Minor Genotype Research Articles

SLCO1B1 Gene Polymorphisms (rs2306283 and rs4149056) and Statin-Induced Myopathy in Jordanian Diabetics.

The use of statins to lower high serum cholesterol levels may be associated with a number of adverse reactions, including severe myopathy. The solute carrier organic anion transporter 1B1 (SLCO1B1) gene, which encodes the organic anion-transporting polypeptide OATP1B1, is related to the intracellular transport of statins. The aim of this research was to study the association of rs2306283 and rs4149056 genetic polymorphism of the SLCO1B1 gene with the development of statin-induced myopathy in Jordanian diabetics receiving statins. We included 413 patients attending the Diabetes Clinics of the National Center for Diabetes, Endocrinology and Genetics, Amman, Jordan. The study was approved by the Institutional Review Board of NCDEG. Myopathy was defined as the elevation of creatine kinase more than 3 times the upper limit of normal. Every subject signed an informed consent form and donated 3-5 mL of venous blood. Genome DNA was extracted from lymphocytes of peripheral blood. Genotypes were identified using the Tetra Amplification Refractory Mutation System of SLCO1B1. The minor allele frequencies of rs2306283 [G] and rs4149056 [C] were 0.38 and 0.23, respectively. The two SNPs followed the Hardy-Weinberg equilibrium. The development of SIM was significantly associated with the homozygous and heterozygous minor allele genotype of rs4149056 (CC and CT), and the homozygous wild type allele genotype of rs2306283 (AA). There was no linkage disequilibrium between the two SNPs in the studied subgroups. Genetic polymorphism in the SLCO1B1 Gene is a risk factor for the development of SIM in Jordanian patients.

Abstract 3493: Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women

Abstract Purpose: A decreased circulating adiponectin concentration is associated with obesity and an increased breast cancer risk among postmenopausal women. Yet, the interplay between adiponectin-associated genetic variants, obesity, and breast cancer risk is unclear in African American (AA) postmenopausal women. We examined adiponectin pathway polymorphisms for their association with breast cancer risk among AA postmenopausal women. We also explored a gene-environment interaction between adiponectin pathway polymorphisms and obesity for the risk of breast cancer. Method: Using the Women's Health Initiative SNP Health Association Resource Study, we identified 37 single-nucleotide polymorphisms (SNPs) in relation to the adiponectin pathway. Body-fat distributions were determined using three independent indices including body mass index (BMI), waist-to-hip ratio (WHR), and waist circumference (WC). We used multiple Cox proportional hazards regression models to estimate hazard ratios and 95% confidence intervals (CIs) for the association with breast cancer. Obesity-stratified analysis and tests for the joint effects with the SNPs were conducted. Results: Of 7,991 AA postmenopausal women, 402 reported of having an invasive breast cancer with a mean follow-up of 14.5 years. The majority were obese, had low WHR (< 0.85), and had high WC (< 88 cm). Of 37 adiponectin pathway-related SNPs, 3 SNPs were significantly associated with breast cancer risk (KCNK9 rs2468677, OR8S1-LALBA rs11168618, and EIF4A2 rs266719). Among women who have under or normal bodyweight, the minor allele GG genotype of NMU rs13434995 had an elevated risk of postmenopausal breast cancer compared to those with the major allele AA genotype. Women who carry the heterozygous TC genotype of OR8S1-LALBA rs11168618 and are obese jointly increased the risk of breast cancer (relative excess risk due to interaction = 0.58, 95% CI = 0.35, 0.80). Conclusion: Our findings revealed the association between the previously confirmed adiponectin pathway-related SNPs and breast cancer risk among AA postmenopausal women. We also demonstrated that obesity plays an important role as an effect modifier in the relationship between the SNPs and breast cancer, suggesting 1) the potential use of metabolic and genetic biomarkers for identifying a greater risk for breast cancer and 2) support for the research to promote interventions to those with risk genotypes, thus reducing breast cancer risk. Citation Format: Gina E. Nam, Zuo-Feng Zhang, Jianyu Rao, Hua Zhou, Su Yon Jung. Interactions between adiponectin pathway polymorphisms and obesity on breast cancer risk among African American postmenopausal women [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3493.

Fatty liver and impaired hepatic metabolism alter the congener-specific distribution of polychlorinated biphenyls (PCBs) in mice with a liver-specific deletion of cytochrome P450 reductase

Polychlorinated biphenyls (PCBs) are persistent organic pollutants that are linked to adverse health outcomes. PCB tissue levels are determinants of PCB toxicity; however, it is unclear how factors, such as an altered metabolism and/or a fatty liver, affect PCB distribution in vivo. We determined the congener-specific disposition of PCBs in mice with a liver-specific deletion of cytochrome P450 reductase (KO), a model of fatty liver with impaired hepatic metabolism, and wild-type (WT) mice. Eight-week-old male WT (MWT, n = 3), male KO (MKO, n = 5), female WT (FWT, n = 4), and female KO mice (FKO, n = 4) were exposed orally to Aroclor 1254. PCBs were quantified in adipose, blood, brain, and liver tissues by gas chromatography-mass spectrometry. The ΣPCB levels followed the rank order adipose > liver ∼ brain > blood in WT and adipose ∼ liver > brain > blood in KO mice. PCB levels were much higher in the liver of KO than WT mice, irrespective of the sex. A comparison across exposure groups revealed minor genotype and sex-dependent differences in the PCB congener profiles (cos Θ > 0.92). Within each exposure group, tissue profiles showed small differences between tissues (cos Θ = 0.85 to 0.98). These differences were due to a decrease in metabolically more labile PCB congeners and an increase in congeners resistant to metabolism. The tissue-to-blood ratio of PCBs decreased for adipose, increased for the brain, and remained constant for the liver with an increase in chlorination. While these ratios did not follow the trends predicted using a composition-based model, the agreement between experimental and calculated partition coefficients was reasonable. Although the distribution of PCBs differs between KO and WT mice, the magnitude of the partitioning of PCBs from the blood into tissues can be approximated using composition-based models.

MAVS Genetic Variation Is Associated with Decreased HIV-1 Replication In Vitro and Reduced CD4+ T Cell Infection in HIV-1-Infected Individuals.

The mitochondrial antiviral protein MAVS is a key player in the induction of antiviral responses; however, human immunodeficiency virus 1 (HIV-1) is able to suppress these responses. Two linked single nucleotide polymorphisms (SNPs) in the MAVS gene render MAVS insensitive to HIV-1-dependent suppression, and have been shown to be associated with a lower viral load at set point and delayed increase of viral load during disease progression. Here, we studied the underlying mechanisms involved in the control of viral replication in individuals homozygous for this MAVS genotype. We observed that individuals with the MAVS minor genotype had more stable total CD4+ T cell counts during a 7-year follow up and had lower cell-associated proviral DNA loads. Genetic variation in MAVS did not affect immune activation levels; however, a significantly lower percentage of naïve CD4+ but not CD8+ T cells was observed in the MAVS minor genotype. In vitro HIV-1 infection of peripheral blood mononuclear cells (PBMCs) from healthy donors with the MAVS minor genotype resulted in decreased viral replication. Although the precise underlying mechanism remains unclear, our data suggest that the protective effect of the MAVS minor genotype may be exerted by the initiation of local innate responses affecting viral replication and CD4+ T cell susceptibility.

Molecular epidemiology of multidrug resistant tuberculosis in Mongolia and Eastern Siberia: two independent dissemination processes for dominant strains

Mongolia and Russia are among the countries with the high tuberculosis (TB) burden. The prevalence of tuberculosis, including multidrug-resistant tuberculosis (MDR), in Eastern Siberia bordering Mongolia is significantly higher than in the European part of Russia. In addition, unlike Mongolia, Eastern Siberia is characterized by a high prevalence of HIV infection. The cross-border spread of socially significant infections in these countries seems to occur due to their wide-range cooperation and cultural exchange. Whereas the HIV infection has no epidemiological significance for Mongolia at the moment, tuberculosis, however, has a similar prevalence on both sides of the border. The aim was to evaluate the cross-border MDR M. tuberculosis distribution in Mongolia and Eastern Siberia by using molecular genetic data. Materials and methods. A total of 1045 M. tuberculosis strains isolated in Mongolia (291) and the three regions of Eastern Siberia (754) were studied by using the MIRU-VNTR-24 loci genotyping. The CC2/W148 and CC1 subtypes were identified by the specific deletion in the kdpD gene and SNP in the pks17 gene at position 1887060, respectively. Phylogenetic analysis of MIRU-VNTR patterns was carried out by generating UPGMA tree and maximum likelihood tree. Results. The Beijing genotype was found in 75.3% (219/291) and 69.0% (520/754) from Mongolian and East Siberian collection, respectively. Common minor genotypes were LAM (11.0% and 15.1%), T (10.3% and 4.5%), and Haarlem (1.4% and 2.4%) found in Mongolia and Eastern Siberia, respectively. The genotypes S (1.3%) and Ural (5.0%) were found solely in the Russia-derived samples. The main epidemic Beijing subtypes in each country belonged to different clonal complexes (CC): the majority of Mongolian Beijing strains displayed profiles 342-32, 3819-32, 1773-32 MLVA types and belonged to the CC4 subtype; Russian Beijing strains mainly belonged to the CC1 (43.7% — 227/520) and CC2/W148 (34.8% — 181/520) subtypes. The MDR level and distribution patterns differed significantly between Mongolia and Eastern Siberia. Modeling of Beijing strain expansion evidences about extremely subtle contribution of the M. tuberculosis cross-border transmission between Mongolia and Russia. The phylogenetic reconstruction of Beijing CC4 subtype evolution in Mongolia suggests that its distribution is primarily associated with China and other countries of the Western Pacific Region. Three main phylogenetic branches of CC4 subtype were traced, which probably spread throughout Mongolia in the 11—12th centuries. It may be assumed that spreading of the epidemic Beijing CC4 subtype might occur in two stages: early period — emergence of ancestral CC4 variants in Mongolia or their introduction from China (they are homologous to the strains preserved in the Chinese population), later period — dissemination due to the active exchange of M. tuberculosis with countries of Southeast Asia, but not Russia. Conclusion. Using MIRU-VNTR-24 genotyping as well as classification according to specific single nucleotide polymorphisms specific to certain Beijing subtypes, it allowed to describe separate patterns of the epidemic variants spread in Mongolia and Russia. It has been demonstrated that emergence and spread of MDR-TB in Mongolia are entirely iatrogenic in nature, while the epidemic subtypes of the Beijing genotype (subtypes CC1 and CC2/W148) contribute markedly into the MDR-TB spreading in Eastern Siberia.

Genetic Variants of the PLCXD3 Gene Are Associated with Risk of Metabolic Syndrome in the Emirati Population.

Phosphatidylinositol-specific phospholipase C X domain 3 (PLCXD3) has been shown to influence pancreatic β-cell function by disrupting insulin signaling. Herein, we investigated two genetic variants in the PLCXD3 gene in relation to type 2 diabetes (T2D) or metabolic syndrome (MetS) in the Emirati population. In total, 556 adult Emirati individuals (306 T2D and 256 controls) were genotyped for two PLCXD3 variants (rs319013 and rs9292806) using TaqMan genotyping assays. The frequency distribution of minor homozygous CC genotype of rs9292806 and GG genotype of rs319013 were significantly higher in subjects with MetS compared to Non-MetS (p < 0.01). The minor homozygous rs9292806-CC and rs319013-GG genotypes were significantly associated with increased risk of MetS (adj. OR 2.92; 95% CI 1.61–5.3; p < 0.001) (adj. OR 2.62; 95% CI 1.42–4.83; p = 0.002), respectively. However, no associations were detected with T2D. In healthy participants, the homozygous minor genotypes of both rs9292806 and rs319013 were significantly higher fasting glucose (adj. p < 0.005), HbA1c (adj. p < 0.005) and lower HDL-cholesterol (adj. p < 0.05) levels. Data from T2D Knowledge Portal database disclosed a nominal association of rs319013 and rs9292806 with T2D and components of MetS. Bioinformatics prediction analysis showed a deleterious effect of rs9292806 on the regulatory regions of PLCXD3. In conclusion, this study identifies rs319013 and rs9292806 variants of PLCXD3 as additional risk factors for MetS in the Emirati population.

ERCC2 gene single-nucleotide polymorphism as a prognostic factor for locally advanced head and neck carcinomas after definitive cisplatin-based radiochemotherapy

Identifying patients with locally advanced head and neck carcinoma on high risk of recurrence after definitive concurrent radiochemotherapy is of key importance for the selection for consolidation therapy and for individualized treatment intensification. In this multicenter study we analyzed recurrence-associated single-nucleotide polymorphisms (SNPs) in DNA repair genes in tumor DNA from 132 patients with locally advanced head and neck carcinoma (LadHnSCC). Patients were treated with definitive radiotherapy and simultaneous cisplatin-based chemotherapy at six partner sites of the German Cancer Consortium (DKTK) Radiation Oncology Group from 2005 to 2011. For validation, a group of 20 patients was available. Score selection method using proportional hazard analysis and leave-one-out cross-validation were performed to identify markers associated with outcome. The SNPs rs1799793 and rs13181 were associated with survival and the same SNPs and in addition rs17655 with freedom from loco-regional relapse (ffLRR) in the trainings datasets from all patients. The homozygote major rs1799793 genotype at the ERCC2 gene was associated with better (Hazard ratio (HR): 0.418 (0.234–0.744), p = 0.003) and the homozygote minor rs13181 genotype at ERCC2 with worse survival (HR: 2.074, 95% CI (1.177–3.658), p = 0.017) in comparison to the other genotypes. At the ffLRR endpoint, rs1799793 and rs13181 had comparable prognostic value. The rs1799793 and rs13181 genotypes passed the leave-one-out cross-validation procedure and associated with survival and ffLRR in patients with LadHnSCC treated with definitive radiochemotherapy. While findings were confirmed in a small validation dataset, further validation is underway within a prospective biomarker study of the DKTK.

Identification of novel advanced glycation end products receptor gene variants associated with colorectal cancer in Tunisians: A case-control study.

A central role for advanced glycation end products (AGE) and their receptor (RAGE) in the pathogenesis of multiple cancer types, including colorectal cancer (CRC) was reported. We investigated the association between CRC and rs2853807, rs77170610, rs184003, rs1035798, rs2070600, rs1800684, rs1800624, and rs1800625 RAGE gene (AGER) polymorphic variants. Study subjects comprised 293 CRC patients [186 colon cancer (CC) and 107 rectal cancer (RC)] patients), and 264 age-, gender-, BMI-, and ethnicity-matched controls. Minor allele frequency (MAF) of rs77170610 and rs1800625 were significantly lower, while MAF of rs1035798 was significantly higher in CRC patients compared to control subjects, which was associated with reduced and increased risk of CRC, respectively; MAF of the remaining variants was comparable between CRC patients and controls. Significant difference in the distribution of rs2853807 and rs77170610 genotypes was seen between CRC patients and controls, with both variants associated with decreased risk of CRC. Comparison of the distribution of minor allele-carrying genotypes in CC and RC patient subgroups revealed lack of significant difference in the distribution of these genotypes between the patient subgroups. In view of the lack of LD between rs2853807 and rs77170610 with other variants, six-locus (rs184003, rs1035798, rs2070600, rs1800684, rs1800624, rs1800625) haplotypes were constructed. Haplotype analysis did not identify any specific 6-locus AGER haplotype associated with CRC. In conclusion, AGER gene rs2853807 and rs77170610 variants rs77170610 are associated with altered risk of CRC in Tunisians, but with no discrimination between CC and RC types.

Association between Gasdermin A, Gasdermin B Polymorphisms and Allergic Rhinitis Amongst Jordanians.

Gasdermin A (GSDMA) and Gasdermin B (GSDMB) have been associated with childhood and to a lesser extent with adult asthma in many populations. In this study, we investigate whether there is an association between GSDMA (rs7212938, T/G) and GSDMB (rs7216389, T/C) at locus 17q21.2 and risk of Allergic Rhinitis among Jordanians. Also, we aimed to determine if there is an association between such polymorphisms and the IgE level. The study included 112 rhinitis patients and 111 Healthy controls. Gasdermin A (GSDMA) (rs7212938, T/G) and Gasdermin B (rs7216389, T/C) polymorphisms were genotyped using the PCRRFLP method. On the genotype level, three analysis models were applied namely co-dominant, dominant and recessive genotypes. GSDMB CC genotype was found to have a significant protective effect against allergic Rhinitis (< 0.05). cc genotype was also significantly associated with higher IgE level among the studied population. The GSDMB CC of homozygous minor genotype showed a protective effect against Allergic rhinitis. It also was found to be significantly associated with lower IgE level among the studied population. No association was found between GSDMA with the risk of allergic Rhinitis.

Polymorphisms of SOCS-1 Are Associated With a Rapid HIV Progression Rate.

Immune activation, among others driven by interferon (IFN)-α and IFN-γ activation, is a main feature of progressive HIV infection. Suppressor of cytokine signaling (SOCS) 1 and 3 are negative feedback regulators of the IFN-α and IFN-γ axis. Here, we analyzed the role of 9 single-nucleotide polymorphisms (SNPs) within SOCS-1 and SOCS-3 genes for their association with an HIV progression rate in a cohort of 318 rapid vs 376 slow progressors from the Swiss HIV Cohort Study. We analyzed 9 SNPs, which we have identified in Swiss blood donors, in a cohort of HIV-infected patients (n = 1144), which have been categorized according to the decline in CD4 T-cell counts. In all the conducted analyses, we focused on the comparison between rapid and slow progressors with regard to SNPs in SOCS-1 and SOCS-3 and with regard to haplotypes using multivariate logistic regression models. Three SOCS-1 SNPs (rs193779, rs33989964, and rs4780355) are associated with a risk reduction for rapid progression. Two of these SNPs, rs33989964 and rs4780355, are in strong linkage disequilibrium, forming a frequent haplotype. Homozygous carriers of this haplotype are also associated with a risk reduction for rapid progression. By contrast, the minor TT genotype of rs33977706 is associated with twice the risk for rapid progression. No associations have been observed for the 4 SOCS-3 SNPs or the major SOCS-3 haplotypes. Our data suggest that SNPs in SOCS-1 are associated with HIV disease progression and speak in favor that immune activation is causal for the progressive immunodeficiency.

Gene-Environment Interaction of FOXO and Residential Greenness on Mortality Among Older Adults.

Residential greenness is an important environmental factor that is strongly associated with mortality. To our knowledge, there was no previous study on the gene-environment interaction analysis between residential greenness and forkhead box O (FOXO) gene, a candidate longevity gene. Our sample consisted of 3179 participants aged 65 and older from the Chinese Longitudinal Healthy Longevity Survey. Residential greenness was measured by satellite-derived normalized difference vegetation index (NDVI) using a 500-m radius around each residential location. Contemporaneous NDVI, cumulative NDVI, and changes in NDVI over time were calculated. We used Cox-proportional hazard regression models to assess the main effect and gene-environment interaction effect of FOXO single nucleotide polymorphism (SNP) and residential greenness on mortality. We found that participants carrying two minor alleles of the three studied FOXO3A SNPs had lower mortality risk than those without minor allele (hazard ratio [HR]: 0.803 95% confidence interval [CI]: 0.654-0.987 for rs4946936, HR: 0.807 95% CI: 0.669-0.974 for rs2802292, HR: 0.803 95% CI: 0.666-0.968 for rs2253310). We found no difference in mortality among the genotypes of the other three FOXO1A SNPs (rs17630266, rs2755213, or rs2755209). Higher contemporaneous NDVI was associated with lower mortality risk (HR: 0.887 95% CI: 0.863-0.911 for 0.1-U of NDVI). The protective effect of both contemporaneous NDVI and cumulative NDVI was stronger for two minor allele carriers compared with zero minor allele carriers of the three FOXO3A SNPs. Compared with the zero minor allele genotype of the three FOXO3A SNPs, the protective effect on the mortality risk of minor allele homozygotes also increased with the increasing NDVI level at percentile 25, 50, and 75 (interaction term coefficient p < 0.05). We found gene-environment interaction between FOXO and residential greenness on mortality in this population study. A higher level of greenness may interact with FOXO pathways.

The dominant model analysis of Sirt3 genetic variants is associated with susceptibility to tuberculosis in a Chinese Han population.

Tuberculosis (TB) is a complex infectious disease caused by the pathogen Mycobacterium tuberculosis (Mtb) which has coexisted with humanity since the Neolithic. Recent research indicated that SIRT3 plays a pivotal role in promoting the antimycobacterial response of mitochondria and autophagy during Mtb infection. A case-control study comprised 900TB patients and 1534 healthy controls who were retrospectively enrolled to assess the association between Sirt3 gene polymorphisms and TB susceptibility. In total, five single-nucleotide polymorphisms (SNPs) (rs511744, rs3782118, rs7104764, rs536715 and rs28365927) were selected through database 1000 Genomes Project and offline software Haploview V4.2 and genotyped by a customized 2 × 48-Plex SNPscan™ Kit. Our results suggested that the minor allele genotypes (A carriers) of rs3782118 confers the decreased risk of TB susceptibility (pBonferroni = 0.032), and a similar but more significant effect was observed under the dominant model analysis (OR 0.787, 95% CI 0.666-0.931, pBonferroni = 0.026). Haplotype analysis showed that haplotype AGAAG (rs511744/rs3782118/rs7104764/rs536715/rs28365927) was associated with an increased risk of TB (p = 0.023, OR 1.159, 95% CI 1.019-1.317). In stratification analysis, we found that rs3782118 was associated with decreased risk of TB in female subgroup under the dominant model analysis (pBonferroni = 0.016, OR 0.678, 95% CI 0.523-0.878). Moreover, functional annotations for three loci (rs7930823, rs3782116 and rs3782115) which are strongly linked to rs3782118 indicated that they may be responsible for the changes in some motifs. In conclusion, our study suggested that the SNP rs3782118 was associated with a lower susceptibility to TB, especially under the dominant model analysis and that the haplotype AGAAG (containing the major allele G of rs3782118) was associated with an increased risk of TB. Further independent cohort studies are necessary to validate the protective effect of Sirt3 genetic variants on the risk of TB.

LncRNA GAS5 and miR-137 Polymorphisms and Expression are Associated with Multiple Sclerosis Risk: Mechanistic Insights and Potential Clinical Impact.

The pathogenesis of multiple sclerosis (MS) is influenced by the interaction of genetic and epigenetic mechanisms. The long noncoding RNA GAS5 acts as a competing endogenous RNA for microRNA-137 and is involved in demyelination. We investigated the association of GAS5 and miR-137 expression and their polymorphisms with MS susceptibility. One hundred and eight MS patients and 104 healthy controls were included. Expression analysis and genotyping of GAS5-rs2067079 and miR-137-rs1625579 single nucleotide polymorphisms were performed by qPCR. Serum GAS5 was upregulated, while serum miR-137 was downregulated in MS compared with the controls. Serum miR-137 was an excellent discriminator of MS patients from the controls (AUC = 0.97) and a negative independent predictor of MS in multivariate logistic analysis. Serum GAS5 expression was positively correlated with the expanded disability status scale scores in the relapsing-remitting MS patients. The rs2067079TT minor homozygote genotype was associated with an increased MS risk, while the rs1625579G minor allele was protective. rs1625579 showed an age-specific effect, while the rs2067079 affected the MS risk in gender- and age-specific manners. In MS patients, rs2067079TT was associated with a higher serum GAS5 than other genotypes, while serum miR-137 did not differ between rs1625579 genotypes. Our results suggest serum GAS5 and miR-137 as MS biomarkers, with miR-137 as a negative predictor of MS risk and GAS5 as a marker of MS severity. We propose rs2067079 and rs1625579 as novel genetic markers of MS susceptibility, and at least, rs2067079 possibly impacts the crosstalk between GAS5 and miR-137.

Aneurysmal subarachnoid haemorrhage: effect of CRHR1 genotype on fatigue and depression

BackgroundEmotional health disturbances are common after aneurysmal subarachnoid hemorrhage (aSAH) and their causes are largely unexplored. Corticotropin-releasing hormone receptor 1 (CRHR1) is a key factor in stress reactivity and development of mental health disturbances after adverse life-events.MethodsWe explore the effect of CRHR1 genotype on mental health after aSAH in a retrospective cohort study. One hundred twenty-five patients have been assessed using EST-Q mental health questionnaire. Genotyping of CRHR1 single nucleotide polymorphisms (SNP-s) was performed (Rs7209436, Rs110402, Rs242924).ResultsFatigue was present in almost half of aSAH patients, depression and anxiety in one-third. There was a high prevalence of insomnia and panic complaints. Rs110402 minor allele decreased the risk of depression (OR = 0.25, p = 0.027 for homozygotes). Depression was present in 14% vs 41% in minor and major allele homozygotes, respectively. Rs110402, Rs242924 and Rs7209436 minor alleles and TAT-haplotype, formed by them, were protective against fatigue. After Bonferroni correction only the association of Rs110402 with fatigue remained statistically significant (OR = 0.21, p = 0.006 for minor allele homozygotes). Results remained statistically significant when adjusted for gender, admission state, age and time from aSAH. In multiple regression analysis occurrence of fatigue was dependent on anxiety, modified Rankin score and Rs110402 genotype (R2 = 0.34, p < 0.001).ConclusionsCRHR1 minor genotype was associated with a lower risk of fatigue and depression after aSAH. Genetic predisposition to mental health disturbances associated with negative life-events could be a risk factor for fatigue and depression after aSAH and selected patients might benefit from advanced counselling in the recovery phase.

The rs11187533 C>T Variant of the FFAR4 Gene Is Associated with Lower Levels of Fasting Glucose and Decreases in Markers of Liver Injury in Children with Obesity

Introduction: Genetic factors can modulate the development of associated comorbidities in obesity. It has been shown that loss-of-function variants of the free fatty acid receptor 4 (FFAR4) gene negatively affect obesity comorbidities such as insulin resistance and fatty liver disease. Objective: To test the relationships of metabolic factors in children with obesity with variants of the FFAR4 gene. Methods: We performed an association study of 3 single nucleotide polymorphisms (SNPs) of FFAR4 (rs10882273 T>C, rs12243124 T>C, and rs11187533 C>T) covering the last intron and last exon of FFAR4 in a cohort of 203 children with obesity. Cardiometabolic factors were determined, including parameters related to insulin resistance, liver injury, and high-sensitivity C-reactive protein as an inflammatory marker. Results: Significant genotype – phenotype interactions occurred between the rs11187533 SNP and glucose levels (p = 0.011). Moreover, we identified 2 marginally significant associations between this SNP and the hepatic enzymes alanine aminotransferase (p = 0.022) and gamma-glutamyltransferase (p = 0.015). The homozygous minor allele genotype (TT) was associated with a decrease in glucose levels. Conclusion: The homozygous minor allele genotype of the rs11187533 SNP might be protective against metabolic consequences accompanying obesity and could allow the identification of metabolically healthy obese individuals at early ages.

IL-28B variant as a predictor in patients with advanced hepatocellular carcinoma treated with hepatic arterial infusion chemotherapy.

Single-nucleotide polymorphisms (SNPs) of the interleukin-28B (IL-28B) gene are associated with the effectiveness of interferon therapy for chronic hepatitis C infection. Whether the IL-28B genotype affects the course of treatment and the outcomes of patients with advanced hepatocellular carcinoma (HCC) is unknown. We detected the IL-28B SNP (rs8099917) using TaqMan PreDesigned SNP Genotyping Assays to assess the effects of the IL-28B genotype on treatment efficacy and prognosis of patients with advanced HCC treated with hepatic arterial infusion chemotherapy (HAIC) between September 2003 and January 2015. The study included 154 patients who received HAIC to treat advanced HCC, among which 27 (17.5%) had the minor genotype, IL-28B rs8099917 TG or GG, and the others had the major genotype, IL-28B rs8099917 TT. The objective response rates of patients with the minor or major genotype were 51.9% and 29.1% (P=0.022), respectively. Multivariate analysis revealed that the minor genotype remained associated with the response to HAIC (odds ratio, 2.620; P=0.026). The median overall survival of patients with major or minor genotypes was 14.1 and 16.9months, respectively, and the overall survival of patients with the major genotype was significantly shorter than that of patients with the minor genotype (P=0.027). Multivariate analysis revealed that the major genotype was an independent, unfavorable prognostic factor (hazard ratio, 1.720; P=0.024). Consistent results were obtained in selected populations after propensity score matching analysis. The IL-28B SNP (rs8099917) will serve as a useful predictor of the outcomes of patients with advanced HCC treated with HAIC.

Analysis of a Candida auris Outbreak Provides New Insights into an Emerging Pathogen.

Candida auris is an emerging human fungal pathogen that is being increasingly linked to outbreaks. It is concerning to health care workers because of its high mortality rate, due primarily to its antifungal resistance. Among the tools being developed to study this yeast are large cohorts of regional isolates, which can be useful for studying epidemiology, antifungal susceptibility patterns, and diagnostic methods. In this issue of the Journal of Clinical Microbiology, Y. Zhu, B. O'Brien, L. Leach, A. Clarke, et al. (J Clin Microbiol 58:e01503-19, 2020, https://doi.org/10.1128/JCM.01503-19) describe the laboratory findings of a collection of isolates from a large outbreak of C. auris obtained from numerous health care facilities in the New York area. Real-time PCR was used as a screening tool with great accuracy, while internal transcribed spacer (ITS) and D1/D2 sequencing were successfully employed for isolate clade assignment. South Asia clade I was identified as the major genotype, while South American clade IV was a minor genotype. Surveillance isolates from patients confirmed axilla/groin and nare colonization; however, results of quantitative analysis of fungal burdens showed that when the nares are colonized, burdens are significantly higher than for axilla/groin colonization. Antifungal susceptibility testing was in agreement with past studies. High levels of fluconazole resistance were detected, while few isolates were resistant to echinocandins. Resistance to multiple antifungals was frequent, and three isolates were recovered that appeared to be pan-resistant. This type of study is yet another useful tool for investigating C. auris, which is becoming an increasingly important human fungal pathogen that should be monitored very closely.

Recovery, Assessment, and Molecular Characterization of Minor Olive Genotypes in Tunisia.

Olive is one of the oldest cultivated species in the Mediterranean Basin, including Tunisia, where it has a wide diversity, with more than 200 cultivars, of both wild and feral forms. Many minor cultivars are still present in marginal areas of Tunisia, where they are maintained by farmers in small local groves, but they are poorly characterized and evaluated. In order to recover this neglected germplasm, surveys were conducted in different areas, and 31 genotypes were collected, molecularly characterized with 12 nuclear microsatellite (simple sequence repeat (SSR)) markers, and compared with 26 reference cultivars present in the Tunisian National Olive collection. The analysis revealed an overall high genetic diversity of this olive’s germplasm, but also discovered the presence of synonymies and homonymies among the commercialized varieties. The structure analysis showed the presence of different gene pools in the analyzed germplasm. In particular, the marginal germplasm from Ras Jbal and Azmour is characterized by gene pools not present in commercial (Nurseries) varieties, pointing out the very narrow genetic base of the commercialized olive material in Tunisia, and the need to broaden it to avoid the risk of genetic erosion of this species in this country.

Changes in plant function and root mycobiome caused by flood and drought in a riparian tree.

Under increasingly harsh climatic conditions, conservation of threatened species requires integrative studies to understand stress tolerance. Riparian Ulmus minor Mill. populations have been massively reduced by Dutch Elm disease (DED). However, resistant genotypes were selected to restore lost populations. To understand the acclimation mechanisms to the succession of abiotic stresses, ramets of five DED-tolerant U. minor genotypes were subjected to flood and subsequently to drought. Physiological and biochemical responses were evaluated together with shifts in root-fungal assemblages. During both stresses, plants exhibited a decline in leaf net photosynthesis and an increase in percentage loss of stem hydraulic conductivity and in leaf and root proline content. Stomatal closure was produced by chemical signals during flood and hydraulic signals during drought. Despite broad similarities in plant response to both stresses, root-mycobiome shifts were markedly different. The five genotypes were similarly tolerant to moderate drought, however, flood tolerance varied between genotypes. In general, flood did not enhance drought susceptibility due to fast flood recovery, nevertheless, different responses to drought after flood were observed between genotypes. Associations were found between some fungal taxonomic groups and plant functional traits varying with flood and drought (e.g. proline, chlorophyll and starch content) indicating that the thriving of certain taxa depends on host responses to abiotic stress.

Re.Ger.O.P.: An Integrated Project for the Recovery of Ancient and Rare Olive Germplasm.

The olive tree is one of the most important economic, cultural, and environmental resources for Italy, in particular for the Apulian region, where it shows a wide diversity. The increasing attention to the continuous loss of plant genetic diversity due to social, economic and climatic changes, has favored a renewed interest in strategies aimed at the recovery and conservation of these genetic resources. In the frame of a project for the valorization of the olive Apulian biodiversity (Re.Ger.O.P. project), 177 minor genotypes were recovered in different territories of the region. They were submitted to morphological, molecular, technological and phytosanitary status analysis in comparison with reference cultivars, then they were propagated and transferred in an ex situ field. All the available information was stored in an internal regional database including photographic documentation and geographic position. The work allowed obtaining information about the genetic diversity of Apulian germplasm, to clarify cases of homonymy and synonymy, to check the sanitary status, and to identify candidate genotypes useful both to set up breeding programs and to enrich the panel of olive cultivars available to farmers for commercial exploitation.