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SHORT COMMUNICATION - Suppressor of cytokine signaling-3 in pregnant females with or without hypertension.

Byline: Huma Shoukat Ali, Mubeen Ali, Sabah Farhat and Syeda Sadia Fatima

Keywords: Hypertension, Pregnancy, SOCS-3, Obesity.

Introduction

Pregnancy induced hypertension (PIH) is the development of new hypertension in a pregnant woman 20 weeks after gestation without the presence of protein in the urine or other signs of preeclampsia.PIH complicates around 6-10% of all pregnancies around the world.1 These complications include pre-eclampsia, nervous system dysfunction, pulmonary oedema, elevated liver enzymes during pregnancy in the mother2 and for the foetus, it may lead to intrauterine growth restriction (IUGR), premature birth or even death in extreme conditions.1 In Pakistan itself, the morbidity and mortality are significantly higher - of 100 cases admitted for PIH, complications were seen in 98, one of them resulting in death due to inadequate antenatal management.3,4 The underlying cause of gestational hypertension in humans is commonly believed to be an improperly implanted placenta, or abnormal levels of inflammatory cytokines.

The hypothesised mechanism by which PIH occurs is that the pro inflammatory state seen in pregnancy can lead to vascular damage and hypertension. This can be accounted by multiple possible factors, such as a low anti-oxidant/oxidant ratio, which would suggest that reactive oxygen species are able to cause more damage to the blood vessels in the pregnant females.1 Some cases have been seen where there is increased natural killer cell function (due to increased production of stimulatory cytokines) which is the potential cause for the damage that leads to the development of high blood pressure.5 One such protein is called the Suppression of Cytokine Signaling (SOCS) which has a family of eight members (SOCS1-7 and CIS). These are modulators of the inflammatory pathway, that act by inhibiting the activation of Janus kinase-signal transducer and is activator of transcription (JAK-STAT) pathway to transmit their information into the cell nucleus.

This is achieved by three potential routes (a) inhibiting JAK proteins that have been activated directly, (b) being a competitive antagonist for STAT proteins, and (c) up regulating the proteasome lists of the STAT complexes. In this way, SOCS is said to be involved in the regulation of the inflammatory mediators, controlling the degree of the adverse effect.6 Lately, additional roles are identified in suppressing the inflammatory pathways in the immune system and in cancer biology.7 Yet, the functional importance of SOCS-3 in regulating vascular health is largely unknown but may be taken as an upcoming marker for metabolic diseases8 (Figure-1A). Therefore, we aimed to estimate SOCS-3 levels in 2nd trimester pregnant females and correlate the levels with blood pressure.

Subjects and Methods

A case control study was conducted at the Aga Khan University, Karachi from January 2017 till February 2018. Inclusion criteria included pregnant females in their 2nd trimester (13 to 27 weeks) between the ages of 20-35 years. While females with any comorbid such as gestational diabetes, twin pregnancies, chronic cardio metabolic illness or infectious diseases such as HIV, HBV, HCV or females on anti-inflammatory medication, were excluded from the study. Furthermore, females with pre-existing hypertension, and complicated cases were excluded from this study. The sample size was calculated using the Open-Epi website,9 with 1:1 distribution of cases and controls, where confidence level of 95%, power of 80%, least extreme odds ratio (OR) of 2 and a pregnancy hypertension prevalence of 8% was chosen as this was the result according to previously published data sources.10

The minimum sample size calculated for this research was 106.More than 150 pregnant ladies were contacted from the outpatient clinics and community health centre waiting room areas, and a total of 111 females agreed to participate and were recruited for this study. All the study participants gave a written and informed consent to participate in the study. Weight, height, BMI at the time of admittance, gestational age, family history lipid, profile and blood glucose level were recorded for all subjects. A blood pressure measurement was performed on each subject and previous two blood pressure readings were recorded from the subject's file. The subjects were then classified for having pregnancy induced hypertension (PIH) following the ACOG Guideline which states that "A blood pressure of >140/90 mm Hg is considered as PIH (n=50),11 and normotensive (n= 61) by the convienient randomn technique.

Written informed consent was obtained from the participants and five milliliters blood sample was collected after an overnight fast. Serum was separated and stored for comparative analysis. ELISA assays were used to detect SOCS-3 levels (kit cat # H1415 by Glorybioscince, Belgium). The study was approved by the Ethics and Review Committee of Aga Khan University (ERC-4523-BBS-16).

Statistical Analysis

Data was analysed by using SPSS version 23. Quantitative variables were expressed as mean +- standard deviation. The Mann Whitney U test was used to compare the level of SOCS-3 between pregnant females, with and without hypertension and chi square or Fischer extact test is applied wherever applicable. The Spearman ranks correlation was applied to test the association of SOCS-3 with hypertension and obesity. In all instances, a p value of <0.05 was considered significant.

Table: Parameters of study subjects.

Variable###Normotensive(n= 61)###Hypertensive(n= 50)###p value

Age(year)###26.59 +- 5.26###27.21+- 5.93###0.602

Weight(kg)###65.52 +- 13.40###72.37 +- 16.11###0.032

BMI(kg/m2)###25.69 +- 4.94###27.95 +- 5.79*###0.050

Gestational Age(weeks)###26.22 +- 2.15###27.17 +- 1.24###0.848

Parity###Primi###40(65.57)###33(66.0)###0.648

###Multi###21(34.42)###17(34.0)

Previous mode of delivery###LSCS###5(8.19)###3(6.00)###0.843

###SVD###56(91.80)###47(94.0)

FBG(mg/dl)###93.32 +- 26.02###91.53 +- 19.56###0.733

TAG(mg/dl)###144.32 +- 58.25###147.62 +- 60.04###0.798

HDL(mg/dl)###50.96 +- 8.613###51.65 +- 6.98###0.698

SBP(mmHg)###110.98 +- 10.44###148.75 +-16.60*###<0.001

DBP(mmHg)###70.00 +- 8.63###101.25 +-10.99*###<0.001

SOCs3(pg/ml)###16.75 +- 7.402###30.43 +- 13.505*###0.05). Furthermore, obesity and lipid derangement are confounding factors for hypertension, SOCS-3 is associated with inhibiting insulin signaling which in turn inhibits the lipid reabsorption into the adipose tissue and liver.12 Therefore, in this study, we wanted to assess if there was any lipid derangement along with the disruption of SOCs-3 in the study subjects. No difference in the lipid profile levels was observed, suggesting that SOCs-3 may act as an independent marker for blood pressure in pregnancy. However, hypertensive pregnant females were obese and had a higher BMI compared to normotensive females (p<0.05). Higher SOCS-3 levels were seen in hypertensive group (30 pg/ml) versus normotensive (16 pg/ml) (Table).

When we stratified ours groups based on BMI in order to assess the difference in SOCS-3 levels; higher levels were observed in hypertensive group across all BMI categories (Table-1). Lastly, we plotted a relationship curve between the biomarker, BMI and blood pressure. Both Systolic blood pressure (r=0.520; p<0.001) and diastolic blood pressure (r=0.490; p<0.001) showed a significant positive correlation with SOCS-3 level, whereas a non-significant association was observed with BMI (r=0.351; p=0.101) (Figure). The results of this study indicate that there is a positive correlation between SOCS-3 and hypertension. This signifies that SOCS-3 may play a role in the pathogenesis of the disease, and hence opening a possible area of research and treatment route for PIH.

Previous studies have shown that a low level of SOCS-3 was related to disease processes such as inhibition of differentiation of epithelial to mesenchymal cells and cellular proliferation in kidney proximal tubule cells.13 However, our results show a higher SOCS-3 level in hypertensive individuals, suggests the possibility that SOCS-3 is being produced as a result of the inflammatory environment during pregnancy and obesity in an attempt to limit the inflammatory damage and maybe prevent the catastrophic effects of hypertension. We cannot comment on the role of SOC-3 an anti inflammtory marker as we were limited to measuring cytokine levels in the study subjects due to budget constraints. Yet more observations and information about SOCS-3 as a chemical (as to the exact effects in the body, the production and the potential side effects it's administration may have) would be required before considering this route.

It is important to note that only a few studies were available on SOCS-3, obesity,14 diabetes and inflammatory cytokines.15 However, no articles were available that established associated levels of SOCS-3 with obesity or hypertension in pregnant females. Once a relationship between the two is established, levels of SOCS-3 can be monitored and changed through intervention to avoid comorbids like hypertension and other associated complications.

Disclaimer: None to declare.

Conflict of Interest: The authors declare that they have no conflict of interest.

Funding Source: Research Module Funds, Aga Khan University.

References

1. Kintiraki E, Papakatsika S, Kotronis G, Goulis DG, Kotsis V. Pregnancy-Induced hypertension. Hormones (Athens). 2015;14:211-23.

2. Vest AR, Cho LS. Hypertension in pregnancy. Curr Atheroscler Rep. 2014;16:395.

3. Riaz S, Habib S, Jabeen A. Frequency of maternal mortality and morbidity in pregnancy-induced hypertension. J Ayub Med Coll Abbottabad. 2011; 23:61-3.

4. Slack E, Rankin J, Jones D, Heslehurst N. Effects of maternal anthropometrics on pregnancy outcomes in South Asian women: a systematic review. Obes Rev. 2018; 19:485-500.

5. Rodriguez-Iturbe B, Pons H, Johnson RJ. Role of the Immune System in Hypertension. Physiol Rev. 2017; 97:1127-64.

6. Sorokina LN, Mineev VN, Lim VV. [Role of negative regulators of SOCS1, SOCS3, and SOCS5 gene transcription in the negative cell signaling regulation system in asthma]. Ter Arkh. 2017;89:43-7.

7. Rottenberg ME, Carow B. SOCS3, a major regulator of infection and inflammation. Front Immunol. 2014; 5:58.

8. Pedroso JA, Ramos-Lobo AM, Donato J. SOCS3 as a future target to treat metabolic disorders. Hormones (Athens). 2018:1-10.

9. Dean AG SK, Soe MM. OpenEpi: Open Source Epidemiologic Statistics for Public Health, Version. [Online] 2013 [Cited 2015 Dec 10]. Available from: URL: http://www.openepi.com/Menu/OE_Menu.htm

10. Perveen S. Frequency and impact of hypertensive disorders of pregnancy. J Ayub Med Coll Abbottabad. 2014; 26:518-21.

11. Magee LA, Pels A, Helewa M, Rey E, von Dadelszen P, Audibert F, et al. Diagnosis, evaluation, and management of the hypertensive disorders of pregnancy: executive summary. J Obstet Gynaecol Can. 2014; 36:416-41.

12. Jorgensen SB, O'Neill HM, Sylow L, Honeyman J, Hewitt KA, Palanivel R, et al. Deletion of skeletal muscle SOCS3 prevents insulin resistance in obesity. Diabetes. 2013; 62:56-64.

13. Neuwirt H, Eder IE, Puhr M, Rudnicki M. SOCS-3 is downregulated in progressive CKD patients and regulates proliferation in human renal proximal tubule cells in a STAT1/3 independent manner. Lab Invest. 2013; 93:123-34.

14. Emanuelli B, Peraldi P, Filloux C, Chavey C, Freidinger K, Hilton DJ, et al. SOCS-3 inhibits insulin signaling and is up-regulated in response to tumor necrosis factor-alpha in the adipose tissue of obese mice. J Biol Chem. 2001; 276:47944-9.

15. Mirza S, Hossain M, Mathews C, Martinez P, Pino P, Gay JL, et al. Type 2-diabetes is associated with elevated levels of TNF-alpha, IL-6 and adiponectin and low levels of leptin in a population of Mexican Americans: a cross-sectional study. Cytokine. 2012; 57:136-42.
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Publication:Journal of Pakistan Medical Association
Article Type:Report
Date:Aug 31, 2019
Words:2047
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