Maternal Age at Menarche Gene Polymorphisms Are Associated with Offspring Birth Weight

Abstract

In this study, the association between maternal age at menarche (AAM)-related polymorphisms and offspring birth weight (BW) was studied. The work was performed on a sample of 716 pregnant women and their newborns. All pregnant women underwent genotyping of 50 SNPs of AAM candidate genes. Regression methods (linear and Model-Based Multifactor Dimensionality Reduction (MB-MDR)) with permutation procedures (the indicator pperm was calculated) were used to identify the correlation between SNPs and newborn weight (transformed BW values were analyzed) and in silico bioinformatic examination was applied to assess the intended functionality of BW-associated loci. Four AAM-related genetic variants were BW-associated including genes such as POMC (rs7589318) (βadditive = 0.202/pperm = 0.015), KDM3B (rs757647) (βrecessive = 0.323/pperm = 0.005), INHBA (rs1079866) (βadditive = 0.110/pperm = 0.014) and NKX2-1 (rs999460) (βrecessive = −0.176/pperm = 0.015). Ten BW-significant models of interSNPs interactions (pperm ≤ 0.001) were identified for 20 polymorphisms. SNPs rs7538038 KISS1, rs713586 RBJ, rs12324955 FTO and rs713586 RBJ–rs12324955 FTO two-locus interaction were included in the largest number of BW-associated models (30% models each). BW-associated AAM-linked 22 SNPs and 350 proxy loci were functionally related to 49 genes relevant to pathways such as the hormone biosynthesis/process and female/male gonad development. In conclusion, maternal AMM-related genes polymorphism is associated with the offspring BW.

Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk

“…The present study revealed associations of rs12444979 GPRC5B with FGR both independently (the T allele of this SNPs was risky for FGR, OR = 1.56–1.67) and as part of SNP interactions models (50% of FGR risk models included this SNPs). Also, in our previously performed genetic study in this population (Russian women of Central Russia), the relationship of maternal rs12444979 GPRC5B (as part of interloci “dialogue” models) with offspring birth weight (BW) [ 40 ] was shown. rs12444979 GPRC5B was AAM-bounded [ 41 , 42 ] and BMI-involved [ 43 , 44 , 45 , 46 ], wherein the T allele of this SNP correlated with a later AAM [ 41 ], and an alternative genetic variant for it, the C allele, was associated with increased BMI [ 43 , 44 , 46 ].…”

“…(our in silico materials). In previous studies, rs7538038 KISS1 was linked with AAM (the G allele was a genetic factor of early AAM) [ 53 ], central precocious puberty in girls (allele G was risky for central precocious puberty) [ 54 ], BW and endometrial hyperplasia (as part of inter-genic interworkings, [ 31 , 40 ], respectively). So, we can generalize that the AAM-reducing allele G rs7538038 KISS1 , also associated with central precocious puberty of girls, is an FGR-protective factor.…”

“…This SNP has a high functional potential: it was involved in the enhancer or/and promoter activity regulating disorder-linked cultured cells such as the derived CD184+_endoderm, the CD56+_ectoderm, the H1_BMP4_mesendoderm, etc., determining the nucleic acids binding with such 5TrFs as STAT, AIRE, Foxa, Arid5a, Pax-45 and controlling SFTA3 gene splicing in the thyroid (FGR-risk allele A was linked with high SFTA3 sQTL). Previously, associations of rs999460 NKX2-1 with AAM [ 53 ], female BMI [ 36 ], endometrial hyperplasia [ 31 ], and offspring BW [ 40 ] were presented. Interestingly, the AAM-boosting A allele rs999460 NKX2-1 [ 53 ] determined a high risk of FGR (OR = 1.37–2.41, our data) and was associated with a low BW [ 40 ].…”

“…Previously, associations of rs999460 NKX2-1 with AAM [ 53 ], female BMI [ 36 ], endometrial hyperplasia [ 31 ], and offspring BW [ 40 ] were presented. Interestingly, the AAM-boosting A allele rs999460 NKX2-1 [ 53 ] determined a high risk of FGR (OR = 1.37–2.41, our data) and was associated with a low BW [ 40 ].…”

“…Importantly, all the abovementioned pregnancy course/outcomes directly correlate with FGR [ 2 , 18 ]. AAM gene association with female reproductive organ diseases [ 31 , 32 , 33 ], BMI-related phenotypes (height; weight; BMI) of adults [ 34 , 35 , 36 , 37 , 38 , 39 ], newborn weight [ 40 ], and complications of pregnancy (gestational diabetes) [ 27 ] has been demonstrated. Notwithstanding, the relationship of AAM genes with FGR has not been studied to date.…”