|Year : 2015 | Volume
| Issue : 3 | Page : 103-107
Study of the LMNA 1908 C/T gene polymorphism in type 2 diabetic Egyptians with vascular complications
Heba Mostafa1, Manal Eldeeb1, Ahmed Hamdy MD 1, Rasha M Abdel Samie1, Badawy El-Kholy2, Nahla Fawzy2, Ahmed Eltaweel2, Nahed M Ibrahim2
1 Department of Internal Medicine, Faculty of Medicine, Cairo University, Cairo, Egypt
2 Department of Clinical and Chemical Pathology, Faculty of Medicine, Cairo University, Cairo, Egypt
|Date of Submission||27-May-2015|
|Date of Acceptance||23-Jun-2015|
|Date of Web Publication||15-Sep-2015|
Faculty of Medicine, Cairo University, Kasr Al Aini Street, Cairo 11562
Source of Support: None, Conflict of Interest: None
Vascular complications are the main cause of morbidity and mortality in type 2 diabetic patients. Genetic susceptibility is associated with the evolution of diabetic complications. One such gene is the lamin A and C gene located on chromosome 1q21, a susceptibility locus for type 2 diabetes mellitus, and encodes nuclear lamins A and C. The LMNA 1908 C/T polymorphism has been reported to be associated with dyslipidemia, metabolic syndrome, and obesity, suggesting that this polymorphism increases the risk of atherosclerosis and vascular disease. The present study aims to elucidate the association between the LMNA 1908 C/T single nucleotide polymorphism and the prevalence of vascular complications in a sample of type 2 diabetic Egyptian patients.
Materials and methods
Genomic DNA from 47 type 2 diabetic patients with vascular complications and 20 control participants was analyzed for the LMNA 1908 C/T polymorphism using PCR-RFLP.
Carriers of the LMNA 1908 T-allele showed a significantly higher prevalence in patients with diabetic nephropathy than carriers of the C-allele (P < 0.05). Multiple regression analysis showed that the LMNA 1908 T-allele tended to be independent risk factor for diabetic nephropathy (P = 0.012, odds ratio = 5.460).
The findings of this study suggest that the LMNA 1908 C/T single nucleotide polymorphism is associated with the development of diabetic nephropathy in Egyptian type 2 diabetic patients.
Keywords: LMNA 1908 C/T , type 2 diabetes, vascular complications
|How to cite this article:|
Mostafa H, Eldeeb M, Hamdy A, Abdel Samie RM, El-Kholy B, Fawzy N, Eltaweel A, Ibrahim NM. Study of the LMNA 1908 C/T gene polymorphism in type 2 diabetic Egyptians with vascular complications. Egypt J Intern Med 2015;27:103-7
|How to cite this URL:|
Mostafa H, Eldeeb M, Hamdy A, Abdel Samie RM, El-Kholy B, Fawzy N, Eltaweel A, Ibrahim NM. Study of the LMNA 1908 C/T gene polymorphism in type 2 diabetic Egyptians with vascular complications. Egypt J Intern Med [serial online] 2015 [cited 2019 Sep 22];27:103-7. Available from: http://www.esim.eg.net/text.asp?2015/27/3/103/165440
| Introduction|| |
Type 2 diabetes mellitus is a major health problem worldwide. In Egypt, type 2 diabetes is a major health issue. The current prevalence of diabetes in Egypt is among the world's 10 highest countries. The expected number of individuals with diabetes in Egypt (20-79 age groups) will be 8.6 million in 2030 [1-3].
Type 2 diabetes is characterized by peripheral insulin resistance with an insulin-secretory defect that varies in severity. Insulin resistance in the offspring of patients with type 2 diabetes has been known to be the best predictor of the development of the disease .
Vascular complications are the main cause of morbidity and mortality in diabetes mellitus. Hyperglycemia, obesity, hypertension, dyslipidemia, and insulin resistance are factors that contribute toward the development of diabetic vascular complications . Diabetes mellitus and subsequent microvascular and macrovascular complications occur as a result of interactions between environmental factors and genetic susceptibility [4,6].
The LMNA gene is located on chromosome 1q 21, a susceptibility locus for type 2 diabetes. Mutations in the LMNA gene, which encodes the nuclear structural proteins lamins A and C, cause one form of familial partial lipodystrophy, a monogenic syndrome of extreme insulin resistance, abnormal fat distribution, dyslipidemia, hypertension, diabetes, and vascular complications [7,8]. The LMNA 1908 C/T polymorphism is the most common LMNA single nucleotide polymorphism (SNP) that encodes a silent mutation that alters the relative amounts of lamins A and C. It has been shown to be associated with dyslipidemia as it is considered to be a high risk factor for atherosclerosis and vascular disease; thus, LMNA 1908 C/T SNP might play a role in susceptibility to diabetic vascular complications .
| Materials and methods|| |
This was a prospective study carried out over a period of 1 year and included 47 type 2 diabetes patients with diabetic vascular complications who were attending the Internal Medicine Clinics, Diabetes Clinic, and Internal Medicine Hospital of Kasr El Aini Hospital, Faculty of Medicine, Cairo University, and 20 healthy control participants.
All patients and control groups were subjected to the following:
- Full assessment of history including age of onset of diabetes, duration of diabetes, and complications.
- Thorough clinical examination, general, cardiac, neurological, and fundus examination, and calculation of BMI.
Laboratory investigations: fasting blood glucose (mg/dl), serum lipid profile including total cholesterol, triglycerides, HDL-cholesterol, LDL-cholesterol (mg/dl), fasting serum insulin level (μU/ml), calculation of insulin resistance by homeostasis model assessment (HOMA-IR) as fasting insulin concentration (μU/ml)×fasting glucose concentration (mg/dl)/405 , urinary albumin excretion (mg/24 h), and genomic DNA extraction, and analysis of the LMNA 1908 C/T gene polymorphism using PCR, followed by restriction fragment length polymorphism analysis.
Patients with nondiabetic renal disease, microscopic hematuria, clinical pyuria, or evidence of bacterial infection in urine culture were excluded; also in addition, patients with apparent cardioembolic cerebral infarction or an undetermined subtype of infarction were excluded. The protocol of this study was approved by the review board of the department of Internal Medicine according to the Declaration of Helsinki.
The SPSS 10.0 for windows (SPSS Inc., Chicago, Illinois, USA) was used for data management and analysis. Quantitative data were presented as mean ±SD. For comparison of the means of both groups, Student's t-test was used. The association between qualitative data was assessed using the χ2 -test. Risk estimate was carried out by odds ratio (OR). A P value was considered significant at 0.05.
| Results|| |
A total of 47 patients and 20 healthy controls were enrolled. The patient group included 20 men and 27 women (ranging age between 35 and 67 years), whereas the control group included 11 men and nine women (ranging in age between 32 and 63 years).
The BMI and the laboratory parameters among the studied groups are compared in [Table 1], which showed statistical significance for fasting blood sugar (FBS), total cholesterol, LDL-C, triglycerides, HOMA, and microalbumin urea in diabetic patients in comparison with the control group.
The number of patients and percentages of different vascular complications in group I (diabetic patients) were as follows: diabetic nephropathy (DN) (N = 17) (36.2%), retinopathy (N = 16) (34%), neuropathy (14) (29.8%), coronary heart disease (CHD) (N = 10) (21.3%), and cerebrovascular disease (CVD) (N = 8) (17%).
Allele frequency and risk ratio of the LMNA 1908 C/T allele between cases and controls are shown in [Table 2], which showed statistical significance in the diabetic group in the allele mutation in comparison with the control group (P = 0.031).
|Table 2: Allele frequency and risk ratio of the LMNA 1908 C/T allele between cases and controls|
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The LMNA 1908 C/T genotype frequency and risk ratio in cases and controls are shown in [Table 3]. [Table 4] shows a comparison of the clinical features and laboratory parameters among the diabetic group according to the LMNA 1908 C/T genotype.
|Table 3: Comparison between the LMNA 1908 C/T genotype frequency and risk ratio in cases and controls|
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|Table 4: Comparison of clinical features and laboratory parameters among the diabetic group according to the LMNA 1908 C/T genotype|
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The LMNA 1908 C/T genotype frequency and risk ratio in cases with nephropathy, CVD, CHD, retinopathy, and neuropathy are shown in [Table 5] and [Table 6].
|Table 5: LMNA 1908 C/T genotype frequency and risk ratio in cases with nephropathy|
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|Table 6: LMNA 1908 C/T genotype frequency in cases with cerebrovascular disease, coronary heart disease, retinopathy, and neuropathy|
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Carriers of the LMNA 1908 T-allele showed a significantly higher prevalence of DN than carriers of the C-allele (P < 0.05). Multiple regression analysis showed that the LMNA 1908 T-allele tended to be an independent risk factor for DN (P = 0.012, OR = 5.460).
| Discussion|| |
Type 2 diabetes is a major global health problem that affects over 170 million individuals worldwide; it will be certainly one of the major diseases of the 21st century and should be recognized as a priority .
The genetic component in the pathogenesis of type 2 diabetes and development of vascular complications is very significant, but has been shown to be complex, as single gene disorders are only seldom responsible. Patterns of inheritance suggest that type 2 diabetes is both polygenic and heterogeneous as multiple genes are involved and different combinations of genes play a role in different subsets of individuals .
One of these contributor genes is the LMNA gene; the most common genetic variant in the LMNA gene is the C to T substitution at position 1908 in exon 10. Although it is a silent mutation, it could alter mRNA splicing and thus the relative amount of lamins A and C mRNA and related proteins . Conflicting results have been reported on the association of LMNA SNPs and diabetes mellitus, some of which suggest modest positive associations, whereas others did not report any convincing association . The aim of this study, therefore, was to investigate the association between the LMNA 1908 C/T polymorphism and the prevalence of vascular complications in a group of Egyptian patients with type 2 diabetes.
This study included two groups: group I included 47 type 2 diabetic patients with vascular complications; there were 20 men (42.6%) and 27 women (57.4%) ranging in age from 35 to 67 years (52.9+8.9). Group II included 20 healthy adult volunteers as a control group: 11 men (55%) and nine women (45%) ranging in age from 32 to 63 years (43.9+10.6).
According to the type of macrovascular or microvascular complications, group I included 17 patients with DN (36.2%), 16 patients with retinopathy (34%), 14 patients with neuropathy (29.8%), 10 patients with CHD (21.3%), and eight patients with CVD (17%).
The mean age of patients recruited in this study with the wild genotype (CC) was 49.5+10.4 years, whereas the mean age of patients with the mutant genotype (CT and TT) was 51.6+10.1 years. This was in agreement with the study by Liang et al.  who reported a mean age of 56 (46-62) and 54 (44-63) years for patients with wild and mutant genotypes, respectively.
Comparison of the clinical features and laboratory parameters of the study participants according to the LMNA 1908 C/T genotype indicated a statistically significant increase in fasting plasma glucose levels in carriers of the T-allele than carriers of the C-allele (P = 0.004). This finding was in agreement with that of Wegner et al.  who reported, in a Danish cohort study, that the T-allele was associated with increased fasting glucose concentration (P = 0.008). Also, fasting insulin and HOMA-IR showed a statistically significant increase in carriers of the T-allele than carriers of the C-allele, with P-values of 0.00 and 0.00, respectively, which indicates that the LMNA 1908 C/T SNP may play a role in hyperinsulinemia and development of insulin resistance in type 2 diabetes patients. These findings were not in agreement with those of Murase et al.  who reported, in a Japanese study, that LMNA 1908 C/T SNP was a factor predisposing to insulin resistance (P = 0.01); also, Mukti et al.  reported that this gene variant is associated with insulin resistance and generalized obesity in Indians.
In the present study, 24 h urinary microalbumin was significantly increased in patients with the T-allele than those with the C-allele (P = 0.01), which indicates that LMNA C/T 1908 SNP may lead to the risk of developing nephropathy in type 2 diabetic patients.
This study found no statistically significant difference in BMI between carriers of the T-allele and the C-allele (P = 0.065), and this result was in agreement with Wolford et al.  in a Pima Indian study and Liang et al.  in a Japanese study. This result is not in agreement with the study by Hegele et al.  who reported that carriers of LMNA 1908 C/T SNP had higher BMI and indices of obesity. The discrepancy between the previous observations may be because of linkage disequilibrium of the 1908 T SNP with other ethnicity-specific polymorphisms.
In the current study, genomic DNA analysis of the LMNA 1908 gene showed that the frequency of the wild genotype (CC) was 57.4 and 85%, whereas that of the mutant genotype (CT and TT) was 42.6 and 15% in the patient and control groups, respectively. This indicated a statistically significant increase in the frequency of the mutant genotype in the diabetic patients compared with the control participants [OR = 4.19, 95% confidence interval (CI) = 1.081-16.302, P = 0.048]. This result was in agreement with the study by Wegner et al.  (P = 0.04).
In this study, the frequency of the T-allele was 23.4 and 7.5%, whereas that of the C-allele was 76.6 and 92.5% for cases and controls, respectively; there was a statistically significant increase in the mutant allele in cases compared with the control participants, with P = 0.031, OR = 3.76, and 95% CI = 1.059-13.41. When subgroup analysis of type 2 diabetic patients was stratified according to their vascular complications, it was found that carriers of the mutant genotype (CT and TT) were more prevalent in diabetic patients with nephropathy than those with the wild genotype (CC) (OR = 4.27, 95% CI = 1.20-15.15, P = 0.021). Also, the frequency of the T-allele was 38.3 and 15%, whereas the frequency of the C-allele was 61.7 and 85% in diabetic patients with nephropathy and those without nephropathy, respectively (P = 0.011); on estimating the risk ratio of the mutant allele, the OR was 3.508 and 95% CI was 1.303-9.443.
These results indicate that type 2 diabetic patients harboring the LMNA 1908 T-allele showed a higher risk for development of DN than those harboring the C-allele. These findings are in agreement with those of Liang and colleagues, who carried out their study on Japanese participants and reported that the frequencies of LMNA 1908 C/T and TT genotypes were 65.7 and 45%, whereas the frequencies of the of CC genotype were 34.3 and 55% in patients with DN and those without DN, respectively (P = 0.036); they also reported that the frequency of the T-allele was 38.6 and 24%, whereas that of the C-allele was 61.4 and 76% in patients with DN and those without DN, respectively (P = 0.022) .
This study did not find an association between 1908 C/T SNP and development of CVD in type 2 diabetic patients (P = 0.258); this was in contrast to the result reported by Liang et al. , who found an association between this SNP and development of CVD in type 2 diabetes patients (0.003). This may be attributed to the relatively smaller number of participants included in the present study.
The present study found no association between 1908 C/T SNP and development of CHD, retinopathy, or neuropathy in type 2 diabetes patients (P = 0.481, 0.615, 0.978, respectively). These results were in agreement with those of Liang et al. . By applying a logistic regression analysis for risk factors for DN on the data of the present study, it was found that the LMNA T genotype is an independent risk factor for development of DN, with OR = 5.460, 95% CI = 1.464-20.366, and P = 0.012. This is in agreement with the study by Liang et al. , who found a significant correlation between the LMNA 1908 T-allele and DN (OR = 2.97, 95% CI = 0.89-9.94, and P = 0.047).
In conclusion, these results suggest that the LMNA 1908 C/T SNP is associated with the development of DN in Egyptian type 2 diabetic patients.
Financial support and sponsorship
Conflicts of interest
There are no conflicts of interest.
| References|| |
International Diabetes Federation. IDF diabetes atlas
. 5th ed. Brussels, Belgium: International Diabetes Federation 2011.
Bos M, Agyemang C. Prevalence and complications of diabetes mellitus in Northern Africa: a systematic review. BMC Public Health 2013; 13:387.
Badran M, Laher I. Type II diabetes mellitus in Arabic-speaking countries. Int J Endocrinol 2012; 2012:902873.
Doria A, Patti ME, Kahn CR. The emerging genetic architecture of type 2 diabetes. Cell Metab 2008; 8:186-200.
Liang H, Murase Y, Katuta Y, Asano A, Kobayashi J, Mabuchi H. Association of LMNA 1908C/T polymorphism with cerebral vascular disease and diabetic nephropathy in Japanese men with type 2 diabetes. Clin Endocrinol (Oxf) 2005; 63:317-322.
Bansal S, Chawla D, Banerjee BD, Madhu SV, Tripathi AK. Association of RAGE gene polymorphism with circulating AGEs level and paraoxonase activity in relation to macro-vascular complications in Indian type 2 diabetes mellitus patients. Gene 2013; 526:325-330.
Owen KR, Groves CJ, Hanson RL, Knowler WC, Shuldiner AR, Elbein SC, et al
. Common variation in the LMNA gene (encoding lamin A/C) and type 2 diabetes: association analyses in 9518 subjects. Diabetes 2007; 56:879-883.
Mory PB, Crispim F, Kasamatsu T, Gabbay MA, Dib SA, Moisés RS. Atypical generalized lipoatrophy and severe insulin resistance due to a heterozygous LMNA p.T10I mutation. Arq Bras Endocrinol Metabol 2008; 52:1252-1256.
Yokoyama H, Emoto M, Fujiwara S, Motoyama K, Morioka TK, omatsu M, et al.
Quantitative insulin sensitive check index and the reciporcal index of homeostasis model assessment in normal range weight and moderately obese type 2 diabetic patients. Diabetic Care 2003; 26:2426-2432.
Fontaine-Bisson B, Alessi MC, Saut N, Fumeron F, Marre M, Dutour A, et a
l. Polymorphisms of the lamina maturation pathway and their association with the metabolic syndrome: the DESIR prospective study. J Mol Med (Berl) 2010; 88:193-201.
Wegner L, Andersen G, Sparso T, Grarup N, Glümer C, Borch-Johnsen K, et al.
Common variation in LMNA increases susceptibility to type 2 diabetes and associates with elevated fasting glycemia and estimates of body fat and height in the general population: studies of 7495 Danish whites. Diabetes 2007; 56:694-698.
Murase Y, Yagi K, Katsuda Y, Asano A, Koizumi J, Mabuchi H. An LMNA variant is associated with dyslipidemia and insulin resistance in the Japanese. Metabolism 2002; 51:1017-1021.
Mukti S, Annop M, Naval V, Bhatt S, Shivani C, Neha G, et al.
Genotype of the LMNA 1908 C/T variant is assaociated with generalized obesity in Asian Indians in north India. Clin Endocrinol (Oxf) 2011; 75:642-645.
Wolford JK, Hanson RL, Bogardus C, Prochazka M. Analysis of the lamin A/C gene as a candidate for type II diabetes susceptibility in Pima Indians. Diabetologia 2001; 44:779-782.
Hegele RA, Cao H, Harris SB, Zinman B, Hanley AJ, Anderson CM. Genetic variation in LMNA modulates plasma leptin and indices of obesity in aboriginal Canadians. Physiol Genomics 2000; 3:39-44.
[Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6]