This review provides an introduction to the rapidly expanding field of pharmacogenomics and personalised medicine, with especial relevance and focus for those working in clinical Histocompatibility and Immunogenetics (H&I) laboratories supporting HLA and disease immunogenetic testing and transplantation programmes. Drug efficacy and adverse drug reactions (ADRs) are defined, and the historical background to the field is introduced, along with a current overview of established clinically actionable gene-drug interactions. HLA associations with ADRs are reviewed, including those associations already tested for in many H&I laboratories worldwide, along with a broader overview of published HLA and ADRs, to determine which-if any-associations are likely to be of clinical significance and might be added to the testing repertoire. This review is intended to inform such decision-making. In addition, pharmacogenomics as related to the transport and metabolism of immunosuppressive drugs used in clinical transplantation is considered, again with relevance to the testing repertoire of clinical H&I laboratories. Finally, the expanding role of HLA genotyping in cancer immunotherapies is discussed, along with future developments in the broader pharmacogenomics field and how H&I laboratories can contribute to this.

Ankylosing spondylitis (AS) is a chronic inflammatory disease primarily affecting the axial skeleton and sacroiliac joints, with both genetic and environmental factors playing a role in its pathogenesis. Toll-like receptor 4 (TLR4) has been implicated in immune response and inflammation, but its genetic variations have not been extensively studied in AS. This study investigates the association between the TLR4 rs41426344 polymorphism and AS susceptibility and disease activity in a Turkish population. A total of 200 participants (100 AS patients and 100 healthy controls) were recruited. Genotyping of the TLR4 rs41426344 (G/C) polymorphism was performed using real-time PCR melting curve analysis. Disease activity was assessed using Bath Ankylosing Spondylitis Functional Index (BASFI), Bath Ankylosing Spondylitis Disease Activity Index (BASDAI) and Ankylosing Spondylitis Disease Activity Score with C-reactive protein (ASDAS-CRP) scores. Statistical analyses were conducted to determine the association between genotypes and disease risk. The CC genotype was significantly associated with AS susceptibility, with an odds ratio (OR) of 10.000 (95% CI: 4.091-24.431, p<0.0000001), indicating a strong genetic risk factor. Additionally, CC genotype carriers exhibited higher BASFI, BASDAI and ASDAS-CRP scores, suggesting greater disease severity and inflammation levels. A statistically significant difference (p<0.05) was observed in ASDAS-CRP scores between CC and GC genotypes This is the first study to investigate the TLR4 rs41426344 polymorphism in AS, and our findings indicate a strong association with both disease susceptibility and severity in the Turkish cohort. These findings reinforce the role of innate immunity in AS pathogenesis and suggest that TLR4 polymorphisms may serve as potential genetic markers for AS risk assessment and disease activity monitoring.

The authors declare no conflicts of interest. Data supporting this study are available upon reasonable request.

ABSTRACTPrimary HIV‐associated thrombocytopenia (PHAT) is an isolated thrombocytopenia in HIV‐positive individuals in the absence of secondary causes. The presence of certain Human Leukocyte Antigens (HLA) has been linked to individuals’ immune response to HIV and the development of immune‐mediated thrombocytopenic disorders. Considering the established associations between HLA and HIV infection and HLA and immune‐mediated thrombocytopenias, we hypothesise that specific HLA alleles may also increase the risk of developing PHAT, a condition that links both HIV and immune‐mediated thrombocytopenia. Therefore, the study aimed to determine the frequency of high‐resolution HLA alleles in patients presenting with possible PHAT. Following a detailed screening process, we evaluated the HLA profiles of 43 participants with probable PHAT using the Axiom Precision Medicine Diversity Array (PMDA) Kit on the GeneTitan Multi‐Channel instrument. No single HLA allele was found to be more prominent in our PHAT population. However, 93.02% of participants had both HIV‐protective and HIV‐susceptible alleles. The potential mechanism causing thrombocytopenia to be the only clinically relevant haematological abnormality in these patients remains to be explored. We concluded that the presence of both an HIV‐protective and HIV‐susceptibility allele in the same individual may cause antagonistic immune reactions, resulting in thrombocytopenia in HIV‐positive individuals. We propose future long‐term follow‐up studies to determine the progression and outcome in patients with PHAT.

Systemic auto-inflammatory diseases (SAID) are rare inherited conditions characterized by dysregulation of the immune system, which leads to recurrent episodes of fever and systemic inflammation. Recent studies have identified pathogenic variants in the nucleotide-binding leucine-rich repeat-containing receptor 12 (NLRP12) gene as potential contributors to autoinflammatory syndromes. Therefore, evaluating NLRP12 gene variants is crucial for the differential diagnosis of patients presenting symptoms associated with autoinflammatory diseases, specifically those known as NLRP12-associated autoinflammatory disease (NLRP12-AID). This study aims to identify causal variants in the NLRP12 gene encoding for NLRP12 and to discuss its pathogenesis, clinical features, and emerging treatment approaches. We used specific keywords for a systematic literature review via EMBASE, Scopus, ScienceDirect, Web of Science, and PubMed. Out of 874 articles, 27 met the inclusion criteria. To our knowledge, 103 patients with NLRP12 variants have been reported in the literature. All 60 variants in the NLRP12 coding gene were identified, including 49 classified as variants of uncertain significance (VUS), pathogenic, and likely pathogenic. The results show that the mean age of onset was 13.18 years. Fever was reported as the main symptom in 90% of cases of NLRP12-AID. Other symptoms, such as rash and urticaria, occurred in 59% of cases, myalgia and arthralgia in 39% of cases, arthritis in less than 20%, and abdominal pain/diarrhea in 50% of patients. In summary, the clinical features of NLRP12-AID are diverse and impact several tissues, particularly the musculoskeletal and gastrointestinal systems. In addition to familial cold autoinflammatory syndrome (FCAS) symptoms. Owing to its variable expression and incomplete penetrance, NLRP12-AID is often misdiagnosed. Therefore, we believe that patients with a syndrome of undifferentiated recurrent fever should also undergo genetic evaluation for NLRP12.

C1q deficiency is a rare autosomal recessive disease associated with recurrent skin lesions, chronic infections and an increased risk of autoimmune disorders, particularly systemic lupus erythematosus (SLE) or SLE-like disorders. Additionally, it has been linked to chronic glomerulonephritis and renal failure. C1q is the initial subcomponent of the classical pathway of the complement system and serves as a crucial linking factor between innate and acquired immunity. The C1 complex comprises three proteins: C1q, C1r and C1s. C1q comprises three chains: the A, B and C. The C1QB gene encodes the B-chain polypeptide of the serum complement subcomponent C1q. We report the case of an Iranian girl from a consanguineous family who suffers from C1q deficiency, presenting with some SLE symptoms that have not previously been described in the literature. She presented with progressive weakness in walking, tissue injury, skin lesions and subjective cognitive complaints regarding concentration and memory. The proband exhibited mild asymmetric uptake in the pelvic region, resulting in a waddling gait. Additionally, she showed abnormal circulating homocysteine levels, skin abnormalities and early inflammatory arthritis symptoms associated with SLE. Whole-exome sequencing (WES) was performed on the proband. A novel homozygous likely pathogenic missense variant in the C1QB gene, NM_001378156.1:c.263G>A, was identified. The variant was confirmed by Sanger sequencing in the proband, her parents and her healthy sister. This case highlights the significance of identifying a novel mutation in the C1QB gene, which expands the clinical spectrum of C1q deficiency. This finding contributes to the broader understanding of the disease's phenotype, helping to refine diagnostic criteria, particularly in cases with atypical manifestations. Furthermore, identifying such mutations in consanguineous families aids in genetic counselling and early diagnosis, allowing for better clinical management and prevention strategies.

The COVID-19 pandemic, caused by the SARS-CoV-2 virus, has significantly impacted global health, with Morocco reporting over 1.2 million confirmed cases and more than 16,300 deaths. The severity of COVID-19 varies, ranging from asymptomatic cases to mild symptoms, acute respiratory failure and death. Genetic factors are believed to influence individual responses to the virus. This study investigates the association between two common single nucleotide polymorphisms (SNPs) in Toll-like receptors (TLRs)-TLR2 rs3804099 (+597 C/T) and TLR4 rs4986790 (+896 A/G)-and disease severity and inflammatory markers in Moroccan COVID-19 patients. A total of 452 COVID-19 patients (259 with mild/moderate disease and 193 with severe disease) were included. TLR2 and TLR4 SNPs were genotyped using a predesigned TaqMan real-time allelic discrimination assay. Complete blood count samples, along with levels of C-reactive protein (CRP), ferritin, procalcitonin and D-dimer, were assessed using automated methods. No significant associations were observed between either SNP in TLR2 and TLR4 and disease severity under various genetic models. However, in severe cases, TLR4 rs4986790 showed a significant association with ferritin levels (p=0.0002) and lymphocyte count (p<0.0001). TLR2 rs3804099 was linked to CRP levels in severe patients (p=0.036). No associations were observed with anti-receptor-binding domain (RBD) IgG or anti-N IgG levels in severe cases (p>0.05). These findings suggest that although TLR4 and TLR2 polymorphisms are not directly associated with COVID-19 severity, they may influence the inflammatory response. Specifically, TLR4 rs4986790 and TLR2 rs3804099 appear to modulate ferritin and CRP levels, potentially impacting disease progression in severe cases.

Extended RBC antigens typing is very valuable in transfusion immunology since it is highly recommended to ensure better transfusion practices and avoid transfusion-related complications and to establish registries for rare blood donors as recommended by the International Society of Blood Transfusion and World Health Organization. A group of 236 Tunisian blood donors were genotyped for 19 common blood loci using the Sequence-specific primers polymerase chain reaction (SSP-PCR) method. The statistical analysis was done using the HaploView Software. The study showed the dominance of the loci: RHCE*e, KEL*02, FY*02 and CO*01; and the absence of the homozygous state of the CO*02 allele. Furthermore, two complete linkage disequilibrium leading to the absence of the two alleles RHCE*C-RHCE*E (C-E) and FY*01N.01 (FY*Anull) were detected. Additionally, it appeared that approximately 91% of these blood donors are positive for the RHD gene; and all subjects who lacked the RHD exon 10 are homozygous for the RHCE*c and RHCE*e variants. The study also revealed that the RH1 negative blood cannot be universal to the Rh system because almost all RH1 negative donated blood is RH:-2,4,-3,5 (ccee), which may constitute a risk in some recipients carrying the anti-RH4 and/or anti-RH5 antibodies. Considering that some donated RBC units may contain blood with very immunogenic phenotypes, greatcautionisrequired when transfusing some subjects, especially in emergency situations because it can be a step towards subsequent complex or multiple alloimmunization.