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Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians

¹ John P. Robarts Research Institute
² Centre for Studies in Family Medicine, University of Western Ontario, London, Ontario N6A 5K8
³ Samuel Lunenfeld Research Institute and Department of Medicine, Mount Sinai Hospital, University of Toronto, Ontario, Canada M5G 1X5

	ABSTRACT

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Hegele, Robert A., Henian Cao, Stewart B. Harris, Bernard Zinman, Anthony J. Hanley, and Carol M. Anderson. Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians. Physiol Genomics 3: 39–44, 2000.—We previously showed that a rare mutation in LMNA, which encodes lamins A and C, underlies autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD). Because FPLD is an extreme example of genetically disturbed adipocyte differentiation, it is possible that common variation in LMNA is associated with obesity-related phenotypes. We therefore analyzed the relationships between the common LMNA 1908T/C single nucleotide polymorphism (SNP) and plasma leptin and anthropometric indices in 306 nondiabetic Canadian Oji-Cree. We found that subjects with the LMNA 1908T/1908T genotype had significantly higher plasma leptin than the subjects with either the 1908C/1908T or 1908C/1908C genotypes, after adjustment for age and sex. Physical indices of obesity, such as body mass index, percent body fat, and ratio of waist-to-hip circumference, were also higher among Oji-Cree subjects with the LMNA 1908T/1908T genotype than the subjects with either the 1908C/1908T or 1908C/1908C genotypes. The results suggest that common genetic variation in LMNA may be an important determinant of plasma leptin and obesity-related quantitative traits.

association study; complex disease; metabolism; obesity

	INTRODUCTION

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OBESITY IS A COMPLEX METABOLIC disorder with a strong genetic component (2). There are many candidate genes for obesity and its related phenotypes. Some genes are candidates for obesity because mutations in them cause rare genetic syndromes affecting adipocyte differentiation (2). For example, patients with autosomal dominant Dunnigan-type familial partial lipodystrophy (FPLD; OMIM 151660) are born with normal adipocyte distribution but after puberty experience adipocyte degeneration in their extremities, trunk, and gluteal region (3, 9, 22). Subjects with FPLD have insulin resistance preceding the development of diabetes, which is often associated with dyslipidemia and atherosclerosis. Recently, we discovered that mutant LMNA underlies FPLD (4). Rare mutations in LMNA also underlie autosomal dominant Emery-Dreifuss muscular dystrophy (EMD2; OMIM 181350), which is characterized by regional and progressive myocyte degeneration (1), and a form of dilated cardiomyopathy (CMD1A; OMIM 115200) (7).

Our rationale to focus on LMNA as a candidate gene in FPLD was based on deductive reasoning: FPLD had been mapped to chromosome 1q21-q22, and there was analogy between the specificity of the adipocyte wasting in FPLD and the site-specific cellular degeneration in EMD2 and CMD1A. After our initial discovery, other LMNA mutations in FPLD were subsequently reported (30, 31), some of which indicated that lamin A is specifically mutated in FPLD. The LMNA gene products, lamins A and C, are important elements of the nuclear lamina (23). Alternative splicing at exon 10 of LMNA gives lamins A and C sequence identity for the first 566 residues, but distinctive COOH termini (23). Lamins A and C are co-expressed in many tissues, including myocytes and adipocytes (23). Lamins A and C both have globular head and tail domains and a central rod domain (23). Hydrophobic residues within the rod domains of lamin A promote dimerization of the -helices, and surface charges orient the filaments to form the dense laminar latticework of the nuclear inner membrane. The mechanisms through which LMNA mutations cause wasting of specific cell types and associated abnormal phenotypes are unknown. However, because it is mutated in FPLD, LMNA is clearly a candidate gene for adipose tissue metabolism.

In addition to the rare LMNA mutations in FPLD, we identified a common single nucleotide polymorphism (SNP) in exon 10 of LMNA, namely a silent TC substitution at nt 1908 (1908T/C), affecting the third base within codon 566, which is the last codon shared in common between lamin A and C before alternative splicing gives rise to the two distinct proteins (23). Because FPLD caused by mutant LMNA is associated with aberrant adipocyte differentiation in FPLD, we hypothesized that common LMNA variation might be associated with adipose tissue phenotypes, such as plasma leptin concentration and anthropometric indices of obesity, in the general population. We thus analyzed the relationships between plasma leptin and the common LMNA 1908T/C SNP in 306 nondiabetic Canadian Oji-Cree.

	MATERIALS AND METHODS

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Study subjects.
The community of Sandy Lake, Ontario, is located about 2,000 km northwest of Toronto, in the subarctic boreal forest of central Canada. Approximately 72% of eligible subjects had volunteered to participate in this community-wide diabetes prevalence study (11, 12). Type 2 diabetes, impaired glucose tolerance (IGT), and normal glucose tolerance (nondiabetic) were diagnosed using established pre-1997 criteria (27, 32). The 306 adult Oji-Cree subjects, aged 18 years and above, not known to be related, who were free of diabetes or IGT, had sufficient clinical data and adequate plasma and cellular material available for all analyses. Subjects with a medical diagnosis of and/or treatment for type 2 diabetes mellitus or IGT and/or abnormal concentrations of fasting and/or 2 h post 75 g glucose challenge were excluded (27, 32). The body mass index (BMI in kg/m²), percentage body fat (PBF) assayed using bioelectrical impedance (13), and ratio of waist-to-hip circumference (WHR) were determined in all subjects. The project was approved by the University of Toronto Ethics Review Board.

Biochemical analyses.
Plasma samples were obtained with informed consent after fasting overnight for 12 h. Exclusion criteria were an inadequate blood sample available for all biochemical and/or genetic determinations. Blood was centrifuged at 2,000 rpm for 30 min and the plasma was stored at -70°C. Concentrations of fasting glucose were determined as described (12). Concentrations of fasting plasma insulin and C-peptide were determined by radioimmunoassay (Pharmacia, Mississauga, ON). Concentrations of fasting plasma leptin were determined using a radioimmunoassay (Linco Research, St. Charles, MO), which had a minimal detectable concentration of 0.5 ng/ml, a limit of linearity of 100 ng/ml, and a coefficient of variation <9.0%

Genetic analysis.
The LMNA 1908T/C SNP genotype was determined from leucocyte DNA using amplification with primers LMNASNP1908F 5'-GCA AGA TAC ACC CAA GAG CC-3' and LMNASNP1908R 5'-ACA CCT GGG TTC CCT GTT C-3' over 30 amplification cycles and an annealing temperature of 60°C. The 1,069-bp amplification product was then digested with Pml I and electrophoresed in 1.5% agarose gels. Digestion of the 1908C allele gave two fragments with sizes 887 and 182 bp, whereas digestion of the 1908T allele gave a single fragment with size 1,069 bp.

Statistical analyses.
Statistical analyses were performed using SAS statistical software, version 6.12 (29). Between-sex differences in baseline clinical and biochemical traits were assessed using Bonferroni t-tests. Deviation of genotype frequencies from Hardy-Weinberg equilibrium were assessed using ² analysis. The association of LMNA genotype with quantitative traits was tested by ANOVA using a general linear model, with levels of significance computed from type III sums of squares, which is most appropriate for an unbalanced study design and reports significance after all covariates are taken into account.

The LMNA 1908T/C SNP genotype was introduced as a dichotomous variable in the analyses: subjects who carried at least one 1908C allele were compared with subjects who were homozygous for 1908T/1908T (i.e., a recessive model for 1908T). Values for BMI, PBF, and WHR and plasma concentrations of leptin, insulin, and C-peptide were log transformed, which in each case produced a variable whose distribution was not significantly different from normal. We also created a variable defined as the ratio of leptin to BMI (leptin:BMI ratio), as previously reported (25), to intrinsically correct for variation in leptin that was related to BMI. One ANOVA was performed each for BMI, PBF, WHR, leptin, and leptin:BMI ratio using the transformed value for each as the dependent variable and the LMNA genotype, age, and sex as the independent variables. One ANOVA was performed each for fasting plasma concentration of insulin and C-peptide, using the transformed value for each as the dependent variable and using LMNA genotype, age, sex, and BMI as the independent variables. Confirmatory post hoc analyses of between-genotype differences were conducted with the nonparametric Kruskal-Wallis ² approximation test of the Wilcoxon rank sums, as previously reported (15). Post hoc parametric analyses were also conducted for each sex separately, using LMNA genotype and age as independent variables.

When a new significant genotype-phenotype association was identified, the mean values for the trait were compared between genotypic classes using pairwise comparisons of least squares means. Least squares means are also called "population marginal means" and reflect means after adjustment for covariates used in the model. The percent contribution of the genotype to variation in the quantitative traits was estimated from partial regression coefficients obtained from multivariate regression analysis. A forward stepwise regression procedure was used to assist in the model building, with the P value for inclusion set at <0.15. The dependent variables in each regression analysis included transformed BMI, PBF, and WHR and fasting plasma concentrations of insulin, C-peptide, and leptin, and leptin:BMI ratio. The independent variables in the model for each analysis included LMNA genotype, age, and sex. BMI was also included as an independent variable for insulin and C-peptide.

	RESULTS

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Clinical and biochemical attributes.
The clinical and biochemical attributes of 306 adult nondiabetic Oji-Cree subjects are shown in Table 1. None of the subjects had diabetes, muscular dystrophy, cardiomyopathy, or conduction system disease. None of the study subjects was taking oral hypoglycemic, antihypertensive, or antihyperlipidemic medications. We noted between-sex differences in most obesity related traits (Table 1). Women were found to have higher mean BMI and PBF and plasma insulin, leptin, and leptin:BMI ratio than men. In contrast, women had lower mean WHR than men. Mean BMI and plasma C-peptide were not significantly different between the sexes.

View larger version (52K): [in this window] [in a new window]   Fig. 1. Genotyping of LMNA 1908C/T: 1.5% agarose gel electrophoresis of PCR amplified segments of LMNA exon 10 after digestion with Pml I. Digestion of the 1908C allele gave 2 fragments with sizes 887 and 182 bp, of which the smaller was not visible on these gels. Digestion of the 1908T allele gave a single fragment with size 1,069 bp. The molecular weight marker is in the lane M, and marker sizes are shown on the left. P1, P2, C1, C2, and C3 are all patient samples. The fragment sizes are indicated on the right.

	DISCUSSION

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The widely expressed LMNA gene products, lamins A and C, are important elements of the nuclear lamina. Alternative splicing at exon 10 of LMNA gives lamins A and C sequence identity for the first 566 residues, but distinctive COOH termini (23). Since the LMNA 1908T/C SNP is silent at the amino acid level, it is probable that the associations were the result of linkage disequilibrium with a functional variant elsewhere at this locus. However, we have observed no other LMNA coding sequence variants in the Oji-Cree, suggesting that this possibility is unlikely. It is also possible that there was unmeasured variation within flanking noncoding regulatory sequences of LMNA, or within a nearby gene on chromosome 1q21-q22, which we have not yet ruled out. Finally, it is possible that the LMNA 1908T/C SNP may mark a DNA change that has a functional molecular consequence. The affected residue is at the third base of LMNA codon 566, which is the last codon shared in common between lamin A and C before alternative splicing gives rise to the two distinct proteins (23). Although we are unaware of a precedent in which a common SNP at a crucial position affects message splicing, the proximity of this variant site to such a focal nucleotide in LMNA might be more than coincidental, especially in light of the phenotypic associations.

The mechanism underlying the association between common variation in LMNA and plasma leptin and indices of obesity is not clear. Lamins A and C are members of the intermediate filament multigene family and are present in most differentiated cells. Lamin A and C polymerize to form part of the nuclear lamina, a structural meshwork of 10-nm filaments on the nucleoplasmic side of the inner nuclear membrane (23). Lamins A and C form dimers through their rod domains. Thus variation in LMNA could simply affect lamin dimerization. However, any mechanism that so fundamentally undermines the nuclear envelope might be expected to have more widespread consequences.

The association of variant LMNA with plasma leptin and indices of obesity might alternatively have resulted from modified interactions between variant lamin and either chromatin, nuclear inner membrane integral proteins, transcription factors, and/or other nuclear and cytoplasmic proteins. Any of these mechanisms might impair proliferation of pre-adipocytes, differentiation of mature adipocytes, modulation of apoptosis, or other cellular or metabolic changes that would affect adipose tissue mass (8, 16).

A key question is whether the LMNA-associated changes in plasma leptin are simply related to differences in adiposity or whether they occur through an independent mechanism. Basal plasma concentrations of leptin are, in general, proportional to adipose tissue mass (6, 18, 24). We previously showed that plasma leptin concentration in the Oji-Cree was strongly correlated with adiposity (11). Thus the association of LMNA 1908T/1908T genotype with higher plasma leptin is consistent with the higher BMI and WHR. This suggests that the LMNA variation is more directly associated with differences in adiposity and that the increase in plasma leptin is secondary to the anthropometric changes. However, the significant difference in leptin:BMI ratio also suggests an association with plasma leptin that is independent of obesity.

So far, none of the genomic scans for genetic determinants of plasma leptin concentrations has indicated linkage with chromosome 1q21-q22. For example, a genomic scan performed in Mexican Americans indicated that a quantitative trait locus (QTL) on chromosome 2 was linked with plasma leptin (5), which subsequent studies indicated might be POMC, which encodes pro-opiomelanocortin (19). Hager et al. (10) found loci on 5cen-q and 2p that showed suggestive linkage with plasma leptin concentrations, but no genes were identified. The absence of significant QTLs for plasma leptin on chromosome 1q in the region containing LMNA in other studies might be related to genetic heterogeneity for the trait or to differences in allele frequencies between populations, both of which have been shown to create disparities between the results of association and linkage analysis (17).

Among candidate genes, Meirhaeghe et al. (25) reported that plasma leptin was associated with noncoding variation in the PPARG gene on chromosome 3p25, which encodes the nuclear receptor peroxisome proliferator-activated receptor gamma (PPAR). Montague et al. (26) reported that homozygosity for a frameshift mutation in LEP on chromosome 7q, which encodes leptin, results in congenital deficiency of leptin and morbid obesity. Oksanen et al. (28) found that variation near LEP was associated with plasma leptin, but this could not be confirmed by Karvonen et al. (21). Finally, Janssen et al. (20) found no association between the Y64R variant in ADRB3 on chromosome 8p12-p11, which encodes the ß3-adrenergic receptor, and plasma leptin in Dutch adults. Thus previous studies of candidate gene associations with plasma leptin have been inconsistent, which could be related to the recognized limitations of genetic association studies (17).

In conclusion, we report novel associations between the LMNA 1908T/C SNP and circulating leptin, leptin:BMI ratio, BMI, PBF, and WHR in adult, nondiabetic Oji-Cree. The variation in these traits attributable to LMNA 1908T/C SNP was modest, ranging from 1.6% to 25.2%, consistent with the notion that these quantitative traits have a complex genetic basis. There is growing appreciation among investigators in the area of complex diseases that small or modest effects upon quantitative phenotypes will likely be the rule rather than the exception in human genetics (14). Although the desire to describe a large genetic effect on a complex quantitative trait is understandable, experience to this point indicates that biological reality is more complex (14). The genetic component of obesity in the general population is very likely to be the aggregate of numerous small effects, such as that due to LMNA in this study (14). However, just because an effect is small does not mean that it has no biological or clinical relevance (14). Further epidemiological and genetic studies of the LMNA gene locus and nearby SNPs are required to improve our understanding of the complex regulatory mechanisms governing leptin expression by adipocytes and their importance in obesity.

	ACKNOWLEDGMENTS

 
We acknowledge the Chief and Council of the community of Sandy Lake, the Sandy Lake community surveyors, the Sandy Lake nurses, and the staff of the University of Toronto Sioux Lookout Programme.

This work was supported by National Institutes of Health Grant DK-44597-01, Ontario Ministry of Health Grant 04307, Medical Research Council of Canada Grant MT13430, the Canadian Diabetes Association (in honor of Rheta Maude Gilbert), Heart and Stroke Foundation of Ontario Grant 3628, and the Blackburn Group. R. A. Hegele is a Career Investigator of the Heart and Stroke Foundation of Ontario (2729). S. B. Harris is a Career Investigator of the Ontario Ministry of Health. A. J. Hanley was supported by Health Canada through a National Health Research and Development Program Research Training Award.

	FOOTNOTES

 
Article published online before print. See web site for date of publication (http://physiolgenomics.physiology.org).

Address for reprint requests and other correspondence: R. A. Hegele, Blackburn Cardiovascular Genetics Laboratory, Robarts Research Institute, 406-100 Perth Drive, London, Ontario, Canada N6A 5K8 (E-mail: robert.hegele{at}rri.on.ca).

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