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

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.

Association of genetic variants of PD1 with recurrent pregnancy loss

“…Inhibition of IL‐2 production by the PD1/PDL1 pathway causes immune tolerance and the SNPs of PD1 have been shown to be related to the susceptibility to some diseases. In SLE, the A allele of rs11568821 (7146G/A) was significantly less frequent in Spanish female patients and the C allele of rs2227981 (7785C/T) was significantly higher in Indian SLE patients and Malay controls . In regard to RA susceptibility, the A allele of rs36084323 was associated with a decreased risk of developing RA .…”

“…In SLE, the A allele of rs11568821 (7146G/A) was significantly less frequent in Spanish female patients 20 and the C allele of rs2227981 (7785C/T) was significantly higher in Indian SLE patients and Malay controls. 21 In regard to RA susceptibility, the A allele of rs36084323 was associated with a decreased risk of developing RA. 18 In the present study, in contrast to the aforementioned effect on RA susceptibility, the A alleles of rs36084323 and rs34819629 were identified as risk factors for RPL.…”

“…In this study was examined the association with RPL of three SNPs of the PD1 gene, two SNPs of the PDL1 gene, and four SNPs of the CTLA4 gene by a univariate analysis in a case‐control study of Japanese women. Those SNPs that have been reported to date as showing an association with some diseases were chosen . As data on the combined effect of maternal age and genetic risk factors are still lacking, a cohort study also was conducted in order to examine, in relation to several factors, whether a subsequent pregnancy would result in further loss or a normal delivery.…”

“…These findings were further investigated in human autoimmune diseases and SNPs on the human PD1 gene were found to be linked with systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type I diabetes. 17 The haplotypes of PD1 have been shown to be associated with RA, 18,19 SLE, 20,21 and subacute sclerosing panencephalitis (SSPE) in the Japanese population. 22 PDL1 is expressed abundantly in the placenta, syncytiotrophoblast, and extravillous cytotrophoblast, both of which lie in direct contact with the maternal blood and tissue.…”

“…Those SNPs that have been reported to date as showing an association with some diseases were chosen. [18][19][20][21][22] As data on the combined effect of maternal age and genetic risk factors are still lacking, a cohort study also was conducted in order to examine, in relation to several factors, whether a subsequent pregnancy would result in further loss or a normal delivery. Furthermore, the expression levels of PDL1 in the decidual cells in cases of miscarriage were evaluated by immunohistochemistry and the association between PD1 SNPs and the expression level of the PD1 gene by expression quantitative trait locus (eQTL) analysis.…”