Next Article in Journal
Microfluidic Impedance Flow Cytometry Enabling High-Throughput Single-Cell Electrical Property Characterization
Next Article in Special Issue
Anti-NR2A/B Antibodies and Other Major Molecular Mechanisms in the Pathogenesis of Cognitive Dysfunction in Systemic Lupus Erythematosus
Previous Article in Journal
Changing the Face of Kynurenines and Neurotoxicity: Therapeutic Considerations
Previous Article in Special Issue
miRNAs in the Pathogenesis of Systemic Lupus Erythematosus
 
 
Search for Articles:
Title / Keyword
Author / Affiliation / Email
Journal
Article Type
 
 
Advanced Search
 
Section
Special Issue
Volume
Issue
Number
Page
 
Journals
IJMS
Volume 16
Issue 5
10.3390/ijms16059794
ijms-logo
Submit to this Journal Review for this Journal Propose a Special Issue
► Article Menu

Article Menu

share Share announcement Help format_quote Cite question_answer Discuss in SciProfiles thumb_up
...
Endorse textsms
...
Comment
first_page
settings
Order Article Reprints
Font Type:
Arial Georgia Verdana
Font Size:
Aa Aa Aa
Line Spacing:
Column Width:
Background:
Article

Association between PDCD1 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus in Three Main Ethnic Groups of the Malaysian Population

by
Kek Heng Chua
1,*,
Lay Hoong Lian
1,†,
Xiu Jia Sim
1,†,
Tien Eang Cheah
2,† and
Tze Pheng Lau
1,3
1
Department of Biomedical Science, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
2
Division of Rheumatology, Department of Medicine, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
3
Department of Pathology, Faculty of Medicine, University of Malaya, 50603 Kuala Lumpur, Malaysia
*
Author to whom correspondence should be addressed.
†
These authors contributed equally to this work.
Int. J. Mol. Sci. 2015, 16(5), 9794-9803; https://doi.org/10.3390/ijms16059794
Submission received: 10 February 2015 / Revised: 20 April 2015 / Accepted: 21 April 2015 / Published: 29 April 2015
(This article belongs to the Special Issue Molecular and Cellular Mechanisms in the Pathogenesis of Systemic Lupus Erythematosus)
Versions Notes

Abstract

:
The programmed cell death 1 (PDCD1) gene encodes for the PD-1 (programmed death 1) molecule, which negatively regulates self-reactive T- and B-cells in the maintenance of peripheral tolerance. A previous report had shown the development of lupus-like phenotypes in PD-1-deficient C57BL/6 mice, was suggestive to the role of PDCD1 in predisposing to systemic lupus erythematosus (SLE). Hence, we aimed to investigate the association between PDCD1 and SLE susceptibility in the Malaysian population. A TaqMan-based real-time PCR was employed to screen for PD1.1, PD1.3, PD1.5 and PD1.6 in both SLE and healthy control groups of 200 samples each. The observed frequency for PD1.5C/C genotype was significantly higher in Indian SLE patients and Malay controls (p < 0.01). On the other hand, the PD1.5C/T genotype might predispose the Malays to SLE, but confer a protective effect among the Indians (p < 0.01). The PD1.1, PD1.3 and PD1.6 were, however, not correlated to genetic predisposition of SLE in our Malaysian population. In conclusion, PD1.5 variant was significantly associated to SLE susceptibility in our Malaysian cohort. Our failure in replicating the association between other investigated PDCD1 variants and risk of getting SLE might due to ethnic and geographic variations in the distribution of these genetic variants.

1. Introduction

Systemic lupus erythematosus (SLE) is an autoimmune disease where the dysregulated T-cells activation, over-production of auto-antibodies and accumulation of immune complexes contribute to its phenotypes (e.g., photosensitivity, skin rashes, prolonged fatigue) and complications (e.g., lupus nephritis, coronary artery disease and osteoporosis) [1]. Worldwide, the SLE incidence is more prevalent among the Asians, Afro-Americans, Afro-Caribbeans and Hispanic Americans, than the Caucasians [2]. There also exists a sex difference in the prevalence of SLE where a ratio of seven women to men was reported [3]. In Malaysia, the prevalence of SLE varies among the three main ethnic groups, i.e., 57/100,000 for Chinese, 33/100,000 for Malays and 14/100,000 for Indians [4]. Over the past decades, the underlying genetic basis in the development of SLE was unraveled by numerous genetic linkage analyses and association studies [5].
In Malaysia, several potential SLE-predisposing candidate genes involved in immune functions, i.e., genes encode for chemokines, interleukins and their receptors, tumour necrosis factors, T-cell surface receptors, components of the classical complement cascade, as well as major histocompatibility complex have been previously studied [6,7,8,9,10,11,12,13,14,15,16,17]. Adding to this expanding list, our present study investigated the relationship between the programmed cell death 1 (PDCD1) gene and the development of SLE, which has not yet been reported in our Malaysian population. PDCD1 is mapped to chromosome 2q37.3 and encodes for PD-1 molecule, which is an immunoinhibitory receptor of the CD28/B7 family. This PD-1 receptor is inducibly expressed on the activated T- and B cells, as well as myeloid cells. It plays a crucial role in the regulation of peripheral tolerance which involves the inactivation or suppression of self-reactive T- and B-cells through the activation-induced cell death or allergy in preventing autoimmunity [18,19,20]. This was proven when the C57BL/6-PDCD1−/− mice presented with autoimmune features resembling to SLE, e.g., lupus-like glomerulonephritis with the deposition of IgG3 and C3, arthritis and splenomegaly [21,22].
Genetic association studies were performed in different populations, i.e., European, Caucasian, Mexican, European American, African American and Han Chinese, to examine the correlation between PDCD1 gene polymorphisms and SLE susceptibility [23,24,25,26,27]. Nevertheless, the causative role of PDCD1 gene remains inconclusive owing to inter-study heterogeneity in the SNP studied or allele involved [28]. We therefore, aimed to study four identified PDCD1 SNPs, i.e., PD1.1 (G>A; promoter region), PD1.3 (G>A; intron 4), PD1.5 (C>T; exon 5) and PD1.6 (G>A; 3'-UTR), in our Malaysian SLE cohort.

2. Results

All the genotypes of these biallelic polymorphisms were reported in our population, except PD1.3 which AA genotype was absent (Table 1). The observed genotype frequencies among the unaffected controls were conformed to the Hardy-Weinberg Equilibrium (p > 0.05). In this study, the allele and genotype frequencies of all PDCD1 SNPs were not significantly different between the SLE patient and control groups (p > 0.05) (Table 1). We also observed the absence of significant association between SLE and PD1.1, PD1.3, PD1.5 and PD1.6 SNPs, irrespective of the model of inheritance used.
Table
Table 1. Allele and genotype frequencies of programmed cell death 1 (PDCD1) single nucleotide polymorphisms (SNPs) among systemic lupus erythematosus (SLE) patients and healthy controls.
Table 1. Allele and genotype frequencies of programmed cell death 1 (PDCD1) single nucleotide polymorphisms (SNPs) among systemic lupus erythematosus (SLE) patients and healthy controls.
Allele/GenotypeFrequency, n (%)Fisher’s (p Value)OR (95% CI)
SLE PatientControl
PD1.1
A156 (39.0)157 (39.2)1.00000.9896 (0.7449–1.3145)
G244 (61.0)243 (60.8)
AA37 (18.5)36 (18.0)1.00001.0341 (0.623–1.718)
AG82 (41.0)85 (42.5)0.83930.9402 (0.632–1.399)
GG81 (40.5)79 (39.5)0.91871.0425 (0.699–1.555)
PD1.3
A2 (0.5)2 (0.5)1.00001.0000 (0.1402–7.1343)
G398 (99.5)398 (99.5)
AA0 (0)0 (0)1.0000-
AG2 (1.0)2 (1.0)1.00001.0000 (0.140–7.170)
GG198 (99.0)198 (99.0)1.00001.0000 (0.140–7.170)
PD1.5
C273 (68.2)276 (69.0)0.87890.9658 (0.7164–1.3019)
T127 (31.8)124 (31.0)
CC88 (44.0)90 (45.0)0.91990.9603 (0.647–1.425)
CT97 (48.5)96 (48.0)1.00001.0202 (0.689–1.510)
TT15 (7.5)14 (7.0)1.00001.0772 (0.506–2.295)
PD1.6
A228 (57.0)216 (54.0)0.43391.1292 (0.8543–1.4926)
G172 (43.0)184 (46.0)
AA72 (36.0)61 (30.5)0.28851.2818 (0.845–1.945)
AG84 (42.0)94 (47.0)0.36520.8166 (0.550–1.212)
GG44 (22.0)45 (22.5)1.00000.9715 (0.606–1.556)
Further analysis was performed by stratifying our study cohort into three ethnic groups, i.e., Chinese, Malays and Indians. No relationship was observed between PD1.1, PD1.3 and PD1.6 polymorphisms, and SLE susceptibility in either of the ethnic groups (p > 0.05) (Table 2). However, statistically significant difference in genotype frequency of PD1.5 between SLE patients and healthy controls was observed in both Malay and Indian groups (p < 0.01) (Table 2). Table 3 shows the association analysis of different models of inheritance for PD1.5 and SLE among the Malays and Indians. The association between PD1.5 and SLE was statistically significant with a p value of 0.0003 and OR of 3.50 (95% CI = 1.74–7.05) under the best-fitting over-dominant model among the Malays (Table 3). On the other hand, the Indian group showed a significant inverse association between PD1.5 and SLE under the best-fitting over-dominant model (p < 0.0001) (Table 3).
Table
Table 2. Genotype frequencies of PDCD1 SNPs among SLE patients and healthy controls of different ethnics.
Table 2. Genotype frequencies of PDCD1 SNPs among SLE patients and healthy controls of different ethnics.
SNPGenotype Frequency, n
ChineseMalayIndian
SLEControlp ValueSLEControlp ValueSLEControlp Value
PD1.1
AA2828ns87ns10ns
AG5353273320
GG343435301215
PD1.3
AA00ns00ns00ns
AG001111
GG11511569691414
PD1.5
CC5646ns25440.0022700.0063
CT496042210.00066150.0007
TT10935ns20ns
PD1.6
AA5247ns1814ns20ns
AG4955333524
GG141319211111
ns: Non-significant; p value in bold: significant.
Table
Table 3. Inheritance model analysis of PD1.5 and SLE in Malay and Indian groups.
Table 3. Inheritance model analysis of PD1.5 and SLE in Malay and Indian groups.
Inheritance ModelGenotypeMalayIndian
OR (95% CI)p ValueAICOR (95% CI)p ValueAIC
DominantC/C1.000.0012187.61.000.000633.7
C/T-T/T3.05 (1.53–6.06)0.00 (0.00–NA)
RecessiveC/C-C/T1.000.46197.51.000.08842.7
T/T0.58 (0.13–2.54)NA (0.00–NA)
Co-dominantC/C1.000.0015187.11.000.000331.1
C/T3.52 (1.72–7.22)0.00 (0.00–NA)
T/T1.06 (0.23–4.80)1.00 (0.00–NA)
Over-dominantC/C-T/T1.000.0003185.11.00<0.000129.1
C/T3.50 (1.74–7.05)0.00 (0.00–NA)
Log-additive-2.01 (1.12–3.58)0.016192.30.25 (0.05–1.31)0.07142.3
p Value in bold: significant; AIC: Akaike Information Criterion; NA: not applicable.

3. Discussion

Genome wide linkage scanning for SLE susceptibility loci in Icelandic and Swedish families had revealed a favourable linkage to the long arm of chromosome 2 at 2q37 [29]. The new susceptibility locus for SLE, SLEB2, was then identified via further mapping in a combined set of Nordic families (Icelandic, Swedish and Norwegian) [30]. In view of the biological role of PD-1 in the regulation of peripheral tolerance, the PDCD1 gene that is located within this locus might serve as a potential predisposing gene to SLE. The interaction between PD-1 and its ligands, PD-L, was found to negatively co-stimulate and attenuate the auto-reactive T- and B-cells through the inhibition of cytokine production and cell cycle arrest in G0/G1 phase [31]. The deficiency of PDCD1 gene expression had been proven in vivo to result in inadequate auto-reactive lymphocytes removal and auto-antibodies production [22,31,32]. It was thus evidenced that the PD-1-PD-L pathway is pivotal in maintaining peripheral self-tolerance and preventing autoimmune diseases, e.g., SLE [20].
In our multiethnic sample cohort, the similar distribution of allele and genotype frequencies for PDCD1 polymorphisms were observed in both SLE and control groups. Our findings corresponded well with three earlier reports on Taiwanese and Caucasian SLE patients, where the efforts to demonstrate the association between PDCD1 gene and SLE susceptibility were failed [33,34,35]. However, statistically significant association was reported for PD1.5 following further sample stratification of our Malaysian cohort into different ethnic groups. Our association analysis revealed that the PD1.5C/T genotype was significantly associated to SLE susceptibility in Malays with a 3.5-fold increased risk compared to the homozygotes when the over-dominant model was assumed. On the other hand, the heterozygous genotype of this exonic polymorphism was significantly correlated to the Indian healthy controls under the same inheritance model. These differences in SNP association to disease in different ethnics revealed a possible interaction with other genetic or environmental factor in determining the predisposition to SLE [36]. In a study by Lee et al. (2009) [28], the relationship between PD1.5C allele and SLE susceptibility was also established among the Europeans.
Of all, the PD1.3 is the most extensively investigated. The PD1.3 G to A substitution was demonstrated to abolish the binding of the runt-related transcription factor 1 (RUNX-1) by altering its binding site. This disruption in PDCD1 transcription will lead to the hyperactivity of self-reactive lymphocytes and subsequent breakdown of peripheral tolerance. Further evidences had shown the correlation between PD1.3A allele and a decreased expression of PD-1 receptor in SLE patients [23,37]. In addition, the relationship of PD1.3 variant and the surface level of PD-1 receptor on activated CD4+CD25+ T cells also grounded its functional involvement in SLE. These regulatory T cells are crucial in maintaining our body’s self-tolerance by curbing the hazardous activities of self-reactive T cells [37,38].
Despite its strong functional grounds, the association between this intronic polymorphism and SLE was failed to address with sufficient consistency. Prokunina et al. and Sanchez et al. had demonstrated the association between PD1.3A allele and SLE susceptibility in the European, Mexican, Swedish and Argentine cohorts [23,26,39]. On the contrary, a protective effect of PD1.3A allele on SLE was reported among the Spanish cohort [19]. This variant however, was not associated to SLE in our Malaysian population, as well as previously reported northern Sweden, U.S. and Polish cohorts [40,41,42]. Our failure in replicating this relationship might be due to the relatively low minor allele frequency of PD1.3 variant in our population (0.5%) compared to the Europeans (13%) [43]. Hence, the possibility for the minor allele of PD1.3 to be an important predisposing variant in SLE was excluded owing to its extreme rarity in populations of non-European descent, e.g., 0.008% in Asians [24].

4. Experimental Section

4.1. Study Subjects

Our study cohort was comprised of three main ethnics of the Malaysian population, i.e., Malays, Chinese and Indians. A total of 200 SLE patients admitted to the University Malaya Medical Centre (UMMC), Kuala Lumpur, Malaysia were volunteered for this case-control association study. Two hundred age- and race-matched healthy individuals were also recruited in the control group. The study protocol was approved by the Medical Ethics Committee (Ref. No. 380.1), and written informed consent was also obtained from the study participants.

4.2. Genotyping of PDCD1 Polymorphisms

Venous blood samples were collected and genomic DNA was extracted with a similar DNA extraction approach as reported previously [44,45,46]. Next, the genotyping of PDCD1 variants was performed via real-time polymerase chain reaction (PCR) using pre-designed TaqMan SNP Genotyping Assays on an Applied Biosystems (Foster City, CA, USA) 7500 Fast Real-Time PCR System (Table 4). The real-time PCR was conducted under universal thermal cycling conditions: denaturation step at 95 °C for 20 s, followed by 40 cycles of denaturation step at 95 °C for 3 s and annealing/extension step at 60 °C for 30 s. The singleplex PCR reaction mixture consists of 5 μL of 2× TaqMan GTXpress master mix, 0.5 μL of 20× pre-designed TaqMan SNP Genotyping Assay, 1 μL of 20 ng/μL DNA template, and deionized water in a total reaction volume of 10 μL.
Table
Table 4. Pre-designed TaqMan SNP Genotyping Assays for genotyping of PDCD1 genetic variants.
Table 4. Pre-designed TaqMan SNP Genotyping Assays for genotyping of PDCD1 genetic variants.
SNPAssay ID for Pre-Designed TaqMan SNP Genotyping Assay
PD1.1C_57931321_10 ([V]: Allele G; [F]: Allele A)
PD1.3C_57931290_10 ([V]: Allele G; [F]: Allele A)
PD1.5C_57931286_20 ([V]: Allele T; [F]: Allele C)
PD1.6C_172862_10 ([V]: Allele G; [F]: Allele A)
[V]: VIC-Probe; [F]: 6-FAM-Probe.

4.3. Statistical Analysis

Allele and genotype frequencies of the studied PDCD1 SNPs were determined in both SLE and healthy control groups, and subgroup analyses were performed following ethnic stratification. The observed genotype frequencies were tested for concordance to Hardy-Weinberg Equilibrium (HWE) by using a Chi-squared (χ2) test. The Fisher’s Exact Test was used to assess the significance of the differences in observed allele and genotype frequencies between the diseased and control group. Odds ratio (OR) with 95% confidence interval (CI) was also determined. The SNP association to SLE was measured on (i) dominant model; (ii) recessive model; (iii) co-dominant model; (iv) over-dominant model; and (v) log-additive model. The Akaike Information Criterion (AIC) was calculated to determine the best-fit model of inheritance.

5. Conclusions

Of all the investigated PDCD1 variants, only PD1.5 was significantly associated to the genetic predisposition to SLE in our Malaysian population. The remarkable ethnic and geographic variations in the distribution of PDCD1 variants might explain the discordant findings related to its contribution in SLE susceptibility. On the other hand, the lack of consistent association between PDCD1 gene and SLE in different population background might rule out its direct involvement in disease predisposition, implying instead a possible gene-environment interaction.

Acknowledgments

This research was supported by Fundamental Research Grant Scheme, FP073/2010B.

Author Contributions

Kek Heng Chua, Lay Hoong Lian and Tien Eang Cheah conceived and designed the experiments; Xiu Jia Sim and Tze Pheng Lau performed the experiments and analysed the data; All authors were involved in drafting and approving the final manuscript.

Conflicts of Interest

The authors declare no conflict of interest.

References

  1. Isenberg, D.; Manzi, S. Lupus, 1st ed.; Oxford University Press: New York, NY, USA, 2008. [Google Scholar]
  2. Wallace, D.J.; Hahn, B.; Dubois, E.L. Dubois’ Lupus Erythematosus, 7th ed.; Lippincott Williams & Wilkins: Philadelphia, PA, USA, 2007. [Google Scholar]
  3. Manzi, S. Epidemiology of systemic lupus erythematosus. Am. J. Manag. Care 2001, 7, 474–479. [Google Scholar]
  4. Wang, F.; Wang, C.L.; Tan, C.T.; Manivasagar, M. Systemic lupus erythematosus in Malaysia: A study of 539 patients and comparison of prevalence and disease expression in different racial and gender groups. Lupus 1997, 6, 248–253. [Google Scholar] [CrossRef] [PubMed]
  5. Harley, J.B.; Kelly, J.A.; Kaufman, K.M. Unraveling the genetics of systemic lupus erythematosus. Springer Semin. Immunopathol. 2006, 28, 119–130. [Google Scholar] [CrossRef] [PubMed]
  6. Puah, S.M.; Lian, L.H.; Chew, C.H.; Chua, K.H.; Tan, S.Y. A study of association of the complement C4 mutations with systemic lupus erythematosus in the Malaysian population. Lupus 2007, 16, 750–754. [Google Scholar] [CrossRef] [PubMed]
  7. Chew, C.H.; Chua, K.H.; Lian, L.H.; Puah, S.M. PCR-RFLP genotyping of C1q mutations and single nucleotide polymorphisms in Malaysian patients with systemic lupus erythematosus. Hum. Biol. 2008, 80, 83–93. [Google Scholar] [CrossRef] [PubMed]
  8. Chua, K.H.; Kee, B.P.; Tan, S.Y.; Lian, L.H. Genetic polymorphisms of interleukin-4 third intron region in the Malaysian patients with systemic lupus erythematosus. J. Med. Sci. 2008, 8, 437–442. [Google Scholar] [CrossRef]
  9. Chua, K.H.; Lau, T.P.; Foo, C.T.; Tan, S.Y.; Lian, L.H. Genetic polymorphisms of the TNF-α and TNF-β genes in Malaysian SLE patients. Int. J. Biomed. Pharm. Sci. 2008, 2, 28–33. [Google Scholar]
  10. Lau, T.P.; Lian, L.H.; Puah, S.M.; Chew, C.H.; Tan, S.Y.; Chua, K.H. Lack of association between CD28 IVS3 +17T/C SNP and the susceptibility to SLE in the Malaysian population. AsPac. J. Mol. Biol. Biotechnol. 2008, 16, 85–88. [Google Scholar]
  11. Lau, T.P.; Lian, L.H.; Tan, S.Y.; Chua, K.H. VNTR polymorphisms of the IL-1RN gene: IL-1RN*1 allele and the susceptibility of SLE in the Malaysian population. Int. J. Biomed. Pharm. Sci. 2008, 2, 34–37. [Google Scholar]
  12. Chua, K.H.; Kee, B.P.; Tan, S.Y.; Lian, L.H. Interleukin-6 promoter polymorphisms (−174G/C) in Malaysian patients with systemic lupus erythematosus. Braz. J. Med. Biol. Res. 2009, 42, 551–555. [Google Scholar] [CrossRef] [PubMed]
  13. Chua, K.H.; Lau, T.P.; Tee, Z.Y.; Tan, S.Y.; Lian, L.H. Genetic polymorphisms of the interleukin-1β (IL-1β) −511 and +3954 single nucleotide polymorphisms (SNPs) in Malaysian systemic lupus erythematosus (SLE) patients. J. Health Sci. 2009, 55, 657–662. [Google Scholar] [CrossRef]
  14. Chua, K.H.; Puah, S.M.; Chew, C.H.; Tan, S.Y.; Lian, L.H. Study of the CTLA-4 gene polymorphisms in systemic lupus erythematosus (SLE) samples from Malaysia. Ann. Hum. Biol. 2010, 37, 274–280. [Google Scholar] [CrossRef] [PubMed]
  15. Lian, L.H.; Kee, B.P.; Ng, H.L.; Chua, K.H. Lack of association between RANTES-28, SDF-1 gene polymorphisms and systemic lupus erythematosus in the Malaysian population. Genet. Mol. Res. 2011, 10, 2841–2850. [Google Scholar] [CrossRef] [PubMed]
  16. Lian, L.H.; Ching, A.S.; Chong, Z.Y.; Chua, K.H. Complement components 2 and 7 (C2 and C7) gene polymorphisms are not major risk factors for SLE susceptibility in the Malaysian population. Rheumatol. Int. 2012, 32, 3665–3668. [Google Scholar] [CrossRef] [PubMed]
  17. Chai, H.C.; Phipps, M.E.; Othman, I.; Tan, L.P.; Chua, K.H. HLA variants rs9271366 and rs9275328 are associated with systemic lupus erythematosus susceptibility in Malays and Chinese. Lupus 2013, 22, 198–204. [Google Scholar] [CrossRef] [PubMed]
  18. Shinohara, T.; Taniwaki, M.; Ishida, Y.; Kawaichi, M.; Honjo, T. Structure and chromosomal localization of the human PD-1 gene (PDCD1). Genomics 1994, 23, 704–706. [Google Scholar] [CrossRef] [PubMed]
  19. Ferreiros-Vidal, I.; Gomez-Reino, J.J.; Barros, F.; Carracedo, A.; Carreira, P.; Gonzalez-Escribano, F.; Liz, M.; Martin, J.; Ordi, J.; Vicario, J.L.; et al. Association of PDCD1 with susceptibility to systemic lupus erythematosus: Evidence of population-specific effects. Arthritis Rheumatol. 2004, 50, 2590–2597. [Google Scholar] [CrossRef]
  20. Okazaki, T.; Wang, J. PD-1/PD-L pathway and autoimmunity. Autoimmunity 2005, 38, 353–357. [Google Scholar] [CrossRef] [PubMed]
  21. Nishimura, H.; Minato, N.; Nakano, T.; Honjo, T. Immunological studies on PD-1 deficient mice: Implication of PD-1 as a negative regulator for B cell responses. Int. Immunol. 1998, 10, 1563–1572. [Google Scholar] [CrossRef] [PubMed]
  22. Nishimura, H.; Nose, M.; Hiai, H.; Minato, N.; Honjo, T. Development of lupus-like autoimmune diseases by disruption of the PD-1 gene encoding an ITIM motif-carrying immunoreceptor. Immunity 1999, 11, 141–151. [Google Scholar] [CrossRef] [PubMed]
  23. Prokunina, L.; Castillejo-Lopez, C.; Öberg, F.; Gunnarsson, I.; Berg, L.; Magnusson, V.; Brookes, A.J.; Tentler, D.; Kristjansdottir, H.; Grondal, G.; et al. A regulatory polymorphism in PDCD1 is associated with susceptibility to systemic lupus erythematosus in humans. Nat. Genet. 2002, 32, 666–669. [Google Scholar] [CrossRef] [PubMed]
  24. Thorburn, C.M.; Prokunina-Olsson, L.; Sterba, K.A.; Lum, R.F.; Seldin, M.F.; Alarcon-Riquelme, M.E.; Criswell, L.A. Association of PDCD1 genetic variation with risk and clinical manifestations of systemic lupus erythematosus in a multiethnic cohort. Genes Immun. 2007, 8, 279–287. [Google Scholar] [CrossRef] [PubMed]
  25. Wang, Q.; Ye, D.; Yin, J.; Li, X.; Zhang, G.; Zhang, Y.; Zhang, X. Programmed cell death 1 genotypes are associated with susceptibility to systemic lupus erythematosus among Chinese. Arch. Dermatol. Res. 2008, 300, 91–93. [Google Scholar] [CrossRef] [PubMed]
  26. Sanchez, E.; Webb, R.D.; Rasmussen, A.; Kelly, J.A.; Riba, L.; Kaufman, K.M.; Garcia-de la Torre, I.; Moctezuma, J.F.; Maradiaga-Cecena, M.A.; Cardiel-Rios, M.H.; et al. Genetically determined Amerindian ancestry correlates with increased frequency of risk alleles for systemic lupus erythematosus. Arthritis Rheumatol. 2010, 62, 3722–3729. [Google Scholar] [CrossRef]
  27. Sanchez, E.; Comeau, M.E.; Freedman, B.I.; Kelly, J.A.; Kaufman, K.M.; Langefeld, C.D.; Brown, E.E.; Alarcon, G.S.; Kimberly, R.P.; Edberg, J.C.; et al. Identification of novel genetic susceptibility loci in African American lupus patients in a candidate gene association study. Arthritis Rheumatol. 2011, 63, 3493–3501. [Google Scholar] [CrossRef] [Green Version]
  28. Lee, Y.H.; Woo, J.H.; Choi, S.J.; Ji, J.D.; Song, G.G. Association of programmed cell death 1 polymorphisms and systemic lupus erythematosus: A meta-analysis. Lupus 2009, 18, 9–15. [Google Scholar] [CrossRef] [PubMed]
  29. Lindqvist, A.K.B.; Steinsson, K.; Johanneson, B.; Kristjansdottir, H.; Arnasson, A.; Grondal, G.; Jonasson, I.; Magnusson, V.; Sturfelt, G.; Truedsson, L.; et al. A susceptibility locus for human systemic lupus erythematosus (hSLE1) on chromosome 2q. J. Autoimmun. 2000, 14, 169–178. [Google Scholar] [CrossRef] [PubMed]
  30. Magnusson, V.; Lindqvist, A.K.; Castillejo-Lopez, C.; Kristjansdottir, H.; Steinsson, K.; Grondal, G.; Sturfelt, G.; Truedsson, L.; Svenungsson, E.; Lundberg, I.; et al. Fine mapping of the SLEB2 locus involved in susceptibility to systemic lupus erythematosus. Genomics 2000, 70, 307–314. [Google Scholar] [CrossRef] [PubMed]
  31. Carter, L.; Fouser, L.A.; Jussif, J.; Fitz, L.; Deng, B.; Wood, C.R.; Collins, M.; Honjo, T.; Freeman, G.J.; Carreno, B.M. PD-1: PD-L inhibitory pathway affects both CD4+ and CD8+ T cells and is overcome by IL-2. Eur. J. Immunol. 2002, 32, 634–643. [Google Scholar] [CrossRef] [PubMed]
  32. Wang, J.; Yoshida, T.; Nakaki, F.; Hiai, H.; Okazaki, T.; Honjo, T. Establishment of NOD-PDCD1−/− mice as an efficient animal model of type I diabetes. Proc. Natl. Acad. Sci. USA 2005, 102, 11823–11828. [Google Scholar] [CrossRef] [PubMed]
  33. Lin, S.C.; Yen, J.H.; Tsai, J.J.; Tsai, W.C.; Ou, T.T.; Liu, H.W.; Chen, C.J. Association of a programmed death 1 gene polymorphism with the development of rheumatoid arthritis, but not systemic lupus erythematosus. Arthritis Rheumatol. 2004, 50, 770–775. [Google Scholar] [CrossRef]
  34. Nielsen, C.; Laustrup, H.; Voss, A.; Junker, P.; Husby, S.; Lillevang, S.T. A putative regulatory polymorphism in PD-1 is associated with nephropathy in a population-based cohort of systemic lupus erythematosus patients. Lupus 2004, 13, 510–516. [Google Scholar] [CrossRef] [PubMed]
  35. Wang, S.C.; Chen, Y.J.; Ou, T.T.; Wu, C.C.; Tsai, W.C.; Liu, H.W.; Yen, J.H. Programmed death-1 gene polymorphisms in patients with systemic lupus erythematosus in Taiwan. J. Clin. Immunol. 2006, 26, 506–511. [Google Scholar] [CrossRef] [PubMed]
  36. Ferreiros-Vidal, I.; D’ Alfonso, S.; Papasteriades, C.; Skopouli, F.N.; Marchini, M.; Scorza, R.; Migliaresi, S.; Sebastiani, G.D.; Endreffy, E.; Mavromati, M.; et al. Bias in association studies of systemic lupus erythematosus susceptibility due to geographical variation in the frequency of a programmed cell death 1 polymorphism across Europe. Genes Immun. 2007, 8, 138–146. [Google Scholar] [CrossRef] [PubMed]
  37. Kristjansdottir, H.; Steinsson, K.; Gunnarsson, I.; Gröndal, G.; Erlendsson, K.; Alarcón-Riquelme, M.E. Lower expression levels of the programmed death 1 receptor on CD4+CD25+ T cells and correlation with the PD-1.3A genotype in patients with systemic lupus erythematosus. Arthritis Rheumatol. 2010, 62, 1702–1711. [Google Scholar] [CrossRef]
  38. Bennett, F.; Luxenberg, D.; Ling, V.; Wang, I.M.; Marguette, K.; Lowe, D.; Khan, N.; Veldman, G.; Jacobs, K.A.; Valge-Archer, V.E.; et al. Program death-1 engagement upon TCR activation has distinct effects on costimulation and cytokine-driven proliferation: Attenuation of ICOS, IL-4 and IL-21, but not CD28, IL-7 and IL-15 responses. J. Immunol. 2003, 170, 711–718. [Google Scholar] [CrossRef] [PubMed]
  39. Prokunina, L.; Gunnarsson, I.; Sturfelt, G.; Truedsson, L.; Seligman, V.A.; Seldin, M.F.; Criswell, L.A.; Alarcon-Riguelme, M.E. The systemic lupus erythematosus-associated PDCD1 polymorphism PD1.3A in lupus nephritis. Arthritis Rheumatol. 2004, 50, 327–333. [Google Scholar] [CrossRef]
  40. Sanghera, D.K.; Manzi, S.; Bontempo, F.; Nestlerode, C.; Kamboh, M.I. Role of an intronic polymorphism in the PDCD1 gene with the risk of sporadic systemic lupus erythematosus and the occurrence of antiphospholipid antibodies. Hum. Genet. 2004, 115, 393–398. [Google Scholar] [CrossRef] [PubMed]
  41. Johansson, M.; Arlestig, L.; Moller, B.; Rantapaa-Dahlqvist, S. Association of a PDCD1 polymorphism with renal manifestations in systemic lupus erythematosus. Arthritis Rheumatol. 2005, 52, 1665–1669. [Google Scholar] [CrossRef]
  42. Mostowska, M.; Wudarski, M.; Chwalinska-Sadowska, H.; Jagodzinski, P.P. The programmed cell death 1 gene 7209C>T polymorphism is associated with the risk of systemic lupus erythematosus in the Polish population. Clin. Exp. Rheumatol. 2008, 26, 457–460. [Google Scholar] [PubMed]
  43. </i>Mori, M.; Yamada, R.; Kobayashi, K.; Kawaida, R.; Yamamoto, K. Ethnic differences in allele frequency of autoimmune-disease-associated SNPs. J. Hum. Genet. 2005, 50, 264–266. [Google Scholar] [CrossRef] [PubMed]
  44. Chua, K.H.; Puah, S.M.; Chew, C.H.; Wong, C.H.; Goh, K.L. Interaction between a novel intronic IVS3+172 variant and N29I mutation in PRSS1 gene is associated with pancreatitis in a Malaysian Chinese family. Pancreatology 2011, 11, 441–444. [Google Scholar] [CrossRef] [PubMed]
  45. Tan, J.A.M.A.; Lee, P.C.; Wee, Y.C.; Tan, K.L.; Mahali, N.F.; George, E.; Chua, K.H. High prevalence of α and β-thalassemia in the Kadazandusuns in East Malaysia: Challenges in providing effective health care for an indigenous group. J. Biomed. Biotechnol. 2010. [Google Scholar] [CrossRef]
  46. Ng, Z.X.; Kuppusamy, U.R.; Tajunisah, I.; Fong, K.C.S.; Koay, A.C.A.; Chua, K.H. 2245G/A polymorphism of the receptor for advanced glycation end-products (RAGE) gene is associated with diabetic retinopathy in the Malaysian population. Br. J. Ophthalmol. 2012, 96, 289–292. [Google Scholar] [CrossRef] [PubMed]

Share and Cite

MDPI and ACS Style

Chua, K.H.; Lian, L.H.; Sim, X.J.; Cheah, T.E.; Lau, T.P. Association between PDCD1 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus in Three Main Ethnic Groups of the Malaysian Population. Int. J. Mol. Sci. 2015, 16, 9794-9803. https://doi.org/10.3390/ijms16059794

AMA Style

Chua KH, Lian LH, Sim XJ, Cheah TE, Lau TP. Association between PDCD1 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus in Three Main Ethnic Groups of the Malaysian Population. International Journal of Molecular Sciences. 2015; 16(5):9794-9803. https://doi.org/10.3390/ijms16059794

Chicago/Turabian Style

Chua, Kek Heng, Lay Hoong Lian, Xiu Jia Sim, Tien Eang Cheah, and Tze Pheng Lau. 2015. "Association between PDCD1 Gene Polymorphisms and Risk of Systemic Lupus Erythematosus in Three Main Ethnic Groups of the Malaysian Population" International Journal of Molecular Sciences 16, no. 5: 9794-9803. https://doi.org/10.3390/ijms16059794

Article Metrics

Back to TopTop