Effects of Pre-Pregnancy Overweight/Obesity on the Pattern of Association of Hypertension Susceptibility Genes with Preeclampsia

Abstract

The aim of this study was to explore the effects of pre-pregnancy overweight/obesity on the pattern of association of hypertension susceptibility genes with preeclampsia (PE). Ten single-nucleotide polymorphisms (SNPs) of the 10 genome-wide association studies (GWAS)-significant hypertension/blood pressure (BP) candidate genes were genotyped in 950 pregnant women divided into two cohorts according to their pre-pregnancy body mass index (preBMI): preBMI ≥ 25 (162 with PE and 159 control) and preBMI < 25 (290 with PE and 339 control). The PLINK software package was utilized to study the association (analyzed four genetic models using logistic regression). The functionality of PE-correlated loci was analyzed by performing an in silico database analysis. Two SNP hypertension/BP genes, rs805303 BAG6 (OR: 0.36–0.66) and rs167479 RGL3 (OR: 1.86), in subjects with preBMI ≥ 25 were associated with PE. No association between the studied SNPs and PE in the preBMI < 25 group was determined. Further analysis showed that two PE-associated SNPs are functional (have weighty eQTL, sQTL, regulatory, and missense values) and could be potentially implicated in PE development. In conclusion, this study was the first to discover the modifying influence of overweight/obesity on the pattern of association of GWAS-significant hypertension/BP susceptibility genes with PE: these genes are linked with PE in preBMI ≥ 25 pregnant women and are not PE-involved in the preBMI < 25 group.

Sex-Specific Features of the Correlation between GWAS-Noticeable Polymorphisms and Hypertension in Europeans of Russia

“…Concurrently, there are some discrepancies in the results of these studies: SNP BAG6 rs805303 G > A has a protective value for HTN in men (not in women!) (OR = 0.30), but in parallel, this polymorphism marks a low risk of developing pre-eclampsia in pregnant women as a whole (OR = 0.55-0.78) [104] and among women with a BMI ≥ 25 (OR = 0.36-0.66) [105]. One of the possible reasons for these sex-specific differences in the value of the BAG6 rs805303 G > A locus in the development of pathology with elevated BP may be the modifying effect on the phenotypic manifestation of this polymorphism of an unequal confounder factor list taken into account in these studies (BMI, TC, TG, HDL-C, LDL-C, blood glucose, smokers-present study; age, family history of PE, pre-pregnancy BMI, obesity, number of gravidities, spontaneous/induced abortions, stillbirths, smokers-previous study [104]).…”

“…It is quite interesting that the data of this work are largely consistent with our previously published materials in which, during an associative study of a women sample with pre-eclampsia/without pre-eclampsia from the identical population of Europeans in Central Russia (the list of studied loci was analogous), it was found that the HFE rs1799945 C > G increased the pre-eclampsia risk (for allele G OR = 2.24) and BAG6 rs805303 G > A decreased the pre-eclampsia risk (for allele A OR = 0.55-0.78) [104] including this pregnancy complication risk in women with BMI ≥ 25 (for allele A OR = 0.36-0.66) [105]. So, the polymorphic variant G rs1799945 HFE increases both the HTN risk in women (data from this work, OR = 11.15 for genotype GG) and the pre-eclampsia risk in women (a specific symptom of this complication of pregnancy is increased BP (OR= 2.24 [104])), which may indicate the "universality" of this genetic marker as a risk factor for the development of hypertensive conditions in European women in Central Russia, and allows us to recommend its use in practical medicine in order to distinguish women with a high risk of developing elevated BP.…”

“…We gathered peripheral blood (leukocytes) to extract genomic DNA [113] (the phenol/chloroform DNA extraction methodology was presented earlier [114]). The ten specially selected polymorphisms (confirmed associations of GWAS level with blood pressure (BP) parameters and/or HTN in European (Table S17) and assumed functional ability [104,105,115] (HaploReg information was regarded [116]) (Table S18)) were considered. The list of studied loci was as follows: (PLCE1) rs932764 A > G, (AC026703.1) rs1173771 G > A, (CERS5) rs7302981 G > A, (HFE) rs1799945 C > G, (OBFC1) rs4387287 C > A, (BAG6) rs805303 G > A, (RGL3) rs167479 T > G, (ARHGAP42) rs633185 C > G, (TBX2) rs8068318 T > C and (ATP2B1) rs2681472 A > G. All ten loci were correlated with BP in Europeans and all ten SNPs were associated with HTN: eight SNPs were HTN-linked in Europeans and two loci (rs4387287 OBFC1 and rs2681472 ATP2B1) were disorder-associated in the sample with a predominance (>85%) of Europeans (Table S17).…”

Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk

“…The participants of present research have previously been involved in other genetic studies of disorders/outcomes of pregnancy (newborn weight, preeclampsia, FGR) (detailed data on the results of these studies are contained in previous publications [ 40 , 75 , 76 , 78 , 79 , 80 , 81 , 82 ]). Table 1 presents the biological/medical characteristics of the FGR/FGR free cohorts formed.…”

Intergenic Interactions of SBNO1, NFAT5 and GLT8D1 Determine the Susceptibility to Knee Osteoarthritis among Europeans of Russia

“…The probable KOA effector SNPs/genes (taking into account proxy SNPs, r 2 ≥ 0.80 [ 60 , 61 ]) have been chosen for their functionality (the in silico approach was applied [ 62 , 63 ] based on online integrated resources of bioinformatics information [ 64 , 65 , 66 ] including the GTEx [ 67 ], PolyPhen2 [ 68 ], HaploReg [ 39 ], Blood eQTL [ 69 ], SIFT [ 70 ], GeneMANIA [ 71 ]).…”