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The Journal of Clinical Endocrinology & Metabolism Vol. 83, No. 9 3239-3242
Copyright © 1998 by The Endocrine Society

Original Studies

Identification of New Sequence Variants in the Leptin Gene

Matti K. Karvonen, Ullamari Pesonen, Paula Heinonen, Markku Laakso, Aila Rissanen, Hannu Naukkarinen, Raisa Valve, Matti I. J. Uusitupa and Markku Koulu

Department of Pharmacology and Clinical Pharmacology, University of Turku (M.K.K., U.P., P.H., M.K.), Turku; the Departments of Medicine (M.L.) and Clinical Nutrition (R.V., M.I.J.U.), University of Kuopio (M.L.), Kuopio; and the Eating Disorder Unit, University Hospital of Helsinki (A.R.), and the Department of Psychiatry, University of Helsinki (H.N.), Helsinki, Finland

Address all correspondence and requests for reprints to: Matti Karvonen, B.M., Department of Pharmacology and Clinical Pharmacology, University of Turku, Kiinamyllynkatu 10, FIN-20520 Turku, Finland. E-mail:matti.karvonen{at}utu.fi


   Abstract
Top
 Abstract
Introduction
 Subjects and Methods
 Results
 Discussion
 References
 
The leptin gene (LEP) has been linked to extreme obesity. However, no common obesity-related gene variants have been found to exist in the LEP. The present study was designed to investigate the LEP for variants by screening both the putative promoter and the coding region of this gene in obese Finnish subjects (n = 200; body mass index, >27 kg/m2). PCR-amplified DNA samples were subjected to single strand conformation analysis. A G144A substitution in codon 48 and a G328A substitution in codon 110 were identified in two obese subjects, both of whom had very low serum leptin levels. A rare silent C538T polymorphism was detected 33 bp downstream of the translation stop codon (TGA). A common polymorphism A19G was identified in the untranslated exon 1. This polymorphism was not associated with traits of obesity; in agreement, the allele frequencies were similar between 64 normal weight and 141 obese Finns. In summary, this study failed to find a common gene variant in the LEP associated with obesity, but introduces 2 rare mutations associated with very low serum leptin concentrations in 2 obese subjects.


   Introduction
Top
 Abstract
 Introduction
Subjects and Methods
 Results
 Discussion
 References
 
THE LEPTIN gene (Lep) was originally identified in the ob/ob mice using positional cloning (1). The ob mutation is a C to T substitution resulting in a change of arginine at position 105 to the stop codon (1). Although the gene product is evidently inactive, the ob mutation is associated with a 20-fold increase in the expression of Lep messenger ribonucleic acid (mRNA) in the white adipose tissue (1). A separate mutation in the Lep in mice also exists; an insertion of a retroviral-like transposon in the first intron is the cause of the total absence of mature Lep mRNA in the coisogenic obese SM/Ckc-+Dacob2J/ob2J mouse (2). Phenotypically, both forms of these ob/ob mice are obese, hyperphagic, and hyperinsulinemic.

The Lep product leptin is a peptide hormone consisting of 167 amino acids, including a 21-amino acid signal peptide (1). Leptin is highly conserved among different species, including man (1). It is released from adipose tissue to the circulation and transported to the brain by still poorly understood mechanisms. Leptin influences the hypothalamic neuroendocrine centers regulating energy balance via activation of specific receptors that have several different splicing variants (3). Leptin receptor gene (Lepr) was originally cloned from the mouse choroid plexus homogenates using the expression cloning method (4). Subsequently, several groups characterized the db mutation in the diabetic db/db mouse (3, 5). The db mutation turned out to be a point mutation resulting in a 106-bp intronic insertion, including an early chain termination codon in the Lepr that leads to a short inactive form of the hypothalamic leptin receptor (Lepr) (3, 5). Furthermore, the fa mutation in the Zucker rat was identified as a point mutation in the Lepr, changing glutamate to proline at position 269 of the extracellular domain (5, 6, 7). All these three rodent models, in which either the absence of circulating leptin or insufficient leptin signaling lead to obesity, hyperphagia, and insulin resistance, strongly suggest that leptin and LEPR play important roles in the control of energy balance. Thus, LEP is one of the most interesting candidate genes for human obesity.

Several studies have demonstrated that obese people have raised serum immunoreactive leptin levels, which are positively correlated with body mass index (BMI), body weight, and especially with adiposity (8, 9, 10, 11, 12). The expression of LEP mRNA in adipocytes is markedly increased in obese subjects (13, 14). It is therefore obvious that lack of leptin in the circulation is not a common cause for obesity in humans.

The homology of the mouse ob mutation has not been detected in man (15). The sequence of the human LEP has been screened for gene variants, but common mutations that associate with obesity-related traits have not been detected (16, 17, 18, 19, 20, 21). LEP was found to be linked with extreme obesity in a French study (22), in a study conducted on a Pennsylvanian population (23), and in a study group of German children (24). However, no linkage to obesity or diabetes was found in Pima Indians (25) or in Mexican-American patients with noninsulin-dependent diabetes mellitus (26).

The genomic structure of the human LEP was published (Fig. 1Go), making it possible to screen for variants not only in the coding region but also in the promoter of the LEP (27, 28).



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  		Figure 1. The genomic structure of LEP. The double line represents the putative promoter region followed by the short untranslated exon 1 in which the A19G19 polymorphism is located. The coding regions are divided into exons 2 and 3. The variants found are indicated by vertical arrows: I = A19G, II = third base A144G mutation at codon 48, III = G328A leading to Ala110Met substitution, and IV = C538T mutation 33 bp after TGA termination codon.

 
In our study we screened the promoter, untranslated exon 1, and the coding regions of the human LEP in Finnish obese subjects with the PCR-single strand conformation analysis (SSCA) method.


   Subjects and Methods
Top
 Abstract
 Introduction
 Subjects and Methods
Results
 Discussion
 References
 
Subjects for SSCA and association analyses

DNA samples from 200 native Finns, including 31 binge-eating disorder patients, were used in screening the LEP for gene variants.

The association analyses was carried out in the 141 subjects who participated in a weight reduction study (29). The mean ± SD age was 43 ± 8 yr, and the mean BMI was 34.7 ± 3.8 kg/m2; all had normal liver, kidney, and thyroid function. None of the subjects had diabetes or a history of alcohol or drug abuse known to affect basal metabolic rate (BMR) or glucose metabolism. All phenotype measurements were performed in the morning after a 12-h fast using standardized methods. The measurements included weight; BMI; lean body mass; fat mass; body fat; waist and hip circumferences; waist to hip ratio; respiratory quotient; BMR; fasting (f) serum leptin, glucose, and insulin; and lipoprotein a and lipid levels. The analytical methods have been described in detail previously (29, 30). Serum leptin was measured by a commercially available RIA kit (Linco Research, St. Charles, MO). The normal weight (BMI, <27 kg/m2) control subjects used for genotype frequency comparisons were a random control population sample, consisting of 65 (27 men and 38 women) normoglycemic nondiabetic healthy Finns, aged 45–64 yr, selected during 1979–1981 from the population registers of Kuopio County, Finland. The control subjects have been described in detail previously (31). The protocol was approved by the ethics committees of the Universities of Kuopio and Helsinki, and informed consent was obtained from all study subjects.

PCR-SSCA analysis

Three primer pairs were chosen to cover the putative promoter region, the untranslated exon 1, and the entire coding region of the LEP. The PCR primer pairs, with respective annealing temperatures in parentheses, were: pair 1: forward, 5'-GCCCCGCGAGGTGCACACTG-3'; and reverse, 5'-GAGCGCGCCGGGGCCTTAC-3' (69 C); pair 2: forward, 5'-CCAAGAAGCCCATCCTG-3'; and reverse, 5'-CCTTGTCCC-CGGATACTCT-3' (54 C); and pair 3: forward, 5'-GCAGTCAGTCTCCTCCAA-3'; and reverse, 5'-GTCCTGGATAAGGGGTGT-3' (59 C). The PCR reaction mix (total of 5 µL) contained 100 ng genomic DNA isolated from whole blood, 1.0 µmol/L deoxy-NTPs, 75 nmol/L [33P]deoxy-CTP, 2.5 µmol/L of each primer, and 0.25 U of AmpliTaq polymerase (Perkin-Elmer/Cetus, Norwalk, CT). PCR conditions were optimized using PCR Optimizer (Invitrogen, San Diego, CA). Samples were amplified with a GeneAmp PCR System 9600 (Perkin-Elmer/Cetus), 30 cycles consisting of 1 min at 94 C, 1 min at annealing temperature, and 1 min at 72 C, followed by a final 7-min elongation at 72 C. PCR products were directly used in the SSCA analysis, except for the product of primer pair 3, which was digested with the HindIII restriction enzyme. The amplified samples were mixed with SSCA buffer containing 95% formamide, 10 mmol/L NaOH, 0.05% xylene cyanol, and 0.05% bromophenol blue (total volume of 25 µL). Before loading, samples were denatured for 5 min at 95 C and kept for 5 min on ice. Three microliters of the mixture were loaded on a MDE SSCA gel (AT Biochem, Malvern, PA). SSCA gel electrophoresis was performed at two different running conditions: on 3% MDE gel at room temperature and on 6% MDE gel at 4 C. Electrophoresis was run at 4 watts constant power for 20 h. The gel was dried, and autoradiography was performed by exposing a Kodak BIO MAX film (Eastman Kodak, Rochester, NY) for 24 h at room temperature.

Sequencing

Basing on the findings of SSCA, the possibly polymorphic DNA samples were sequenced with the Thermo Cycle Sequenase kit (Amersham Life Science, Cleveland, OH).

Genotyping

The A19 to G19 substitution creates a restriction site for the MspAI enzyme, and digestion of the PCR product of primer pair 1 results in the 175- and 29-bp fragments. DNA of 170 obese subjects and 65 normal weight control subjects was amplified with PCR, and the products were digested with MspAI and electrophoresed on a 2% agarose gel.

Statistical analysis

All calculations were performed using the SPSS/WIN program version 6.0 (SPSS, Chicago, IL). Statistical difference between the genotype groups was assessed with ANOVA followed by Student-Newman-Keuls test as a post-hoc analysis. The genotype frequencies were tested for Hardy-Weinberg equilibrium and compared using the {chi}2 test.


   Results
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
Discussion
 References
 
Four exonic gene variants were identified: 1) a common A19G change was found in the untranslated exon 1; 2) a third base G144A substitution was found at codon 48; 3) G328A was found at codon 110, resulting in an Ala110Met substitution; and 4) a C538T polymorphism 33 bp downstream of the TGA termination codon was detected.

The genotype frequencies of the A19G polymorphism in the obese and control subjects are shown in Table 1Go. Allele frequencies were in Hardy-Weinberg equilibrium. The genotype distributions were similar in obese and control men and in obese and control women. The men and women were analyzed separately in the association study of metabolic parameters comparing the three genotype groups at nucleotide 19. The results of the association analysis are presented in Table 2Go.


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  		Table 1. Genotype distribution of the A19G polymorphism in exon 1 of the leptin gene (LEP) in obese and control Finns (%)

 

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  		Table 2. Demographic and metabolic characteristics of the obese subjects according to the genotype of the leptin gene (LEP) exon 1 variant

 
The male subject (weight, 100 kg; height, 171 cm; BMI, 34.0 kg/m2) with the heterozygous codon 48 third base G to A substitution had a fasting serum leptin level of 3.3 µg/L, and the male subject (weight, 125 kg; height, 181 cm; BMI, 38.2 kg/m2) with the heterozygous Ala110Met substitution had a leptin level of 4.6 µg/L. The mean leptin level among obese subjects was 32.5 ± 12.7 µg/L (available for 87 subjects and these 2 polymorphic subjects not included; Table 3Go).


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  		Table 3. Characteristics of the subjects having variants in the leptin gene (LEP)

 

   Discussion
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
References
 
The present study is in agreement with earlier reports indicating that there are no common gene variants in the coding region of the LEP in Finnish obese subjects (16, 17, 18, 19, 20, 21). Our study extends previous studies by also covering the putative promoter area of the LEP. We found an A19G substitution in the untranslated exon 1, which has been recently reported by other investigators (18). The A19G polymorphism was rather common in Finns. Allele frequencies were similar between obese and lean subjects. The A19G polymorphism was not associated with any obesity-related variables, including weight, BMI, fat mass, waist/hip ratio, respiratory quotient, and BMR. We also report the identification of two new variants in the LEP: 1) a third base A144G mutation in codon 48 that locates at the exon-intron boundary, and 2) the G328A polymorphism, resulting in the substitution of Ala110Met. The latter has also been reported in one subject in another study (21). These polymorphisms were found in two obese subjects, both of whom are heterozygotes for the mutant. Both had very low serum levels of immunoreactive leptin, especially when their fat mass was taken into account (Fig. 2Go). Codon 48 is the last codon of exon 2. Generally, the sequence of the intronic nucleotides determines the splicing site, but the last exonic nucleotides may also play a role in the splicing. In about 90% of cases of primate exon-intron boundaries, the last exonic nucleotide is G, which has a role in forming the complementary base-pairings with the small nuclear ribonucleic acid (snRNA) (32). Therefore, it is possible that the third base substitution A144G in codon 48 may result in alternative splicing. As the subject was heterozygote for the mutation, it remains possible that the normal expression and synthesis of leptin are affected by the mutated allele, and/or one normal allele is not sufficient for normal leptin production. Unfortunately, we had no access to adipose tissue samples for expression studies from this individual. The Ala110 to Met110 substitution in the leptin sequence may modify the biological activity of leptin or change its immunoreactivity so that it is not adequately detected by the commercially available RIA kit. It is possible, although not proven, that these two rare variants in LEP may lead to physiologically less active circulatory leptin, which could contribute to the development of obesity. The only direct evidence that leptin plays an important role in human endocrinology and obesity is based on two recent reports. Two early-onset morbidly obese cousins carrying a mutation in the LEP (33) and a missense LEP mutation leading to hypogonadism and morbid obesity (34) have been found. A study of leptin receptor gene in a large cohort of massively obese subjects failed to give positive association of LEPR intronic variant with obesity-related phenotypic parameters (35), but a point mutation in LEPR leading to truncated receptor protein was identified in families with obesity and pituitary hypogonadism (36).



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  		Figure 2. Correlating serum leptin levels with fat mass in the association study population (n = 87). II is the leptin level related to fat mass of the subject with the A144G mutation at codon 48, and III is the leptin level related to fat mass of the subject with the Ala110Met mutation.

 
We also identified a rare mutation, C538T, located 33 bp downstream from the translation termination codon TGA of the LEP in six obese subjects and two of the normal weight controls. This gene variant was found in three individuals in the association study and in three other morbidly obese subjects, all belonging to the same family that was excluded from the association study. All six subjects were heterozygotes for the substitution. Fasting serum leptin was measured in four of these six obese subjects, and all had high serum leptin levels. When corrected for fat mass, however, serum leptin levels were not different from those in the other obese subjects. In general, the 3'-flanking sequence is considered to play a role in the cellular processing of mRNA. Theoretically, the C538T substitution could thus have some impact on the expression of leptin mRNA, but this possibility requires further investigation.

It is concluded that there are no common gene variants in the leptin gene, including the putative promoter area, which would associate with traits of obesity in obese Finnish subjects. Two rare LEP variants were identified, both of which were associated with very low serum leptin levels.

Received April 6, 1998.

Revised June 3, 1998.

Accepted June 15, 1998.


   References
Top
 Abstract
 Introduction
 Subjects and Methods
 Results
 Discussion
 References
 

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