Significant Differences In Allele Frequencies Research Articles

Association of the IRF6 rs2235371 and rs861019 Polymorphisms with Non-Syndromic Cleft Lip with or without Cleft Palate in the Yakut Population

Background: Non-syndromic cleft lip with or without cleft palate (NSCL/P) is one of the most common birth defects. NSCL/P can be broadly divided into cleft lip only (CLO), cleft palate only (CPO), and cleft lip with cleft palate (CLP) based on clinical presentation. The aim of this study was to investigate the relationship between the IRF6 gene polymorphisms and non-syndromic cleft lip with or without cleft palate (NSCL/P) in the Yakut population. Methods and Results: In 23 OFC patients and 58 unrelated control subjects from the Yakut population, we tested two SNPs (rs2235371 and rs861019) with a minor allele frequency of more than 5% in the candidate gene IRF6. We found that the SNP marker rs861019 showed significant differences in allele frequencies (OR=2.07, 95%CI: 1.01–4.23, P=0.04) between the NSCL/P patients and the comparison group. Analysis of allele frequencies for rs861019 SNP in subgroups showed that there was a difference in the frequency between CLP and control (OR=5, 95% CI: 1.61-15.53, P=0.11); however, this result was not significant. Genotype analysis showed significant differences in patients from the CLP subgroup in comparison with controls for homozygous (AA compared with GG) (OR=9.00, 95% CI: 1.03–78.58, P=0.03), heterozygous (GA compared with GG) (OR=5.50, 95% CI: 1.05-28.75, P=0.04,), recessive (GG compared with GA + AA) (OR=6.67, 95% CI: 1.61-27.58; RR=4.78, 95% CI: 1.42–16.10, P=0.008,) and co-dominant (GG compared with GA, compared with AA) (P=0.02) inheritance models. Diplotype analysis showed that the NSCL/P group was more likely to have the [CC]-[GG] diplotype than the comparison group. This diplotype carries the risk GG genotype (rs861019) (30.4%) and does not carry the risk T allele(rs2235371). In the CLP subgroup, two diplotypes ([CT]-[GG] and [CC]-[GG]) were found more often than in the comparison group. Both diplotypes carry the risk GG genotype(rs861019; 33.3%). In the CPO subgroup, the [CT]-[GG] diplotype was more common. In the CLO subgroup, only two diplotypes ([CC]-[GA] and [CC]-[GG]) were found, both of which were more common than in the comparison group (75% and 25%).. It is likely that these results for the CLO and CPO subgroups were influenced by the small size of both samples. Unlike the NSCL/P and CLP groups, in these samples, diplotypes with the homozygous genotype GG (rs861019) without the homozygous genotype TT (rs2235371) were more common. Diplotypes with a homozygous genotype of the TT risk allele were not found in the studied groups except for the comparison group, where the [TT]-[AA] diplotype was represented by a low frequency (0.17%). Conclusion: The present study provides strong statistical support (for the first time to our knowledge) that genetic variants of the IRF6 rs861019 SNP are associated with NSCL/P in Yakuts.

NLRP3 Influences Cognitive Function in Schizophrenia in Han Chinese.

It has been proposed that immune abnormalities may be implicated with pathophysiology of schizophrenia. The nod-like receptor pyrin domain-contraining protein 3 (NLRP3) can trigger immune-inflammatory cascade reactions. In this study, we intended to identify the role of gene encoding NLRP3 (NLRP3) in susceptibility to schizophrenia and its clinical features. For the NLRP3 mRNA expression analysis, 53 drug-naïve patients with first-episode schizophrenia and 56 healthy controls were enrolled. For the genetic study, a total of 823 schizophrenia patients and 859 controls were recruited. Among them, 239 drug-naïve patients with first-episode schizophrenia were enrolled for clinical evaluation. There is no significant difference in NLRP3 mRNA levels between patients with schizophrenia and healthy controls (p = 0.07). We did not observe any significant differences in allele and genotype frequencies of rs10754558 polymorphism between the schizophrenia and control groups. We noticed significant differences in the scores of RBANS attention and total scores between the patients with different genotypes of rs10754558 polymorphism (p = 0.001 and p < 0.01, respectively). Further eQTL analysis presented a significant association between the rs10754558 polymorphism and NLRP3 in frontal cortex (p = 0.0028, p = 0.028 after Bonferroni correction). Although our findings did not support NLRP3 confer susceptibility to schizophrenia, NLRP3 may be a risk factor for cognitive impairment, especially attention deficit in this disorder.

Genetic Diversity and Distribution of Vitamin D Receptor (VDR) Genotypes in Breast Cancer Cases from Pakistan

Background: Breast carcinoma is one of the most commonly diagnosed invasive malignancies in females. In Pakistan, it is more commonly detected in women at a young age as compared to the West. Among all women, the risk of developing breast cancer is equal irrespective of their ethnic or racial basis. The aim of the study was to determine vitamin D receptor gene polymorphisms (FokI and TaqI) and allele frequency distribution in Pakistani women with newly diagnosed breast cancer. This study also aimed to find and compare genetic diversity of VDR polymorphisms among breast cancer cases in different population groups. Methods: Newly diagnosed women having breast cancer (n=300) were selected for the study. Blood samples of all the participants were analyzed for vitamin D levels and isolated DNA was subjected to PCR-RFLP analysis. Results: Results revealed that allelic frequency of FokI and TaqI was ‘F’; ‘f’ 50.67 and 49.33% and ‘T’ and ‘t’ was 46.67 and 53.33 respectively in Pakistani women with breast cancer. The genotypic frequency is significantly (P&lt;0.05) distributed.Conclusion: The current study concluded significant difference in genotypes and allele frequency of VDR gene polymorphism in Pakistani population suffering from breast cancer when compared with other population.

Association between plasminogen activator inhibitor-1 gene polymorphisms and susceptibility to Parkinson's disease in Chinese patients.

Parkinson's disease (PD) is a neurodegenerative disease that usually leads to memory impairment, cognitive decline and dementia. Previous studies have reported that plasminogen activator inhibitor-1 (PAI-1) gene polymorphisms play important roles in cardiovascular diseases, obesity, inflammation and other diseases. However, the role of PAI-1 in the diagnosis of Parkinson's disease has not been reported so far. This study was a case-control study. This study included 131 PD patients and 97 healthy volunteers. polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP) was used to analyze the polymorphic loci of five different regions in PAI-1 gene (rs2227631, rs1799889, rs6092, rs2227694 and rs7242). 60 PD patients and 60 healthy volunteers were selected to detect the plasma PAI-1 concentration. The allele and genotype frequencies of SNPs were assessed using the SHEsis program. We found that GG genotype frequency and G allele frequency of rs2227631 was significantly higher in the PD patients. Statistically significant difference for rs1799889 could be observed in overdominant model. In subgroup analysis, a significant difference in genotype frequency distribution and allele frequency was found for rs2227631 and rs1799889 between early-onset PD group and the control group. For cognitive dysfunction, the subcomponent showed that GG genotype frequency and G allele frequency of rs2227631 was significantly higher in normal cognition group. The codominant model of rs1799889 was significantly different between the cognitive impairment group and the control group. In addition, the expression of PAI-1 in plasma of PD patients was significantly higher than that of controls, and further analysis showed that the expression of PAI-1 in patients with cognitive impairment was significantly higher than that in patients with cognitive normal. Our results indicate that the PAI-1 gene rs2227631 and rs1799889 polymorphisms were significantly associated with PD susceptibility in the Chinese Han population. PAI-1 has the potential to become a new therapeutic target and diagnostic marker.

The influence of polymorphic variants rs2305619 и rs3816527 of the PTX3 gene on clinical profile and outcomes in patients with hypertrophic cardiomyopathy: results of a 11-years follow-up

The objective of this study was to determine the association of polymorphic variants rs2305619 and rs3816527 of the PTX3 gene with clinical profile and outcomes in hypertrophic cardiomyopathy (HCM) patients.Methods and materials. The study population consisted of 153 patients ≥18 years old with a confirmed diagnosis of HCM. The control group included 200 healthy donors. Duration of follow-up was 11 years (2008–2019 yrs.). The study design included a new model for determining variants of the clinical profile and outcomes of HCM. Polymorphic variants rs2305619 and rs3816527 of the PTX3 gene were genotyped by polymerase chain reaction.Results. The mortality rate in patients ≥18 years old with 1, 2 and 3 adverse pathways of HCM progression was significantly higher, compared with those without adverse pathways (р&lt;0.001). A combination of chronic heart failure (CHF) with midrange and reduced LVEF (&lt;49 %) with 1, 2 and 3 adverse pathways in HCM patients occurred more frequently, compared with those who had CHF with preserved LVEF (≥50 %) (odds ratio (OR) = 0.168, 95 % confidence interval (CI) =0.068–0.412, р&lt;0.001). The genetic testing showed no significant differences in genotype and allele frequencies of polymorphic variants rs2305619 and rs3816527 of the PTX3 gene in patients with HCM and control groups. It was found a tendency for increase in GG genotype frequency (p&lt;0.068) and significant increase in G allele frequency of rs2305619 of the PTX3 gene in HCM patients ≥18 years old and CHF with mid-range and reduced LVEF (&lt;49 %) (A:G, OR=0.521, 95 % CI=0.301–0.902, p&lt;0.019). HCM patients (age – 63 [58; 75] years) and type 2 diabetes mellitus demonstrated high prevalence in AG and GG genotypes (p&lt;0.008) and G allele frequencies of rs2305619 of the PTX3 gene (A:G, OR =1.952, 95 % CI=1.076–3.542, p&lt;0.026).Conclusions. HCM progression along 1 and more adverse pathways in patients ≥18 years old has been characterized with adverse outcome. G allele of rs2305619 of the PTX3 gene is associated with CHF with mid-range and reduced LVEF (&lt;49 %) in HCM patients ≥18 years old. The associations of G allele and AG and GG genotypes of rs2305619 of the PTX3 gene with diabetes type 2 are observed in elderly HCM patients.

Clinical Utility of Hematopathologist-Triaged NGS Testing When Investigating Patients with Suspected MDS

The recognition of MDS is challenging in early stages, where diagnosis may rely solely upon morphological criteria for dysplasia, a non-specific finding prone to inter-observer variation. Patients with equivocal bone marrow (BM) findings may be discharged from Hematology clinics and lost to follow up, or subjected to serial, invasive BM investigations and diagnostic delays. We therefore aimed to demonstrate the importance of hematopathologist-triaged, targeted NGS in identifying clonal cytopenias of undetermined significance (CCUS) in cases where MDS diagnostic criteria are not met based on morphology or cytogenetic analysis. We explored this using three REB-approved cohorts.Our first cohort was retrospective with BM samples ranging from 2010-14, involving cases that were previously suspicious for but non-MDS diagnostic. This included 70 patients from Sunnybrook (SHSC) and Kingston Health Sciences Centres (KHSC): 16 age-matched controls (8 negative lymphoma staging, 8 non-MDS cytopenias); 18 suspicious for MDS; 20 MDS; and 16 MDS/MPN. DNA was extracted and NGS was performed using our custom 48-gene Ion Torrent AmpliSeq myeloid panel (ThermoFisher).We identified suspected mutations in 2/16 (13%) controls (i.e. CHIP), 12/18 (67%) suspicious cases, 17/20 (85%) MDS cases, and 16/16 (100%) MDS/MPN cases. The mean and median number of mutations per suspicious patient (respectively 0.89 and 1; most commonly in SF3B1, TET2, RUNX1, and ASXL1) were lower than MDS (1.85 and 2; p=0.011) and MDS/MPN (3.13 and 3; p<0.0001). There was a significant difference in the average variant allele frequency (VAF) per patient (those with ≥1 mutation) between control and suspicious groups (p=0.022), however, there were no significant differences in the average VAF between suspicious, MDS, and MDS/MPN cases. Furthermore, of the 16 patients with BM suspicious for MDS, 7 went on to get MDS. 4 of these patients had at least 1 clinically relevant somatic variant, while 3 had none. Of those with at least 1 variant, 3 had IPSS-level cytopenias at the time, indicating that had their mutational status been known at the time of their assessment, they would have been diagnosed with the provisional CCUS entity (while the rest would be classified as CHIP).To supplement these findings, we are amassing a prospective cohort involving cases at SHSC where patients have either idiopathic cytopenias (ICUS), or confirmed MDS diagnoses with one or more previously non-diagnostic BM. To date, we have performed sequencing for 36 of these patients, including 23 ICUS and 13 diagnosed MDS cases. Of the ICUS cases, 10 (44%) had at least 1 variant (mean # variant/patient = 1, mean variant allele frequency (VAF) = 34.0%) consistent with CCUS, while 12/13 (92%) of MDS patients had at least 1 variant (mean # variants/patient = 2, mean VAF = 42.3%). These findings are consistent with CCUS being common in suspicious MDS cases, with similar clonal size but lesser mutational burden than diagnosed MDS. In addition to these preliminary findings, 15/36 patients have serial samples that we are currently processing for NGS (among other cases we are accruing to present at the ASH meeting). By exploring serial cases with molecular results pre- and post- MDS diagnosis, we aim to further elucidate which features of CCUS may predict progression to MDS.Finally, we assessed clonality in cases suspicious for myeloid malignancy in our existing prospective myeloid NGS cohort at KHSC (Ferrone et al, JMD 2021). In this cohort of 168 patients, when focusing on cytopenias yet to be diagnosed, 71 patients had suspected MDS, MPN, or MDS/MPN prior to NGS (completed using the Oncomine Myeloid Assay; ThermoFisher). 36/71 (51%) were found to have variants that indicate clonality. This facilitated diagnoses of either myeloid malignancies or pre-malignant states, with nine cases in total of ICUS resulting in the identification of variants that were non-diagnostic of MDS (mainly in TET2), but indicative of CHIP (n=2) or CCUS (n=7). Furthermore, for the limited number with available follow up data, we found no significant difference in survival between individuals with low-grade MDS (n=10) and CCUS (n=6) (p=0.457).This evidence is in keeping with recent findings that the clinical features of CCUS may be consistent with low-risk MDS, emphasizing the importance of closely monitoring these patients, and even the possibility of assessing and treating them similarly to those with low-risk MDS. DisclosuresNo relevant conflicts of interest to declare.

Genetic analysis of NLRP3 in recurrent pericarditis

Abstract Background The mechanisms underlying recurrent pericarditis are poorly understood, although the efficacy of colchicine and targeted inhibitors of the interleukin-1 pathway implicate auto-inflammation in its pathogenesis. NLRP3 (NACHT, leucine-rich repeat, and pyrin domain containing protein 3) forms part of the NLRP3 inflammasome that mediates post-translational processing of interleukin-1, and colchicine has also been demonstrated to inhibit this pathway. Pathogenic mutations in exon 3 of NLRP3 cause the auto-inflammatory disease cryopyrin associated periodic syndrome, and the management of this disease and other auto-inflammatory diseases has been transformed over the last two decades by the use of targeted anti-interleukin-1 agents. More recently, NLRP3 inflammasome activity has been demonstrated to be upregulated in the pericardia of patients with recurrent pericarditis. Purpose Given that mutations in exon 3 of NLRP3 are known to cause auto-inflammatory disease and NLRP3 activity is implicated in recurrent pericarditis, we undertook a genetic analysis of exon 3 of NLRP3 in 99 patients with recurrent pericarditis to determine whether pathogenic mutations in this gene are associated with the disease. Methods Exon 3 of NLRP3 was analysed either by Sanger (n=30) or amplicon-based next generation (n=69) sequencing. Variants identified by next generation sequencing were validated by Sanger sequencing. Minor allele frequencies were compared to those in the healthy reference population in the Genome Aggregation database (gnomAD) using Fisher's exact test. p values &amp;lt;0.05 were considered statistically significant. Results No known pathogenic mutations in exon 3 of NLRP3 were identified in 99 patients with recurrent pericarditis. Three patients harboured variants of unknown significance (V198M, T543M, Q703K) in NLRP3. A burden association test comparing the combined frequency of all variants in exon 3 of NLRP3 in this cohort against that observed in healthy controls in gnomAD found no significant difference in allele frequency. Conclusions This is the first reported genetic analysis of NLRP3 in a cohort of patients with recurrent pericarditis and found no evidence to implicate mutations in this gene in the disease. Whilst access to effective therapies for pericarditis is widening, decisions on treatment duration and identification of patients at risk of recurrent or treatment refractory disease remain significant clinical challenges. Further work exploring the mechanisms by which NLRP3 activity is upregulated in recurrent pericarditis is therefore indicated to identify biomarkers of disease activity and to stratify patients at risk of recurrence. Given the recent successes of agents targeting this pathway in coronary artery disease in clinical trials, such studies may also provide important insights that are of wider interest to the field of cardiovascular medicine. Funding Acknowledgement Type of funding sources: Foundation. Main funding source(s): British Heart Foundation Clinical Research Training Fellowship

Coronary artery disease association with serum concentration and genetic variation of MMP-9 in Ukrainian population

Abstract Introduction Coronary artery disease (CAD) is one of the main cause of death in European countries. The mortality associated with CAD has been rising for the past 30 years in Central and Easten Europe (including Ukraine). It is known that atherosclerosis is the primary risk factor of CAD development and Matrix metalloproteinase-9 (MMP-9) is involved in all stages of atherosclerosis and thus may contribute to CAD aggravation. It is very important to find specific mechanisms of atherosclerosis progression, the impact of genetic and external factors which influence on the development of CAD in different populations. Therefore, the aim of this study was to investigate the influence of MMP-9 concentration and functional rs17576 single nucleotide polymorphism (SNP) on risk of CAD development in Ukrainian population. Materials and methods In our study 128 patients were recruited. All of them we divided into three groups: 1 - with angiogrphically normal (intact) coronary arteries; 2 - patients with acute coronary syndrome (ACS) and 3 - with chronic coronary syndrome (CCS). The study protocol was approved by the Institutioal Ethics Committee and each participant was required to provide a writing informed consent. We recorded clinical data, biochemical analysis, performed electrocardiogram, coronary angiography and echocardiography. Blood for detection of MMP-9 and rs 17567 MMp-9 polymorphism was draw under standardized conditions before coronary angiography. Levels of MMP-9 were assessed using commercial ELISA immunoassay following manufacturer's instruction. The genotyping for MMP-9 rs17567-single nucleotide polymorphism was done by Real-time PCR. All statistical calculations were done using Statistical Package for the Social Sciences software. Results The results of analysis of association between MMP-9 rs17576 and CAD development demonstrate a weak link with borderline significance between MMP-9 concentration and ACS presence both before (Pc=0.026; ORc=1.003, 95% CI: 1–1.006) and after the adjustment for covariates (Pa=0.04; ORa=1.003, 95% CI: 1–1.006). In contrast, no significant association was detected for CCS group (Pa&amp;gt;0.05). There were no statistically significant differences in genotype and allele frequencies in compared groups (P&amp;gt;0.05) and association between MMP-9 serum concentration and MI occurrence. But we found the statistically significant differences in genotypes distribution (P=0.025) while the alleles distribution was similar (P&amp;gt;0.05) among compared groups. Additionally, AG-carriers had the lower risk of MI development in crude (Pc=0.033; ORc=0.359, 95% CI: 0.14–0.922) and adjusted (Pa=0.023; ORa=0.299, 95% CI: 0.106–0.848) overdominant model of inheritance. Conclusion In the present research we have analyzed the link of MMP-9 serum concentration and MMP-9 rs17567-polymorphic variant with CAD development among Ukrainians. We found lower risk of MI occurrence for AG-carriers. Funding Acknowledgement Type of funding sources: None.

PSXV-10 Study of allelic pattern of PLAG1 gene in the historical and modern populations of two oldest Russian dairy cattle breeds

Abstract Increasing animal stature is one of the goals of modern breeding programs for many dairy cattle breeds, because stature related to higher milk yield. The PLAG1 gene was shown to be a strong candidate responsible for stature in different cattle breeds. The polymorphic SNP BovineHD1400007259, located within PLAG1 gene, is considered as a causal mutation responsible for stature. The aim of our work was to evaluate the effect of long selection for the increased body height on the alterations of the allele’s frequencies of the PLAG1 gene in the historical and modern populations of the Russian Yaroslavl and Kholmogor dairy cattle breeds. The historical specimens of Yaroslavl (n = 22) and Kholmogor (n = 12) cattle dated by the first quarter of the 20th century were derived from the craniological collection of the E.F. Liskun Museum for Animal Husbandry. The modern representatives of Yaroslavl (n = 31) and Kholmogor (n = 25) breeds were used for comparison. All works with historical samples were performed in dedicated facility of the L.K. Ernst Research Center for Animal Husbandry. The samples were genotyped using high-density DNA arrays (Illumina Inc., USA). The historical DNA was treated by USER enzyme before genotyping to avoid the misincoporated nucleotides occurred due to postmortem DNA damage. We observed significant differences in allele frequencies of PLAG1 genes between historical and modern populations of both breeds. The frequencies of G allele, which is associated with higher stature, were increased from 0.114 in historical Yaroslavl cattle and from 0.167 in historical Kholmogor cattle to 0.633 and 0.860 in the modern breeds’ representatives, respectively. Our data suggest that PLAG1 gene was affected by artificial selection in studied cattle breeds. The research results will be useful for elucidation of the history of these two oldest Russian dairy cattle breeds. The study was funded by the RSF No. 21-66-00007.

Genetic polymorphisms of BDNF on cognitive functions in drug-naive first episode patients with schizophrenia

Brain-derived neurotrophic factor (BDNF) is reported to be involved in cognitive decline in patients with schizophrenia (SZ). Previous studies have found that cognitive deficits remain stable during the chronic disease phase in SZ, but the findings were inconsistent. The role of BDNF in cognitive deficits at different stage of illness remains unclear. This study aimed to examine the effect of BDNF polymorphisms on cognitive deficits in drug-naïve first-episode (DNFE) patients and chronic patients with SZ. 262 DNFE patients, 844 chronic patients, and 1043 healthy controls were recruited to compare 4 polymorphisms in BDNF gene and cognitive function. We found that there was no significant difference in genotype and allele frequencies between SZ patients and controls. However, they were closely related to cognitive functioning. BDNF rs2030324 polymorphism played a strong role in language performance only in DNFE patients with SZ. The language index of DNFE patients with rs2030324 TT and TC genotypes was worse than that of chronic patients, but there was no significant difference in CC genotypes between DNFE and chronic patients. Rs6265 had no significant effect on cognitive functioning in patients and controls. Our result suggests BDNF gene polymorphisms were related to different domains of cognitive function at the different stage of SZ, especially language in DNFE patients.

CKM Gene rs8111989 Polymorphism and Power Athlete Status.

Multiple genetic variants are known to influence athletic performance. These include polymorphisms of the muscle-specific creatine kinase (CKM) gene, which have been associated with endurance and/or power phenotypes. However, independent replication is required to support those findings. The aim of the present study was to determine whether the CKM (rs8111989, c.*800A>G) polymorphism is associated with power athlete status in professional Russian and Lithuanian competitors. Genomic DNA was collected from 693 national and international standard athletes from Russia (n = 458) and Lithuania (n = 235), and 500 healthy non-athlete subjects from Russia (n = 291) and Lithuania (n = 209). Genotyping for the CKM rs8111989 (A/G) polymorphism was performed using PCR or micro-array analysis. Genotype and allele frequencies were compared between all athletes and non-athletes, and between non-athletes and athletes, segregated according to population and sporting discipline (from anaerobic-type events). No statistically significant differences in genotype or allele frequencies were observed between non-athletes and power athletes (strength-, sprint- and speed/strength-oriented) athletes. The present study reports the non-association of the CKM rs8111989 with elite status in athletes from sports in which anaerobic energy pathways determine success.

The "GG" genotype of rs26802 variant in the ghrelin gene is a potential protective factor against nonalcoholic fatty liver disease.

Nonalcoholic fatty liver disease (NAFLD) is an emerging global chronic liver disease worldwide. Considering the powerful association between NAFLD, insulin resistance (IR) and obesity, as well as the key role of ghrelin in these metabolic disorders, we hypothesized that some single nucleotide polymorphisms (SNPs) of the ghrelin (GHRL) and ghrelin receptor (GHSR) genes might be associated with NAFLD. We conducted a case-control retrospective study of 150 cases with biopsy-proven NAFLD and 155 controls. The diagnosis of NAFLD was established before the start of the genotyping process. All the 305 subjects were genotyped for GHRL SNP rs26802 or -501T>G and GHSR SNP rs572169 or Arg159Arg using the PCR-RFLP method. The GHRL rs26802 "GG" genotype compared with the "TT" genotype and "TT+TG" genotype appears to be a marker of decreased NAFLD susceptibility even after adjustment for confounding factors (P = 0.006; OR = 0.14, 95% CI = 0.03-0.56 and P = 0.003; OR = 0.16, 95% CI = 0.05-0.53, respectively). However, we observed no significant difference in genotype or allele frequencies between the cases and controls for GHSR SNP rs572169. These findings proposed, for the first time, that the GHRL rs26802 "GG" genotype has a protective effect against NAFLD. Nonetheless, this observation warrants further investigations in other populations.

C3435T Polymorphism of the ABCB1 Gene in Polish Patients with Inflammatory Bowel Disease: A Case-Control and Meta-Analysis Study.

P-glycoprotein encoded by the ABCB1 gene constitutes a molecular barrier in the small and large bowel epithelium, and its different expression may influence susceptibility to inflammatory bowel disease (IBD). We aimed to assess the contribution of the C3435T polymorphism to disease risk in the Polish population. A total of 100 patients (50 Crohn’s disease (CD), 50 ulcerative colitis (UC)) and 100 healthy controls were genotyped for the single nucleotide polymorphism (SNP) C3435T by using the PCR-RFLP method. Patients were classified on the basis of disease phenotype and the specific treatment used. A meta-analysis was carried out of our results and those from previously published Polish studies. There was no significant difference in allele and genotype frequencies in IBD patients compared with controls. For CD patients, a lower frequency of TT genotype in those with colonic disease, a lower frequency of T allele, and a higher frequency of C allele in those with luminal disease were observed, whereas for UC patients, a lower frequency of CT genotype was observed in those with left-sided colitis. A meta-analysis showed a tendency towards higher prevalence of CC genotype in UC cases. These results indicate that the C3435T variants may confer a risk for UC and influence disease behaviour.

MP33-02 UNRAVELING GENOMIC ALTERATIONS OF CRIBRIFORM AND INTRADUCTAL PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research & Pathophysiology I (MP33)1 Sep 2021MP33-02 UNRAVELING GENOMIC ALTERATIONS OF CRIBRIFORM AND INTRADUCTAL PROSTATE CANCER Rui Bernardino, Rui Henrique, Herminia Pereira, Luis Severo, Rune Matthiesen, João Pimentel, and Luis Campos Pinheiro Rui BernardinoRui Bernardino More articles by this author , Rui HenriqueRui Henrique More articles by this author , Herminia PereiraHerminia Pereira More articles by this author , Luis SeveroLuis Severo More articles by this author , Rune MatthiesenRune Matthiesen More articles by this author , João PimentelJoão Pimentel More articles by this author , and Luis Campos PinheiroLuis Campos Pinheiro More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002042.02AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Intraductal Prostate Cancer (IDC-P) is often under-reported due to the difficulty of discriminating IDC-P from cribriform (CR) morphology or high-grade prostatic intraepithelial neoplasia. Both IDC-p and CR patterns are independent prognostic factors for poor outcome. Our objective was to profile molecular features of IDC-P and CR morphology from formalin-fixed paraffin embedded tissue (FFPE) of patients submitted to radical prostatectomy (RP). METHODS: We analyzed IDC-P and CR from 20 RP specimens (10 each) containing a significant percentage (>30%) of the lesions in the specimen. Each lesion was sequenced twice: 1 - all tumor material present in the slide; 2 - only previously macrodissected CR or IDC-p pattern. The patterns were identified in the representative hematoxylin and eosin stain were subsequently macrodissected. Targeted next-generation deep sequencing to evaluate cancer-related genes was carried out, using FoundationOne®CDx. RESULTS: From the 20 samples tested, only one failed technically-No major differences among the frequencies of genes altered were found comparing the two methods (1 and 2).The genes alterered, prevalence and allele frequency (AF) are shown in table a. CONCLUSIONS: TMPRSS2-ERG gene fusion, mutations in PTEN, TP53 and BRAC2 were often identified in IDC-P and CR, in line with previous reports. IDC-P showed a molecular profile enriched for oncogenic driver mutations in MAPK/PI3K pathway. CR discloses higher TMB than IDC-p and the difference was larger in Method 2. The observed mutations among the two patterns, seem to be different (graph b). No significant difference in AF using method 1 or 2 were depicted.New variants of PARP1/2 were also disclosed. The challenge exists to widen PARP inhibitors use by identifying new properties and deepening the role of PARP in tumor biology. PTCH1 alterations were also found. PTCH1 expression in malignant tissue as a prognostic marker for biochemical recurrence was reported. IDC-p and CR TMB levels foresee low clinical benefit of checkpoint inhibitors. These patterns also appear to be MS. Source of Funding: No © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e606-e607 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Rui Bernardino More articles by this author Rui Henrique More articles by this author Herminia Pereira More articles by this author Luis Severo More articles by this author Rune Matthiesen More articles by this author João Pimentel More articles by this author Luis Campos Pinheiro More articles by this author Expand All Advertisement Loading ...

Clinical Study of the Impact of ACE I/D Gene Variation on the Clinical Parameters of Patients with Polycystic Ovary Syndrome

To investigate the relationship between angiotensin Ⅰ-converting enzyme (ACE) insertion/deletion (I/D) gene polymorphism and the genetic risks for polycystic ovary syndrome (PCOS) and to evaluate the impact of ACE I/D genotypes on clinical, hormonal, metabolic and oxidative stress parameters in patients with PCOS. This was a retrospective case-control study involving a total of 1 020 PCOS patients and 825 female controls who visited the outpatient clinic of the Department of Reproductive Endocrinology, West China Second Hospital of Sichuan University between 2006 and 2019. The ages of the subjects ranged between 17 and 44. The ACE I/D genotypes were determined by polymerase chain reaction (PCR) and gel electrophoresis. 667 PCOS patients and 527 controls were selected for an analysis of their genotypes and the hormonal, metabolic and oxidative stress parameters. The genotype distributions of the ACE I/D single nucleotide polymorphism was in Hardy-Weinberg equilibrium in both the PCOS group and the control group (all P>0.05), which was representative of the population. There were no statistically significant differences in genotype and allele frequencies between the PCOS and the control groups ( P>0.05). After adjusting for both age and body mass index (BMI), there was no statistically significant difference in clinical characteristics among all genotypes in either the PCOS group or the control group. In the PCOS group, compared with the II genotype subgroup, the ID genotype subgroup had lower luteinizing hormone (LH)/follicle-stimulating hormone (FSH) ratio, while the DD genotype subgroup had higher homeostatic model assessment of insulin resistance (HOMA-IR) and malondialdehyde (MDA) levels. Compared with the ID genotype subgroup, the DD genotype subgroup had lower serum sex hormone binding globulin (SHBG) level, but higher total cholesterol (TC) and low-density lipoprotein cholesterol (LDL-C) levels ( P<0.05). In the control group, II genotype subgroup had a higher level of total oxidant status (TOS) than that of the DD genotype subgroup. ACE I/D genetic polymorphism is not associated with risks for PCOS. The I/D variation of ACE gene may be related to insulin resistance, dyslipidaemia, hyperandrogenemia and oxidative stress in PCOS patients.

Molecular Analysis of Single-Nucleotide Polymorphisms of TRAF5 Gene in Patients with Behçet's Disease from the Azeri Population of Northwest Iran

Background: Behçet's disease (BD) is a chronic inflammatory disease with unknown causes. The geographical distribution is mostly consistent with the historic Silk Road. The role of tumor necrosis factor receptor-associated factor 5 (TRAF5) gene in the inflammation signaling pathway leads more attention to the potency of different polymorphisms of the TRAF5 gene, in the development of BD. Methods: This was a case-control study conducted among the Azeri Turk ethnic group (50 BD patients and 50 persons with no history of autoimmune disease), Tabriz, Iran. Four different TRAF5 gene polymorphisms were assessed via the Polymerase Chain Reaction-Restriction Fragment Length Polymorphism technique. Data were analyzed by SPSS Version 20. Results: Genotypic distributions of four studied Single nucleotide polymorphisms (SNPs) had no significant difference between case and control groups (rs6540679 (p=0.50), rs12569232 (p=0.86), rs10863888 (p=0.14), and rs7514863 (p=0.24). There were also found no significant differences in SNP allelic frequencies between cases and controls

Association between C-Maf-inducing protein gene rs2287112 polymorphism and schizophrenia.

BackgroundSchizophrenia is a severely multifactorial neuropsychiatric disorder, and the majority of cases are due to genetic variations. In this study, we evaluated the genetic association between the C-Maf-inducing protein (CMIP) gene and schizophrenia in the Han Chinese population.MethodsIn this case-control study, 761 schizophrenia patients and 775 healthy controls were recruited. Tag single-nucleotide polymorphisms (SNPs; rs12925980, rs2287112, rs3751859 and rs77700579) from the CMIP gene were genotyped via matrix-assisted laser desorption/ionization time of flight mass spectrometry. We used logistic regression to estimate the associations between the genotypes/alleles of each SNP and schizophrenia in males and females, respectively. The in-depth link between CMIP and schizophrenia was explored through linkage disequilibrium (LD) and further haplotype analyses. False discovery rate correction was utilized to control for Type I errors caused by multiple comparisons.ResultsThere was a significant difference in rs287112 allele frequencies between female schizophrenia patients and healthy controls after adjusting for multiple comparisons (χ2 = 12.296, Padj = 0.008). Females carrying minor allele G had 4.445 times higher risk of schizophrenia compared with people who carried the T allele (OR = 4.445, 95% CI [1.788–11.046]). Linkage-disequilibrium was not observed in the subjects, and people with haplotype TTGT of rs12925980–rs2287112–rs3751859–rs77700579 had a lower risk of schizophrenia (OR = 0.42, 95% CI [0.19–0.94]) when compared with CTGA haplotypes. However, the association did not survive false discovery rate correction.ConclusionThis study identified a potential CMIP variant that may confer schizophrenia risk in the female Han Chinese population.

Polymorphisms in the FKBP5 gene are associated with attention deficit and hyperactivity disorder in Korean children

Attention deficit hyperactivity disorder (ADHD) is a common and heritable childhood psychiatric disorder. Recently, many studies reported a down-regulated hypothalamus–pituitary–adrenal axis (HPA-axis) with low cortisol levels in children with ADHD. The FK506 binding protein 5 or FKBP5 gene regulates the negative feedback of the HPA-axis, and genetic variants in this gene showed an association with ADHD. We investigated the genetic association between FKBP5 gene polymorphisms and susceptibility to ADHD in Korean children. We conducted a case-control study with 150 ADHD children and 322 controls. Genotyping of FKBP5 rs9394309 and rs7748266 was performed by using polymerase chain reaction - restriction fragment length polymorphism (PCR-RFLP). Our results showed that rs7748266 polymorphism has significant genotype (p = 0.021) and allele (p = 0.009) frequency differences between children with ADHD and the control group. CT genotype [odds ratio (OR) 1.70, 95 % confidence interval (CI) 1.134–2.540, p = 0.010] and T allele (OR 1.54, 95 % CI 1.114–2.117, p = 0.009) were associated with increased risk of ADHD. In addition, dominant (p = 0.006) and over-dominant genetic (p = 0.016) models showed significant associations with ADHD. In the stratified analysis, a significant result was obtained from the girl samples (p = 0.048). The OR of the girls with ADHD with CT genotype was 2.29 (95 % CI 1.170–4.469, p = 0.014). In contrast to rs7748266 polymorphism, rs9394309 polymorphism did not show any significant result (p > 0.05). Haplotype analysis also revealed a significant difference of the TG haplotype for rs7748266 – rs9394309 (p = 0.028, global haplotype association p-value of 0.0091). Conclusively, we confirmed that FKBP5 gene polymorphisms were associated with ADHD in Korean children. These results suggested that FKBP5 may factor in the development of ADHD.

The Relationship between Genotype of Serotonin-transporter-linked Polymorphic Region (5-HTTLPR) and Migraine combined with Depression.

The aim of this study is to explore whether there is an association between the genotype of serotonin-transporter-linked polymorphic region (5-HTTLPR) and migraine combined with depression. One hundred and sixteen patients with migraine and depressive disorder (Group A) and 116 patients with simple migraine (Group B) admitted in Mental Health Center, Zhejiang University School of Medicine, China, from January 2018 to April 2020 were included in the present study. Polymerase chain reaction (PCR) and restriction fragment length polymorphism techniques were used for detection of 5-HTTLPR genotype. The 5-HTTLPR genotype and allele frequency between the two groups were compared. The results showed that there was no significant difference in 5-HTTLPR genotype (L/L, L/S and S/S) frequency and allele (S and L) frequency between Group A and Group B (p=0.794 and 0.491, respectively). In conclusion, 5-HTTLPR genotype might not be related to the onset of migraine combined with depression. Key Words: Migraine, Depressive disorder, Serotonin-transporter-linked polymorphic region (5-HTTLPR).

G6PD distribution in sub-Saharan Africa and potential risks of using chloroquine/hydroxychloroquine based treatments for COVID-19

Chloroquine/hydroxychloroquine have been proposed as potential treatments for COVID-19. These drugs have warning labels for use in individuals with glucose-6-phosphate dehydrogenase (G6PD) deficiency. Analysis of whole genome sequence data of 458 individuals from sub-Saharan Africa showed significant G6PD variation across the continent. We identified nine variants, of which four are potentially deleterious to G6PD function, and one (rs1050828) that is known to cause G6PD deficiency. We supplemented data for the rs1050828 variant with genotype array data from over 11,000 Africans. Although this variant is common in Africans overall, large allele frequency differences exist between sub-populations. African sub-populations in the same country can show significant differences in allele frequency (e.g. 16.0% in Tsonga vs 0.8% in Xhosa, both in South Africa, p = 2.4 × 10−3). The high prevalence of variants in the G6PD gene found in this analysis suggests that it may be a significant interaction factor in clinical trials of chloroquine and hydroxychloroquine for treatment of COVID-19 in Africans.