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Association of leptin receptor gene polymorphisms with post-transplant diabetes mellitus: Short report and literature review

Jin Sug Kim

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

E-mail : bhuvaneswari.bibleraaj@uhsm.nhs.uk

Chun Gyoo Ihm

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

Tae Won Lee

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

Yang Gyun Kim

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

Ju Young Moon

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

Sang Ho Lee

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

Joo-Ho Chung

Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Korea

Su Kang Kim

Kohwang Medical Research Institute, School of Medicine, Kyung Hee University, Seoul, Korea

Yeong Hoon Kim

Division of Nephrology, School of Medicine, Inje University, Busan, Korea

Kyung Hwan Jeong

Division of Nephrology, School of Medicine, Kyung Hee University, Seoul, Korea

DOI: 10.15761/TiT.1000221

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Abstract

Background: Post-transplant diabetes mellitus (PTDM) is a common and important metabolic complication after renal transplantation. Although genetic variants of the leptin (LEP) and leptin receptor (LEPR) gene have been reported to be associated with insulin resistance and diabetes mellitus, few studies have examined these variants in patients with post-transplant diabetes mellitus (PTDM). In this study, we investigated the association between LEP and LEPR polymorphisms and PTDM in renal transplant recipients. We also reviewed the literature on the genetic variants associated with development of PTDM.

Methods: A total of 301 patients who received renal transplants and had no history of diabetes were included in this study. We analyzed the associations between development of PTDM and the five single nucleotide polymorphisms (SNPs) in LEP (rs1322837 and rs2167270) and LEPR (rs8179183, rs1137100, and rs1137101).

Results: PTDM developed in 48 of the 301 patients studied (15.9%). Patients with PTDM had significantly higher allele frequency of the LEPR rs1137100*G allele and rs1137101*G allele. After adjustment for age, gender, and tacrolimus usage, rs113700 and rs 1137101 in LEPR showed significant association with the development of PTDM.

Conclusions: LEPR polymorphisms were significantly associated with PTDM in renal transplant recipients. These data suggest that SNPs of LEPR may be associated with the pathogenesis of PTDM and may act as genetic markers for the development of PTDM.

Key words

leptin, leptin receptor, gene polymorphism, post-transplant diabetes mellitus, renal transplantation 

Introduction

The development of post-transplant diabetes mellitus (PTDM) is a devastating metabolic complication after renal transplantation [1]. It affects 2–50% of renal transplant recipients and is associated with graft failure, cardiovascular complications, infection, and mortality [2,3]. As in type 2 diabetes mellitus (T2DM), decreased insulin secretion, increased insulin resistance, or a combination of both are believed to be involved in PTDM [3,4]. Although various risk factors such as older age, obesity, hepatitis C infection, and type of immunosuppressive regimen are well established, they do not fully account for the development of PTDM [3]. Recently, many studies have been conducted to analyze genetic polymorphisms as markers for PTDM [5,6]. These studies have suggested that the development of PTDM is related to the genotypes of several genes, such as adiponectin (ADIPOQ), transcription factor 7-like 2 (TCF7L2), potassium voltage-gated channel subfamily Q member 1 (KCNQ1), and C-C motif ligand 5 (CCL5), which are involved in insulin resistance and sensitivity [7-10]. Leptin (LEP) and leptin receptor (LEPR) gene polymorphisms have been reported to be associated with insulin resistance, obesity, and diabetes mellitus [11,12]. However, only a few studies have evaluated the clinical impact of LEP and LEPR polymorphisms on the development of PTDM [13].

In this study, we ascertained whether LEP and LEPR polymorphisms are associated with PTDM in Korean patients who underwent renal transplantation. We also reviewed literature that investigated associations between gene polymorphisms and PTDM in renal transplant recipients.

Methods

A total of 301 renal transplant recipients were recruited at three transplant centers in the Republic of Korea (Kyung Hee University Medical Center, Kyung Hee University Hospital at Gangdong, and Inje University Busan Paik Hospital) from 2000 to 2009. Patients were excluded when they had a history of diabetes or impaired fasting glucose (fasting glucose level 100-125 mg/dL) before transplantation. All study procedures complied with the ethical guidelines of the 1975 Declaration of Helsinki, as revised in 2000. This study was approved by the ethics review committees of all three transplant centers and written informed consent was obtained from each subject.

PTDM was diagnosed based on American Diabetes Association guidelines [14]. SNPs were selected in LEP and LEPR using the NCBI dsSNP database, version 131 (http:// www.ncbi.nlm.nih.gov/SNP) and the database of the International Hapmap Project (http://www.hapmap.org/index.html). Two LEP (rs1322837 and rs2167270) and three LEPR SNPs (rs8179183, rs1137100, and rs1137101) were ultimately selected and used to genotype the patients. Blood samples were collected from each subject and then stored at -20℃. Genomic DNA was isolated from blood samples with a commercially available Qiagen DNA extraction kit (Qiagen, Tokyo,Japan). SNP genotyping was conducted by direct sequencing. Genomic DNA was amplified with specific primers for two LEP and three LEPR SNPs (Table 1). The amplified products were sequenced with an ABI PRISM 3730XL analyzer (PE Applied Biosystems, Foster City, Calif, USA), and sequence data were analyzed with SeqManII software (DNASTAR Inc., Madison, Wisc., USA).

Results

The overall incidence of PTDM in the study population was 17.9% (54 of 301 patients). Table 1 shows the baseline characteristics of the study population according to the development of PTDM (PTDM vs. non-PTDM group). The mean follow-up duration for all 301 patients was 87.9 months. Patients in the PTDM group were significantly older than those in the non-PTDM group (45.17 ± 9.26 vs. 38.58 ± 11.20 years, respectively; p <0.001). Patients in the PTDM group used tacrolimus more frequently than did those in the non-PTDM group (p = 0.044).

Table 1. Clinical characteristics of the study population (PTDM vs. non-PTDM).

 

PTDM (n=54)

non-PTDM (n=247)

p

Follow-up duration (months)

91.54 ± 85.36

76.85 ± 75.49

0.208

Age (years)

45.17 ± 9.26

38.58 ± 11.20

<0.001

Sex (male: female)

 28:26

 155:92

0.137

BMI (kg/m2)

22.57 ± 3.39

22.47 ± 3.47

0.859

Dialysis duration (months)

33.20 ± 58.44

23.90 ± 34.09

0.336

HLA total mismatching (n)

3.10 ± 1.54

3.24 ± 1.53

0.512

HCV (+) (n, %)

0 (0%)

6 (2.36%)

0.244

Acute rejection (n, %)

13 (25.49%)

44 (17.32%)

0.197

Calcineurin inhibitor, n (%)

Tacrolimus

24 (45.3%)

74 (30.8%)

0.044

Cyclosporine

29 (53.7%)

166 (67.2%)

0.098

Antimetabolite, n (%)

Azathioprine

10 (18.5%)

72 (29.1%)

0.582

MMF

34 (62.9%)

165 (66.8%)

0.702

Serum creatinine (mg/dL)

     

At 6 months after transplantation

1.27 ± 0.56

1.32 ± 0.49

0.529

At 12 months after transplantation

1.29 ± 0.36

1.37 ± 0.87

0.507

PTDM: post-transplantation diabetes mellitus; BMI: body mass index; HLA: human leukocyte antigen; HCV: hepatitis C virus; MMF: mycophenolate mofetil

Allele frequencies are shown in Table 2. The PTDM group had a significantly higher allele frequency compared to the non-PTDM group for the rs1137100*G allele (OR = 1.924; 95% CI: 1.024–1.192; p = 0.025) and the rs1137101*G allele (OR = 1.131; 95% CI: 1.045–1.1225; p = 0.019). The effect of genotype on development of PTDM remained significant even when adjusting for age, gender, and tacrolimus usage (Table 3). We nest, tested whether the LEPR haplotype was associated with PTDM. To demonstrate pair-wise linkage disequilibrium (LD), we analyzed three SNPs and found that they were in LD. The D’ values between rs8179183 and rs1137100, and between rs8179183 and rs1137101, between rs1137100 and rs1137101 were 0.572, 0.655, and 0.876, respectively. The r2 values between SNPs were also calculated. The r2 values between rs8179183 and rs1137100, and between rs8179183 and rs1137101, between rs1137100 and rs1137101 were 0.328, 0.509, and 0.647, respectively.

Table 2. Allele frequencies for 5 SNPs in the LEP and LEPR genes in PTDM and non-PTDM subjects.

Gene

SNP

Allele

PTDM n (%)

Non-PTDM n (%)

OR (95% CI)

p

LEP

rs2167270

G

91 (84.2%)

388 (78.5%)

0.68(0.39 - 1.19)

0.182

.

 

A

17 (15.8%)

106 (21.5%)

 

 

LEP

rs13228377

A

91 (84.2%)

380 (76.9%)

0.62(0.35 - 1.08)

0.094

.

 

G

17 (15.8%)

114 (23.1%)

 

 

 LEPR

rs8179183

G

97 (89.8%)

454 (91.9%)

1.28 (0.63- 2.59)

0.480

.

 

C

11 (10.2%)

40 (8.1%)

 

 

 LEPR

rs1137100

G

93 (86.1%)

377 (76.3%)

1.92 (1.02-1.19)

0.025

 

 

A

15 (13.9%)

117 (23.7%)

 

 

LEPR

rs1137101

G

101 (94%)

421 (85%)

1.13 (1.05-1.23)

0.019

 

 

A

7 (6%)

73 (15%)

 

 

SNPs: single nucleotide polymorphisms; PTDM: post-transplantation diabetes mellitus; LEP: leptin; LEPR: leptin receptor

Table 3. Logistic regression analysis of LEP and LEPR polymorphisms in PTDM and non-PTDM subjects adjusted for age, sex, and tacrolimus usage

Gene

SNP

Model

Type

PTDM, n (%)

Non-PTDM, n (%)

OR (95% CI)

p

LEP

rs2167270

Codominant

G/G

39 (72.2%)

147 (59.8%)

0.55 (0.27-1.11)

0.200

A/G

13 (24.1%)

92 (37.4%)

A/A

2 (3.7%)

7 (2.8%)

Dominant

G/G

39 (72.2%)

147 (59.8%)

0.60 (0.31-1.16)

0.12

A/G + A/A

15 (27.8%)

99 (40.2%)

Recessive

G/G+A/G

52 (96.3%)

239(97.2%)

1.58 (0.30-8.24)

0.60

A/A

2 (3.7%)

7 (2.8%)

rs13228377

Codominant

A/A

39 (72.2%)

142 (57.7%)

0.54 (0.27-1.08)

0.19

A/G

13 (24.1%)

94 (38.2%)

G/G

2 (3.7%)

10 (4.1%)

Dominant

A/A

39 (72.2%)

142 (57.7%)

0.55 (0.28-1.07)

0.073

A/G+G/G

15 (27.8%)

104 (42.3%)

Recessive

A/A+G/G

52 (96.3%)

236 (95.9%)

0.83 (0.17-4.09)

0.81

A/G

2 (3.7%)

10 (4.1%)

LEPR

rs8179183

Codominant

G/G

43 (79.6%)

207 (84.2%)

1.37 (0.63-2.97)

0.55

C/G

11 (20.4%)

38 (15.4%)

C/C

0 (0%)

1 (0.4%)

Dominant

G/G

43 (79.6%)

207 (84.2%)

1.32 (0.61-2.85)

0.44

C/G + C/C

11(20.4%)

39 (15.8%)

Recessive

G/G + C/G

54(100%)

245 (99.6%)

1.09 (0.48-2.47)

0.840

C/C

0 (0%)

1 (0.4%)

rs1137100

Codominant

G/G

40 (74.1%)

145 (58.9%)

0.55 (0.27-1.11)

0.09

A/G

13 (24.1%)

87 (35.4%)

A/A

1 (1.8%)

14 (5.7%)

Dominant

G/G

40 (74.1%)

145 (58.9%)

2.00 (1.02-3.93)

0.037

A/G+A/A

14 (25.9%)

101 (41.1%)

Recessive

G/G+A/G

53 (98.2%)

232 (94.3%)

1.61 (0.80-3.23)

0.17

A/A

1 (1.8%)

14 (5.7%)

rs1137101

Codominant

G/G

47 (87%)

179 (72.8%)

2.48 (1.05-5.87)

0.029

A/G

7 (13%)

62 (25.2%)

A/A

0 (0%)

5 (2%)

Dominant

G/G

47 (87%)

179 (72.8%)

2.69 (1.14-6.35)

0.014

A/G+A/A

7 (13%)

37 (27.2%)

Recessive

G/G+A/G

184 (74.8%)

47 (13%)

0.00 (0.00-NA)

0.17

A/A

0 (0%)

5 (2%)

PTDM: post-transplantation diabetes mellitus; SNPs: single nucleotide polymorphisms

Discussion

This is the first study to evaluate the genetic association of LEPR and PTDM in renal transplant recipients. Our study demonstrated that two SNPs in LEPR (rs1137100 and rs1137101) were significantly associated with the development of PTDM in Korean renal transplant patients. LEP is a hormone which is synthesized and secreted by adipose tissue, and is known to be important in regulating several neuropeptides and energy homeostasis. It has been reported to play an important role in regulation of body weight, fat metabolism, and glucose uptake [11,15]. Patients with T2DM showed decreased LEP expression in adipose tissue, and had lower serum LEP levels [16]. LEP modulates insulin secretion and action via LEPRs present in the hypothalamus, pancreatic cells, adipose tissue, and muscles [17]. In previous studies, LEPR polymorphisms were reported to be associated with diabetes, insulin resistance, metabolic syndrome, and obesity [18-20]. A hypothetical explanation for these results is that polymorphisms of the LEPR result in dysfunction of the LEP-associated signaling pathway and inhibition of the favorable effects of LEP [21].

In addition to the present study, our group previously reported that polymorphisms in AGT, CCL5, IL17E, IL17RA, IL17RB, IL1B, IL2, IL4, IL7R, MMP2, TLR4, and TLR6 were significantly associated with the development of PTDM in Korean renal transplant recipients [10,22-25]. Considering the clinical impact of each gene, our previous data suggests that impaired insulin secretion, decreased insulin sensitivity, inflammation of islet β-cells, and activation of the innate immune system may play essential roles in the pathogenesis of PTDM.

In the last decade, numerous other genetic studies for PTDM have been conducted in renal transplant recipients, and nearly 50 loci have been established as suspected loci (Table 4) [7-10,13,22-41]. Polymorphisms in AIPOQ, CAPN10, CDKAL1, CDKN2A/B, HHEX, KCN11, KCNQ1, SLC30A8, and TCFL2 are known to be associated with T2DM. Yang et al. [32] reported that polymorphisms in IRS1 and HNF4 increased the risk of PTDM in a Hispanic population. Elens et al. [37] showed that PPARα and POR polymorphisms are significantly associated with PTDM in renal transplant patients treated with tacrolimus. The CYP4F2 gene, which is known to be the main gene involved in creation of 20-hydroxyeicosatetraenoic acid, was also reported as an independent risk factor for PTDM [30]. These genes are associated with decreased insulin secretion through β-cell impairment (CCL2, CCL5, CDKAL1, CDKN2A/B, HNF4A, KCNJ11, KCNQ1, MMPs, NFATc4, SLC30A8, and TCF7L2), increased peripheral insulin resistance (ADIPOQ, AGT, IRS1, and LEP), inflammation (ILs, TLR4, and TLR6), and oxidative stress (GPX1). In light of these results, PTDM is caused by an imbalance between insulin secretion and resistance, and β-cell dysfunction may be a dominant mechanism.

Table 4. Previous candidate gene studies evaluating genetic susceptibility to PTDM in renal transplant recipients.

Gene

SNPs

Ethnicity

PTDM Case

Control

References

ADIPOQ

rs1501299

Asian (Korean)

154

421

Kang et al. [7]

rs1501299

Caucasian

83

187

Nicoletto et al. [26]

AGT

rs4762

Asian (Korean)

49

253

Lee et al. [22]

CAPN10

rs5030952

Caucasian

56

158

Kurzawski et al. [27]

CCL2

rs1024611

Caucasian

43

272

Dabrowska-Zamojcin et al. [28]

CCL5

rs2107538

Asian (Korean)

56

255

Jeong et al. [10]

rs2280789

Asian (Korean)

56

255

Jeong et al. [10]

rs3817655

Asian (Korean)

56

255

Jeong et al. [10]

CDKAL1

rs10946398

Asian (Korean)

145

444

Kang et al. [29]

CDKN2A/B

rs10811661

Asian (Korean)

145

444

Kang et al. [29]

CYP4F2

rs2108622

Caucasian

34

130

Gervasini et al. [30]

GPX1

rs1050450

Caucasian

21

138

Dutkiewicz et al. [31]

HHEX

rs1111875

Asian (Korean)

145

444

Kang et al. [29]

rs5015480

Asian (Korean)

145

444

Kang et al. [29]

rs7923837

Asian (Korean)

145

444

Kang et al. [29]

HNF4A

rs1884614

Hispanic

133

170

Yang et al. [32]

rs2144908

Hispanic

133

170

Yang et al. [32]

IL17E

rs1124053

Asian (Korean)

53

253

Kim et al. [23]

IL17F

rs763780

Caucasian

23

146

Romanowski et al. [33]

IL17RA

rs2229151

Asian (Korean)

53

253

Kim et al. [23]

rs4819554

Asian (Korean)

53

253

Kim et al. [23]

IL17RB

rs1025689

Asian (Korean)

53

253

Kim et al. [23]

rs1043261

Asian (Korean)

53

253

Kim et al. [23]

IL1B

rs3136558

Asian (Korean)

53

253

Kim et al. [23]

IL2

rs2069762

Asian (Korean)

53

253

Kim et al. [23]

rs2069763

Asian (Korean)

53

253

Kim et al. [23]

IL4

rs2070874

Asian (Korean)

53

253

Kim et al. [23]

rs2243250

Asian (Korean)

53

253

Kim et al. [23]

IL6

rs1800795

Caucasian

59

302

Bamoulid et al. [41]

IL7R

rs1494558

Asian (Korean)

53

253

Kim et al. [23]

rs2172749

Asian (Korean)

53

253

Kim et al. [22]

IRS1

rs1801278

Hispanic

133

170

Yang et al. [32]

KCNJ11

rs5219

Caucasian

115

205

Tavira et al. [34]

rs5210

Asian (Indian)

140

500

Khan et al. [9]

KCNQ1

rs2237892

Asian (Korean)

145

444

Kang et al. [29]

rs2237895

Caucasian

145

260

Tavira et al. [35]

rs2283228

Asian (Indian)

140

500

Khan et al. [9]

LEP

re2167270

Caucasian

43

280

Romanowski et al. [30]

MMP2

rs1132896

Asian (Korean)

52

257

Ong et al. [24]

rs243849

Asian (Korean)

52

257

Ong et al. [24]

NFATc4

rs10141896

Hispanic

162

157

Chen et al. [36]

POR

rs1057868

Caucasian

9

76

Elens et al. [37]

PPARα

rs4253728

Caucasian

9

76

Elens et al. [37]

SLC30A8

rs13266634

Asian (Korean)

174

450

Kang et al. [38]

rs13266634

Asian (Indian)

42

98

Khan et al. [39]

TCF7L2

rs7903146

Asian (Korean)

119

392

Kang et al. [40]

rs7903146

Caucasian

114

958

Ghisdal et al. [8]

rs7903146

Asian (Indian)

42

98

Khan et al. [39]

TLR4

rs1927914

Asian (Korean)

51

254

Kim et al. [25]

TLR6

rs1039559

Asian (Korean)

51

254

Kim et al. [25]

2021 Copyright OAT. All rights reserv

PTDM: post-transplantation diabetes mellitus; SNPs: single nucleotide polymorphisms; ADIPOQ: adiponectin; AGT: angiotensinogen; CAPN10: calpain-10 gene; CCL2: C-C motif chemokine ligand 2; CCL5: C-C motif chemokine ligand 5; CDKAL1 cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1; CDKN2A/B: cyclin-dependent kinase inhibitor-2A/B; CYP4F2: cytochrome P450 family 4 subfamily F member 2; GPX1: glutathione peroxidase 1; HHEX: hematopoietically expressed homeobox; HNF4A: hepatocyte nuclear factor 4 alpha; IL: interleukin; IRS1: insulin receptor substrate 1; KCNJ11: potassium voltage-gated channel subfamily J member 11; KCNQ1: potassium voltage-gated channel subfamily Q member 1; LEP: leptin; MMP2: matrix metalloproteinase 2; NFATc4: nuclear factor of activated T cells: cytoplasmic: calcineurin dependent 4; POR. P450 oxidoreductase; PPAR α, p eroxisome proliferator-activated receptor α; SLC30A8: solute carrier member 3 zinc transporter member 8; TCF7L2: transcription factor 7 like 2; TLR; toll-like receptor

However, most of these studies are underpowered and were conducted in relatively small populations. To overcome these limitations, alternative approaches such as genome-wide association studies (GWAS) and meta-analyses are performed. McCaughan et al. [2] performed GWAS with secondary validation. They reported 26 SNPs that were associated with PTDM, and the association was validated for 8 SNPs. These SNPs were associated with apoptosis of beta cells, and the authors suggested that beta cell dysfunction and death play a crucial role in the pathogenesis of PTDM. Benson et al. [6] conducted a comprehensive meta-analysis of 18 polymorphisms in 12 genes which were reported to be genetic markers of PTDM. Of these various polymorphisms, CDKAL1 rs10946398, KCNQ1 rs2237892, and TCF7L2 rs7903146 were significantly associated with PTDM (p < 0.05).

In conclusion, we demonstrated a significant association between LEPR polymorphisms and the development of PTDM in Korean renal transplant patients. Considering our present results and the above mentioned studies, genetic susceptibility plays an essential role in the pathogenesis of PTDM. Discovery of precise genetic polymorphisms that impact the development of PTDM is important to understanding its mechanisms and contributing to early diagnosis and proper management of the condition. Prospective, large-scale investigations that include assessment of the biological effects of gene polymorphisms are needed.

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  22. Lee, Sr., Moon JY, Lee SH, Ihm CG, Lee TW, et al. (2013) Angiotensinogen polymorphisms and post-transplantation diabetes mellitus in Korean renal transplant subjects. Kidney Blood Press Res 37: 95-102.
  23. Kim YG, Ihm CG, Lee TW, Lee SH, Jeong KH, et al. (2012) Association of genetic polymorphisms of interleukins with new-onset diabetes after transplantation in renal transplantation. Transplantation 93: 900-907.
  24. Ong S, Kang SW, Kim YH, Kim TH, Jeong KH, et al. (2016) Matrix Metalloproteinase Gene Polymorphisms and New-Onset Diabetes After Kidney Transplantation in Korean Renal Transplant Subjects. Transplant Proc 48: 858-863.
  25. Kim JS, Kim SK, Park JY, Kim YG, Moon JY, et al. (2016) Significant Association between Toll-Like Receptor Gene Polymorphisms and Posttransplantation Diabetes Mellitus. Nephron 133: 279-286.
  26. Nicoletto BB, Souza GC, Fonseca NK, Centenaro A, Manfro RC, et al. (2013) Association between 276G/T adiponectin gene polymorphism and new-onset diabetes after kidney transplantation. Transplantation 96: 1059-1064.
  27. Kurzawski M, Dziewanowski K, Kedzierska K, Gornik W, Banas A, et al. (2010) Association of calpain-10 gene polymorphism and posttransplant diabetes mellitus in kidney transplant patients medicated with tacrolimus. Pharmacogenomics J 10: 120-125.
  28. Dabrowska-Zamojcin E, Romanowski M, Dziedziejko V, Maciejewska-Karlowska A, Sawczuk M, et al. (2016) CCL2 gene polymorphism is associated with post-transplant diabetes mellitus. Int Immunopharmacol 32: 62-65. [Crossref]
  29. Kang ES, Kim MS, Kim CH, Nam CM, Han SJ, et al. (2009) Association of common type 2 diabetes risk gene variants and posttransplantation diabetes mellitus in renal allograft recipients in Korea. Transplantation 88: 693-698.
  30. Gervasini G, Luna E, Garcia-Cerrada M, Garcia-Pino G, Cubero JJ (2016) Risk factors for post-transplant diabetes mellitus in renal transplant: Role of genetic variability in the CYP450-mediated arachidonic acid metabolism. Mol Cell Endocrinol 419: 158-164.
  31. Dutkiewicz G, Domanski L, Pawlik A, Binczak-Kuleta A, Safranow K, et al. (2010) Polymorphisms of superoxide dismutase, glutathione peroxidase and catalase genes in patients with post-transplant diabetes mellitus. Arch Med Res 41: 350-355.
  32. Yang J, Hutchinson, II, Shah T, Min DI (2011) Genetic and clinical risk factors of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. Transplantation 91: 1114-1119.
  33. Romanowski M, Domanski L, Pawlik A, Osekowska B, Dziedziejko V, et al. (2015) Interleukin-17 gene polymorphisms in patients with post-transplant diabetes mellitus. Eur Rev Med Pharmacol Sci 19: 3152-3156. [Crossref]
  34. Tavira B, Coto E, Torres A, Diaz-Corte C, Diaz-Molina B, et al. (2012) Association between a common KCNJ11 polymorphism (rs5219) and new-onset posttransplant diabetes in patients treated with Tacrolimus. Mol Genet Metab 105: 525-527.
  35. Tavira B, Coto E, Díaz-Corte C, Ortega F, Arias M, et al. (2011) KCNQ1 gene variants and risk of new-onset diabetes in tacrolimus-treated renal-transplanted patients. Clin Transplant 25: E284-291. [Crossref]
  36. Chen Y, Sampaio MS, Yang JW, Min D, Hutchinson IV (2012) Genetic polymorphisms of the transcription factor NFATc4 and development of new-onset diabetes after transplantation in Hispanic kidney transplant recipients. Transplantation 93: 325-330.
  37. Elens L, Sombogaard F, Hesselink DA, van Schaik RH, van Gelder T (2013) Single-nucleotide polymorphisms in P450 oxidoreductase and peroxisome proliferator-activated receptor-alpha are associated with the development of new-onset diabetes after transplantation in kidney transplant recipients treated with tacrolimus. Pharmacogenet Genomics 23: 649-657.
  38. Kang ES, Kim MS, Kim YS, Kim CH, Han SJ, et al. (2008) A polymorphism in the zinc transporter gene SLC30A8 confers resistance against posttransplantation diabetes mellitus in renal allograft recipients. Diabetes 57: 1043-1047.
  39. Khan IA, Jahan P, Hasan Q, Rao P (2015) Validation of the association of TCF7L2 and SLC30A8 gene polymorphisms with post-transplant diabetes mellitus in Asian Indian population. Intractable Rare Dis Res 4: 87-92.
  40. Kang ES, Kim MS, Kim YS, Hur KY, Han SJ, et al. (2008) A variant of the transcription factor 7-like 2 (TCF7L2) gene and the risk of posttransplantation diabetes mellitus in renal allograft recipients. Diabetes Care 31: 63-68.
  41. Bamoulid J, Courivaud C, Deschamps M, Mercier P, Ferrand C, et al. (2006) IL-6 promoter polymorphism -174 is associated with new-onset diabetes after transplantation. J Am Soc Nephrol 17: 2333-2340. [Crossref]

Editorial Information

Editor-in-Chief

Article Type

Review Article

Publication history

Received date: January 15, 2017
Accepted date: January 26, 2017
Published date: January 30, 2017

Copyright

© 2017 Kim JS. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Citation

Kim JS, Ihm CG, Lee TW, Kim YG, Moon JY, et al. (2017) Association of leptin receptor gene polymorphisms with post-transplant diabetes mellitus: Short report and literature review Trends in Transplantation 2: DOI: 10.15761/TiT.1000221

Corresponding author

Kyung Hwan Jeong

Division of Nephrology, Department of Internal Medicine, School of Medicine, Kyung Hee University, #1 Hoeki-Dong, Dongdaemoon-Gu, Seoul, 130-702, Republic of Korea, Tel: +82-2-958-8200, Fax: +82-2-968-1848

Table 1. Clinical characteristics of the study population (PTDM vs. non-PTDM).

 

PTDM (n=54)

non-PTDM (n=247)

p

Follow-up duration (months)

91.54 ± 85.36

76.85 ± 75.49

0.208

Age (years)

45.17 ± 9.26

38.58 ± 11.20

<0.001

Sex (male: female)

 28:26

 155:92

0.137

BMI (kg/m2)

22.57 ± 3.39

22.47 ± 3.47

0.859

Dialysis duration (months)

33.20 ± 58.44

23.90 ± 34.09

0.336

HLA total mismatching (n)

3.10 ± 1.54

3.24 ± 1.53

0.512

HCV (+) (n, %)

0 (0%)

6 (2.36%)

0.244

Acute rejection (n, %)

13 (25.49%)

44 (17.32%)

0.197

Calcineurin inhibitor, n (%)

Tacrolimus

24 (45.3%)

74 (30.8%)

0.044

Cyclosporine

29 (53.7%)

166 (67.2%)

0.098

Antimetabolite, n (%)

Azathioprine

10 (18.5%)

72 (29.1%)

0.582

MMF

34 (62.9%)

165 (66.8%)

0.702

Serum creatinine (mg/dL)

     

At 6 months after transplantation

1.27 ± 0.56

1.32 ± 0.49

0.529

At 12 months after transplantation

1.29 ± 0.36

1.37 ± 0.87

0.507

PTDM: post-transplantation diabetes mellitus; BMI: body mass index; HLA: human leukocyte antigen; HCV: hepatitis C virus; MMF: mycophenolate mofetil

Table 2. Allele frequencies for 5 SNPs in the LEP and LEPR genes in PTDM and non-PTDM subjects.

Gene

SNP

Allele

PTDM n (%)

Non-PTDM n (%)

OR (95% CI)

p

LEP

rs2167270

G

91 (84.2%)

388 (78.5%)

0.68(0.39 - 1.19)

0.182

.

 

A

17 (15.8%)

106 (21.5%)

 

 

LEP

rs13228377

A

91 (84.2%)

380 (76.9%)

0.62(0.35 - 1.08)

0.094

.

 

G

17 (15.8%)

114 (23.1%)

 

 

 LEPR

rs8179183

G

97 (89.8%)

454 (91.9%)

1.28 (0.63- 2.59)

0.480

.

 

C

11 (10.2%)

40 (8.1%)

 

 

 LEPR

rs1137100

G

93 (86.1%)

377 (76.3%)

1.92 (1.02-1.19)

0.025

 

 

A

15 (13.9%)

117 (23.7%)

 

 

LEPR

rs1137101

G

101 (94%)

421 (85%)

1.13 (1.05-1.23)

0.019

 

 

A

7 (6%)

73 (15%)

 

 

SNPs: single nucleotide polymorphisms; PTDM: post-transplantation diabetes mellitus; LEP: leptin; LEPR: leptin receptor

Table 3. Logistic regression analysis of LEP and LEPR polymorphisms in PTDM and non-PTDM subjects adjusted for age, sex, and tacrolimus usage

Gene

SNP

Model

Type

PTDM, n (%)

Non-PTDM, n (%)

OR (95% CI)

p

LEP

rs2167270

Codominant

G/G

39 (72.2%)

147 (59.8%)

0.55 (0.27-1.11)

0.200

A/G

13 (24.1%)

92 (37.4%)

A/A

2 (3.7%)

7 (2.8%)

Dominant

G/G

39 (72.2%)

147 (59.8%)

0.60 (0.31-1.16)

0.12

A/G + A/A

15 (27.8%)

99 (40.2%)

Recessive

G/G+A/G

52 (96.3%)

239(97.2%)

1.58 (0.30-8.24)

0.60

A/A

2 (3.7%)

7 (2.8%)

rs13228377

Codominant

A/A

39 (72.2%)

142 (57.7%)

0.54 (0.27-1.08)

0.19

A/G

13 (24.1%)

94 (38.2%)

G/G

2 (3.7%)

10 (4.1%)

Dominant

A/A

39 (72.2%)

142 (57.7%)

0.55 (0.28-1.07)

0.073

A/G+G/G

15 (27.8%)

104 (42.3%)

Recessive

A/A+G/G

52 (96.3%)

236 (95.9%)

0.83 (0.17-4.09)

0.81

A/G

2 (3.7%)

10 (4.1%)

LEPR

rs8179183

Codominant

G/G

43 (79.6%)

207 (84.2%)

1.37 (0.63-2.97)

0.55

C/G

11 (20.4%)

38 (15.4%)

C/C

0 (0%)

1 (0.4%)

Dominant

G/G

43 (79.6%)

207 (84.2%)

1.32 (0.61-2.85)

0.44

C/G + C/C

11(20.4%)

39 (15.8%)

Recessive

G/G + C/G

54(100%)

245 (99.6%)

1.09 (0.48-2.47)

0.840

C/C

0 (0%)

1 (0.4%)

rs1137100

Codominant

G/G

40 (74.1%)

145 (58.9%)

0.55 (0.27-1.11)

0.09

A/G

13 (24.1%)

87 (35.4%)

A/A

1 (1.8%)

14 (5.7%)

Dominant

G/G

40 (74.1%)

145 (58.9%)

2.00 (1.02-3.93)

0.037

A/G+A/A

14 (25.9%)

101 (41.1%)

Recessive

G/G+A/G

53 (98.2%)

232 (94.3%)

1.61 (0.80-3.23)

0.17

A/A

1 (1.8%)

14 (5.7%)

rs1137101

Codominant

G/G

47 (87%)

179 (72.8%)

2.48 (1.05-5.87)

0.029

A/G

7 (13%)

62 (25.2%)

A/A

0 (0%)

5 (2%)

Dominant

G/G

47 (87%)

179 (72.8%)

2.69 (1.14-6.35)

0.014

A/G+A/A

7 (13%)

37 (27.2%)

Recessive

G/G+A/G

184 (74.8%)

47 (13%)

0.00 (0.00-NA)

0.17

A/A

0 (0%)

5 (2%)

PTDM: post-transplantation diabetes mellitus; SNPs: single nucleotide polymorphisms

Table 4. Previous candidate gene studies evaluating genetic susceptibility to PTDM in renal transplant recipients.

Gene

SNPs

Ethnicity

PTDM Case

Control

References

ADIPOQ

rs1501299

Asian (Korean)

154

421

Kang et al. [7]

rs1501299

Caucasian

83

187

Nicoletto et al. [26]

AGT

rs4762

Asian (Korean)

49

253

Lee et al. [22]

CAPN10

rs5030952

Caucasian

56

158

Kurzawski et al. [27]

CCL2

rs1024611

Caucasian

43

272

Dabrowska-Zamojcin et al. [28]

CCL5

rs2107538

Asian (Korean)

56

255

Jeong et al. [10]

rs2280789

Asian (Korean)

56

255

Jeong et al. [10]

rs3817655

Asian (Korean)

56

255

Jeong et al. [10]

CDKAL1

rs10946398

Asian (Korean)

145

444

Kang et al. [29]

CDKN2A/B

rs10811661

Asian (Korean)

145

444

Kang et al. [29]

CYP4F2

rs2108622

Caucasian

34

130

Gervasini et al. [30]

GPX1

rs1050450

Caucasian

21

138

Dutkiewicz et al. [31]

HHEX

rs1111875

Asian (Korean)

145

444

Kang et al. [29]

rs5015480

Asian (Korean)

145

444

Kang et al. [29]

rs7923837

Asian (Korean)

145

444

Kang et al. [29]

HNF4A

rs1884614

Hispanic

133

170

Yang et al. [32]

rs2144908

Hispanic

133

170

Yang et al. [32]

IL17E

rs1124053

Asian (Korean)

53

253

Kim et al. [23]

IL17F

rs763780

Caucasian

23

146

Romanowski et al. [33]

IL17RA

rs2229151

Asian (Korean)

53

253

Kim et al. [23]

rs4819554

Asian (Korean)

53

253

Kim et al. [23]

IL17RB

rs1025689

Asian (Korean)

53

253

Kim et al. [23]

rs1043261

Asian (Korean)

53

253

Kim et al. [23]

IL1B

rs3136558

Asian (Korean)

53

253

Kim et al. [23]

IL2

rs2069762

Asian (Korean)

53

253

Kim et al. [23]

rs2069763

Asian (Korean)

53

253

Kim et al. [23]

IL4

rs2070874

Asian (Korean)

53

253

Kim et al. [23]

rs2243250

Asian (Korean)

53

253

Kim et al. [23]

IL6

rs1800795

Caucasian

59

302

Bamoulid et al. [41]

IL7R

rs1494558

Asian (Korean)

53

253

Kim et al. [23]

rs2172749

Asian (Korean)

53

253

Kim et al. [22]

IRS1

rs1801278

Hispanic

133

170

Yang et al. [32]

KCNJ11

rs5219

Caucasian

115

205

Tavira et al. [34]

rs5210

Asian (Indian)

140

500

Khan et al. [9]

KCNQ1

rs2237892

Asian (Korean)

145

444

Kang et al. [29]

rs2237895

Caucasian

145

260

Tavira et al. [35]

rs2283228

Asian (Indian)

140

500

Khan et al. [9]

LEP

re2167270

Caucasian

43

280

Romanowski et al. [30]

MMP2

rs1132896

Asian (Korean)

52

257

Ong et al. [24]

rs243849

Asian (Korean)

52

257

Ong et al. [24]

NFATc4

rs10141896

Hispanic

162

157

Chen et al. [36]

POR

rs1057868

Caucasian

9

76

Elens et al. [37]

PPARα

rs4253728

Caucasian

9

76

Elens et al. [37]

SLC30A8

rs13266634

Asian (Korean)

174

450

Kang et al. [38]

rs13266634

Asian (Indian)

42

98

Khan et al. [39]

TCF7L2

rs7903146

Asian (Korean)

119

392

Kang et al. [40]

rs7903146

Caucasian

114

958

Ghisdal et al. [8]

rs7903146

Asian (Indian)

42

98

Khan et al. [39]

TLR4

rs1927914

Asian (Korean)

51

254

Kim et al. [25]

TLR6

rs1039559

Asian (Korean)

51

254

Kim et al. [25]

PTDM: post-transplantation diabetes mellitus; SNPs: single nucleotide polymorphisms; ADIPOQ: adiponectin; AGT: angiotensinogen; CAPN10: calpain-10 gene; CCL2: C-C motif chemokine ligand 2; CCL5: C-C motif chemokine ligand 5; CDKAL1 cyclin-dependent kinase 5 regulatory subunit-associated protein 1-like 1; CDKN2A/B: cyclin-dependent kinase inhibitor-2A/B; CYP4F2: cytochrome P450 family 4 subfamily F member 2; GPX1: glutathione peroxidase 1; HHEX: hematopoietically expressed homeobox; HNF4A: hepatocyte nuclear factor 4 alpha; IL: interleukin; IRS1: insulin receptor substrate 1; KCNJ11: potassium voltage-gated channel subfamily J member 11; KCNQ1: potassium voltage-gated channel subfamily Q member 1; LEP: leptin; MMP2: matrix metalloproteinase 2; NFATc4: nuclear factor of activated T cells: cytoplasmic: calcineurin dependent 4; POR. P450 oxidoreductase; PPAR α, p eroxisome proliferator-activated receptor α; SLC30A8: solute carrier member 3 zinc transporter member 8; TCF7L2: transcription factor 7 like 2; TLR; toll-like receptor