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Table of Contents
ORIGINAL ARTICLE
Year : 2019  |  Volume : 62  |  Issue : 5  |  Page : 196-202

Adrenergic receptor beta-3 rs4994 (T>C) and liver X receptor alpha rs12221497 (G>A) polymorphism in Pakistanis with metabolic syndrome


1 Department of Physiology and Cell Biology, University of Health Sciences; Lahore Medical and Dental College, Lahore, Pakistan
2 Department of Physiology and Cell Biology, University of Health Sciences, Lahore, Pakistan

Date of Submission02-Jun-2019
Date of Decision18-Sep-2019
Date of Acceptance25-Sep-2019
Date of Web Publication24-Oct-2019

Correspondence Address:
Dr. Uzma Zafar
Department of Physiology and Cell Biology, University of Health Sciences, Lahore; Lahore Medical and Dental College, Lahore
Pakistan
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/CJP.CJP_45_19

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  Abstract 

The present study aimed to determine the association of adrenergic receptor beta-3 (ADRB3) rs4994 T>C and liver X receptor alpha (LXR-α) rs12221497 G>A polymorphism with metabolic syndrome (Met S) and the related traits in Pakistanis. Patients of Met S were recruited from the Endocrinology and Diabetic Clinic of Sheikh Zayed Hospital Lahore, over the time span of 6 months from July to December 2016. Single-nucleotide polymorphism (SNP) of ADRB3 was determined by restriction fragment length polymorphism and of LXR-α by amplification refractory mutation system polymerase chain reaction. The frequency of TT variant of ADRB3 T>C in Met S was 69 (34.5%) and in controls 89 (44.5%), frequency of TC 103 (51.5%) and 96 (48%), and of CC 28 (14%) and 15 (7.5%), respectively. In the recessive model (CC: TT + TC), CC genotype was found to be associated with the increased risk of Met S (P = 0.027; odds ratio [OR] = 2.09; confidence interval [CI] =1.08–4.03) and the association remained significant after controlling for the confounders such as age and sex. The frequency of GG variant of LXR-α G>A in Met S was 35 (17.5%) and in controls 15 (7.5%), GA 129 (64.5%) and 137 (68.5%), and AA 36 (18%) and 48 (24%), respectively. In the recessive model (GG: GA + AA), GG genotype was found to be associated with the increased risk of Met S (P = 0.004; OR = 2.52; CI = 1.33–4.80) and the association remained significant after controlling for the confounders such as age and sex. It was concluded that SNP of ADRB3 (190 T>C) and LXR-α (−115 G>A) were associated with the risk of Met S and might increase the susceptibility to the obesity-related traits.

Keywords: Adrenergic receptor beta-3, energy homeostasis, liver X receptor alpha, metabolic syndrome, single-nucleotide polymorphism


How to cite this article:
Zafar U, Khaliq S, Ali Z, Lone KP. Adrenergic receptor beta-3 rs4994 (T>C) and liver X receptor alpha rs12221497 (G>A) polymorphism in Pakistanis with metabolic syndrome. Chin J Physiol 2019;62:196-202

How to cite this URL:
Zafar U, Khaliq S, Ali Z, Lone KP. Adrenergic receptor beta-3 rs4994 (T>C) and liver X receptor alpha rs12221497 (G>A) polymorphism in Pakistanis with metabolic syndrome. Chin J Physiol [serial online] 2019 [cited 2019 Nov 20];62:196-202. Available from: http://www.cjphysiology.org/text.asp?2019/62/5/196/269835


  Introduction Top


“Metabolic syndrome” (Met S), a term used for the constellation of risk factors such as hypertension, central obesity, and impaired lipid and glycemic parameters is a low-grade chronic inflammatory state resulting from complex interaction of genetic and different environmental factors.[1] The exact cause of this condition is not understood, but previous studies have revealed robust linkage of Met S with insulin resistance (IR), oxidative strain, visceral obesity, and adipose dysfunction.[2] Met S and associated traits significantly increase the risk of type 2 diabetes mellitus (T2DM), acute coronary syndrome, cerebrovascular accident, and hepatic steatosis.[3] Observations of the previous studies demonstrate that IR and related components such as T2DM, obesity and dyslipidemias exhibit a strong genetic predisposition and it is also very high for the other features of IR such as increases in body mass index (BMI) and blood pressure (BP).[4],[5] Adrenergic receptor beta-3 (ADRB3) is involved in energy homeostasis by increasing thermogenesis and lipolysis. It is predominantly expressed in white and brown adipose tissue and on stimulation by its ligands “Catecholamines” it increases the intracellular levels of cyclic adenosine monophosphate.[6],[7] A missense mutation of ADRB3 gene 190 T>C (rs4994) results in the replacement of tryptophan at the 64th position with arginine in the receptor protein. This change in amino acid sequence alters the affinity of this receptor for its ligands and was reported to be associated with an increase in weight gain and BMI in universal pattern.[8] Allelic frequencies of this polymorphism vary in different races and ethnicities. High frequency of this polymorphism was found to be present in Japanese.[9] A high frequency of this mutation has also been reported in Pima Indians.[10] However, no association of Try64Arg polymorphism was found with T2DM in Caucasians.[11] In another study from Mexico city, this polymorphism was found to be associated with T2DM and Met S.[12]

Liver X receptor (LXR) that belongs to the class of nuclear family of receptors, plays an essential role in modulating cellular lipid metabolism.[13] LXR-α and LXR-β are the two isoforms of this receptor. The former is mainly expressed in the hepatocytes, macrophages, kidney, and intestine.[14] Natural ligands for LXR are oxysterols which accumulate as a result of the increased concentration of cholesterol in the cells.[15] LXR acts as cell cholesterol sensor and when the levels of oxysterol exceed the acceptable limit, it turns on the genes required for the disposal of cholesterol from the cells such as genes involved in; reverse transport of cholesterol, increased conversion of cholesterol to bile acid, and decreased absorption of cholesterol.[16],[17] LXR is considered as a potential therapeutic target in preventing cardiac failure, atherosclerosis, and other metabolic derangements such as IR and DM.[18] Gene for LXR-α is present on the chromosome 11p11.2.[19] This gene is involved in cholesterol metabolism and also suppresses the production of proinflammatory chemokines and cytokines.[20] Recent studies have reported significant association of LXR-α G>A (rs12221497) polymorphism with T2DM and Met S.[21],[22] In a study on Han Chinese, A allele of G>A LXR-α polymorphism was associated with two times increased risk of ischemic stroke.[20] Results from the INVEST-GENES study revealed that A allele of LXR-α G>A variant was associated with the reduced risk of adverse cardiovascular events.[23] In adolescents of HALENA study reduced high-density lipoprotein cholesterol (HDL-c) levels were reported in the minor A variant of LXR-α −115 G>A.[24] Although ADRB3 and LXR genetic variations exhibit polymorphic associations, single-nucleotide polymorphism (SNP) of these receptors by altering the ligand-binding ability and gene regulation are involved in the pathogenesis of Met S and related traits.[25] Various studies have shown the association of LXR-α and ADRB3 polymorphisms with Met S and IR while others are equivocal.[12],[24],[26],[27] There is no previous study from Pakistan reporting the association of ADRB3 and LXR-α polymorphism with Met S or related traits. In this study, we determined the prevalence of ADRB3 (190 T>C) and LXR-α (−115 G>A) polymorphism in Pakistanis with and without Met S and also evaluated their association with Met S and the related traits.


  Materials and Methods Top


Ethics

The study was conducted in compliance with the Helsinki Declaration of human rights. It was approved by the Institutional Review Board of the University of Health Sciences, Lahore (IRB number: UHS/Education/126-16/1267) and Sheikh Zayed Hospital, Lahore (F.P.G.M.I Lahore; Diary No: 1965). All participants were fully informed of the study and written informed consent was obtained.

Study design

This was a cross-sectional comparative study.

Selection and description of the study participants

Patients of Met S were recruited from the Endocrinology and Diabetic Clinic of Sheikh Zayed Hospital Lahore, over the time span of 6 months (July to December 2016). Available data and investigations with the participants were checked. Met S was defined according to the International Diabetes Federation criteria.[28] All the selected cases of Met S were centrally obese, males having waist circumference (WC) >90 cm and females having WC >80 cm with two or more of the following four features: (1) Serum triglycerides ≥150 mg/dl or on lipid lowering agent, (2) Serum HDL-c <40 mg/dl for men and <than 50 mg/dl for women or on treatment for dyslipidemia, (3) Fasting blood sugar >100 mg/dl or on treatment for DM, and (4) BP >130/85 or on treatment for hypertension. If two of the above four features were present along with the central obesity participants were diagnosed to have Met S. All those already taking anti-hypertensive or lipid-lowering agents were considered to be dyslipidemic or hypertensive irrespective of their present status. Written informed consent was obtained from all the selected participants. To take fasting blood sample, fasting status of the participants was inquired and fasting was defined as no caloric intake for the past 8–10 h.[29] A volume of 8 ml venous blood was drawn from each participant with sterile syringe and with aseptic techniques. 4.0 ml blood was secured in ethylenediaminetetraacetate coated vacutainers for DNA extraction. 1.0 ml blood was secured in gray topped vacutainers (containing sodium fluoride and potassium oxalate) for glucose estimation and the rest 5 ml was stored in yellow topped vacutainers for serum extraction. Age- and sex-matched controls were selected from the general population. They were hospital staff or nonblood-related attendants of the patients. Selection criteria for the controls were WC ≤90 cm in men and ≤80 cm in females, nonhypertensive and nondiabetic. There was no history of intake of lipid-lowering agents or any medications for diabetes and hypertension. Fasting and 2 h postprandial blood sugar and BP of controls were checked on two separate days. Those participants were included having fasting blood sugar <100 mg/dl, 2 h after meals <140 mg/dl, and BP <130/85.[30],[31]

Measurement of clinical and biochemical parameters

BMI, BP, and WC were recorded by the standard methods. BP was recorded from the left arm in sitting position after 10 min of rest. Two measurements were taken after 5-min interval and an average of two recordings was noted. WC was measured at the mid-point between the lower border of the last rib and the upper rim of the anterior-superior iliac crest. Fasting serum glucose and lipid profile, including serum triglycerides, HDL-c were measured using the colorimetric method with Randox reagents (Randox Laboratories Ltd., Crumlin, Co. Antrium, BT29QY, United Kingdom).

DNA extraction and determination of single-nucleotide polymorphism

DNA extraction was done with Favor Prep Blood Genomic DNA Extraction Kit (FAVORGEN Biotech Corp, Pingtung, Taiwan). DNA yield in ng/μl was checked by the Nanodrop. LXR-α −115 G>A SNP was determined by amplification refractory mutation system (http://primer1.soton.ac.uk/primer1.html; Southampton SO 16 6YD, UK) polymerase chain reaction using following primers:

Outer forward 5'-AATTCCTAGACTAGCCTGGGCA AAATAG-3'

Outer reverse 5'-GAATGAAGCTTACCAGGAGGA ATGTC-3'

Inner forward 5'-GCTGATATTGTTGATATTGATAA AATGG-3'

Inner reverse 5'-CTCAGCTCCCTTCTCCACCTGATCATT-3'

PCR reaction made was of total 15 μL containing 0.3 μL of each primer, 2 μL (50 ng) genomic DNA, 7.5 μL master mix and 4.3 μL double distilled water. The PCR cycling conditions were denaturation for 5 min at 95°C followed by 30 cycles of denaturation for 30 s at 95°C, annealing for 30 s at 62°C, extension for 27 s at 72°C with a final extension at 72°C for 5 min to allow for complete extension of all PCR products. The amplicons were run for 60 min on 3% agarose gel stained with ethidium bromide and checked under ultraviolet (UV) gel documentation system (Gel Doc XR + System, Bio-Rad, USA). The product sizes for rs12221497 G>A were as: outer PCR product 304-bp, G allele 199-bp, and A allele 160-bp [Figure 1]a and [Figure 1]b.
Figure 1: (a and b) Gel electrophoresis after ARMS-PCR amplification of liver X receptor alpha rs12221497 (G>A); DNA ladder = 50 - base pair; GG = 304 - and 199 - base pair; GA = 304 -, 199 - and 160 - base pair; AA = 304 - and 160 - base pair. ARMS-PCR: Amplification refractory mutation system-polymerase chain reaction, bp: Base pair

Click here to view


ADRB3 SNP 190 T>C was genotyped by restriction fragment length polymorphism using the following primers.[27]

Forward 5'-CAATACCGCCAACACCAGTGG-3'

Reverse 5'GGTCATGGTCTGGAGTCTCG-3'

The PCR was carried out in Thermal Cycler (Bio-Rad, USA) as follows: denaturation at 95°C for 15 min initially, followed by 34 cycles of denaturation at 95°C for 30 s, annealing at 60°C for 30 s, extension at 72°C for 30 s and a final extension of 72°C for 10 min. After PCR, amplicon analysis was carried out on 3% agarose gel for 151-bp product. The amplified product was digested by Msp I, (Thermofisher Scientific, US; Product information: Msp I, #ER 0541) at 37°C overnight.[27] The reaction was set in a volume of 10 μL amplicons, 1 μL of Msp1, 2 μL ×10 buffer R and 18 μL of nuclease free water. The digested products were separated on 3% agarose gel and visualized under UV gel documentation system (Gel Doc XR + System, Bio-Rad, USA). Msp I, restriction yielded: TT 151-bp, CC 124- and 27-bp, TC 151-, 124- and 27-bp [Figure 2].
Figure 2: Gel electrophoresis after PCR amplification and restriction of adrenergic receptor beta 3 rs4994 (T>C); DNA ladder = 100-base pair; TT = 151-base pair; TC = 151 -, 124 - and 27 - base pair; CC = 124 - and 27 - base pair. RFLP-PCR: Restriction fragment length polymorphism-polymerase chain reaction, bp: Base pair

Click here to view


Statistical analysis

The data were entered and analyzed using the Statistical Package for the Social Sciences version 22.0 (IBM Corp, Armonk, New York, USA). Distribution of the data was checked by “Shapiro–Wilk's” statistics and as value of P < 0.05, data were considered to be nonnormally distributed. Median with interquartile range was given for nonnormally distributed quantitative variables. Frequencies and percentages were given for categorical variables. A value of P < 0.05 was considered to be statistically significant. Genotypic and allelic frequencies were calculated and Hardy–Weinberg equilibrium was determined by online genetic epidemiology tool (http/www.oege.org). Allelic frequencies of two groups were compared by the online MedCalc Statistical Software version 16.43 (Medcalc Software Bvba, Ostend, Belgium; http://www.medcalc.org; 2016). To study the association of genotypes with Met S three genetic models Co-dominant, Dominant, and Recessive were constructed. Genotype frequencies of the two groups were compared using the Chi-square test and odds ratio (OR) was calculated. Logistic regression was applied to see the association of genotypes with Met S after controlling for age and sex.


  Results Top


The present study included 400 participants, of these 200 were the patients of Met S and 200 were the healthy controls. All the Met S cases were centrally obese, 88% (176/200) were diabetic, 12% (24/200) had impaired blood glucose, 78% (156/200) were hypertensive, and dyslipidemia was found in 93% (186/200) of the participants or they were on lipid-lowering drugs. Duration of Met S was less than a year in 60% of the cases and more than a year in 40% of the cases. In Met S group, 77% (155) were males and 23% (45) were females. In the healthy group, 82.5% (165) were males and 17.5% (35) were females. Mean ± standard deviation ages of the participants with Met S and controls were 47.20 ± 8.03 and 46.52 ± 8.24 years, respectively. There was no significant difference between the mean age of the two groups. Clinical characteristics of the study participants have already been described and presented in the previous study.[32]

Comparison of adrenergic receptor beta 3 rs4994 (T>C) genotypes among the study groups

The frequency of TT variant of ADRB3 T>C in Met S was 69 (34.5%) and in controls 89 (44.5%), frequency of TC 103 (51.5%) and 96 (48%), and of CC was 28 (14%) and 15 (7.5%), respectively. The genotype frequencies in cases and controls were in the Hardy–Weinberg equilibrium (χ2 < 3.84; P < 0.05). In the co-dominant model [Table 1], there was a significant difference between the genotypes of ADRB3 T>C, in cases and the controls (P = 0.035). Frequencies of the minor C allele in cases and controls were 159 (40%) and 126 (31.5%) and frequencies of the major T allele were 241 (60%) and 274 (68.5%), respectively. There was significant association of the minor C allele with the increased risk of Met S (P = 0.015; OR = 1.43: Confidence interval [CI] =1.07–1.92). In the recessive model, CC genotype was found to be associated with the increased risk of Met S (P = 0.027; OR = −2.09; CI = 1.08–4.03) and in the dominant model, TT genotype was found to be associated with the decreased risk of Met S (P = 0.041; OR = 0.658; CI = 0.44–0.98). The association of the recessive CC genotype remained significant after controlling for the confounders such as age and sex (P = 0.019; OR = 2.23; CI = 1.14–4.38), while association of the dominant model did not remain significant (P = 0.094; OR = 0.7; CI = 0.46–1.06).
Table 1: Comparison of adrenergic receptor beta 3 rs4994 (190 T>C) genotypic and allelic frequencies among the study groups

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On comparison of the study parameters in the three genotypes of ADRB3, diastolic BP, WC, BMI, and serum triglycerides were significantly higher and serum HDL was significantly lower (P < 0.05) in the recessive CC genotype of ADRB3 as compared to the TT in Met S group; while WC, serum triglycerides, and cholesterol were also found to be significantly higher (P < 0.05) in the CC genotypes as compared to the TT in the healthy group [Table 2] and [Table 3].
Table 2: Comparison of the study parameters in the different genotypes of adrenergic receptor beta 3 rs4994 (190 T>C) in metabolic syndrome group

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Table 3: Comparison of the study parameters in the different genotypes of adrenergic receptor beta 3 rs4994 (190 T>C) in the healthy group

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Comparison of liver X receptor alpha rs12221497 (G>A) genotypes among the study groups

The frequency of GG variant of LXR-α G>A in Met S was 35 (17.5%) and in controls 15 (7.5%), frequency of GA was 129 (64.5%) and 137 (68.5%), and of AA was 36 (18%) and 48 (24%), respectively. The genotype frequencies in cases and controls deviated from Hardy–Weinberg equilibrium (χ2 > 3.84; P > 0.05). In the co-dominant model, there was a significant difference between the genotypes of LXR-α G>A, in cases and the controls (P = 0.007). Frequency of the “G” allele in cases and controls was 199 (49.75%) and 167 (41.75%) and frequency of the “A” allele was 201 (50.25%) and 233 (58.25%), respectively. There was significant association of the G allele with the increased risk of Met S (P = 0.023; OR = 1.8: CI = 1.04–1.82). In the recessive model, GG genotype was found to be associated with the risk of Met S (P = 0.004; OR = −2.52; CI = 1.33–4.80); however in the dominant model, AA genotype was not found to be associated with it (P = 0.141), [Table 4]. The association of the recessive GG genotype remained significant after controlling for the confounders such as age and sex (P = 0.001; OR = 3.12; CI = 1.6–6.07). There was no significant difference between the anthropometric and lipid parameters in different genotype models of LXR-α (P > 0.05).
Table 4: Comparison of liver X receptor alpha rs12221497 (−115 G>A) genotypic and allelic frequencies among the study groups

Click here to view



  Discussion Top


In the present study, the minor CC genotype of ADRB3 190 T>C was found to be associated with the increased risk of Met S, and the association remained significant after controlling for the age and sex. This result was in concordance with that of the previous longitudinal study in the U.S., reporting increased susceptibility to cardiovascular events in women having 190 T>C ADRB3 genetic variant.[33] The C allele of ADRB3 T>C was found to increase the risk of T2DM in Han-Chinese and was also reported to be associated with coronary artery disease in patients from Lucknow, India.[34],[35] ADRB3 rs4994 T>C is a nonsynonymous polymorphism, resulting in the replacement of tryptophan with arginine in ADRB3 protein. The change of amino acid sequence alters the affinity of ADRB3 for its ligands and this “Tryptophan64Arginine” (T>C) variant was reported to be associated with the higher body fat and adverse cardiovascular outcomes.[36] However in another study on the Brazilian-Caucasian population, the minor Arginine allele of ADRB3 (Tryptophan64Arginine) polymorphism was found to be protective against obesity and higher BMI. Carriers of the minor Arginine allele had higher blood HDL levels and this genetic variant was not found to be associated with T2DM.[37] However, in the present study, on comparison of study parameters in different genotypes of ADRB3, diastolic BP, BMI, WC, and serum triglycerides were significantly higher in the minor CC genotype as compared to the wild type TT. These results were supported by previously published studies that also observed association of adrenergic receptor polymorphisms with IR and cardiovascular complications; it was found that this genetic variation can influence lipid metabolism and onset of metabolic derangements in T2DM and other insulin resistant states.[33],[36],[37],[38] The minor allele C of ADRB3 was also found to be associated with hypertriglyceridemia and central obesity in Polish and overweight Saudi population.[25],[39]

In the present study, LXR-α rs12221497 −115 G>A variant was evaluated and “G” allele was found to be associated with the increased risk of Met S while “A” allele was protective. In a previous genetic sub-study of Verapamil clinical trial, the minor “A” allele was associated with the reduced risk of adverse cardiovascular outcomes.[23] On the contrary, among the Han Chinese population, the minor “A” allele was found to be associated with the significant increase in the risk of stroke.[20] In the previous two French population-based studies, A allele of LXR-α rs11039155 was associated with the reduced risk of Met S, while no association of A allele of rs12221497 was observed with the Met S; it was concluded that polymorphisms of LXR-α might have considerable influence on the expression of ATP-binding cassette transporter 1 and other genes influencing the lipid metabolism.[24] In the present study, frequencies of the A and G alleles of LXR −115 G>A turned to be 0.54 and 0.45, respectively. Frequency of the allele “A” was considerably higher in the current study as compared to the previous ones and this allele was also observed to be more prevalent in the controls than the cases.[20],[23] On the basis of the frequency distribution, GG was the minor, while AA was the major genotype and the minor GG genotype was found to be significantly associated with the increased risk of Met S after controlling for the confounders such as age and sex (P = 0.001; OR = 3.12; CI = 1.60–6.07). We were unable to find any significant difference in the anthropometric and serum parameters of obesity such as WC, BMI, serum triglycerides, and HDL-levels in the different genotypes of LXR-α −115 G>A SNP. This lack of association might be due to the reason as participants with Met S were on lipid and glucose lowering therapy; that might interfere with the normal energy and metabolic hemostasis.[40],[41] However, control group was not taking any medication and we were unable to find any significant difference in the above-mentioned clinico-biochemical parameters in them as well.


  Conclusion Top


It was concluded that the SNP of ADRB3 (190 T>C) and LXR-α (−115 G>A) were associated with the increased risk of Met S and might increase the susceptibility to the obesity-related traits.

Acknowledgments

We are thankful to all the study participants and technical staff of the hospital for their cooperation.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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