Rheumatoid arthritis (RA) is a commonly diagnosed systemic chronic inflammatory disorder/condition that affects about 1% of the global population [1]. It is characterized by polyarthritis, immunologic abnormalities, autoimmune reactions, high comorbidity, and early death. It is also known to cause gradual joint destruction and impairment [2]. Extracellular matrix degradation, which causes the normal breakdown of cartilage, tendons, bone, and ligaments, is a defining characteristic of RA. Beside this, different constitutional symptoms include fever, asthenia, weight loss, malaise and anorexia [3]. RA is mostly caused by interaction of genetic and environmental factors [4–6]. Other risk factors include age, gender and environmental exposure i.e., smoking, different air pollutants and infectious agents [7, 8]. RA is typically classified into two types seropositive or seronegative. The classification is based on presence or absence of rheumatoid factor and Anti-citrullinated protein antibodies [9–11].
This condition affects approximately 5 to 10 individuals out of every 1,000 in developed nations [12]. It's worth noting that from 1990 to 2017, RA had a significant impact on people's health worldwide, resulting in a loss of 3.4 million of life [13, 14]. In the period 1980–2018, the prevalence of RA was 460 patients per 100,000 people worldwide with a prediction level of 95% (0.07–1.29%) [15, 16]. The prevalence of RA is more in northern America and Europe as compared to other areas [17–19]. A study from 2011 state that prevalence of RA is 0.5 to 1% in Pakistan but it would be increasing as there is not much data present from Pakistani population [20, 21]. The prevalence is more in women as compared to men in Pakistan [22, 23].
Different genetic factors are identified to be associated with RA. Among different genetic factors, HLA DRB1 alleles are investigated in several studies and found to be significantly associated with RA [24, 25]. This association has been identified in different populations across the world. The strength of different alleles varies in different population [26–30]. Other genetic factors associated with RA include tumor necrosis factor (TNF), corticotrophin releasing hormone (CRH), CYP19 (aromatase), IFN-γ and other cytokines. Some study suggests that different auto immune disease such as insulin dependent diabetes, locus on chromosome X may be associated with RA [31].
The human leukocyte antigen (HLA) system, which correlates to the major histocompatibility complex (MHC) in humans, is critical in the antigen presentation of intracellular and extracellular peptides as well as the control of innate and adaptive immune responses [24, 32]. The conventional HLA loci are the class I (HLA-A, -B, -C, -E, -F, and -G) and class II (HLA-DR, -DQ, -DM, and -DP) molecules known for their roles in antigen presentation to CD8 + and CD4 + T lymphocytes, respectively. They are transcribed by the most variable area in the human genome, a 4-Mb region of human chromosome 6p21 and are classified as MHC. MHC plays major role in immunity as well as risk associated with different auto immune diseases [33].
The role of HLA DRB1 in susceptibility to RA is estimated to be 50% [32]. The HLA DRB1 gene comprises of 6 exons with each exon encoding different domain [34]. The leader peptide is encoded by exon 1, the extracellular domains by exons 2 and 3, the trans-membrane domain by exon 4, and the cytoplasmic tail by exon 5 [35]. Exon 1 encodes amino acid patterns that make up the first hyper variable region (HVR1); Exon 2 encodes similar epitope motifs and the third region (HVR3). About 2960 alleles have been identified in HLA DRB1 gene out of which only few are identified to have role in RA [24]. Several HLA DRB1 alleles have been identified as playing a critical role in the severity and susceptibility to rheumatoid arthritis. These alleles possess a sequence motif in the third HVR of the HLA DRB1 gene, referred to "shared epitope (SE)", which is composed of five amino acids at positions 70–74 of the HLA DRB1 chain. Specifically, this SE contains one of three amino acid sequences: RRRAA, QKRAA or QRRAA [36]. While the DERAA pattern seems to be primarily accountable for the beneficial protective effects [37]. The SE sequences facilitate the presentation of self-antigens to T cells, which is believed to be a critical factor in the onset of RA [38]. Current studies suggest that, RA is primarily initiated by the specific binding of citrullinated peptides by HLA-DR molecules that possess the SE sequence. The HLA-DRB1 SE allele is found in 64–82% of RA cases, a significantly higher occurrence compared to their first-degree relatives (53.9–55%) and the healthy individual population (39–52%). Approximately one-fifth of individuals with RA are estimated to lack the SE alleles. The autoimmune reaction in RA is believed to be triggered by the citrullination of self-peptides, which results in changes to their characteristics. This can cause the stimulation of immune responses and the production of specific ACPA, which are observed in about 75% of individuals with RA [24].
There are contradictory results regarding HLA DRB1 alleles association with RA. Many studies from different populations have proved its association with RA [27, 39–42]. However, no such study is present from Pakistani KP population. Hence this study will help in determining the association of HLA DRB1 alleles especially HLA DRB1*01, *04, *12, *15 with RA in Pakistani KP population.