Research Article: Association of protein tyrosine phosphatase non-receptor type 22 gene functional variant C1858T, HLA-DQ/DR genotypes and autoantibodies with susceptibility to type-1 diabetes mellitus in Kuwaiti Arabs

Date Published: June 20, 2018

Publisher: Public Library of Science

Author(s): Mohammad Z. Haider, Majedah A. Rasoul, Maria Al-Mahdi, Hessa Al-Kandari, Gursev S. Dhaunsi, Petr Heneberg.

http://doi.org/10.1371/journal.pone.0198652

Abstract

The incidence of type-1 Diabetes Mellitus (T1DM) has increased steadily in Kuwait during recent years and it is now considered amongst the high-incidence countries. An interaction between susceptibility genes, immune system mediators and environmental factors predispose susceptible individuals to T1DM. We have determined the prevalence of protein tyrosine phosphatase non-receptor type 22 (PTPN22) gene functional variant (C1858T; R620W, rs2476601), HLA-DQ and DR alleles and three autoantibodies in Kuwaiti children with T1DM to evaluate their impact on genetic predisposition of the disease. This study included 253 Kuwaiti children with T1DM and 214 ethnically matched controls. The genotypes of PTPN22 gene functional variant C1858T (R620W; rs2476601) were detected by PCR-RFLP method and confirmed by DNA sequencing. HLA-DQ and DR alleles were determined by sequence-specific PCR. Three autoantibodies were detected in the T1DM patients using radio-immunoassays. A significant association was detected between the variant genotype of the PTPN22 gene (C1858T, rs2476601) and T1DM in Kuwaiti Arabs. HLA-DQ2 and DQ8 alleles showed a strong association with T1DM. In T1DM patients which carried the variant TT-genotype of the PTPN22 gene, 93% had at least one DQ2 allele and 60% carried either a DQ2 or a DQ8 allele. Amongst the DR alleles, the DR3-DRB5, DR3-3, DR3-4 and DR4-4 showed a strong association with T1DM. Majority of T1DM patients who carried homozygous variant (TT) genotype of the PTPN22 gene had either DR3-DRB5 or DRB3-DRB4 genotypes. In T1DM patients who co-inherited the high risk HLA DQ, DR alleles with the variant genotype of PTPN22 gene, the majority were positive for three autoantibodies. Our data demonstrate that the variant T-allele of the PTPN22 gene along with HLA-DQ2 and DQ8 alleles constitute significant determinants of genetic predisposition of T1DM in Kuwaiti children.

Partial Text

Type 1 diabetes mellitus (T1DM) has a multifactorial etiology and is considered to result from T cell-mediated beta-cell destruction in pancreas of the genetically susceptible individuals. The incidence rate of T1DM has increased rapidly in the Arabian Gulf region and globally is predicted to double in children under 5 years of age by 2020 [1]. It has been suggested that T1DM is caused by an autoimmune process involving both genetic and environmental factors and results in the destruction of insulin-producing pancreatic beta cells [2]. The genetic component to T1DM onset has been studied extensively during the last few decades [3]. These studies showed human leukocyte antigen (HLA) region as the main locus associated with T1DM susceptibility [3–4]. By using various approaches, >60 loci have been identified which are involved in genetic susceptibility to T1DM [2, 5–12]. In many of these ‘susceptibility loci’, the underlying causative genes, and/or the molecular mechanism by which they confer susceptibility are not yet known. In spite of rapid progress made by the genetic association studies, much remain to be elucidated about contribution of the susceptibility loci in different populations/ethnic groups.

This study included 253 newly diagnosed T1DM patients which were recruited from three major hospitals (Mubarak Al-Kabeer, Adan and Farwania). A sub-set of T1DM patients from this report had been included in our earlier study on the serum Vitamin D status in T1DM patients [45]. The details of patient diagnosis and recruitment have been described previously and was based on the criteria recommended in ISPAD protocol [46–47]. The information on gender, age and other characteristics of the study subjects has been presented in Table 1. The T1DM patient group was divided into three sub-groups on the basis of age-of-onset of the disease 0-4y, 4-6y and 6-14y as previously reported [47]. HbA1c was used to determine the glycemic status of the study subjects. In the T1DM patient group, 194/253 (77%) had their HbA1c between 7–10% and in 59/253 (23%) it was >10% (Table 1). A total of 214 non-diabetic controls were also studied in addition to the T1DM patients. The selection of control subjects was random, they were Kuwaiti Nationals and had comparable general characteristics to the T1DM patients. The controls were healthy volunteers and their health status was evaluated by a specialist. All the controls had their HbA1c below 6.5%. This study was approved by the Joint Ethics Committee of the Faculty of Medicine, Kuwait University and the Kuwait Institute of Medical Specializations, Ministry of Health, Kuwait. Written informed consent was obtained from the participants and/or their parents according to the prescribed rules of the Ethics Committee.

In this study, we report a significant association of the rs2476601 (C1858T) functional variant in the PTPN22 gene with T1DM in Kuwaiti Arabs. Collectively, the variant T-allele was present in homozygous and heterozygous combinations in almost 37% of the Kuwaiti Arab T1DM patients. Although these results are generally consistent with several previous meta-analysis and case-control studies from European populations [18–24], the incidence of variant PTPN22 genotype detected in Kuwaiti Arabs is amongst the highest. This is in contrast to a report from Greek T1DM patients, in which, no association was reported [5245]. Also, some previous studies reported a lack of this variant in Asians (mainly from China and South Asia) [27–28]. A more recent report from China however, did find an association between the PTPN22 gene and T1DM [53]. In Egyptian T1DM patients, the TT genotype was detected in only 2% patients [54]. Similarly, in T1DM patients from North India, although the frequency of T allele of the PTPN22 gene was higher in T1DM patients (8%) compared to (2%) in the controls, none of the patients were homozygous for the TT genotype [55].

The data reported in this study demonstrate that the variant T-allele of the PTPN22 gene along with HLA-DQ2, DQ8, DR3 and DR4 alleles constitute significant determinants of genetic susceptibility to T1DM in Kuwaiti Arabs.

 

Source:

http://doi.org/10.1371/journal.pone.0198652

 

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