one study in which polymorphism of ACE gene had no significant relation with GDM.
AGT gene encodes the precursor of all peptides of angiotensin. This gene is located on chromosome 1 (lq42-43) and has been considered as hypertension gene (Yagil and Yagil, 2004) and preeclampsia (Bernard and Giguere, 2003; Yang et al., 2013).To our knowledge, this study is the first one that evaluates the influence of this common SNP on GDM in Egyptian women. Our findings showed that significant associations between the TT genotype and T allele of AGT and the risk of GDM. A study done by Ludwi et al., 1997 which suggested that T allele of AGT M235T polymorphism as an independent risk factor for CAD. While Gurkan et al., 2009 findings did not support the idea that persons with T allele of AGT 235 gene will have high levels of AGT and so will yield more Ang. II, which lead to destruction of the tissue, as this genetic variant was more frequent in healthy subjects Furthermore, we observed a significant correlation between the recessive model of AGT (MM+MT/ TT) with BMI, hypertension, and HOMA-IR.
An earlier Japanese study was in agreement with our results, in which M235T reported a positive association with visceral obesity in obese women and T2DM morbid obese patients (Yasuto et al.,2006; Pacholczyk et al., 2015). M235T, also, has been investigated and showed a positive relation with T2DM in the Tunisian population (Mehri et al., 2010). Association between AGT rs699 and hypertension induced by pregnancy was investigated by another meta-analysis in the Chinese population. This meta-analysis found that the dominant genetic model (MT+TT) and the recessive genetic model (MT+MM) have significant associations (Zhu et al., 2012).
Angiotensin II acts as a final hormone affecting the rennin-angiotensin system. Its reactive production baseline can be increased by variants of angiotensinogen as M235T. Auto regulatory mechanisms could be provoked by continues over-stimulation which leads to increase vascular tone and vascular hypertrophy. This state can exaggerate the imbalance between vasoconstrictors and vasodilator factors, so that increasing vascular tone and hypertrophy. The sensitivity to angiotensin II then increased and the plasma levels of most angiotensinogen systems are reduced; Mutter and Karumanchi, 2008).
Strong evidence for the ARNT-like protein-I (BMALI) gene role has been provided in T2DM pathogenesis (Marcheva et al., 2010; Stamenkovic et al., 2012; Kelly et al., 2012; Konig and Shuldiner, 2012). Given the genetic and pathophysiological feature's similarities between T2DM and GDM, in this study, we investigated the informative variants of the relationship between the BMAL1 gene and GDM in Egyptian women.GDM susceptibility knowledge is still limited, concerning genes or epigenetic alterations induced by glucose which occur during gestation, despite the wide spread of active research using genomic technologies.(Watanabe, 2012; Kwaketal., 2012).
This study provides evidence that the clock gene variants of the ARNT like the protein-1 (BMAL1) gene, may be a predisposing factor to GDM in the Egyptian population. There was a positive association between the mutant genotype AA and A allele and the development of GDM. Our findings were consistent with the previous studies conducted by PappaKI. et al.,2013 who indicated for the first time that the rs7950226 (G > A) of the BMAL1 gene can be associated with increased GDM susceptibility. To our knowledge, these polymorphisms were found to be associated with T2DM in current studies (Kelly et al., 2012), further increasing the list of sharing genetic parameters and common variants between GDM and T2DM. Also, the results are in agreement with Woon et al.,
2007, who reported T2DM patients independently, and found that the same polymorphisms in rs7950226 (G > A) were highly associated with T2DM susceptibility. However, our findings differ from Kelly et al., 2013, who displayed that the haplotype of rs7950226A/rs11022775T of the BMAL1 gene has a positive association with T2DM.
The circadian clock distribution differences in gene polymorphism frequencies between populations worldwide were recently highlighted, giving us a powerful genetic component associated with the environment, not as a result of natural selection (Ciarleglio et al., 2008). Specifically, the significant role of the clock genes, mainly BMAL1, in circadian self-keeping oscillations involved in glucose metabolism, growth, and pancreatic islets insulin signaling, has been recently underscored. This delayed phase oscillations when applied on mutant mice by conditional β-cell knockout leads to hypoinsulinemia and diabetes (Marcheva et al., 2010). The phenotype resulted from that may be of clinical relevance. An early stage of dysfunction of β-cell may be reflected as a temporal derangement of the secretion of insulin. This also augments the clock (s) function of dynamic relation links in different tissues and increases the impact of disruption leading to T2DM (Pappa et al., 2013).
As for the assumed GDM pathophysiological mechanisms that involve the clock genes, also regarding common features between both types of diabetes (T2DM and GDM) such as decreased insulin secretion and β-cell dysfunction, and increased insulin resistance during gestation, it is believable that the associated decrease in clock genes allele variants especially BMAL1 gene, as it was documented in this study, may increase the risk of GDM and glucose intolerance (Konig and Shuldiner, 2012). Besides, decreased susceptibility of the GDM alleles makes complementary β-cell mass increase (Lee et al., 2011; Pappa et al., 2011; Watanabe, 2012; Konig and Shuldiner, 2012). The related deficiency of the allele variants of the clock genes and particularly of the BMAL1 gene, as recognized in our study, might further result in the increased risk of glucose intolerance and GDM