Inflammatory bowel disease (IBD) is a chronic, heterogeneous, autoimmune disorder of unknown aetiology that causes inflammation of the gastrointestinal tract (GIT). IBD’s main forms are Ulcerative Colitis (UC) and Crohn's Disease (CD), idiopathic relapsing and remitting disorders of the GIT that manifest both overlapping and distinct pathological and clinical manifestations. The estimated worldwide prevalence of IBD in 1990 was 79.5 per 105, which rose to 84.3 per 105 by 2017. Correspondingly, in Kingdom of Saudi Arabia (KSA), the prevalence increased by 6.3 % in that period [1]. There has been a sharp increase in incidence of patients diagnosed with IBD, with a reported overall incidence of 0.94/105 (0.5/105 in children) by 2002 [2]. About 56 % of such patients were from the central region of Saudi Arabia [2], and the annual incidence of IBD in Riyadh (central region) thus increased from 0.32/105 to 0.94/105 over a period of 20 years [3]. A cross-sectional study in Jeddah in 2022 included 776 participants, of whom 10.8 % (n = 84) had IBD, indicating a relatively low prevalence, however, which was mirrored in surrounding areas such as Kuwait city (2.8 per 105, 2011), Riyadh (0.94 per 105, 2004), and Oman (1.35 per 105, 2004) [4]. Major differences in IBD incidence and prevalence rates also exist among distinct populations and ethnic groups, suggesting that genetic makeup may contribute to disease susceptibility. However, chronic inflammation along the GIT occurs due to the interaction of several factors, including host immune response, intestinal microbiota, environmental factors, and genetic polymorphism [5]. Family history must thus be examined among other risk factors, though first-degree relatives of patients have a 4- to 20-times higher risk of developing the disease [6].

Genetic association is a significant aspect of the aetiology of IBD. Many studies done in United States of America (USA) and Canada have exhibited genetic linkages to the development of IBD: in particular, CD was initially linked to the IBD5 locus on chromosome 5q31, as this genomic region includes interleukin as well as members of the solute carrier family SLC22A4 and SLC22A5 that encode for the organic cation/carnitine transporters OCTN1 and OCTN2 [7,8]. Five genetic variants C1672T (SLC22A4), G-207C (SLC22A5) G113A, C4136A and 35delA (DLG5) were also reported to have significant associations with IBD in Caucasians [[9], [10], [11], [12]], while various genetic mutations have been associated with the development of IBD in Czech, Greek, and Turkish populations [[13], [14], [15]].

The C1672T alteration in SLC22A4 exon 9 rs1050152 has also been suggested to have a functional effect [16] in terms of CD and IBD [17], with a 1.9-fold increased risk of developing CD in patients with homozygous mutants [18]. However, C1672T, G-207C, G908R, R702w (NOD2/CARD15) and the DLG5 variants were absent in Chinese [19] and Japanese [20] IBD populations.

A meta-analysis of six Crohn's disease genome-wide association studies identified 71 distinct susceptible loci with genome-wide significant (P < 5 × 10−8) associations with Crohn's disease. The SNP T-1031C rs1799964 on tumour necrosis factor alpha (TNF-α), a gene involved in regulating cell differentiation, proliferation, immune response, growth and programmed death was one of these, which appeared to increase susceptibility to IBD [21]. Later this SNP was found to have linkage to IBD in many populations [22,23], and many common treatments for IBD now seek to inhibit this gene expression.

In 2012, Azzam et al. described the association of three genetic variants, Leu1007fsinsC, Gly908Arg, and Arg702Trp, with CD development in a case control study in Riyadh, KSA. This study examined 46CD patients, and 50 healthy controls, concluding that the aforementioned genetic variants were associated with the development of CD [24]. However, a later study did found no association with CD and these three polymorphisms or the earlier established G-207C and C1672T (SLC22A5), C4136A (DLG5) and D299G polymorphisms (TLR4) [25]. The association of apolipoprotein E (APOE) polymorphisms with susceptibility to IBD was determined through elevated ε2, ε4 alleles and lowered ε3 allele frequency in IBD patients [26], however, and a recent study on genetic variants P268S and R702w (NOD2) and G149R and R381Q (IL23R), as associated with IBD in Caucasian populations, concluded that there was no association between these SNPs and IBD development in the Saudi population, thereby confirming that genetic susceptibly varies by ethnicity [27].

There are vanishingly few studies on the genetic background to IBD in KSA specifically. This study thus aimed to assess the association of the SLC22A4 genetic variant rs1050152 and TNF-α variant rs1799964 with IBD patients at King Fahad University Hospital (KFUH), Al Khobar, in the Eastern Province of KSA.