Genetic variation in leptin receptor gene is associated with type 2 diabetes and body weight: The Finnish Diabetes Prevention Study

Abstract

OBJECTIVE: Genetic variation in leptin receptor (LEPR) gene has been reported to associate with insulin and glucose metabolism and adiposity in different study settings and various populations. We wanted to evaluate the association between LEPR polymorphisms, diabetes risk and body weight in Finnish subjects with impaired glucose tolerance (IGT). METHODS: We investigated the associations of the three LEPR polymorphisms (Lys109Arg, Gln223Arg, 3 0 UTR Del/Ins) with the conversion to type 2 diabetes and the changes in body weight in 507 individuals with IGT participating in the Finnish Diabetes Prevention Study. Participants were randomized to either an intensive diet and exercise intervention group or a control group. RESULTS: After 3 years, the odds ratio for the development of type 2 diabetes in individuals in the control group with the Lys109Lys genotype was 2.38-fold higher than in individuals with other genotype combinations (P ¼ 0.016). Irrespective of group individuals with the Gln223Gln genotype had higher conversion to type 2 diabetes (OR 2.01 (95% CI 1.03-3.93)) than the Arg223 allele carriers (P ¼ 0.042). The risk was more pronounced in the control group than in the intervention group. Individuals having the 3 0 UTR Del/Del genotype had a slightly higher body weight throughout the study than those with the insertion allele (P ¼ 0.020), although no difference in weight change was observed. CONCLUSION: Two polymorphisms (Lys109Arg, Gln223Arg) in the extracellular domain of the leptin receptor predicted the conversion to type 2 diabetes in high-risk individuals with IGT. The Del/Ins polymorphism in the 3 0 UTR of LEPR was associated with body weight.

Funkcjonalne polimorfizmy genów leptyny i receptora leptyny korelują z długowiecznością oraz z ryzykiem zawału mięśnia serca i cukrzycy 2 typu

“…We showed that its AA genotype is significantly less common in the C group than in the Y, MI and DM2 groups. This remains in agreement with previous findings that this genotype is associated with obesity [44] and with increased DM2 risk [45].…”

Common SNPs in LEP and LEPR associated with birth weight and type 2 diabetes-related metabolic risk factors in twins

“…In literature, both alleles of these SNPs have been reported as risk alleles for type 2 diabetes and obesity, and a metaanalytic study reported nonsignificant associations. [23][24][25][26][27][28][29][30][31][32][33][34][35][36][37][38][39]48 Consequently, additional studies in larger populations need to be carried out, to verify the involvement of these coding LEPR SNPs in the 'fetal insulin hypothesis'.…”

“…In this study we therefore examined the effect of common SNPs in LEP and LEPR on birth weight and adult metabolic risk factors for type 2 diabetes measured in young twins recruited from the East Flanders Prospective Twin Survey (EFPTS). The SNPs studied have previously been associated with type 2 diabetesrelated traits in other populations, [19][20][21][22][23][24][25][26][27][28][29][30][31][32][33][34][35][36][37] and are either nonsynonymous or located in a region that might be of importance in the regulation of gene expression.…”

Type 2 diabetes-associated genetic variants of FTO, LEPR, PPARg, and TCF7L2 in gestational diabetes in a Brazilian population

“…Caucasians with the AA genotype are 2-fold more likely to develop T2DM than those with other genotypes (47). The LEPR rs1137101 polymorphism (Q223R; Gln223Arg; 668A > G) is an A> G substitution resulting in the exchange of glutamine for arginine at position 668 of LEPR (Figure 1).…”