Leptin in association with common variants of MC3R mediates hypertension

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.