Assessment of immunological anti-platelet factor 4 antibodies for vaccine-induced thrombotic thrombocytopenia (VITT) in a large Australian cohort: A multicenter study comprising 1284 patients.

BACKGROUND: Vaccine-induced thrombotic thrombocytopenia (VITT) is a rare complication of adenovirus-based vaccines aimed to prevent and minimize COVID-19 and related pathophysiology. OBJECTIVES: To describe patterns of testing for anti-platelet factor 4 (PF4) antibodies using various ELISA assays in a large Australian cohort and comparative functional platelet activation assays in a subset. PATIENTS/METHODS: Asserachrom HPIA IgG ELISA was performed in 1284 patients over a period of 12 months, supplemented in select cohorts by comparative ELISA using three other methods (n = 78-179), three different functional assays (flow cytometry, serotonin release assay, and/or Multiplate; n = 476), and rapid immunological chemiluminescence anti-PF4 assay (n = 460), in a multicenter study. RESULTS: For first episode presentations, 190/1284 (14.8%) ELISA tests were positive. Conversely, most (445/460; 96.7%) chemiluminescence anti-PF4 test results were negative. All functional assays showed associations of higher median ELISA optical density with functional positivity and with high rates of ELISA positivity (64.0% to 85.2%). Data also identified functional positivity in 14.8%-36.0% of ELISA negative samples, suggesting false negative VITT by HPIA IgG ELISA in upward of one third of assessable cases. CONCLUSION: To our knowledge, this is the largest multicenter evaluation of anti-PF4 testing for investigation of VITT. Discrepancies in test results (ELISA vs. ELISA or ELISA vs. functional assay) in some patients highlighted limitations in relying on single methods (ELISA and functional) for PF4 antibody detection in VITT, and also highlights the variability in phenotypic test presentation and pathomechanism of VITT.

Interactions among genetic variants in tobacco metabolizing genes and smoking are associated with head and neck cancer susceptibility in North Indians.

It is becoming clearly evident that single gene or single environmental factor cannot explain susceptibility to diseases with complex etiology such as head and neck cancer. In this study, we applied the multifactor dimensionality reduction method to explore potential gene-environment and gene-gene interactions that may contribute to predisposition to head and neck cancer in the North Indian population. We genotyped 203 patients with head and neck cancer and 201 healthy controls for 13 functional polymorphisms in genes coding for tobacco metabolizing enzymes; CYP1A1, CYP2A13, GSTM1, and UGT1A7 using polymerase chain reaction-restriction fragment length polymorphism method, real-time polymerase chain reaction quantitative assay, and denaturing high-performance liquid chromatography followed by direct sequencing. We found that GSTM1 copy number variations were the most influential factor for head and neck cancer. We also observed significant gene-gene interactions among GSTM1 copy number variants, CYP1A1 T3801C and UGT1A7 T622C variants among smokers. Multifactor dimensionality reduction approach showed that the three-factor model, including smoking status, CYP1A1 T3801C, and GSTM1 copy number variants, conferred more than fourfold increased risk of head and neck cancer (odds ratio 4.89; 95% confidence interval: 3.15-7.32, p < 0.01). These results support the hypothesis that genetic variants in tobacco metabolizing genes may contribute to head and neck cancer risk through gene-gene and gene-environmental interactions.

Combined effect of smoking and polymorphisms in tobacco carcinogen-metabolizing enzymes CYP1A1 and GSTM1 on the head and neck cancer risk in North Indians.

Tobacco consumption contributes to the etiology of majority of cancers, and polymorphisms in tobacco-metabolizing enzymes may modulate susceptibility to head and neck cancer (HNC). The aim of this study was to determine whether genetic polymorphisms in genes CYP1A1 and GSTM1, involved in metabolism of major classes of tobacco-derived carcinogens, may predispose to development of HNC in a North Indian population. In this case-control study, 203 HNC patients and 201 control subjects were genotyped for four variants of CYP1A1 using polymerase chain reaction-restriction fragment length polymorphism, and GSTM1 was analyzed for copy number variations by real-time polymerase chain reaction. Haplotype analysis was performed for the CYP1A1 gene using PHASE version 2.1. CYP1A1 CC (T3801C) (odds ratio [OR], 3.49; 95% confidence interval [CI], 1.34-9.05), GSTM1 single copy (OR, 2.63; 95% CI, 1.54-4.51), and null genotypes (OR, 4.37; 95% CI, 2.61-7.29) were found to be significantly associated with an increased risk of HNC. The gene-environment interactions revealed significant interactions among smokers carrying CYP1A1 AG (A2455G) and GSTM1 copy number variants. CYP1A1 haplotypes carrying variant 3801C allele, C-A-C (OR, 2.45; 95% CI, 1.56-3.83), and C-G-C (OR, 2.39; 95% CI, 1.35-4.25) were found to be associated with a twofold increased risk of HNC. GSTM1 copy number variations and CYP1A1 polymorphisms individually as well in interaction with tobacco consumption may increase the risk of HNC.

Association of angiotensin converting enzyme and angiotensin type 2 receptor gene polymorphisms with renal damage in posterior urethral valves.

OBJECTIVE: To examine the association with renal damage in patients with posterior urethral valves (PUV) of two renin-angiotensin system gene polymorphisms: angiotensin converting enzyme insertion/deletion (ACE I/D) and angiotensin type 2 receptor (AT2R A1332G), PATIENTS AND METHODS: In 120 patients with PUV, after stabilization, transurethral fulguration or a Blocksom vesicostomy was performed. Records were reviewed for age at diagnosis, biochemical renal function at diagnosis, results of urine cultures, voiding cystourethrograms, radiologic, sonographic and nuclear medicine scan findings, and follow-up data. ACE I/D genotypes were determined by the polymerase chain reaction using allele specific primers. RESULTS: The frequency of the ACE DD genotype was significantly higher in patients with chronic kidney disease (P=0.02) and renal scarring (P=0.05). These genotypes were also associated with a statistically higher incidence of vesicoureteral reflux, diurnal incontinence, proteinuria and hypertension. A significantly higher frequency of the AT2R GG genotype was found in PUV patients as compared to healthy unrelated control subjects (P=0.001), and in PUV patients with scarring (P=0.02). CONCLUSION: The ACE DD and AT2R GG genotypes are associated with chronic kidney disease and scarring in PUV patients. The GG genotype incidence is higher among PUV patients compared to the control population, and further studies in this area may help understanding of the genetic basis of PUV.