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).
We investigated the associations of the three LEPR polymorphisms (Lys109Arg, Gln223Arg, 3′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.
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=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=0.042). The risk was more pronounced in the control group than in the intervention group. Individuals having the 3′UTR Del/Del genotype had a slightly higher body weight throughout the study than those with the insertion allele (P=0.020), although no difference in weight change was observed.
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′UTR of LEPR was associated with body weight.
About 60–90% of all subjects with type 2 diabetes are or have been obese.1 Insulin resistance is a characteristic feature in abdominal obesity. Both diabetes and obesity have a strong genetic component,2, 3 and their inheritance is polygenic.1, 4 Furthermore, they may share a common genetic background, that is, the risk alleles for obesity may also be involved in the increased risk of developing type 2 diabetes.
Leptin receptor (LEPR) gene has been studied as a candidate gene for obesity because of its role in the regulation of food intake and energy expenditure. Leptin is secreted from adipocytes as a signal of body fat stores and it acts as a satiety hormone. Leptin receptors are located mainly in the hypothalamus but also in tissues regulating glucose homeostasis, for example, in the pancreatic beta-cells,5 where they mediate leptin-induced inhibition of insulin secretion. Thus, LEPR can be considered as a candidate gene for diabetes as well.
A common CTTTA-pentanucleotide deletion/insertion (Del/Ins) polymorphism of the 3′-untranslated (3′-UTR) part of the LEPR gene generates an A+U-rich sequence, that should be able to form a stem-loop structure, which may affect mRNA stability in the cell,6 but no functional studies on this polymorphism have been conducted. The Del/Ins polymorphism has been found to be associated with serum insulin levels,6, 7, 8 serum HDL-cholesterol and ApoA-I levels9 and susceptibility to type 2 diabetes.8 Lakka et al8 showed that the carriers of the insertion allele had a 79% reduced risk of diabetes. No studies have shown any associations with body weight, although Thompson et al10 suggested that the putative mutation in obese Pima Indians could lie in the 3′ end of the LEPR gene.
Even though both codon 109 and 223 nucleotide alterations in the LEPR gene produce amino-acid changes and may thus have functional consequences, no true evidence of their functionality is available. A Lys109Arg polymorphism in exon 4 in the extracellular domain of the leptin receptor has been associated with the magnitude of the effects of regular physical activity on glucose homeostasis11 and with the insulin response after an oral glucose load,12 but does not seem to have any major effect on body weight and fat mass10, 13, 14, 15, 16 or resting metabolic rate.17 The Gln223Arg variant, located in exon 6 in the extracellular domain of the leptin receptor, has been found to be associated with glucose and insulin homeostasis,12, 18, 19 energy expenditure,20 body weight and fat mass.15, 21, 22, 23, 24 However, one meta-analysis13 and some other studies10, 16 did not find any association of Gln223Arg with body weight.
The aim of this study was to explore the impact of genetic and lifestyle factors on the risk of diabetes. The effects of three known polymorphisms of the LEPR gene were assessed on the conversion from impaired glucose tolerance (IGT) to type 2 diabetes and change in body weight. The study subjects who had IGT known to be at particularly high risk for diabetes, were prospectively followed in the Finnish Diabetes Prevention Study (DPS).25, 26
Subjects and methods
Study population and design
DPS is a randomized, controlled, multicentre study carried out in Finland in 1993–2000. Altogether 522 individuals (172 men and 350 women) with IGT were randomized into either a lifestyle intervention or control group in five centres. The main inclusion criteria were as follows: BMI≥25 kg/m2, age 40–64 y, IGT based on the mean values of two oral glucose tolerance tests (OGTT). Randomization to the intervention and control groups was done stratified according to the centre, sex and the mean plasma glucose concentration 2 h after an oral glucose load (7.8–9.4 or 9.5–11.0 mmol/l). The study design and methods used have been reported in detail elsewhere.25, 26
The individuals in the intervention group received detailed and individually tailored counselling on lifestyle, diet and exercise. The goals were a reduction in weight of ≥5%, a reduction in total intake of fat to <30% of daily energy intake and to reduce the intake of saturated fat to <10% of daily energy consumed; an increase in fibre intake at least to 15 g per 1000 kcal; and moderate exercise for at least 30 min per day. Each individual in the intervention group had seven individual sessions with a clinical nutritionist during the first year of the study and then one session every 3 months. The intervention group also received individual guidance on increasing the level of physical activity. The control group received general advices about healthy food and the importance of weight reduction and increased physical activity.27
DNA was available for 507 subjects (166 men and 341 women). Their mean BMI was 31.2±4.5 kg/m2 and age 55.3±7.1 y. The study protocol was approved by the Ethics Committee of the National Public Health Institute in Helsinki, Finland and all the study participants gave written informed consent.
A medical history was taken and a physical examination performed at baseline and at each annual follow-up visit.26 In this study, measurements from baseline to the 3-y examination were used, including height, weight, BMI, waist and hip circumference, waist-to-hip ratio and 2 h OGTT with glucose and insulin levels before (0 min) and after 75 g glucose load (120 min).26 Plasma glucose was measured at each centre by standard methods. The serum insulin concentration was measured in a central laboratory by a radioimmunoassay method (Pharmacia, Uppsala, Sweden). Homeostasis model assessment for insulin resistance (HOMA-IR) was calculated using the formula fasting plasma glucose (mmol/l) × fasting serum insulin (mU/l)/22.5 and homeostasis model assessment for insulin secretion (HOMA-IS) was calculated as 20 × fasting serum insulin (mU/l)/(fasting plasma glucose (mmol/l)−3.5).28
The three polymorphisms were detected by PCR-RFLP method. PCR amplification was conducted in a 10 μl volume containing 20 ng genomic DNA, 5 pmol of each primer, 10 mmol/l Tris-HCl (pH 8.8), 50 mmol/l KCl, 1.5 mmol/l MgCl2 and 0.1% Triton X-100, 0.25 U of DNA polymerase (DynaZyme DNA Polymerase; Finnzymes, Espoo, Finland) and 100 μmol/l dNTP. PCR products were digested overnight with BsuRI, MspI and RsaI at 37°C for detection of Lys109Arg, Gln223Arg and Del/Ins polymorphisms, respectively. The digested samples were separated on 2 or 2.5% agarose gel (Gln223Arg and Lys109Arg, respectively) or on 9% polyacrylamide gel (Del/Ins).
The data were analysed using the SPSS/WIN program version 11.5 (SPSS, Chigago, IL, USA). Data are given as means±s.d., unless otherwise indicated. The normality of distributions of study variables was tested with the Kolmogorov–Smirnov test and logarithmic or 1/x transformation was used whenever needed. For variables with skewed distribution, Kruskal–Wallis or Mann–Whitney test was used. Univariate analysis of variance was used to compare the effect of the gene polymorphisms on continuous variables. Adjustment for age, sex and BMI was carried out, when appropriate. χ2 test was used in comparison of categorical variables. Logistic regression analysis was performed to evaluate if the polymorphisms predict the development of type 2 diabetes. In logistic regression analysis of the diabetes risk (OR) adjustment was made for baseline weight, weight change (from baseline to 3-y measurement or to the last measurement), fasting plasma glucose and study group. In logistic regression models the genotypes were coded as follows: Lys109Arg and Gln223Arg: 0=hetero/homozygote for the variant, 1=wild-type; Del/Ins: 0=wild-type, 1=hetero/homozygote for the variant; and study groups were coded as 1=intervention group and 2=control group. Changes in body weight were analysed by repeated measures of General Linear Model (GLM). Three locus haplotype frequencies were estimated by using the EH programme. Pairwise linkage disequilibrium was calculated by using the expectation maximization algorithm (2LD program). At P<0.05, differences were considered statistically significant.
Genotypic and haplotypic frequencies
In the entire DPS study population the frequencies of the genotypes for the Lys109Arg polymorphism were: Lys109Lys: 41%, Lys109Arg: 46% and Arg109Arg: 13%, for the Gln223Arg polymorphism: Gln223Gln: 19%, Gln223Arg: 47% and Arg223Arg: 34% and for the 3′UTR Del/Ins polymorphism: Del/Del: 70%, Del/Ins: 28% and Ins/Ins: 2% (Table 1). For further analysis the relatively rare (only 11 subjects) Ins/Ins genotype was combined with the Del/Ins genotype. The allelic frequencies of the variants in codons 109 and 223 and the 3′UTR were 0.36, 0.57 and 0.16, respectively and they were in the Hardy–Weinberg equilibrium. The three polymorphisms were in strong linkage disequilibrium, with standardized linkage disequilibrium coefficients (D′) of 0.79 between Arg223 and 3′UTR Del alleles, 0.98 between Gln223 and Lys109 alleles and 0.99 between Lys109 and 3′UTR Ins alleles (P<0.001). Of the 27 possible genotype combinations 15 were found and six of the eight predicted haplotypes were observed among the study population, four most common accounting for 97.6% of all observed haplotypes (Table 1).
Baseline and 3-y follow-up characteristics according to genotypes
At baseline (Table 2) and at the 3-y follow-up (data not shown) no significant association was observed between the three polymorphisms examined and body weight, BMI, waist-to-hip-ratio and insulin and glucose levels before or after an oral glucose load.
Changes in weight from baseline to 3 y according to genotypes
For the 3′UTR Del/Ins polymorphism we observed slight differences among the genotypes when weight at timepoints of 0, 1, 2 and 3 y were analysed by repeated measures (General Linear Model, adjusted for baseline body weight). When all subjects were included in the analysis, the trend between the genotypes was similar, but the Del/Del genotype showed the highest and the combined Del/Ins and Ins/Ins genotype (Ins allele) the lowest weight during this 3-y period (P=0.020), but no statistically significant difference was seen in the unadjusted analysis. When the study groups were analysed separately, the trend was significant in the intervention group (P=0.046), where the Del/Del genotype showed the highest weight, but nonsignificant in the control group. Also here, the unadjusted model was nonsignificant both in the intervention and control group. Otherwise, there were no statistically significant differences in weight changes from baseline to the 3-y follow-up between any other genotypes examined (Table 3).
Conversion to type 2 diabetes according to genotypes
During the 3-y follow-up, 72 individuals of those whose DNA sample was available (21 in the intervention group and 51 in the control group) developed type 2 diabetes. Conversion to type 2 diabetes during the 3-y follow-up differed among the three genotypes of the Lys109Arg polymorphism in the control group, however, no association was seen in intervention group. The Lys109Lys genotype vs the Arg109 allele OR was 2.38 (95% CI 1.18–4.81; P=0.016, adjusted for baseline body weight, weight change and baseline glucose concentration) in the control group (Table 4).
Individuals possessing the Gln223Gln genotype also had a higher conversion rate to type 2 diabetes (OR 2.01 (95% CI 1.03–3.93), P=0.042, adjusted for baseline body weight, baseline glucose concentration, study group and weight change) than individuals with the Arg223 allele, when the entire DPS was included in the analysis (Table 4). When the study groups were analysed separately, significant association was seen only in the control group (OR 2.33 (95% CI 1.01–5.36), P=0.047).
There were no significant differences in the conversion to type 2 diabetes among the three genotypes of the 3′UTR Del/Ins polymorphism, either when the entire cohort was analysed or when the study groups were analysed separately (Table 4).
In the present study we evaluated the impact of the LEPR gene polymorphisms on body weight and the conversion to type 2 diabetes in Finnish IGT subjects participating in a lifestyle intervention study aiming to prevent diabetes.25, 26 The particular strength of the Finnish DPS is that it is a prospective intervention study with a high-risk population, applying well-defined diagnostic criteria for type 2 diabetes and that it also provides information regarding the impact of genes vs lifestyle factors on the risk of diabetes.
As the leptin signalling is an essential factor in metabolic control both in rodents and in humans, we screened three known polymorphisms in the LEPR gene and discovered that each of them had an effect on the conversion to diabetes or body weight. Different genotypic combinations did not give any additional information, thus, the three polymorphisms were analysed individually in the statistical analyses.
The main finding of this study is that the benefits of a lifestyle intervention on (i) the risk of type 2 diabetes and (ii) changes in body weight can be modified by variants in the LEPR gene. Since no functional data on these polymorphisms are available, we can only speculate about the mechanisms behind our findings. Furthermore, it is also possible that these variants are markers for some other functional variation in the nearby region. Anyhow, subjects possessing either the Lys109Lys or Gln223Gln genotype were converting more often from IGT to overt diabetes in the control group, whereas logistic regression analyses for the intervention group were nonsignificant and also the interaction term between the study group and the genotype was nonsignificant. Thus, we can conclude that the exonic variation in the LEPR gene is a modulating factor when changing ones lifestyles, suggesting that IGT individuals with Lys109Lys or Gln223Gln genotype are more amenable to benefit from lifestyle intervention than the other genotypes, in order to prevent type 2 diabetes.
In the anthropometric measurements, no differences with respect to different genotypes were seen at baseline or in absolute changes from baseline to the 3-y examination. Yet, when the repeated measures at baseline and at all yearly follow-up visits were analysed, difference was found among the 3′UTR Del/Ins genotypes. In the intervention group the individuals possessing the insertion allele were leaner throughout the study, whereas in the control group no difference between the genotypes was seen. Thus, we suggest that the Del/Ins variation could be involved in body weight regulation.
Oksanen et al6 first demonstrated the 3′ UTR Del/Ins polymorphism, which may affect mRNA stability and abundance in the cell. They also found that the insertion allele associated with lower serum insulin levels in obese individuals; a finding that has been confirmed in subsequent studies.7, 8 None of the earlier studies on this 3′UTR variation have shown any association with body weight, as we demonstrated in the present study. However, none of them included IGT subjects, but morbidly obese subjects,6, 7 young healthy men9 or a population-based cohort.8 To our knowledge there is only one previous association study on LEPR variants in IGT population,12 but it did not cover the Del/Ins polymorphism. In our study, we included only overweight or obese subjects (mean BMI 31.1 kg/m2) with IGT, and 75% of the cohort also had the metabolic syndrome.29 Thus, it is reasonable to expect that the results from these different study settings are not directly comparable with each other. We used repeated measures to analyse weight among the genotypes during the 3-y time period. This analysis is more powerful than cross-sectional analyses, since it takes into account the periodic and random deviation. Test of repeated measures indicates that the Del/Del homozygous individuals in our study had higher weight throughout the study than individuals with the insertion allele.
The Lys109Arg and Gln223Arg polymorphisms are within the region encoding the extracellular domain of the leptin receptor and, therefore, amino-acid changes affect all isoforms of the receptor, since they all have identical extracellular and transmembrane domains. A meta-analysis has been conducted on the association of these polymorphisms with BMI and waist circumference.13 The result was negative, but they concluded that the effect of these polymorphisms could be population specific, and that the alleles might influence intermediate traits or phenotypes.13 We did not find any associations with intermediate traits, but instead a clear association with the conversion to diabetes was observed. Wauters et al12 also studied women with IGT and observed associations of the Lys109Arg and Gln223Arg polymorphisms with glucose and insulin levels. They concluded that the LEPR gene could interact with factors associated with IGT, such as hyperinsulinaemia or insulin resistance. In a recent study, Chiu et al19 found that the Arg223 allele is associated with insulin resistance, explaining 6–7% of the variability of insulin sensitivity. The study was conducted in 67 healthy Caucasian subjects, and it is consistent with other studies on young and healthy populations,15, 20, 30 but inconsistent with studies on postmenopausal women,12, 23 IGT12 or overfeeding.31 They speculated that this polymorphism could contribute to the initiation of the events leading to insulin resistance in a subset of subjects. In the present study, Gln223Gln and Lys109Lys genotypes were associated with the conversion from IGT to overt diabetes.
In the forthcoming studies on the leptin receptor, it will be important to clarify the functionality of different genetic variants, since several studies have found significant associations linking them to several traits of obesity, diabetes or the metabolic syndrome. As the variants are in linkage disequilibrium with each other, it would be important to know which of them are functional, and what is the mechanism of function, or are they all perhaps just markers of another functional variant in nearby intronic region.
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This work has been financially supported by grants from the Academy of Finland (no. 40758 to MU; 38387 and 46558 to JT; 73566 to SK-K), the EVO-fund of the Kuopio University Hospital (no. 5106 to MU; 5194 to ML), the Ministry of Education of Finland and the Finnish Diabetes Research Foundation, Yrjö Jahnsson Foundation and Juho Vainio Foundation.
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