Leptin in association with common variants of MC3R mediates hypertension

Osama Alsmadi, Motasem Melhem, Prashantha Hebbar, Gaurav Thareja, Sumi E. John, Fadi Alkayal, Kazem Behbehani, Thangavel Alphonse Thanaraj

Research output: Contribution to journalArticle

11 Citations (Scopus)

Abstract

BACKGROUND Recent research illustrates the role of central melanocortin signaling and leptin in the regulation ofarterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, β = 4.9). The N-terminus variant (rs3746619 [Thr6→Lys]) is in linkage disequilibrium (r = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, β=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans.

Original languageEnglish
Pages (from-to)973-981
Number of pages9
JournalAmerican Journal of Hypertension
Volume27
Issue number7
DOIs
Publication statusPublished - 1 Jan 2014
Externally publishedYes

Fingerprint

Leptin
Hypertension
Blood Pressure
Melanocortins
Linear Models
Population
Linkage Disequilibrium
Population Groups
Gene Frequency
Haplotypes
Antihypertensive Agents
Exons
Arterial Pressure
Body Mass Index
Down-Regulation
Animal Models
Obesity
Genotype
Research
Genes

Keywords

  • blood pressure
  • hypertension
  • leptin
  • MC3R
  • MC4R
  • melanocortin

ASJC Scopus subject areas

  • Internal Medicine
  • Medicine(all)

Cite this

Alsmadi, O., Melhem, M., Hebbar, P., Thareja, G., John, S. E., Alkayal, F., ... Thanaraj, T. A. (2014). Leptin in association with common variants of MC3R mediates hypertension. American Journal of Hypertension, 27(7), 973-981. https://doi.org/10.1093/ajh/hpt285

Leptin in association with common variants of MC3R mediates hypertension. / Alsmadi, Osama; Melhem, Motasem; Hebbar, Prashantha; Thareja, Gaurav; John, Sumi E.; Alkayal, Fadi; Behbehani, Kazem; Thanaraj, Thangavel Alphonse.

In: American Journal of Hypertension, Vol. 27, No. 7, 01.01.2014, p. 973-981.

Research output: Contribution to journalArticle

Alsmadi, O, Melhem, M, Hebbar, P, Thareja, G, John, SE, Alkayal, F, Behbehani, K & Thanaraj, TA 2014, 'Leptin in association with common variants of MC3R mediates hypertension', American Journal of Hypertension, vol. 27, no. 7, pp. 973-981. https://doi.org/10.1093/ajh/hpt285
Alsmadi, Osama ; Melhem, Motasem ; Hebbar, Prashantha ; Thareja, Gaurav ; John, Sumi E. ; Alkayal, Fadi ; Behbehani, Kazem ; Thanaraj, Thangavel Alphonse. / Leptin in association with common variants of MC3R mediates hypertension. In: American Journal of Hypertension. 2014 ; Vol. 27, No. 7. pp. 973-981.
@article{0636782ef3754ca681ef7e874d436e4f,
title = "Leptin in association with common variants of MC3R mediates hypertension",
abstract = "BACKGROUND Recent research illustrates the role of central melanocortin signaling and leptin in the regulation ofarterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, β = 4.9). The N-terminus variant (rs3746619 [Thr6→Lys]) is in linkage disequilibrium (r = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, β=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans.",
keywords = "blood pressure, hypertension, leptin, MC3R, MC4R, melanocortin",
author = "Osama Alsmadi and Motasem Melhem and Prashantha Hebbar and Gaurav Thareja and John, {Sumi E.} and Fadi Alkayal and Kazem Behbehani and Thanaraj, {Thangavel Alphonse}",
year = "2014",
month = "1",
day = "1",
doi = "10.1093/ajh/hpt285",
language = "English",
volume = "27",
pages = "973--981",
journal = "American Journal of Hypertension",
issn = "0895-7061",
publisher = "Oxford University Press",
number = "7",

}

TY - JOUR

T1 - Leptin in association with common variants of MC3R mediates hypertension

AU - Alsmadi, Osama

AU - Melhem, Motasem

AU - Hebbar, Prashantha

AU - Thareja, Gaurav

AU - John, Sumi E.

AU - Alkayal, Fadi

AU - Behbehani, Kazem

AU - Thanaraj, Thangavel Alphonse

PY - 2014/1/1

Y1 - 2014/1/1

N2 - BACKGROUND Recent research illustrates the role of central melanocortin signaling and leptin in the regulation ofarterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, β = 4.9). The N-terminus variant (rs3746619 [Thr6→Lys]) is in linkage disequilibrium (r = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, β=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans.

AB - BACKGROUND Recent research illustrates the role of central melanocortin signaling and leptin in the regulation ofarterial blood pressure in animal models. Unraveling the genetic basis of interactions between melanocortin and leptin in humans will provide new insight into the regulation of arterial pressure. METHOD Our study population consisted of 332 Kuwaiti natives. Polymorphisms from exons of leptin, MC3R, and MC4R genes were identified by Sanger sequencing. MC3R expression and leptin levels were determined. Linear regression models, adjusted for age, gender, antihypertensive medication, and body mass index, were used to perform statistical association tests. RESULTS We observed a significant association between the MC3R missense variant (rs3827103 [Val81 Ile]) and systolic blood pressure (SBP; P = 0.01, β = 4.9). The N-terminus variant (rs3746619 [Thr6→Lys]) is in linkage disequilibrium (r = 0.65) with the rs3827103 variant. The AA haplotype of rs3746619-rs3827103 is significantly associated with SBP (P = 0.005, β=5.03). Minor allele frequencies of these two variants in the Kuwaiti population are twice those seen in European population. In individuals who harbor these variants, we found that the plasma leptin levels were positively correlated with SBP and that the expression of MC3R was downregulated. Leptin levels correlated with obesity traits irrespective of the genotypes at the variant positions. CONCLUSION An increase in leptin levels is known to increase sympathetic nerve activity that, in turn, increases blood pressure. Thus, it is possible that the observed MC3R variants in association with leptin levels are involved in regulation of blood pressure in humans.

KW - blood pressure

KW - hypertension

KW - leptin

KW - MC3R

KW - MC4R

KW - melanocortin

UR - http://www.scopus.com/inward/record.url?scp=84902522595&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84902522595&partnerID=8YFLogxK

U2 - 10.1093/ajh/hpt285

DO - 10.1093/ajh/hpt285

M3 - Article

VL - 27

SP - 973

EP - 981

JO - American Journal of Hypertension

JF - American Journal of Hypertension

SN - 0895-7061

IS - 7

ER -