The Frequencies distribution of CYP3A5 rs776746 and ABCB1 rs1045642 polymorphisms in the west Algerian population and relationships with pharmacogenetics.

Introduction: Pharmacogenetic markers, such as the ATP Binding Cassette (ABCB1) and cytochrome P450 (CYP) 3A5 enzymes, play a crucial role in personalized medicine by influencing drug efficacy and toxicity based on individuals' or populations' genetic variations.This study aims to investigate the genetic polymorphisms of CYP3A5 (rs776746) and ABCB1 (rs1045642) in the West Algerian population and compare the genotypes and allelic distributions with those of various ethnic groups. Methods: The study involved 472 unrelated healthy subjects from the Western Algerian population. DNA genotyping was performed using TaqMan allelic discrimination assay. The variants in our population were compared to those in other ethnic groups available in the 1000 Genomes Project. Genotype and allele frequencies were calculated using the chi-square test and the Hardy-Weinberg equilibrium (HWE). Results: The minor allele frequencies were found to be 0.21 for CYP3A5 6986A and 0.34 for ABCB1 3435T. These frequencies were similar to those observed in North African populations, while notable differences were observed in comparison to certain Caucasian and African populations. Conclusion: The difference in the allelic and genotypic distribution of these polymorphisms emphasize the need for dose adjustments in drugs metabolized by CYP3A5 and transported by ABCB1 to optimize treatments outcomes.

The effect on the equilibrium sickle cell allele frequency of the probable protection conferred by malaria and sickle cell gene against other infectious diseases.

If a mutated gene with heterozygous advantage against malaria, e.g., hemoglobin S (HbS) gene, is introduced in a small tribe, the gene (allele) frequency (fgene) increases until it reaches a steady state value (feq) where the total mortality from malaria and sickle cell disease is a minimum. This is a classic example of balanced-polymorphism named malaria hypothesis. In a previous in silico study, assuming realistic initial conditions, it has been shown that the feq is around 14%, far less than the fgene observed in certain parts of Africa, 24%. It seems that the malaria hypothesis, per se, could not explain such a high fgene, unless it is assumed that malaria and HbS gene can provide protection against other diseases. Using Monte-Carlo simulation, the current study was conducted to examine the effect on feq of five scenarios was examined. The studied scenarios consisted of different combinations of mortality of other diseases and the possible amounts of protections conferred by malaria and HbS gene against the diseases. Taking into account other diseases causing mortality in the population makes the fgene rate of change steeper over generations. feq is an increasing function of the amount of protection conferred by HbS gene against other diseases. The effect of protection provided by malaria against other diseases on feq, is however, variable-depending on the amount of protection conferred by HbS gene against other diseases, it may increase or decrease feq. If malaria and HbS gene provide protections of 1.5-fold and threefold against other diseases, respectively, the feq is around 24%, the amount reported in certain tribes of Africa. Under certain scenarios, the feq attained is even higher.

NLRP3 (rs10754558) gene polymorphism and tumor necrosis factor alpha as predictors for disease activity and response to methotrexate and adalimumab in psoriasis.

BACKGROUND: Psoriasis has a global prevalence of 1-3%, with variations observed across different ethnic groups and geographical areas. Disease susceptibility and response to anti-tumor necrosis factor-α (TNFα) drugs suggest different genetic regulatory mechanisms which may include NLR family pyrin domain containing 3 (NLRP3) polymorphism. Evaluation of the NLRP3 gene polymorphism, the serum level of CRP and TNFα in psoriasis patients and assessment of the NLRP3 (rs10754558) gene polymorphism, CRP and TNFα with disease severity and their role as biomarkers for response to Methotrexate and Adalimumab in psoriasis. The study had a total of 75 patients diagnosed with psoriasis vulgaris, who were compared to a control group of 75 healthy individuals. RESULTS: There was a highly significant difference in NLRP3 genotypes and alleles distribution between psoriasis patients and controls (P = 0.002,0.004). The heterozygote genotype GC (OR = 3.67,95%CI:1.75-7.68, P = 0.0006), was linked with increased risk of psoriasis. Additionally, The GC genotype was significantly associated with nonresponse to psoriasis therapy (OR = 11.7,95%CI:3.24-42.28, P = 0.0002). Regarding serum CRP and TNFα levels, there was a highly statistically significant difference between psoriasis patients and controls (P < 0.0001), and there was also a highly statistically significant difference between responders and non-responders in psoriasis patients regarding PASI 50 (P < 0.0001). CONCLUSIONS: The NLRP3 (rs10754558) genotypes GC was associated with the severe form of psoriasis and with nonresponse to psoriasis medication. Therefore, NLRP3 (rs10754558) gene polymorphism is an important prognostic biomarker in psoriasis patients. The serum TNFα can be used as a predictor for response to therapy in psoriasis patients. More research for evaluation of role of the NLRP3 gene polymorphism in the genetic risks and treatment outcomes associated with psoriasis is still required.

Association between HLA alleles and haplotypes with age at diagnosis of type 1 diabetes in an admixed Brazilian population: A nationwide study.

To investigate the potential relationship between HLA alleles and haplotypes and the age at diagnosis of type 1 diabetes (T1DAgeD) in an admixed Brazilian population. This nationwide study was conducted in public clinics across 12 Brazilian cities. We collected demographic and genetic data from 1,600 patients with T1D. DNA samples were utilised to determine genomic ancestry (GA) and perform HLA typings for DRB1, DQA1 and DQB1. We explored allele and haplotype frequencies and GA in patients grouped by T1DAgeD categories (<6 years, ≥6-<11 years, ≥11-<19 years and ≥19 years) through univariate and multivariate analyses and primary component analyses. Additionally, we considered self-reported colour-race and identified a familiar history of T1D in first-degree relatives. The homozygosity index for DRB1~DQA1~DQB1 haplotypes exhibited the highest variation among T1DAgeD groups, and the percentages of Sub-Saharan African and European ancestries showed opposite trends in principal component analysis (PCA) analyses. Regarding the association of alleles and haplotypes with T1DAgeD, risk alleles such as HLA-DQB1*03:02g, -DQA1*03:01g, -02:01g, DRB1*04:05g and -04:02g were more frequently observed in heterozygosity or homozygosity in T1D patients with an early disease onset. Conversely, alleles such as DRB1*07:01g, -13:03g, DQB1*06:02g and DQA1*02:01 were more prevalent in older T1D patients. The combination DR3/DR4.5 was significantly associated with early disease onset. However, gender, GA, familiar history of T1D and self-reported colour-race identity did not exhibit significant associations with the onset of T1D. It is worth noting that the very common risk haplotype DRB1*03:01g~DQA1*05:01g~DQB1*02:01g did not differentiate between T1DAgeD groups. In the admixed Brazilian population, the high-risk haplotype DRB1*04:05~DQA1*03:01~DQB1*03:02 was more prevalent in individuals diagnosed before 6 years of age. In contrast, the protective alleles DQA1*01:02g, DQB1*06:02g, DRB1*07:01g and DRB1*13:03g and haplotypes DRB1*13:03g~DQA1*05:01g~DQB1*03:01g and DRB1*16:02g~DQA1*01:02g~DQB1*05:02g were more frequently observed in patients diagnosed in adulthood. Notably, these associations were independent of factors such as sex, economic status, GA, familiar history of T1D and region of birth in Brazil. These alleles and haplotypes contribute to our understanding of the disease onset heterogeneity and may have implications for early interventions when detected in association with well-known genomic risk or protection factors for T1D.

Association of IL-13 rs20541, FOXP3 rs3761548 genes polymorphisms and serum level of IL-13 with allergic asthma in Egyptian patients.

The interleukin 13 (IL-13) gene single nucleotide polymorphisms (SNPs) are frequently linked to increased vulnerability to allergic asthma. Forkhead box protein P3 (FOXP3) is an important molecule in the formation of regulatory T cells (Treg). The genetic variants that alter FOXP3 function may have a role in the development of asthma and other allergic disorders. We aimed to determine the association of IL-13 rs20541, FOXP3 rs3761548 genes SNPs and serum levels of IL-13 with allergic asthma patients. In this case-control study, 41 Egyptian patients with allergic asthma were included. Age and gender matched. 41 normal volunteers were considered the controls. All subjects were examined for IL-13 rs20541 and FOXP3 rs3761548 SNPs by the polymerase chain reaction /restriction fragment length polymorphism technique. The serum level of IL-13 was assessed by the enzyme linked immunosorbent assay (ELISA). AA genotype at IL-13 rs20541 SNP was statistically significantly different between the studied groups (p= 0.042). Also, a statistically significant difference was detected when compared AA genotype to GG genotype as AA genotype was three times at risk for asthma (p1=0.031) (OR=3.95) and A allele increased the risk of asthma by about 3 times (OR=3.2). AA genotype at FOXP3 rs3761548 SNP was statistically significantly different between the studied groups (p=0.013). Also, a statistically significant difference was detected when compared AA genotype to CC genotype as AA genotype was 7 times at risk for asthma (p1=0.003) (OR=7.04) and A allele increased the risk of asthma by about 3 times (p<0.001) (OR=3.07). The serum level of IL-13 was statistically significant different between both groups (p<0.001). We can conclude that IL-13 could be a useful tool for predicting allergic asthma. Patients with AA genotype of IL-13 rs20541 and AA genotype of FOXP3 rs3761548 have a higher risk for developing allergic asthma.

Transcription factor 7 like 2 gene polymorphism and advanced glycation end products as risk factors for diabetic nephropathy.

Hepatocellular carcinoma (HCC) is a multifactorial disease with both genetic and environmental factors contributing to its pathogenesis. ACYP2 is a gene that is related to cell differentiation, apoptosis and prevention of malignant tumors. The ACYP2 gene also affects telomere length. The aim of this study was to evaluate the association between ACYP2 single nucleotide polymorphisms (SNPs) (rs843711), and (rs843706) and incidence of HCC in Egyptian HCC patients. The study included 30 patients with HCC and 30 normal controls. Detection of ACYP2 gene SNPs rs843711, and rs843706 in all study participants was done using real time polymerase chain reaction (RT-PCR). The results showed that all participants including HCC patients and controls carried the heterozygous CA (100%) of the rs843706 SNP (p> 0.05). As for the rs843711, 3.3% of HCC patients had the homozygous TT genotype, 46.7% had the heterozygous CT genotype and 50% had the wild CC genotype, while in the control group, 60% had the heterozygous CT genotype and 40% had the wild CC genotype with no significant difference between both groups (p>0.05). We concluded that there was no association between SNPs ACYP2 rs843706 and rs843711 and occurrence of HCC.

Association between OX40L polymorphism and type 2 diabetes mellitus in Iranians.

INTRODUCTION: Diabetes mellitus (DM) is one of the leading causes of morbidity and mortality worldwide. It is a multifactorial disease that genetic and environmental factors contribute to its development. The aim of the study was to investigate the association of OX40L promoter gene polymorphisms with type 2 diabetes mellitus (T2DM) in Iranians. MATERIALS AND METHODS: Three hundred and sixty-eight subjects including 184 healthy subjects and 184 T2DM patients were enrolled in our study. Polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was applied to detect genotype and allele frequencies of rs3850641, rs1234313 and rs10912580. In addition, SNPStats web tool was applied to estimate haplotype frequency and linkage disequilibrium (LD). RESULTS: The distribution of tested polymorphisms was statistically different between the T2DM patients and healthy subjects (P < 0.01). rs1234313 AG (OR = 0.375, 95% CI = 0.193-0.727, P = 0.004) and rs10912580 AG (OR = 0.351, 95% CI = 0.162-0.758, P = 0.008) genotypes were associated with the decreased risk of T2DM in Iranians. Moreover, our prediction revealed that AAG (OR = 0.46, 95% CI= (0.28-0.76), P = 0.0028) and GAG (OR = 0.24, 95% CI= (0.13-0.45), P < 0.0001) haplotypes were related to the reduced risk of the disease. However, the tested polymorphisms had no effect on biochemical parameters and body mass index (BMI) in the patient group (P > 0.05). CONCLUSION: Our findings revealed that OX40L promoter gene polymorphisms are associated with T2DM. Moreover, genotype and allelic variations were related to the decreased risk of T2DM in Iranians. Further studies are recommended to show whether these polymorphic variations could affect OX40/OX40L interaction or OX40L phenotype.

[Relationship between maternal and fetal ERAP-1 gene polymorphism and pre-eclampsia].

Objective: To investigate the relationship between the polymorphism of endoplasmic reticulum aminopeptidase 1 (ERAP-1) gene and the occurrence of pre-eclampsia (PE). Methods: A case-control study was conducted in Beijing Obstetrics and Gynecology Hospital from October 2018 to October 2021. A total of 51 PE pregnant women with onset gestational age<34 weeks were selected as the PE group, and 48 normal pregnant women during the same period were selected as the control group. Venous blood samples were collected from the pregnant women before delivery and umbilical cord within 5 minutes after delivery. Single nucleotide polymorphisms (SNP) of ERAP-1 gene in the pregnant women and their fetus were detected by next-generation sequencing. Univariate analysis and multivariate logistic regression analysis were used to analyze all the SNP loci and alleles detected in the two groups, and the significant SNP were screened. Results: (1) A total of 13 target SNP loci of maternal ERAP-1 gene were selected by univariate analysis. Among them, the frequency distribution of genotypes at 96096828, 96121524, 96121715, 96122260 and 96122281 showed statistically significant differences between PE group and control group (all P<0.05). Multivariate logistic regression analysis showed that the risk of PE in pregnant women with TC genotype at locus 96121524 was 2.002 times higher than those with TT genotype (95%CI: 0.687-5.831, P=0.020). (2) A total of 4 target SNP loci of ERAP-1 gene in fetal were selected by univariate analysis, and there was no statistical significance in gene polymorphism of the 4 loci between PE group and control group (all P>0.05). Multivariate logistic regression analysis showed that the risk of PE in fetus with genotype AA at locus 96121406 was 0.236 times that of fetus with genotype GG (95%CI: 0.055-1.025, P=0.016). Conclusion: ERAP-1 gene with TC genotype at 96121524 in the mother and GG genotype at 96121406 in the fetus might be related to the incidence of PE.

[Association of the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene with preeclampsia among Chinese women].

OBJECTIVE: To assess the association of -c.108C>T and c.192Q>R polymorphisms of paraoxonase 1 (PON1) gene with preeclampsia (PE) and the influence of genotypes on the metabolic and oxidative stress indexes among Chinese women. METHODS: This case-control study has included 334 patients with PE and 1337 healthy pregnant women. The -c.108C>T and c.192Q>R genotypes were determined by PCR and restriction fragment length polymorphism method. Metabolic and oxidative stress parameters were also analyzed. RESULTS: No statistical difference in the genotypic and allelic frequencies for the -c.108C>T and c.192Q>R polymorphisms of the PON1 gene was found between the PE patients and the healthy controls (P > 0.05). Nevertheless, the 192Q-108T haplotype of these polymorphisms was associated with an increased risk of PE (P = 0.007). Total antioxidant capacity (TAC) and atherosderosis index were higher in patients with the -108TT genotype compared with those with a CT genotype (P < 0.05); whilst total oxidant status was lower in patients with a CT genotype compared with those with a CC genotype (P = 0.036). Malondialdehyde level was higher in patients with a 192RR genotype compared with those with a QQ genotype (P = 0.019). TAC level was higher in patients with a RR genotype compared with those with a QR genotype (P = 0.015). CONCLUSION: The 192Q-108T haplotype of the PON1 gene is associated with the risk for PE. These polymorphisms may be associated with abnormal lipid metabolism and oxidative stress among Chinese PE patients.

Impact of Toll-like receptor 2 (rs5743708) gene polymorphism in pediatric pneumonia: risk and severity.

Pediatric pneumonia is a common respiratory infection that affects children and is thought to be a major source of mortality and morbidity worldwide, particularly in low- and middle-income nations. Toll-like receptor2 (TLR2) is an important receptor involved in the recognition of bacterial pathogens and the activation of the immune response. Genetic variability in TLR2 may partially explain individual differences in susceptibility to infections. The purpose of this study was to investigate the possible contribution of the TLR2 (rs5743708) variant to the risk and severity of pediatric pneumonia infection. The study included 100 pediatric patients diagnosed with pneumonia and 100 normal controls who were age and gender matched. Real-time polymerase chain reaction (PCR) was used to genotype participants for the TLR2 (rs5743708) variant. The analysis revealed that children with the TLR2 (rs5743708) (G/A) genotype showed a 2.52-fold greater risk of having pneumonia (OR: 2.52; 95% CI: 1.32-4.79; p = 0.005) in comparison with patients who have wild homozygous genotypes. Furthermore, we observed that the TLR2 (rs5743708) (A) allele is connected to a greater risk of pneumonia infection in children (OR: 1.612; 95% CI: 1.07-2.43; p = 0.023) but did not significantly influence infection severity. In conclusion, children with the TLR2 (rs5743708) mutant (G/A) genotype and (A) allele had a significantly higher risk of having pneumonia, but they were not at high risk for the severity of the infection.

HLA-A*24 Increases the Risk of HTLV-1-Associated Myelopathy despite Reducing HTLV-1 Proviral Load.

Increased human T-cell leukemia virus type 1 (HTLV-1) proviral load (PVL) is a significant risk factor for HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). There is controversy surrounding whether HTLV-1-specific cytotoxic T lymphocytes (CTLs) are beneficial or harmful to HAM/TSP patients. Recently, HTLV-1 Tax 301-309 has been identified as an immunodominant epitope restricted to HLA-A*2402. We investigated whether HLA-A*24 reduces HTLV-1 PVL and the risk of HAM/TSP using blood samples from 152 HAM/TSP patients and 155 asymptomatic HTLV-1 carriers. The allele frequency of HLA-A*24 was higher in HAM/TSP patients than in asymptomatic HTLV-1 carriers (72.4% vs. 58.7%, odds ratio 1.84), and HLA-A*24-positive patients showed a 42% reduction in HTLV-1 PVL compared to negative patients. Furthermore, the PVL negatively correlated with the frequency of Tax 301-309-specific CTLs. These findings are opposite to the effects of HLA-A*02, which reduces HTLV-1 PVL and the risk of HAM/TSP. Therefore, we compared the functions of CTLs specific to Tax 11-19 or Tax 301-309, which are immunodominant epitopes restricted to HLA-A*0201 or HLA-A*2402, respectively. The maximum responses of these CTLs were not different in the production of IFN-γ and MIP-1ß or in the expression of CD107a-a marker for the degranulation of cytotoxic molecules. However, Tax 301-309-specific CTLs demonstrated 50-fold higher T-cell avidity than Tax 11-19-specific CTLs, suggesting better antigen recognition at low expression levels of the antigens. These findings suggest that HLA-A*24, which induces sensitive HTLV-1-specific CTLs, increases the risk of HAM/TSP despite reducing HTLV-1 PVL.

TLR2 and TLR4 Polymorphisms Are Not Associated with Dental Caries in Polish Children.

The aim of the present study was to analyze the association of the TLR2 (Toll-like receptor 2 gene) 2258G>A (rs5743708), TLR4 (Toll-like receptor 4 gene) 896A>G (rs4986790), and TLR4 1196C>T (rs4986791) polymorphisms with dental caries in Polish children. The participants, 261 15-year-old children, were divided into two groups: 82 cases (i.e., children with DMFT (Decayed, Missing, and Filled Teeth) index >5, having either moderate or high caries experience, assigned as the "higher" caries experience group) and 179 controls (i.e., children with DMFT ≤ 5, having either low or very low caries experience, assigned as the "lower" caries experience group). Genomic DNA was isolated from buccal swabs, and genotyping was determined by means of real-time PCR (polymerase chain reaction). There were no significant differences in the genotype or allele distributions in all tested SNPs (single nucleotide polymorphisms) between children with "higher" caries experience and those with "lower" caries experience. TLR4 haplotype frequencies did not differ significantly between cases and controls. In an additional analysis with another case definition applied (subjects with DMFT ≥ 1 were assigned as "cases", whereas children with DMFT = 0 were assigned as "controls"), no significant differences in the TLR2 and TLR4 genotype, allele frequencies, and TLR4 haplotype frequencies were found between the case and the control groups. The results of the present study broaden our knowledge on the potential genetic factors that might affect caries risk and suggest that TLR2 rs5743708 and TLR4 rs4986790 and rs4986791 SNPs are not associated with dental caries susceptibility in Polish children.

CCR5 Δ32 and CTLA-4 +49 A/G Gene Polymorphisms and Interferon-ß Treatment Response in Croatian and Slovenian Multiple Sclerosis Patients.

The aim of the present study was to investigate the impact of CCR5 Δ32 and CTLA-4 polymorphisms on the response to IFN-ß treatment in our cohort of MS patients from Croatia and Slovenia. Genomic DNA was obtained from 295 MS patients (230 female; 65 male) classified as responders (n = 173) and non-responders (n = 122) based on clinical criteria for treatment efficacy. Genotyping was performed via PCR/PCR-RFLP. No significant differences in the genotype/allele frequencies of CCR5Δ32 and CTLA-4 +49 A/G were detected between male responders and non-responders. A significantly higher prevalence (p = 0.039) of the CTLA-4 +49 AA genotype was found in female responders (42.1%) compared to non-responders (28.9%). Using multiple forward regression analysis, the CTLA-4 +49 AA genotype significantly predicted a positive response to IFN-ß therapy in females (p = 0.011) and contributed to 4.5% of response variability. Furthermore, the combined presence of the CCR5Δ32 wtwt/CTLA-4 +49 AA genotype significantly predicted a positive response to treatment in females (p = 0.025). The age at disease onset, pretreatment relapse rate, and baseline EDSS score were not reliable predictors of treatment response in MS patients. Our results indicate that the presence of the CCR5Δ32 polymorphism was not associated with the response to IFN-ß treatment, whereas the CTLA-4 +49 polymorphism showed a positive correlation with an optimal response in female patients.

Building on the clinical applicability of ctDNA analysis in non-metastatic pancreatic ductal adenocarcinoma.

Pancreatic ductal adenocarcinoma represents one of the solid tumors showing the worst prognosis worldwide, with a high recurrence rate after adjuvant or neoadjuvant therapy. Circulating tumor DNA analysis raised as a promising non-invasive tool to characterize tumor genomics and to assess treatment response. In this study, surgical tumor tissue and sequential blood samples were analyzed by next-generation sequencing and were correlated with clinical and pathological characteristics. Thirty resectable/borderline pancreatic ductal adenocarcinoma patients treated at the Hospital Universitario de Navarra were included. Circulating tumoral DNA sequencing identified pathogenic variants in KRAS and TP53, and in other cancer-associated genes. Pathogenic variants at diagnosis were detected in patients with a poorer outcome, and were correlated with response to neoadjuvant therapy in borderline pancreatic ductal adneocarcinoma patients. Higher variant allele frequency at diagnosis was associated with worse prognosis, and thesum of variant allele frequency was greater in samples at progression. Our results build on the potential value of circulating tumor DNA for non-metastatic pancreatic ductal adenocarcinoma patients, by complementing tissue genetic information and as a non-invasive tool for treatment decision. Confirmatory studies are needed to corroborate these findings.

Evaluation of heritability partitioning approaches in livestock populations.

BACKGROUND: Heritability partitioning approaches estimate the contribution of different functional classes, such as coding or regulatory variants, to the genetic variance. This information allows a better understanding of the genetic architecture of complex traits, including complex diseases, but can also help improve the accuracy of genomic selection in livestock species. However, methods have mainly been tested on human genomic data, whereas livestock populations have specific characteristics, such as high levels of relatedness, small effective population size or long-range levels of linkage disequilibrium. RESULTS: Here, we used data from 14,762 cows, imputed at the whole-genome sequence level for 11,537,240 variants, to simulate traits in a typical livestock population and evaluate the accuracy of two state-of-the-art heritability partitioning methods, GREML and a Bayesian mixture model. In simulations where a single functional class had increased contribution to heritability, we observed that the estimators were unbiased but had low precision. When causal variants were enriched in variants with low (< 0.05) or high (> 0.20) minor allele frequency or low (below 1st quartile) or high (above 3rd quartile) linkage disequilibrium scores, it was necessary to partition the genetic variance into multiple classes defined on the basis of allele frequencies or LD scores to obtain unbiased results. When multiple functional classes had variable contributions to heritability, estimators showed higher levels of variation and confounding between certain categories was observed. In addition, estimators from small categories were particularly imprecise. However, the estimates and their ranking were still informative about the contribution of the classes. We also demonstrated that using methods that estimate the contribution of a single category at a time, a commonly used approach, results in an overestimation. Finally, we applied the methods to phenotypes for muscular development and height and estimated that, on average, variants in open chromatin regions had a higher contribution to the genetic variance (> 45%), while variants in coding regions had the strongest individual effects (> 25-fold enrichment on average). Conversely, variants in intergenic or intronic regions showed lower levels of enrichment (0.2 and 0.6-fold on average, respectively). CONCLUSIONS: Heritability partitioning approaches should be used cautiously in livestock populations, in particular for small categories. Two-component approaches that fit only one functional category at a time lead to biased estimators and should not be used.

Association of interleukin6 rs1800796 gene polymorphism and serum level with bladder cancer in Egyptian population.

BACKGROUND: Urinary bladder cancer (UBC)is a common tumor of the urinary tract. OBJECTIVES: To assess the diagnostic significance of IL6 rs1800796 gene polymorphism and IL6 serum level among Egyptian patients with UBC. DESIGN AND METHODS: One hundred patients with UBC were selected from the Mansoura Urology and Nephrology Center, in addition to 100 healthy control subjects; using PCR and ELISA techniques for IL6 detection. RESULTS: The rs1800796 GC, CC genotypes, and C allele were significantly more prevalent in the cases with bladder cancer compared to the healthy group (p < 0.001, = 0.021, < 0.001 respectively). There was a clear association between elevated levels of IL6 and bladder cancer versus the control group (median = 4.2, 0.89 respectively, p < 0.001). Serum IL6 levels showed significantly higher levels in patients carrying CC, followed by GC then GG genotypes. No significant association was found between IL6 rs1800796 gene polymorphism or serum level with demographic or laboratory data. CONCLUSION: It is suggested that there is a clear link between elevated IL6 levels as well as IL6 rs1800796 gene polymorphism with bladder cancer, suggesting their potential utility as biomarkers for the disease.

Worldwide distribution of genetic factors related to severity of COVID-19 infection.

BACKGROUND: Genome-wide association studies of COVID-19 severity have been carried out mostly on European or East Asian populations with small representation of other world regions. Here we explore the worldwide distribution and linkage disequilibrium (LD) patterns of genetic variants previously associated with COVID-19 severity. METHODS: We followed up the results of a large Spanish genome-wide meta-analysis on 26 populations from the 1000 Genomes Project by calculating allele frequencies and LD scores of the nine most significant SNPs. We also used the entire set of summary statistics to compute polygenic risk scores (PRSs) and carried out comparisons at the population and continental level. RESULTS: We observed the strongest differences among continental regions for the five top SNPs in chromosome 3. European, American, and South Asian populations showed similar LD patterns. Average PRSs in South Asian and American populations were consistently higher than those observed in Europeans. While PRS distributions were similar among South Asians, the American populations showed striking differences among them. CONCLUSIONS: Considering the caveats of PRS transferability across ethnicities, our analysis showed that American populations present the highest genetic risk score, hence potentially higher propensity, for COVID-19 severity. Independent validation is warranted with additional summary statistics and phenotype data.

Apolipoprotein E E3/E4 genotype is associated with an increased risk of premature coronary artery disease.

OBJECTIVE: Dyslipidemia is one of the causes of coronary heart disease (CAD), and apolipoprotein E (APOE) gene polymorphism affects lipid levels. However, the relationship between APOE gene polymorphisms and premature CAD (PCAD, male CAD patients with ≤ 55 years old and female with ≤ 65 years old) risk had different results in different studies. The aim of this study was to assess this relationship and to further evaluate the relationship between APOE gene polymorphisms and PCAD risk in the Hakka population. METHODS: This study retrospectively analyzed 301 PCAD patients and 402 age matched controls without CAD. The APOE rs429358 and rs7412 polymorphisms were genotyped by polymerase chain reaction (PCR) -chip technique. The distribution of APOE genotypes and alleles between the case group and the control group was compared. The relationship between APOE genotypes and PCAD risk was obtained by logistic regression analysis. RESULTS: The frequency of the APOE ɛ3/ɛ4 genotype (18.9% vs. 10.2%, p = 0.001) and ε4 allele (11.1% vs. 7.0%, p = 0.007) was higher in the PCAD patients than that in controls, respectively. PCAD patients with ɛ2 allele had higher TG level than those with ɛ3 allele, and controls carried ɛ2 allele had higher HDL-C level and lower LDL-C level than those carried ɛ3 allele. Regression logistic analysis showed that BMI ≥ 24.0 kg/m2 (BMI ≥ 24.0 kg/m2 vs. BMI 18.5-23.9 kg/m2, OR: 1.763, 95% CI: 1.235-2.516, p = 0.002), history of smoking (Yes vs. No, OR: 5.098, 95% CI: 2.910-8.930, p < 0.001), ɛ3/ɛ4 genotype (ɛ3/ɛ4 vs. ɛ3/ɛ3, OR: 2.203, 95% CI: 1.363-3.559, p = 0.001), ε4 allele (ε4 vs. ε3, OR: 2.125, 95% CI: 1.333-3.389, p = 0.002), and TC level (OR: 1.397, 95% CI: 1.023-1.910, p = 0.036) were associated with PCAD. CONCLUSIONS: In summary, BMI ≥ 24.0 kg/m2, history of smoking, APOE ɛ3/ɛ4 genotype, and TC level were independent risk factors for PCAD. It means that young individuals who are overweight, have a history of smoking, and carried APOE ɛ3/ɛ4 genotype had increased risk of PCAD.

The role of TNF-α and il-6 SNP in polycystic ovary syndrome susceptibility.

OBJECTIVE: Aim: To shed the light on the impact of TNF-α 1031 T/C (rs-1800629) and IL-6 174 G/C (rs1800795) polymorphism with disease susceptibility and development. PATIENTS AND METHODS: Materials and Methods: A case-control study has been established based on 50 women with confirmed diagnosed polycystic ovarian syndrome, and 50 healthy controls. Allele specific PCR have been done in order to study SNP of TNF-alpha and IL-6 in both groups. RESULTS: Result: The findings of the present investigation indicated that there was a signif i cant dif f erence in the frequency distribution of TNF-alpha 1031 T/C SNP according to genotype between patients and controls group p = 0.02. In addition, there is a high significant difference in the frequencies of distribution of alleles (T/C) between patients and control group p = 0.001. There was a signif i cant dif f erence in the frequency distribution of IL-6 174 G/C between patients and controls group p = 0.026. In addition, there is a signif i cant dif f erence in the frequencies of distribution of participants according to allele (G/C) between patients and control group p = 0.047. Genotype GC was significantly lower in patients' group and genotype GG was high significant in patients' group in comparison with a control group and the differences were significant, p = 0.024 and 0.006, respectively. CONCLUSION: Conclusions: The present study concluded that IL-6 174 G/C, (rs:1800795) single nucleotide polymorphism (SNP) and TNF-alpha 1031 T/C (rs-1800629) were associated with PCOS susceptibility, and GG genotype in IL-6 and C allele in TNF are considered as risk factor.

Association of histidine-rich glycoprotein C633T single nucleotide polymorphism and recurrent miscarriage in Iranian women.

BACKGROUND: Recurrent miscarriage (RM) is defined as the occurrence of at least two or three subsequent miscarriages within the 20th -24th weeks of pregnancy. The primary objective of this study was to investigate whether histidine-rich glycoprotein C633T single nucleotide polymorphism (HRG C633T SNP) statistically correlates with the occurrence of RM among Iranian women. METHODS AND RESULTS: Blood samples from 200 women were taken at the outset of the study. Then, the blood samples of 100 women who had a record of RM (case group) were compared with the other 100 women's blood samples who had no record of RM (control group). Following DNA extraction, the polymorphism of histidine-rich glycoprotein C633T (HRG C633T) for every case was specified and all women were genotyped by the amplification-refractory mutation system (ARMS) method. The results of the study revealed that there was a statistically significant difference between T/T genotype (OR = 3.5, CI (1.39-8.77), p = 0.007), and C/T genotype (OR = 1.83, CI (0.99-3.37), p = 0.05) in the case and control groups. Also, a statistically significant association was observed in T allelic frequency in the RM participants compared to the control group (OR = 2.01, CI (1.31-3.09), p = 0.01). CONCLUSIONS: The present study determined that there was a statistically significant relationship between HRG C633T SNP and increased RM regarding allelic and genotypical aspects. Moreover, it became apparent that women with homozygous T/T genotype were more susceptible to the risk of RM.