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Aim: To explore the potential association between the KLF14 rs4731702 polymorphism and metabolic syndrome traits among patients diagnosed with type 1 diabetes (T1D). Methods: The study group included 350 patients with T1D and 250 healthy control subjects. The analysis focused on the genotyping of KLF14 rs4731702 single nucleotide polymorphism (SNP), as well as evaluating serum concentrations of inflammatory markers, blood pressure, lipid profiles, and the quantitative status of CD4 + CD25highFOXP3+ T cells. Results: Patients with T1D carrying the T allele of KLF14 rs4731702 SNP had higher high‐density lipoprotein cholesterol, lower low‐density lipoprotein cholesterol, as well as lower glycated haemoglobin and serum concentration of proinflammatory markers than C allele carriers. They also developed hypertension less often than carriers of the C allele. The analysis of CD4 + CD25highFOXP3+ regulatory T‐cell status based on KLF14 genotype showed that, in T1D patients, those with the TT genotype had the highest frequency of these cells compared to carriers of the CC and CT genotypes. Conclusion: Our study suggests that the T allele of the KLF14 rs4731702 SNP might confer a protective effect against the development of obesity, hypertension, dyslipidaemia, and chronic inflammatory state in patients diagnosed with T1D. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions Sunitinib exhibits considerable interindividual variability in exposure. While the target total plasma concentration of sunitinib and its active metabolite is 50–87.5 ng/mL for the intermittent dosing schedule, ~10–21% of patients experience higher exposures (>87.5 ng/mL), correlated with an increased risk for toxicity. Previous research identified single nucleotide variants (SNVs) in genes from the sunitinib pharmacokinetic pathway to be associated with efficacy and toxicity. However, significant interindividual variability in exposure remains unexplained. Our aim was to identify genetic variants associated with supratherapeutic exposure of sunitinib.This was a genome‐wide association study. Cases were identified during routine therapeutic drug monitoring and consisted of patients with dose‐normalized sunitinib plasma concentrations >87.5 ng/mL (intermittent dosing) or >75 ng/mL (continuous dosing). Controls were sampled from the historical cohort EuroTARGET who tolerated the standard dose of 50 mg in an intermittent schedule. SNVs were tested for an association with sunitinib exposure. A P‐value ≤5 × 10−8 was considered significant and a P‐value between 5 × 10−8 and 5 × 10−6 was considered suggestive.Sixty‐nine cases and 345 controls were included for association analysis. One SNV (rs6923761), located on the gene glucagon‐like peptide 1 receptor, was significantly associated with increased sunitinib exposure (P = 7.86 × 10−19). Twelve SNVs were suggestive for an association with sunitinib exposure (P ≤ 5 × 10−6).While rs6923671 is associated with high sunitinib exposure, the underlying mechanism is not yet clarified and warrants further investigation. We could not confirm the earlier found associations between SNVs in candidate genes involved in the pharmacokinetic pathway of sunitinib and its efficacy and toxicity. [ABSTRACT FROM AUTHOR]

Introduction Methods Results Conclusion The phenotypic consequences of the p.Arg577Ter variant in the α‐actinin‐3 (ACTN3) gene are suggestive of a trade‐off between performance traits for speed and endurance sports. Although there is a consistent association of the c.1729C allele (aka R allele) with strength/power traits, there is still a debate on whether the null allele (c.1729T allele; aka X allele) influences endurance performance. The present study aimed to test the association of the ACTN3 p.Arg577Ter variant with long‐distance endurance athlete status, using previously published data with the Brazilian population.Genotypic data from 203 long‐distance athletes and 1724 controls were analysed in a case–control approach.The frequency of the X allele was significantly higher in long‐distance athletes than in the control group (51.5% vs. 41.4%; p = 0.000095). The R/X and X/X genotypes were overrepresented in the athlete group. Individuals with the R/X genotype instead of the R/R genotype had a 1.6 increase in the odds of being a long‐distance athlete (p = 0.012), whereas individuals with the X/X genotype instead of the R/R genotype had a 2.2 increase in the odds of being a long‐distance athlete (p = 0.00017).The X allele, mainly the X/X genotype, was associated with long‐distance athlete status in Brazilians. [ABSTRACT FROM AUTHOR]

Background: Head and neck cancer encompasses neoplasms affecting the oral cavity, pharynx, larynx, and thyroid. Identifying factors that modulate the carcinogenesis process can aid in identifying subgroups at higher risk of developing the disease, enabling implementation of prevention programs. Vitamin D receptor polymorphisms can affect the carcinogenesis of various tumors by altering vitamin D metabolism and cellular response. Methods: To elucidate the role of vitamin D receptor polymorphisms in head and neck cancer, a systematic review was performed, searching the Embase, PubMed, Scopus, and Lilacs databases. A total of 19 articles met the inclusion criteria. The frequency of vitamin D receptors polymorphism alleles (FokI, ApaI, BsmI, TaqI, Cdx2, rs2107301, rs2238135) was recorded and pooled to calculate the odds ratio in a meta‐analysis using the Review Manager software. Results: Subgroup analysis demonstrated significant associations in the anatomical site of cancer (oral cancer in ApaI and BsmI, and unspecified subsites of head and neck cancer in TaqI), genotyping method (FokI and BsmI), and continent of the study (ApaI, FokI, and BsmI). Conclusion: Our findings were heterogeneous, as with other evidence available in the literature. Therefore, more clinical studies with larger sample sizes are needed to obtain more accurate results on the relationship between vitamin D receptor polymorphism and head and neck cancer. [ABSTRACT FROM AUTHOR]

The genetic diversity of killer cell immunoglobulin‐like receptors (KIRs) and human leukocyte antigen (HLA) genes influences the host's immune response to viral pathogens. This study aims to explore the impact of five single nucleotide polymorphisms (SNPs) in KIR3DL2 and HLA‐A genes on hepatitis C virus (HCV) infection. A total of 2251 individuals were included in the case‐control study. SNPs including KIR3DL2 rs11672983, rs3745902, rs1654644, and HLA‐A rs3869062, rs12202296 were genotyped. By controlling various confounding factors using a modified logistic regression model, as well as incorporating stratified analysis, joint effects analysis, and multidimensional bioinformatics analysis, we analyzed the relationship between SNPs and HCV infection. The logistic regression analysis showed a correlation between KIR3DL2 rs11672983 AA, KIR3DL2 rs3745902 TT, and increased HCV susceptibility (p < 0.01). Stratified analysis indicated that KIR3DL2 rs1654644 and HLA‐A rs3869062 also heightened HCV susceptibility in certain subgroups. A linear trend of rising HCV infection rates was observed when combining KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT (ptrend = 0.007). Bioinformatics analysis suggested these SNPs' regulatory potential and their role in altering messenger RNA secondary structure, implying their functional relevance in HCV susceptibility. Our findings indicate that KIR3DL2 rs11672983 AA and KIR3DL2 rs3745902 TT are significantly associated with increased susceptibility to HCV infection. [ABSTRACT FROM AUTHOR]

Background/Objectives: Clinical responses to naldemedine vary between individuals with advanced cancer. This is a prospective, single‐center, observational study aimed to evaluate the influence of genetic polymorphisms and cachexia status on plasma naldemedine and clinical responses. Methods: Forty‐eight patients being treated with naldemedine for opioid‐induced constipation under treatment of cancer pain were enrolled. Plasma naldemedine concentrations were determined on the fourth day or later after administration of naldemedine, and the associations with genotypes, cachexia status, and clinical responses were assessed. Results: Cancer patients exhibited a large variation in the plasma naldemedine concentrations, and it was correlated with serum total protein level. Patients who were homozygous CYP3A5*3 had a higher plasma concentration of naldemedine than those with the *1 allele. ABCB1 genotypes tested in this study were not associated with plasma naldemedine. A negative correlation was observed between the plasma naldemedine concentration and 4β‐hydroxycholesterol level. The plasma naldemedine concentration was lower in patients with refractory cachexia than in those with precachexia and cachexia. While serum levels of interleukin‐6 (IL‐6) and acute‐phase proteins were higher in patients with refractory cachexia, they were not associated with plasma naldemedine. A higher plasma concentration of naldemedine, CYP3A5*3/*3, and an earlier naldemedine administration after starting opioid analgesics were related to improvement of bowel movements. Conclusion: Plasma naldemedine increased under deficient activity of CYP3A5 in cancer patients. Cachectic patients with a higher serum IL‐6 had a lower plasma naldemedine. Plasma naldemedine, related to CYP3A5 genotype, and the initiation timing of naldemedine were associated with improved bowel movements. [ABSTRACT FROM AUTHOR]

Problem: Bacterial vaginosis (BV) disproportionally impacts Black and Hispanic women, placing them at risk for HIV, sexually transmitted infections and preterm birth. It is unknown whether there are differences by genetic ancestry in BV risk or whether polymorphisms associated with BV risk differ by ancestry. Methods: Women's Interagency HIV Study (WIHS) participants with longitudinal Nugent scores were dichotomized as having (n = 319, Nugent 7–10) or not having BV (n = 367, Nugent 0–3). Genetic ancestry was defined by clustering of principal components from ancestry informative markers and further stratified by BV status. 627 single nucleotide polymorphisms (SNPs) across 41 genes important in mucosal defense were identified in the WIHS GWAS. A logistic regression analysis was adjusted for nongenetic predictors of BV and self‐reported race/ethnicity to assess associations between genetic ancestry and genotype. Results: Self‐reported race and genetic ancestry were associated with BV risk after adjustment for behavioral factors. Polymorphisms in mucosal defense genes including syndecans, cytokines and toll‐like receptors (TLRs) were associated with BV in all ancestral groups. Conclusions: The common association of syndecan, cytokine and TLR genes and the importance of immune function and inflammatory pathways in BV, suggests these should be targeted for further research on BV pathogenesis and therapeutics. [ABSTRACT FROM AUTHOR]

Background and aims: Oral lichen planus (OLP) is an inflammatory mucocutaneous disorder with an immune‐mediated pathogenesis. The tumor necrosis factor‐α (TNF‐α) level in the serum of OLP patients is significantly higher than in the control group. TNF‐α‐857 C/T polymorphism can be related to the increased TNF‐α level in blood circulation. This study investigated the relationship between TNF‐α (‐857 C/T) polymorphism and OLP patients in an Iranian population. Methods: Saliva samples were taken from 200 people, including 100 patients with OLP and 100 healthy people who did not have significant differences in age and sex. Then, DNA was extracted from them and the TNF‐α (‐857 C/T) genotype was identified using the polymerase chain reaction with confronting two‐pair primers method. Statistical Package for the Social Sciences version 16 software analyzed the results. Results: The frequency of C/C, C/T, and T/T genotypes of the TNF‐α‐857 C/T polymorphism in the patient group were 78%, 18%, and 4%, respectively, and in the control group were 72%, 23%, and 5%, respectively. The differences between the two groups regarding allele (χ2 = 0.97, p = 0.32) and genotype (χ2 = 0.96, p = 0.62) frequency among the studied population were insignificant. Conclusion: This study showed that the difference in the frequency of single nucleotide polymorphism TNF‐α‐857 C/T polymorphism in the patient and control group had no significant relationship with the increased OLP incidence. Also, no significant association was observed between allele and genotype frequency of TNF‐α (‐857 C/T) with OLP subtypes. [ABSTRACT FROM AUTHOR]

Background and Aims: Breast cancer is the most common type of cancer in women. The genetic polymorphism in HER (HER1–rs11543848 and HER2–rs1136201) were found to be associated with breast cancer risk in different ethnicities worldwide with inconsistent results. The aim of this research study was to evaluate the association of HER1–rs11543848 and HER2–rs1136201 polymorphisms as a risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. Methods: A total of 314 women including 164 breast cancer patients and 150 age and gender‐matched healthy controls were enrolled from June 2021 to May 2022. All the samples were subjected to DNA extraction followed by Tetra‐ARMS‐PCR for genotyping and gel electrophoresis. Results: Our results indicated that HER1–rs11543848 risk allele A (p = 0.0001) and heterozygous genotype GA (p = 0.0001) displayed highly significant association with breast cancer, while the homozygous mutant genotype AA indicated association but nonsignificant results (odds ratio [OR] = 2.637, 95% confidence interval [CI] = 1.2258–5.6756, p = 0.0833). Similarly, the HER2–rs1136201 risk allele G (p = 0.0023), the heterozygous genotype AG (p = 0.0530) and homozygous mutant genotype GG showed significant association (OR = 2.5946, 95% CI = 0.9876–6.8165, p = 0.0530) with breast cancer risk. Both the SNPs presented a higher but nonsignificant risk of breast cancer in postmenopausal women (OR = 2.242, p = 0.08 and OR = 2.009, p = 0.06). However, both the SNPs showed significant association (p < 0.005) with family history, metastasis, stage, luminal B, and TNBC. Conclusion: In conclusion, HER1–rs11543848 and HER2–rs1136201 polymorphisms are significantly associated with the higher risk of breast cancer in Pashtun population of Khyber Pakhtunkhwa, Pakistan. These findings advocate for further exploration with larger datasets, offering promising avenues for personalized approaches in breast cancer research and potentially enhancing clinical practices for better risk assessment and targeted management strategies. [ABSTRACT FROM AUTHOR]

Aims: The effects of genetic polymorphism on a personalized diet and exercise program for steatotic liver disease (SLD) are still unclear. Methods: Participants of this retrospective cohort study were 203 Japanese patients with SLD diagnosed by abdominal ultrasonography. All of them were introduced the personalized diet and exercise treatment. A diet of 25–30 kcal/kg multiplied by ideal body weight (BW) daily and aerobic and resistance exercise (exercise intensity of 4–5 metabolic equivalents daily, respectively) were performed for 6 days. Treatment efficacy was evaluated in terms of the rate of decrease of liver function tests, glycolipid metabolism markers, physical findings, image findings, and cardiovascular disease (CVD) risk score at 6 months compared with baseline. Furthermore, the impact of genetic polymorphism was also investigated. Results: At 6 months compared with baseline, liver function tests (AST, ALT, γGTP), glycolipid metabolism markers (hemoglobin A1c, triglycerides [TG], low‐density lipoprotein cholesterol), physical findings (BW, body mass index), image finding (liver stiffness measurement), and CVD risk score (Suita score) improved significantly. There was no significant difference in treatment efficacy, except for the rates of decrease of TG, according to genotype PNPLA3 rs738409, TM6SF2 rs58542926, and HSD17B13 rs6834314. The rates of decrease of TG with TM6SF2 CT were significantly higher than those with CC or TT, and the rates of TG with HSD17B13 AA were significantly higher than those with AG by multiple comparisons. Conclusion: Personalized diet and exercise program for SLD improved liver function tests, physical findings, glycolipid metabolism markers, and CVD risk score. Genetic polymorphism might partially affect treatment efficacy. Further studies should be performed to develop an individualized program for SLD, considering genetic polymorphism. [ABSTRACT FROM AUTHOR]

Aims Methods Results Conclusions The aim of this study is to demonstrate the use of PBPK modelling to explore the impact of ethnic differences on drug PK.A PBPK model developed for lansoprazole was used to predict the clinical PK of lansoprazole in Japanese subjects by incorporating the physiological parameters of a Japanese population into the model. Further verification of the developed Japanese population with clinical studies involving eight other CYP substrates—omeprazole, ticlopidine, alprazolam, midazolam, nifedipine, cinacalcet, paroxetine and dextromethorphan—was also carried out.The PK of lansoprazole in both Caucasian and Japanese subjects was well predicted by the model as the observed data were within the 5th and 95th percentiles across all the clinical studies. In age‐ and sex‐matched simulations in both the Caucasian and Japanese populations, the predicted PK (mean ± SD) of a single oral dose of 30‐mg lansoprazole was higher in the Japanese population in all cases, with more than twofold higher AUC of 5.98 ± 6.43 mg/L.h (95% CI: 4.72, 7.24) vs. 2.46 ± 2.45 mg/L.h (95% CI: 1.98, 2.94) in one scenario. In addition, in two out of the nine clinical DDIs of lansoprazole and the additional CYP substrates simulated using the Japanese population, the predicted DDI in Japanese was more than 1.25‐fold that in Caucasians, indicating an increased DDI liability.By accounting for various physiological parameters that characterize a population in a PBPK model, the impact of the different identified interethnic differences on the drug's PK can be explored, which can inform the adoption of drugs from one region to another. [ABSTRACT FROM AUTHOR]

Background and Aims: Gene polymorphisms are responsible for at least part of the variation in caries susceptibility despite similar environmental factors. Genes involved in enamel formation like matrix metalloproteinase‐13 (MMP‐13) may participate in caries process. The aim was to investigate the association between MMP‐13 rs478927 polymorphism and caries susceptibility in 6‐years‐old children from Birjand, Iran. Methods: Six‐years old children from Birjand, Iran, participated in this study. The total decayed, missing, and filled teeth were calculated and defined as caries index (CI). Based on this CI, two groups of high‐caries (case) and low‐caries (control) were taken into account. Saliva samples were collected and DNA was extracted. The allele and genotypes of MMP‐13 rs478927 polymorphism were determined by tetra‐primer amplification refractory mutation system‐polymerase chain reaction (T‐ARMS‐PCR) method. p Value was significant if p < 0.05. Results: Three hundred sixty‐seven children consisted of 186 low‐caries children and 181 high‐caries children were included in this study. The mean CI was 6.02 ± 0.81. There was no significant association between high and low‐caries groups based on socioeconomic status, eating sweet snacks, parents' susceptibility to dental caries, duration of breastfeeding, and the brushing habit (p > 0.05). There wasn't any significant association between genotype distribution of MMP‐13 rs478927 polymorphism and CI groups (p = 0.924). This polymorphism was associated with increased caries susceptibility under all genetic models but this effect was not significant (p > 0.05). Conclusion: The MMP‐13 rs478927 gene polymorphism was not significantly associated with dental caries susceptibility in Birjandi children with mixed dentition. It is recommended to conduct studies on children of different dentitions to better understand the role of this polymorphism on caries susceptibility in primary and permanent teeth of children. [ABSTRACT FROM AUTHOR]

In this study, our aim was to investigate the epidermal growth factor (EGF) and epidermal growth factor receptor (EGFR) gene polymorphisms in oral squamous cell carcinoma (OSCC) patients and non‐OSCC healthy controls. This case–control study comprised 89 OSCC and 107 healthy controls by using polymerase chain reaction (PCR) and restriction fragment length polymorphism methods, the genotypes for EGF + 61 A > G (rs4444903) and EGFR R497K (rs2227983) were analyzed. According to the EGF + 61 A > G genotype distribution, individuals with the GG genotype were more prevalent in the OSCC group when compared to the healthy controls. But the AA genotype frequency was significantly higher in the healthy control group. The frequency of G allele carriers was 2.3 times higher than A allele carriers in OSCC patients (p <.001). For the EGFR R497K genotype, there was no significant difference between the OSCC and healthy control groups. Regarding the study results, the G allele of EGF + 61 A > G polymorphism was associated with OSCC. Larger populations and functional investigations should be used to explore the nature of the interaction between EGF and OSCC. [ABSTRACT FROM AUTHOR]

Background: Iron deficiency can impair immune function, increasing tuberculosis (TB) susceptibility and severity. The research aimed to investigate iron deficiency anemia in TB patients and household contacts and its association with natural resistance‐associated macrophage protein 1 (NRAMP1) polymorphism and expression. Methods: The levels of iron, ferritin, and transferrin were measured in the serum by ELISA (Enzyme‐Linked Immunosorbent Assay). NRAMP1 polymorphisms were determined by polymerase chain reaction (PCR) and sequencing. NRAMP1 gene expression was measured by real‐time PCR. Interferon‐gamma release assay (IGRA) checked on household contacts to screen household contacts with positive IGRA as the control. Results: This study involved 35 TB cases and 35 TB contacts. The results showed that the serum Fe levels were found to be lower in the TB case group (median 149.6 μmol/L) than in the positive IGRA household contacts group (median 628.53 μmol/L) with a p‐value <0.001. Meanwhile, ferritin levels in TB cases tended to be higher, in contrast to transferrin, which was found to tend to be lower in TB cases than household contacts but did not show a significant difference. This study found no association between the polymorphism of exon 15 D543 and active TB. However, NRAMP1 gene expression was lower in TB cases than in positive IGRA household contacts (p = 0.011). Besides, there was a positive correlation between NRAMP1 gene expression and serum Fe levels (r = 0.367, p = 0.006). TB was associated with decreased NRAMP1 gene expression (OR 0.086 95% CI 0.02–0.366, p = 0.001). Besides, TB was associated with low Fe levels (OR 0.533 95% CI 0.453–0.629, p < 0.001). Conclusion: Comparing the TB case to the household contacts group, decreased serum Fe levels were discovered in the TB case group. This study also shows a correlation of NRAMP1 gene expression to Fe levels in TB patients and household contacts and describes that TB may lead to decreased Fe levels by downregulating NRAMP1 expression. [ABSTRACT FROM AUTHOR]

Background: Breast cancer (BC) is common cancer caused by environmental factors and genetic ones. Previous evidence has linked gene MAGUK P55 Scaffold Protein 7 (MPP7) to BC, despite that there has been no research evaluating the relationship between MPP7 genetic polymorphisms and BC susceptibility. We aimed to investigate the potential association of the MPP7 gene with the susceptibility to BC in Han Chinese individuals. Methods: In total, 1390 patients with BC and 2480 controls were enrolled. For genotyping, 20 tag SNPs were chosen. The serum levels of protein MPP7 were measured in all subjects using an enzyme‐linked immunosorbent assay. Genetic association analysis was performed in both genotypic and allelic modes, and the relationship between BC patients' clinical features and genotypes of relevant SNPs was examined. The functional implications of significant markers were also evaluated. Results: After adjusting for Bonferroni correction, SNP rs1937810 was found to be significantly associated with the risk of BC (p = 1.19 × 10−4). The odds ratio of CC genotypes in BC patients was 49% higher than in controls (1.49 [1.23–1.81]). Serum MPP7 protein levels were significantly higher in BC patients than in controls (p < 0.001). The protein level of the CC genotype was the highest, and that of the CT and TT genotypes decreased in turn (both p < 0.001). Conclusions: Our results linked SNP rs1937810 to the susceptibility of BC and the clinical features of BC patients. This SNP is also proved to be significantly related to the serum level of protein MPP7 in both BC patients and controls. [ABSTRACT FROM AUTHOR]

Background: Methylenetetrahydrofolate reductase (MTHFR) is an important enzyme involved in folate and homocysteine metabolism, which are necessary for DNA methylation and nucleotide synthesis. Genetic polymorphisms that reduce MTHFR activity have been linked to several diseases, including prostate cancer. In this study, we aimed to investigate whether MTHFR polymorphisms, along with serum levels of folate, vitamin B12, and homocysteine, are associated with prostate cancer risk in the Algerian population. Methods: A total of 106 Algerian men with newly diagnosed prostate cancer and 125 healthy controls were included in this case‐control study. The MTHFR C677T and A1298C polymorphisms were analyzed using PCR/RFLP and Real‐Time PCR TaqMan® assays, respectively. Serum levels of folate, total homocysteine, and vitamin B12 were measured using an automatic biochemistry analyzer. Results: We found no significant differences in the genotype frequency of A1298C and C677T between prostate cancer patients and controls. Moreover, serum levels of folate, total homocysteine, and vitamin B12 were not significantly associated with prostate cancer risk (p > 0.05). However, age and family history were identified as significant risk factors (OR = 1.178, p = 0.00 and OR = 10.03, p = 0.007, respectively). Conclusion: Our study suggests that MTHFR C677T and A1298C, as well as serum levels of folate, total homocysteine, and vitamin B12, are not associated with prostate cancer risk in the Algerian population. However, age and family history are significant risk factors. Further studies with a larger sample size are required to confirm these findings. [ABSTRACT FROM AUTHOR]

Genetic variation in the MICA and MICB genes located within the major histocompatibility complex region has been reported to be associated with transplantation outcome and susceptibility to autoimmune diseases and infections. Only limited data of polymorphism in these genes in different populations are available. We here report allelic variation at 2‐field resolution and the haplotypes of the MICA and MICB genes in Finland (n = 1032 individuals), a north European population with historical bottleneck and founder effects. Altogether 24 MICA and 18 MICB alleles were found, forming 70 estimated MICA‐MICB haplotypes. As compared to other populations frequency differences were found, for example, MICA*010:01 was found to be at an allele frequency of 0.133 in Finland which is higher than in other European populations (0.021–0.077), but close to Asian populations (0.151–0.220). Three novel alleles with amino acid change are described. The results demonstrate a relatively high level of polymorphism and population differences in MICA and MICB allele distribution. [ABSTRACT FROM AUTHOR]

Objectives: To investigate the relationships between 18 single nucleotide polymorphisms with carotid atherosclerosis and whether interactions among these genes were associated with an increased risk of carotid atherosclerosis. Methods: Face‐to‐face surveys were conducted with individuals aged 40 or older in eight communities. A total of 2377 individuals were included in the study. Ultrasound was used to detect carotid atherosclerosis in the included population. 18 loci of 10 genes associated with inflammation and endothelial function were detected. Gene‐gene interactions were analyzed using generalized multifactor dimensionality reduction (GMDR). Results: Among the 2377 subjects, 445 (18.7%) subjects had increased intima‐media thickness in the common carotid artery (CCA‐IMT), and 398 (16.7%) subjects were detected with vulnerable plaque. In addition, NOS2A rs2297518 polymorphism was associated with increased CCA‐IMT, IL1A rs1609682, and HABP2 rs7923349 polymorphisms were associated with vulnerable plaque. Besides, GMDR analysis showed significant gene‐gene interactions among TNFSF4 rs1234313, IL1A rs1609682, TLR4 rs1927911, ITGA2 rs1991013, NOS2A rs2297518, IL6R rs4845625, ITGA2 rs4865756, HABP2 rs7923349, NOS2A rs8081248, HABP2 rs932650. Conclusion: The prevalences of increased CCA‐IMT and vulnerable plaque were high in Southwestern China's high‐risk stroke population. Furthermore, inflammation and endothelial function‐related gene polymorphisms were associated with carotid atherosclerosis. [ABSTRACT FROM AUTHOR]

Adipocytes play a crucial role in the metabolism of lipids and sugars. Their response varies depending on the circumstances or other factors influenced by physiological and metabolic stresses. People living with HIV (PLWH) experience different effects of HIV and highly active antiretroviral therapy (HAART) on their body fat. Some patients respond well to antiretroviral therapy (ART), while others taking similar regimens do not. The genetic makeup of patients has been strongly linked to the variable responses to HAART among PLWH. The cause of HIV‐associated lipodystrophy syndrome (HALS) is not well understood, but it may be influenced by genetic variations in the host. The metabolism of lipid effectively modulates plasma triglyceride and high‐density lipoprotein cholesterol levels in PLWH. Genes related to drug metabolism and transport play an important role in the transportation and metabolism of ART drugs. Genetic variation in metabolizing enzyme genes of antiretroviral drugs, lipid transport and transcription factor‐related genes could interfere with fat storage and metabolism, contributing to the development of HALS. Hence we examined the impact of genes associated with transport, metabolism and various transcription factors in metabolic complications, and their impact on HALS. A study using databases such as PubMed, EMBASE and Google Scholar was conducted to understand the impact of these genes on metabolic complications and HALS. The present article discuss the changes in the expression and regulation of genes and their involvement in the lipid metabolism, lipolysis and lipogenesis pathways. Moreover, alteration of the drug transporter, metabolizing enzyme and various transcription factors can lead to HALS. Single‐nucleotide polymorphisms in genes that play an essential role in drug metabolism and drug and lipid transportation may also contribute to individual differences in the emergence of metabolic and morphological alterations during HAART treatment. [ABSTRACT FROM AUTHOR]

Introduction: Individual variability of rivaroxaban was observed in clinical application. This study aimed to identify genetic variants associated with the variability of pharmacodynamics and bleeding risk of rivaroxbaban in patients with nonvalvular atrial fibrillation (NVAF). Materials and Methods: From June 2017, and July 2019, this study enrolled 257 patients with NVAF receiving rivaroxaban. Pharmacodynamics was assessed by determining anti‐Factor Xa (anti‐FXa) level 3 h after rivaroxaban administration as peak concentration. Whole‐exome sequencing was performed to detected single nucleotide polymorphisms (SNPs). This study was registered (NCT03161496). Results: The bleeding events within 12 months were significantly related to the peak anti‐FXa level (p =.027). SUSD3 rs76292544 was associated with 12‐month bleeding events (odds ratio [OR]: 4.20, 95% confidence interval [CI]: 2.17–8.14, p = 6.43×10−5). Five SNPs including NCMAP rs4553122 (p = 2.29×10−5), PRF1 rs885821 (p = 7.02×10−5), PRKAG2 rs12703159 (p = 7.97×10−5), PRKAG2 rs13224758 (p = 8.70×10−5), and POU2F3 rs2298579 (p = 8.24×10−5) were associated with peak anti‐FXa level. Genetic variants of 52 SNPs from 36 genes including GOT2 rs14221 and MMP13 rs640198 were potentially related to 12‐month bleeding events caused by rivaroxaban's efficacy. Conclusions: Peak anti‐FXa level was associated with risk of bleeding events in patients with NVAF receiving rivaroxaban. SUSD3 rs76292544 was suggestively associated with 12‐month bleeding events and five SNPs (NCMAP rs4553122, PRF1 rs885821, PRKAG2 rs12703159, rs13224758 and POU2F3 rs2298579) were suggestively associated with peak anti‐FXa level. [ABSTRACT FROM AUTHOR]

Killer‐cell immunoglobulin‐like receptors 2DL4 (KIR2DL4) and the human leukocyte antigen class I‐G (HLA‐G) display vital parts in immune responses against hepatitis C virus (HCV) infection. We select four potentially functional single nucleotide polymorphisms (SNPs) of KIR/HLA to explore the associations between KIR2DL4/HLA‐G genetic variants and HCV infection results. In the present case‐control study, a total of 2225 HCV‐infected high‐risk subjects, including 1778 paid blood donors (PBD) and 447 drug users were consecutively recruited before treatment from 2011 to 2018. KIR2DL4‐rs660773, KIR2DL4‐rs660437, HLA‐G‐rs9380142, and HLA‐G‐rs1707 SNPs were sorted as genotypes in the subdivided groups, involving 1095 uninfected controls subjects, 432 spontaneous HCV clearance subjects and 698 HCV persistent infection subjects. After genotyping experiments using the TaqMan‐MGB assay, modified logistic regression was used to calculate the correlation among the SNPs and HCV infection. The SNPs were functionally annotated using bioinformatics analysis. Following adjusting by age, sex, alanine aminotransferase, aspartate aminotransferase, IFNL3‐rs12979860, IFNL3‐rs8099917, and the infection route, the logistic regression analysis discovered that KIR2DL4‐rs660773 and HLA‐G‐rs9380142 were correlated with vulnerability to HCV infection (all p < 0.05). In a locus‐dosage way, compared with subjects carrying the rs9380142‐AA or rs660773‐AA genotypes, subjects with rs9380142‐AG or rs660773‐AG/GG (all p < 0.05) were more vulnerable to HCV infection; the overall impact of their risk genotypes (rs9380142‐AGrs660773‐AG/GG) was correlated with an elevated incidence of HCV infection (ptrend < 0.001). In the Haplotype analysis, patients with haplotype AG were more likely to contract HCV compared to those with the highest common AA haplotype (p = 0.002) were higher in susceptibility to infect HCV. The SNPinfo web server estimated that rs660773 is a transcription factor binding site, whereas rs9380142 is a potential microRNA‐binding site. In two Chinese high‐risk population (PBD and drug uesrs), KIR2DL4 rs660773‐G and HLA‐G rs9380142‐G alleles polymorphisms are related to HCV susceptibility. KIR2DL4/HLA‐G pathway genes might affect the innate immune responses by regulating KIR2DL4/HLA‐G transcription and translation play a potential role in HCV infection. [ABSTRACT FROM AUTHOR]

Aim: To verify the association of the TNF‐α, IL‐6, and IL‐10 polymorphisms with chronic temporomandibular disorder pain development in female elderly patients. Methods: Participants were evaluated according to Diagnostic Criteria for Temporomandibular Disorders. The genomic DNA was extracted from blood according to the Salting Out method followed by a quantification using the NanoDrop spectrophotometer. The –308G/A TNF‐α polymorphism analysis was performed by the polymerase chain reaction‐restriction fragment length polymorphism technique, the determination of –174G/C IL‐6 polymorphism was performed by polymerase chain reaction, and the evaluation of the –1082A/G IL‐10 polymorphism was carried out by polymerase chain reaction‐ allele‐specific amplification. Data were analyzed using the BioEstat 5.3 software. Results: The –308G/A TNF‐α polymorphism showed a significant difference when genotypes of cases with chronic temporomandibular disorder pain and controls were compared (p =.025). There was a lack of association regarding the –174G/C IL‐6 polymorphism (p =.286) however, a positive association between the –1082A/G IL‐10 polymorphism with chronic temporomandibular disorder was observed (p =.020). Conclusion: The analyzed data of elderly subjects support the possible involvement of the GA genotype of the –308G/A TNF‐α and the AA genotype of the –1082A/G IL‐10 polymorphisms in the pathogenesis of chronic temporomandibular disorder pain. [ABSTRACT FROM AUTHOR]

Background: Previous evidence indicates significant association between genetic polymorphisms and phenotypes related to pain sensitivity in patients with temporomandibular disorders (TMD). Despite the important advances in cataloguing diverse factors such as sleep disorders, anxiety and depression, the interrelated mechanisms of painful TMD aetiopathogenesis still need investigation. Objectives: This case–control study aimed to evaluate the influence of genetic polymorphisms (rs6296, rs6295, rs1799971, rs4680, rs4633, rs4818) and psychosocial factors on the mechanical pain sensitivity and endogenous pain modulation in women with painful TMD and asymptomatic controls. Methods: We evaluated six independent variables: anxiety levels, depression, stress, sleep quality, pain catastrophising and genetic polymorphisms, and four dependent variables: mechanical pain threshold (MPT), pressure pain threshold (PPT), wind‐up ratio (WUR) and conditioned pain modulation (CPM) collected at masseter (trigeminal) and hand (spinal) areas in a sample of 95 painful TMD patients and 85 controls. A regression model was used to test the possible effect of the independent variables on dependent variables. Results: The regression model was significant for MPT (F11,168 = 9.772; R2 =.390). Painful TMD diagnoses and sleep quality were associated with trigeminal MPT (B coefficient = −.499; and B coefficient = −.211, respectively). WUR was associated with rs6295 and rs6746030, respectively, for the spinal and the trigeminal area. Conclusion: Genetic polymorphisms had a slight contribution to endogenous pain modulation as indicated by the significant association with WUR but did not contribute to mechanical pain sensitivity. On the other hand, the presence of painful TMD and the sleep quality contributed significantly to mechanical pain sensitivity. [ABSTRACT FROM AUTHOR]

The severity of COVID‐19 is associated with individual genetic host factors. Among these, genetic polymorphisms affecting natural killer (NK) cell responses, as variations in the HLA‐E‐ (HLA‐E*0101/0103), FcγRIIIa‐ (FcγRIIIa‐158‐F/V), and NKG2C‐ (KLRC2wt/del) receptor, were associated with severe COVID‐19. Recently, the rs9916629‐C/T genetic polymorphism was identified that indirectly shape the human NK cell repertoire towards highly pro‐inflammatory CD56bright NK cells. We investigated whether the rs9916629‐C/T variants alone and in comparison to the other risk factors are associated with a fatal course of COVID‐19. We included 1042 hospitalized surviving and 159 nonsurviving COVID‐19 patients as well as 1000 healthy controls. rs9916629‐C/T variants were genotyped by TaqMan assays and were compared between the groups. The patients' age, comorbidities, HLA‐E*0101/0103, FcγRIIIa‐158‐F/V, and KLRC2wt/del variants were also determined. The presence of the rs9916629‐C allele was a risk factor for severe and fatal COVID‐19 (p < 0.0001), independent of the patients' age or comorbidities. Fatal COVID‐19 was more frequent in younger patients (<69.85 years) carrying the FcγRIIIa‐158‐V/V (p < 0.006) and in older patients expressing the KLRC2del variant (p < 0.003). Thus, patients with the rs9916629‐C allele have a significantly increased risk for fatal COVID‐19 and identification of the genetic variants may be used as prognostic marker for hospitalized COVID‐19 patients. [ABSTRACT FROM AUTHOR]

Ketamine and its enantiomer S‐ketamine (esketamine) are known to produce rapid‐onset antidepressant effects in major depression. Intranasal esketamine has recently come onto the market as an antidepressant. Besides experience from short‐term use in anaesthesia and analgesia, the experience with ketamine as long‐term medication is rather low. The use of ketamine and esketamine is limited due to potential neurotoxicity, psychotomimetic side effects, potential abuse and interindividual variability in treatment response including cessation of therapy. Therefore, taking a look at individual patient risks and potential underlying variability in pharmacokinetics may improve safety and dosing of these new antidepressant drugs in clinical practice. Differential drug metabolism due to polymorphic cytochrome P450 (CYP) enzymes and gene‐drug interactions are known to influence the efficacy and safety of many drugs. Ketamine and esketamine are metabolized by polymorphic CYP enzymes including CYP2B6, CYP3A4, CYP2C9 and CYP2A6. In antidepressant drug therapy, usually multiple drugs are administered which are substrates of CYP enzymes, increasing the risk for drug–drug interactions. We reviewed the potential impact of polymorphic CYP variants and common drug–drug interactions in antidepressant drug therapy affecting ketamine pharmacokinetics, and the role for dose optimization. The use of ketamine or intranasal esketamine as antidepressants demands a better understanding of the factors that may impact its metabolism and efficacy in long‐term use. In addition to other clinical and environmental confounders, prior information on the pharmacodynamic and pharmacokinetic determinants of response variability to ketamine and esketamine may inform on dose optimization and identification of individuals at risk of adverse drug reactions. [ABSTRACT FROM AUTHOR]

The ongoing circulation of SARS‐CoV‐2 variants of concern (VOCs) has caused global concerns, because VOCs could escape current vaccines, antiviral drugs, and diagnosis. Analyzing mutations and intra‐host diversities in different and widespread VOCs can provide important insights to virus adaptive evolution and validity of vaccines, antiviral drugs, and diagnosis. In this study, by analyzing 1744 high‐throughput sequencing data for intra‐host single‐nucleotide variations (iSNVs) and 3,668,205 genome sequences for mutations in different VOCs, it was found that Omicron variant is still evolving at high speed, especially having high iSNVs frequency in its S and N genes. The efficacies of antibodies or detection primers targeting these two genes are at high risks to be invalid. Instead, highly conserved regions such as NSP8 gene could be better therapeutic and detection targets. Furthermore, mutations in later VOCs could be traced to the minor alleles in the previous variant samples such as Alpha and Delta in different countries. Finally, it was found that mutations C14408T in RdRp and A18163G in NSP14 gene might be associated with the higher genetic diversity in Omicron. Our findings not only contribute to understanding the adaptive evolution of SARS‐CoV‐2 VOCs, but also provide useful information for both drugs and diagnostic kits development. [ABSTRACT FROM AUTHOR]

Sexual imprinting is widespread in birds and other species but its existence requires explanation. Our results suggest that sexual imprinting leads to speciation in locally‐adapted populations if a neutral mating cue—e.g., novel plumage coloration—arises through mutation. Importantly, the mating cue locus is not linked to adaptation loci. Local adaptation is a necessary precursor to speciation and occurs when evolution results in stable genetic polymorphisms with one allele predominating in some areas while others predominate elsewhere. Here we use a deterministic two‐niche population genetic model to map the set of migration and selection rates for which polymorphic evolutionary outcomes, i.e., local adaptations, can occur. Approximate equations for the boundaries of the set of polymorphic evolutionary outcomes were derived by Bulmer (American Naturalist, 106, 254, 1972), but our results, obtained by deterministic simulation of the evolutionary process, show that one of Bulmer's equations is inaccurate except when the level of dominance is 0.5, and fails if one of the alleles is dominant. Having an accurate map of the set of migration and selection rates for which polymorphic evolutionary outcomes can occur, we then show using the model of Sibly et al. (Ecology and Evolution, 9, 13506, 2019) that local adaptation in all analyzed cases leads to speciation if a new neutral mating cue arises by mutation. We finish by considering how genome sequencing makes possible testing our model and its predictions. [ABSTRACT FROM AUTHOR]

NK cells monitor altered molecular patterns in tumors and infected cells through an ample array of receptors. Two families of evolutionarily distant receptors have converged to enable human NK cells to sense levels of HLA class I ligands, frequently abnormal in altered cells. Whilst different forms of polymorphism are a hallmark of killer‐cell immunoglobulin‐like receptors and their classic HLA‐A, B, and C ligands, genetic diversity of killer‐cell lectin‐like receptors for the non‐classical HLA‐E (CD94/NKG2 heterodimers) is less conspicuous and has attracted less attention. A common pattern of diversification in both receptor families is evolution of pairs of inhibitory and activating homologs for a common ligand, the genes encoding activating receptors being more frequently affected by copy number variation (CNV). This is exemplified by the gene encoding the activating NKG2C subunit (KLRC2 or NKG2C), which marks an NK‐cell subpopulation that differentiates or expands in response to cytomegalovirus. We have studied NKG2C diversity in 240 South European individuals, using polymerase chain reaction and sequencing methods to assess both gene CNV and single‐nucleotide polymorphisms (SNPs) affecting its promoter, coding and 3′‐untranslated (3′UT) regions. Sequence analysis revealed eight common SNPs—one in the promoter, two in the coding sequence, and five in the 3′UT region. These SNPs associate strongly with each other, forming three conserved extended haplotypes (frequencies: 0.456, 0.221, and 0.117). Homo‐ and heterozygous combination of these, together with complete gene deletion (0.175) and additional haplotypes with frequencies lower than 0.015, generate a diversity of NKG2C genotypes of potential immunological importance. [ABSTRACT FROM AUTHOR]

Introduction: There are few analyses of the 15 red blood group system antigen coding genes found in the Yunnan Yi nationality. This has caused many poteintial dangers relating to clinical blood transfusion. In this report, the coding genes and distribution of 15 blood group antigens system in the Yi nationality were tested and compared with those of Han nationality and other ethnic minorities. Methods: The samples came from the healthy subjects in the first people's Hospital of Qujing, Yunnan Province. Two hundred and three Yunnan Yi and 197 Han nationality individuals were included. Thirty‐three blood group antigens with a low frequency from the 15 blood group systems of Yunnan Yi blood donors were genotyped and analyzed by PCR‐SSP. Sanger sequencing was used to detect A4GALT from the Yunnan Yi nationality. The χ2 test was used to analyze observed and expected values of gene distribution to verify conformation to the Hardy‐Weinberg equilibrium law. Fisher's exact test was used to analyze gene frequency distribution, and the statistical significance was set at p < 0.05. Results: The ABO blood group examination results for the Yi nationality and the local Han nationality in Qujing City, Yunnan Province, showed the majority were type A and type O, while the least prevalent was type AB. RhD+ accounts for more than 98% of the Yi and Han populations. There was a significant difference in ABO blood group antigen distribution between these two nationalities (p < 0.05), but there was no significant difference in the composition ratio of D antigen in the Rh blood group system (p > 0.05). Compared with Tibetan (Tibet), Zhuang (Nanning), and Dong (Guangxi), the gene distribution frequencies of Rh blood group system phenotype CC were significantly lower in the Yunnan Yi nationality (p < 0.05). There were significant differences in six erythrocyte phenotypic antigens in the Yi nationality in Yunnan compared with Han nationality, such as LW(a−b−), JK(a−b+), MMSs, Di(a−b+), Wr(a−b−), and Kp(a−b+) (p < 0.05). There were gene phenotypes with a low frequency in the four rare blood group systems: LW, MNS, Wright, and Colton. Several different mutation types occurred in the P1PK blood group system's A4GALT gene. Conclusion: Yunnan Yi nationality has a unique genetic background. There are some significantly different distributions of blood group system genes with a low frequency in different regions and groups in China. Multiple mutations in the A4GALT gene of the P1PK blood group system may be related to their environment and ethnic evolution. [ABSTRACT FROM AUTHOR]

Background: There have been a large number of epidemiologic studies regarding the association between genetic polymorphisms in DNA repair genes and onset of cervical cancer. However, results are inconsistent. Methods: Articles published before June 2021 and regarding genetic polymorphisms in DNA repair genes and cervical cancer were searched in following databases: PubMed, Web of Science, Google Scholar, and CNKI. With at least three articles for each polymorphism, we made meta‐analysis to compute multivariate odds ratios (ORs) and their 95% confidence intervals (CIs). Results: The present study showed significant associations between XRCC1 Arg399Gln polymorphisms and risk of cervical cancer in Asian, whereas no significant association between them were showed in Caucasian (Asian: GA vs. GG: OR = 1.27, 95%CI 1.06–1.52; AA vs. GG: OR = 1.91, 95%CI 1.29–2.83; GA + AA vs. GG: OR = 1.36, 95%CI 1.12–1.65; AA vs. GG + GA: OR = 1.66, 95%CI 1.17–2.37; Caucasian: GA vs. GG: OR = 1.08, 95%CI 0.83–1.41; AA vs. GG: OR = 2.18, 95%CI 0.75–6.31; GA + AA vs. GG: OR = 1.23, 95%CI 0.85–1.78; AA vs. GG + GA: OR = 1.70, 95%CI 0.69–4.18). In addition, there were significant associations between ERCC2 rs13181 polymorphisms and risk of cervical cancer in Asian (AC vs AA: OR = 0.53, 95%CI 0.37–0.75, I2 = 0.0%, p value of Q test = 0.847; AC + CC vs AA: OR = 0.50, 95%CI 0.36–0.70, I2 = 0.0%, p value of Q test = 0.856). Conclusions: The meta‐analysis showed that there were significant associations between XRCC1 Arg399Gln and ERCC2 rs13181 polymorphisms and risk of cervical cancer. [ABSTRACT FROM AUTHOR]

Objective: To investigate the relationship between NADPH oxidase p22phox subunit (CYBA; C242T) and superoxide dismutase 2 (SOD2; A16V) polymorphisms and the risk of preeclampsia (PE) in Chinese women. Methods: This case‐control study included 325 patients with PE and 1294 controls. The genotypes were determined by polymerase chain reaction‐restriction fragments length polymorphism method. Clinical, metabolic, and oxidative stress parameters were analyzed. Results: Participants with T allele of the CYBA C242T polymorphism had a decreased risk of PE (OR = 0.62, 95% CI: 0.42–0.92, P = 0.016) and those with the A allele of the SOD2 A16V polymorphism had increased risk of PE (OR = 1.44, 95% CI: 1.09–1.89, P = 0.010). The coexistence of the SOD2 AA + AV genotypes and the CYBA CC genotype further increased the risk of PE (OR = 2.32, 95% CI: 1.31–4.10, P = 0.003) when the CT + TT/VV combined genotype was the reference category. Conclusion: The T allele of the CYBA C242T polymorphism is related to a decreased risk of PE, while the A allele of the SOD2 A16V polymorphism and its combination with the CYBA CC genotype are associated with an increased risk of PE in Chinese women. T allele of CYBA C242T polymorphism is a protective factor of PE and A allele of SOD2 A16V polymorphism is a risk factor of PE. [ABSTRACT FROM AUTHOR]

Coronavirus disease 2019 (COVID‐19) is an infectious disease caused by the severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2), but the pathogenesis is unclear. Host genetic background is one of the main factors influencing the patients' susceptibility to several viral infectious diseases. This study aimed to investigate the association between host genetic polymorphisms of two genes, including vitamin D receptor (VDR) and vitamin D binding protein (DBP), and susceptibility to COVID‐19 in a sample of the Iranian population. This case‐control study enrolled 188 hospitalized COVID‐19 patients as the case group and 218 suspected COVID‐19 patients with mild signs as the control group. The VDR (rs7975232, rs731236 and rs2228570) and DBP (rs7041) gene single nucleotide polymorphisms (SNPs) were genotyped by Polymerase Chain Reaction Restriction – Fragment Length Polymorphism (PCR‐RFLP) method. A significant association between rs2228570 SNP in the VDR gene and the susceptibility of COVID‐19 was found between case and control groups. The CT genotype (Heterozygous) of rs2228570 C > T polymorphism showed significant association with a 3.088 fold increased odds of COVID‐19 (p <.0001; adjusted OR: 3.088; 95% CI: 1.902–5.012). In addition, a significant association between CC genotype of rs2228570 CT polymorphism and increased odds of COVID‐19 in male and female groups (p =.001; adjusted OR: 3.125; 95% CI: 1.630–5.991 and p =.002; adjusted OR: 3.071; 95% CI: 1.485–6.354 respectively) were determined. Our results revealed no significant differences in the frequency of genotype and allele of VDR (rs7975232 and rs731236) and DBP (rs7041) between SARS‐CoV‐2‐infected patients and controls (p >.05). Our results showed that polymorphism of VDR (rs2228570) probably could influence individual susceptibility to COVID‐19. The polymorphisms of VDR (rs7975232 and rs731236) and DBP (rs7041) were not associated with SARS‐CoV‐2 infection susceptibility. [ABSTRACT FROM AUTHOR]

Novel coronavirus disease 2019 (COVID‐19) poses a global threat, due to its fluctuating frequency and lethality. Published data revealed associations of COVID‐19 susceptibility and severity with host genetic polymorphisms in renin‐angiotensin‐aldosterone system (RAAS)‐related genes including angiotensin‐converting enzyme (ACE)1, ACE2, and transmembrane protease (TMPRSS)2. However, the findings remain inconclusive. Accordingly, we aimed to clarify associations of genetic variants in those genes with COVID‐19 susceptibility and severity using a systematic review with meta‐analysis. From inception through 1 July 2021, a literature search was performed using PubMed, Scopus, Web of Science, and Cochrane Library databases. Allelic distributions for each polymorphism were calculated as pooled odds ratios (OR) with 95% confidence intervals (CI) to assess the strength of association. A total of 3333 COVID‐19 patients and 5547 controls from 11 eligible studies were included. From a systematic review, ACE1 rs1799752, ACE1 rs4646994, ACE2 rs2285666, and TMPRSS2 rs12329760 were identified as common polymorphisms of RAAS‐related genes. Meta‐analysis showed a significant association between TMPRSS2 rs12329760 C‐allele and an increased risk of developing severe COVID‐19 (OR = 1.32, 95% CI: 1.01, 1.73). Likewise, additional meta‐analyses uncovered that both ACE1 rs4646994 DD‐genotype and ACE2 rs2285666 GG‐genotype carriers had a significantly increased risk of developing severe COVID‐19 (OR = 2.06, 95% CI: 1.45, 2.93; OR = 2.14, 95% CI: 1.26, 3.66; respectively). Genetic polymorphisms of ACE1 rs4646994 DD‐genotype, ACE2 rs2285666 GG‐genotype, and TMPRSS2 rs12329760 CC‐genotype and C‐allele may serve as predictive models of COVID‐19 severity. [ABSTRACT FROM AUTHOR]

Transmissible cancers are parasitic malignant cell lineages that have acquired the ability to infect new hosts from the same species, or sometimes related species. First described in dogs and Tasmanian devils, transmissible cancers were later discovered in some marine bivalves affected by a leukaemia‐like disease. In Mytilus mussels, two lineages of bivalve transmissible neoplasia (BTN) have been described to date (MtrBTN1 and MtrBTN2), both of which emerged in a Mytilus trossulus founder individual. Here, we performed extensive screening of genetic chimerism, a hallmark of transmissible cancer, by genotyping 106 single nucleotide polymorphisms of 5,907 European Mytilus mussels. Genetic analysis allowed us to simultaneously obtain the genotype of hosts – Mytilus edulis, M. galloprovincialis or hybrids – and the genotype of tumours of heavily infected individuals. In addition, a subset of 222 individuals were systematically genotyped and analysed by histology to screen for possible nontransmissible cancers. We detected MtrBTN2 at low prevalence in M. edulis, and also in M. galloprovincialis and hybrids although at a much lower prevalence. No MtrBTN1 or new BTN were found, but eight individuals with nontransmissible neoplasia were observed at a single polluted site on the same sampling date. We observed a diversity of MtrBTN2 genotypes that appeared more introgressed or more ancestral than MtrBTN1 and reference healthy M. trossulus individuals. The observed polymorphism is probably due to somatic null alleles caused by structural variations or point mutations in primer‐binding sites leading to enhanced detection of the host alleles. Despite low prevalence, two sublineages divergent by 10% fixed somatic null alleles and one nonsynonymous mtCOI (mitochondrial cytochrome oxidase I) substitution are cospreading in the same geographical area, suggesting a complex diversification of MtrBTN2 since its emergence and host species shift. see also the Perspective by Adrian Baez‐Ortega and Elizabeth P. Murchison [ABSTRACT FROM AUTHOR]

Saxagliptin is a dipeptidyl peptidase 4 (DPP‐4) inhibitor widely used in patients with type 2 diabetes. It can increase the amount of insulin after meals and lower blood sugar. CYP450 3A4 (CYP3A4) can metabolize about 30%–40% of therapeutic drugs. Individual differences caused by CYP3A4 genetic polymorphisms can lead to treatment failure, unpredictable side effects, or severe drug toxicity. The aim of this study was to evaluate the catalytic activities of 27 CYP3A4 variants on saxagliptin metabolism in vitro, which were identified in human CYP alleles. We successfully constructed 27 kinds of wild‐type and variant vectors of pFast‐dual‐OR‐3A4 by overlap extension PCR and prepared 27 kinds of CYP3A4 highly expressed cell microsomes by baculovirus insect cell expression system. The ultra‐performance liquid chromatography tandem mass spectrometry (UPLC‐MS/MS) was used to detect the concentrations of the metabolite of saxagliptin (5‐hydroxysaxagliptin) and the internal standard. Compared with the wild‐type CYP3A4.1, the intrinsic clearance values of most varieties decreased to 1.91%–77.08%. Most of these varieties showed a decrease in Vmax and an increase in Km values compared with wild type. We are the first to report the vitro metabolic data of 27 CYP3A4 variants of the metabolism of saxagliptin which can deepen our understanding of individualized drug use by combining previous studies about the effects of CYP3A4 variants of drug metabolism. With further in vivo studies, we hope it can guide individualized drug use in the clinic when the variants with low metabolic activity to saxagliptin were sequenced in the human body. [ABSTRACT FROM AUTHOR]

We investigated the association between SLC6A3 gene polymorphisms and changes in dopamine transporter (DAT) availability after glucose loading in humans. An intravenous injection of 18F‐FP‐CIT was administered after infusion of glucose or placebo, and the emission data were acquired over 90 min in 38 healthy male participants. DAT availability expressed in terms of binding potential (BPND) was recorded. The 40‐bp variable number of tandem repeats (VNTR) in the 3′ untranslated region and two single nucleotide polymorphisms (SNPs), rs2652511 and rs2937639, in the SLC6A3 gene were genotyped. Among the 38 participants, those with a VNTR other than 10R/10R (n = 7) were excluded. The alleles of the two SNPs (rs2652511 and rs2937639) appeared to be inherited together in two fixed combinations (C–G or T–A) in 29 of 31 individuals. The BPND in the ventral striatum (VST), caudate nucleus, and putamen was not significantly different after glucose or placebo loading according to genotype. However, BPNDs from the caudate nucleus and putamen of all participants with rs2652511 CT/rs2937639 AG (n = 6) were higher after glucose loading. In conclusion, the SLC6A3 gene polymorphism is associated with the changes in DAT availability after glucose loading. DAT availability after glucose or placebo loading in the VST, caudate nucleus, and putamen did not differ according to the SLC6A3 genotype. [ABSTRACT FROM AUTHOR]

While cognitive dysfunction is an important concern in persons with type 2 diabetes mellitus (T2DM), it has received little attention in the T2DM literature. Although it often remains unrecognized, cognitive dysfunction associated with T2DM can lead to severe consequences. Prior research studies have consistently shown that aerobic exercise enhances cognitive function among healthy subjects. However, very few studies have examined the effects of aerobic exercise on cognitive function in persons with T2DM. In addition, one important single‐nucleotide polymorphism that influences cognition in humans is the brain‐derived neurotrophic factor (BDNF) Val66Met variant. Despite strong evidence suggesting aerobic exercise has a beneficial effect on cognitive function, there is significant variability in individual response to exercise programs on cognitive outcomes among Val/Val versus Met carriers. However, the evidence on how the BDNF Val66Met variant influences cognitive outcomes following an aerobic exercise intervention among individuals with T2DM is currently lacking. Therefore, the purpose of this randomized controlled trial is to pilot‐test a 3‐month supervised exercise program to improve plasma BDNF levels and cognition, overall and according to genotypes of the BDNF Val66Met variant. A total of 81 patients with T2DM will be randomly assigned to either aerobic exercise group (n = 54) or attention control group (n = 27) for 3 months. Outcomes of interest include postintervention changes in plasma BDNF levels, fasting blood glucose, hemoglobin A1c, body mass index, executive function, memory, and processing speed. This study will provide further evidence on use of exercise as a non‐pharmaceutical, low‐cost intervention to improve cognition in this population. [ABSTRACT FROM AUTHOR]

A simple, sensitive, and fully automated liquid chromatography–tandem mass spectrometry (LC–MS/MS) method was developed and validated for the simultaneous quantification of cilostazol (CIL) and its active metabolite, 3,4‐dehydro cilostazol (CIL‐M), in human plasma. Plasma samples were processed by protein precipitation in 2 mL 96‐deep‐well plates, and all liquid transfer steps were performed through robotic liquid handling workstation, enabling the whole procedure fast, compared to the reported methods. Separation of analytes was successfully achieved on a UPLC BEH C18 column (2.1 × 100 mm, 1.7 μm) with mobile phase A (5 mM ammonium formate containing 0.1% formic acid) and mobile phase B (methanol) at a flow rate of 0.30 mL min−1. The total run time was 3.5 min per sample. Mass spectrometric detection was conducted by electrospray ion source in positive ion multiple reaction monitoring mode. Calibration curves were linear over the concentration range of 1.0–800 ng·mL−1 for CIL and 0.05–400 ng·mL−1 for CIL‐M. The coefficient of variation for the assay's precision was 12.3%, and the accuracy was 88.8–99.8%. It was fully validated and successfully applied to assess the influence of CYP genotypes on the pharmacokinetics of CIL after oral administration of 50 mg tablet formulations of CIL to healthy Chinese volunteers. The results suggest that, in Chinese population, the genotype of CYP3A5 affects the plasma exposure of CIL. [ABSTRACT FROM AUTHOR]

CD247 (or CD3‐ζ chain) is an essential adaptor and signal‐transducing molecule of the T‐cell antigen receptor (TCR) complex, and it also couples to NK‐cell activating receptors such as NKp46, NKp30 and CD16A (FcγRIII). Noncoding sequence polymorphisms and variations in CD247 expression, a tightly regulated process, have been related with an altered immune response in multiple health conditions. A single nucleotide polymorphism (T > A) at nucleotide 844 of the CD247 3′‐untranslated region, rs1052231, has been related with lower CD247 gene expression and it has been investigated as a potential biomarker of autoimmune disease. We present here a simple, accurate, reliable, time‐efficient, and cost‐effective method for CD247‐rs1052231 genotyping. Using this method, based on polymerase chain reaction with confronting two‐pair primers (PCR‐CTPP), we have also characterized the CD247‐rs1052231 genotypes in a panel of worldwide available cell lines, which should facilitate study of the role of this polymorphism in immunity and human health. [ABSTRACT FROM AUTHOR]

Background: Some children with asthma experience exacerbations despite long‐acting beta2‐agonist (LABA) treatment. While this variability is partly caused by genetic variation, no genome‐wide study until now has investigated which genetic factors associated with risk of exacerbations despite LABA use in children with asthma. We aimed to assess whether genetic variation was associated with exacerbations in children treated with LABA from a global consortium. Methods: A meta‐analysis of genome‐wide association studies (meta‐GWAS) was performed in 1,425 children and young adults with asthma (age 6‐21 years) with reported regular use of LABA from six studies within the PiCA consortium using a random effects model. The primary outcome of each study was defined as any exacerbation within the past 6 or 12 months, including at least one of the following: 1) hospital admissions for asthma, 2) a course of oral corticosteroids or 3) emergency room visits because of asthma. Results: Genome‐wide association results for a total of 82 996 common single nucleotide polymorphisms (SNPs, MAF ≥1%) with high imputation quality were meta‐analysed. Eight independent variants were suggestively (P‐value threshold ≤5 × 10−6) associated with exacerbations despite LABA use. Conclusion: No strong effects of single nucleotide polymorphisms (SNPs) on exacerbations during LABA use were identified. We identified two loci (TBX3 and EPHA7) that were previously implicated in the response to short‐acting beta2‐agonists (SABA). These loci merit further investigation in response to LABA and SABA use. [ABSTRACT FROM AUTHOR]

Questionnaire‐based studies have suggested genetic differences in sleep symptoms in chronic opioid users. The present study aims to investigate if there is a genetic effect on sleep architecture and quantitative electroencephalogram (EEG) in response to acute morphine. Under a randomized, double‐blind, placebo‐controlled, crossover design, 68 men with obstructive sleep apnea undertook two overnight polysomnographic studies conducted at least 1 week apart. Each night they received either 40 mg of controlled‐release morphine or placebo. Sleep architecture and quantitative EEG were compared between conditions. Blood was sampled before sleep and on the next morning for genotyping and pharmacokinetic analyses. We analysed three candidate genes (OPRM1 [rs1799971, 118 A > G], ABCB1[rs1045642, 3435 C > T] and HTR3B [rs7103572 C > T]). We found that morphine decreased slow wave sleep and rapid eye movement sleep and increased stage 2 sleep. Those effects were less in subjects with HTR3B CT/TT than in those with CC genotype. Similarly, sleep onset latency was shortened in the ABCB1 CC subgroup compared with the CT/TT subgroup. Total sleep time was significantly increased in ABCB1 CC but not in CT/TT subjects. Sleep apnea and plasma morphine and metabolite concentration were not confounding factors for these genetic differences in sleep. With morphine, patients had significantly more active/unstable EEG (lower delta/alpha ratio) during sleep. No genetic effects on quantitative EEG were detected. In summary, we identified two genes (HTR3B and ABCB1) with significant variation in the sleep architecture response to morphine. Morphine caused a more active/unstable EEG during sleep. Our findings may have relevance for a personalized medicine approach to targeted morphine therapy. [ABSTRACT FROM AUTHOR]

Aims: To investigate the impact of cytochrome P450 2D6 (CYP2D6) on dose‐adjusted serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol in a therapeutic drug monitoring (TDM) cohort of psychiatric patients. We also studied the functional impact of CYP2D6*41 on dose‐adjusted serum concentrations in the perphenazine‐treated patients. Methods: Serum concentrations of flupentixol, haloperidol, perphenazine and zuclopenthixol from CYP‐genotyped patients were extracted retrospectively from a routine TDM database in the period March 2005 to May 2019. Samples were divided into three CYP2D6 phenotype subgroups according to genotype; normal metabolizers (NMs), intermediate metabolizers (IMs) and poor metabolizers (PMs). The effect of CYP2D6 phenotype on dose‐adjusted serum concentrations of the four antipsychotics was evaluated by multivariable mixed model analyses. Results: Mean dose‐adjusted serum concentrations of perphenazine (564 samples) were 3.9‐fold and 1.6‐fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P <.001 and P <.01). For zuclopenthixol (658 samples), mean dose‐adjusted serum concentrations were about 1.5‐fold and 1.3‐fold higher in CYP2D6 PMs and IMs, respectively, compared with NMs (P <.01 and P <.001). CYP2D6 was of minor or no importance to haloperidol (320 samples) and flupentixol (115 samples). In our data material, the genotype CYP2D6 *1/*41 appears to have a similar impact on dose‐adjusted serum concentrations of perphenazine as *1/null (null = variant allele encoding no enzyme function). Conclusions: This study shows that CYP2D6 is important for the metabolism of perphenazine and zuclopenthixol, but not for haloperidol and flupentixol. The CYP2D6*41 allele appears to have a reduced function close to nonfunctional variant alleles. [ABSTRACT FROM AUTHOR]

Personalized medicine, the treatment best suited for an individual, is a hot field of clinical research in the world. Many recent studies have shown that genetic variations have a great influence on the treatment. This study aimed to identify the distribution differences of very important pharmacogene (VIP) variants between the Tibetan population and the other 26 populations from the 1000 Genomes project. Based on the PharmGKB database, we successfully genotyped 50 VIP variants located in 27 genes in the Tibetan population. We also compared the genotype frequencies of VIP variants between Tibetan population and the other 26 populations. Without adjustment, the Chi‐square test showed that the only significant variant between Tibetans and every other group was rs1801159 in dihydropyrimidine dehydrogenase (DPYD), followed by rs1800566 in NAD(P)H quinone dehydrogenase 1 (NQO1) and rs1051296 in solute carrier family 19 member 1 (SLC19A1). After Bonferroni's multiple adjustments, the genotype frequencies distribution of DPYD rs1801159 was found to be different in Tibetans compared to the other 26 groups, apart from ACB and ASW. Moreover, genetic structure/F‐statistics (Fst) analysis and the phylogenetic tree illustrated that Tibetans had a closer affinity with CDX, CHB, CHS, JPT and KHV. Our data will complement pharmacogenomics information of the Tibetan population and provide theoretical support for the realization of individualized medical treatment for Tibetans in the future. [ABSTRACT FROM AUTHOR]

Melanocortin‐4 receptor (MC4R) gene plays a key role in the regulation of body weight and energy homeostasis. This study aims to evaluate the association of single nucleotide polymorphisms (SNPs) of the MC4R gene with live body weight and hormonal assays in two breeds of sheep that differ in productive performance, Awassi and Arabi. All known coding sequences of the MC4R gene were covered in this study. DNA samples from 150 animals (Awassi and Arabi breed) were genotyped by PCR‐single‐strand conformation polymorphism (PCR‐SSCP) to assess their pattern of genetic variation. Concerning exon 1, clear heterogeneity was detected with three different SSCP‐banding patterns. The sequencing reactions confirmed these variations by detecting the presence of the two novel SNPs, 107G/C and 138A/C, and three genotypes, GC, AC and AA. The 107G/C SNP was detected in GC genotype, while the 138A/C was detected on both GC and AC genotypes. The other SSCP‐banding pattern (AA genotype) did not show any detectable unique variation. Both SNPs were closely and strongly linked in both breeds (D' and r2 values were 1.00), which signifies that both loci were co‐inherited as one unit. Association analysis indicated that both breeds with GC/AC haplotype showed higher live body weight (37.250 ± 0.790) relative to the GG/AA (30.244 ± 0.968) and CC/CC (47.231 ± 1.230) haplotypes (p <.05). Concerning the genotyping of exon 2, only 362 bp showed heterogeneity with a missense mutation, with no significant association (p >.05) with the measured traits. In conclusion, the two novel SNPs (107G/C and 138 A/C) were highly associated with live body weight in both breeds. Haplotype analysis confirmed that these two novel SNPs were in strong linkage disequilibrium (LD) and could be used as genetic markers for sheep phenotypic trait improvement. [ABSTRACT FROM AUTHOR]

Objective: Neurologic deterioration (ND) and functional outcome after ischemic stroke (IS) are not accurately predicted by clinical pictures on admission. The aim of present study was to investigate the association of variants in P53 apoptotic pathway genes with ND and functional outcome after IS. Methods: Genotypes of nine variants in apoptosis‐relevant genes were measured in patients with acute IS. Gene–gene interactions were analyzed by generalized multifactor dimensionality reduction (GMDR). The primary outcome was ND. ND was diagnosed in patients who worsened ≥2 points (National Institutes of Health Stroke Scale [NIHSS] score) within the first 10 days of stroke onset. The secondary outcome was functional status at 90 days after IS as measured by modified Rankin Scale (mRS) score. Results: A total of 705 enrolled patients, ND occurred in 174 (24.7%) patients, and 184 (26.1%) patients were poor functional outcome (mRS score > 2). Although the nine variants were not significantly associated with ND and functional outcome by univariate analysis, there was a gene–gene interaction among P53rs1042522, MDM‐2rs2279744, and MMP‐9 rs3918242 using GMDR analysis. The high‐risk interaction among the three variants was independently associated with higher risk of ND (HR, 2.04, 95% CI: 1.22–5.64, p =.018) and poor functional outcome (OR, 2.68, 95% CI: 1.68–7.86, p =.004) after adjusting for the covariates. Conclusion: The interactions among P53 rs1042522, MDM‐2 rs2279744, and MMP‐9 rs3918242 may increase the risk of ND and poor functional outcome and may be considered as a genetic marker of predicting ND and poor functional outcome after stroke. [ABSTRACT FROM AUTHOR]

Background: Oxidative stress plays a pivotal role in the pathogenesis of polycystic ovary syndrome (PCOS). Genetic variations in myeloperoxidase (MPO; G‐463A) and NADPH oxidase p22phox subunit (CYBA; C242T) cause inter‐individual variability in enzyme activities. Here, we investigated the associations between MPO activity and the MPO G‐463A and CYBA C242T polymorphisms in Chinese women with PCOS. Methods: This case‐control study included 1003 patients with PCOS and 810 controls. The G‐463A and C242T polymorphisms were detected by polymerase chain reaction and restriction analysis, and clinical, hormonal, metabolic and oxidative stress parameters and MPO activity were analysed. Results: The frequencies of the GA + AA genotype and A allele frequency of the MPO G‐463A polymorphism were significantly higher in the PCOS group than in the control group. Logistic regression analysis showed that the MPO‐463A allele is a risk factor for PCOS (OR = 1.261, 95% CI: 1.042‐1.526, P =.017). Patients with the AA genotype tended to have higher plasma MPO activity than those with the GG genotype. No statistical significance was found in the genotype and allele frequencies of the CYBA C242T polymorphism between the PCOS and control groups. However, we demonstrated that the coexistence of the MPO A allele (GA + AA genotypes) and the CYBA CC genotype was associated with an increased risk of PCOS when compared with the wild‐type GG/CC genotypes (OR = 1.302, 95% CI: 1.030‐1.646, P =.027). Conclusion: The MPO G‐463A variant, but not CYBA C242T variant, is associated with a risk of PCOS in Chinese women. [ABSTRACT FROM AUTHOR]

Aims: Recent studies have provided evidence that interactions between variation in dopaminergic genes and stressful experiences might impact risk of psychosis. However, it remains unknown whether these interactions impact the development of subclinical symptoms, including psychotic‐like experiences (PLEs). In this study, we aimed to test the effects of interactions between variation in dopaminergic genes and traumatic life events (TLEs) on a severity of PLEs. Methods: We assessed TLEs, cognitive biases, PLEs as well as the catechol‐O‐methyltransferase (COMT) rs4680 and the dopamine D2 receptor (DRD2) rs6277 gene polymorphisms in 445 university students at three urban areas. Results: There was a significant effect of the interaction between the COMT rs4680 and a history of any type of TLEs on a severity of PLEs. Among the COMT rs4680 Met allele carriers, a severity of PLEs was higher in individuals with a history of any type of TLEs. Further stratification of the sample revealed that this effect appears only in the group of participants with a high level of cognitive biases. The DRD2 rs6277 C allele was independently associated with a higher level of PLEs. Conclusions: Our results indicate that decreased dopamine catabolism related to the COMT gene polymorphism might increase psychosis proneness in individuals with a history of TLEs and high levels of cognitive biases. Variation in the DRD2 gene might exert independent effects on psychosis proneness. These findings imply that there are various levels of complexity in the models of interactions between genetic and environmental factors explaining the mechanisms underlying psychosis proneness. [ABSTRACT FROM AUTHOR]

Differentially expressed genes in the discovery were examined to determine whether they also showed changes in peripheral blood mononuclear cells (PBMCs) obtained from ICS non-responders (n = 3) and ICS responders (n = 3) from the SLOVENIA study,4 defined based on the presence or absence of asthma exacerbations despite ICS therapy. Asthma treatment, childhood asthma, exacerbations, genetic polymorphism, pharmacogenomics Keywords: asthma treatment; childhood asthma; exacerbations; genetic polymorphism; pharmacogenomics EN asthma treatment childhood asthma exacerbations genetic polymorphism pharmacogenomics 1238 1243 6 04/14/21 20210401 NES 210401 To the Editor, An increasing number of therapies are available to treat asthma, but inhaled corticosteroids (ICS) are still the most commonly prescribed and effective controller asthma medication.1 Both environmental and genetic factors are involved in ICS response. Details about each study are described at the Supporting Information and elsewhere.4 Individuals with asthma exacerbations despite ICS treatment were considered as ICS non-responders and those without asthma exacerbations as ICS responders. [Extracted from the article]

The Toll‐like receptor (TLR) family acts as a bridge connecting innate and acquired immunity. TLR10 remains one of the least understood members of this family. Some studies have examined TLR10 ligands, dimerization of TLR10 with other TLRs, and downstream signalling pathways and functions, but they have often arrived at conflicting conclusions. TLR10 can induce the production of proinflammatory cytokines by forming homodimers with itself or heterodimers with TLR1 or other TLRs, but it can also inhibit proinflammatory responses when co‐expressed with TLR2 or potentially other TLRs. Mutations in the Toll/Interleukin 1 receptor (TIR) domain of TLR10 alter its signalling activity. Polymorphisms in the TLR10 gene can change the balance between pro‐ and anti‐inflammatory responses and hence modulate the susceptibility to infection and autoimmune diseases. Understanding the full range of TLR10 ligands and functions may allow the receptor to be exploited as a therapeutic target in inflammation‐ or immune‐related diseases. Here, we summarize recent findings on the pro‐ and anti‐inflammatory roles of TLR10 and the molecular pathways in which it is implicated. Our goal is to pave the way for future studies of the only orphan TLR thought to have strong potential as a target in the treatment of inflammation‐related diseases. [ABSTRACT FROM AUTHOR]

Objectives: The objective of this study was to establish physiologically based pharmacokinetic (PBPK) models of tramadol and its active metabolite O‐desmethyltramadol (M1) and to explore the influence of CYP2D6 gene polymorphism on the pharmacokinetics of tramadol and M1. Furthermore, we used PBPK modeling to prospectively predict the extent of drug‐drug interactions (DDIs) in the presence of genetic polymorphisms when tramadol was co‐administered with the CYP2D6 inhibitors duloxetine and paroxetine. Methods: Plasma concentrations of tramadol and M1 were used to adjust the turnover frequency (Kcat) of CYP2D6 for phenotype populations with different CYP2D6 genotypes. PBPK models were developed to capture the pharmacokinetics between CYP2D6 extensive metabolizers (EMs), intermediate metabolizers (IMs), poor metabolizers (PMs), and ultra‐rapid metabolizers (UMs). The validated models were then used to support dose adjustment in different CYP2D6 phenotypes and to predict the extent of CYP2D6‐mediated DDIs when tramadol was co‐administered with paroxetine or duloxetine. Results: The PBPK models we built accurately describe tramadol and M1 exposure in the population with different CYP2D6 phenotypes. In our prediction, the area under the concentration‐time curve (AUCinf‐tDlast) of M1 is 70% lower in PMs than in EMs, 27% lower in IMs, and 15% higher in UMs. Based on the models we built, we suggest that the oral dose of tramadol should be 50% higher for IMs and 25% lower for UMs to achieve an approximately equivalent plasma exposure of M1 as in EMs. When tramadol was co‐administered with paroxetine or duloxetine, the magnitude of the inhibitor‐substrate interaction was lowest in EMs (0.45), secondary in IMs (0.39), and highest in PMs (0.18) in terms of M1. Conclusion: The current example uses the PBPK model to guide dose adjustment of tramadol and to predict the effect of CYP2D6 genetic polymorphisms on DDIs for rational clinical use of tramadol in the future. [ABSTRACT FROM AUTHOR]