1 2684 151 EVALUATION OF X CHROMOSOME INACTIVATION WITH RESPECT TO HLA GENETIC SUSCEPTIBILITY IN RHEUMATOID ARTHRITIS AND SYSTEMIC SCLEROSIS. BACKGROUND: AUTOIMMUNE DISEASES, INCLUDING RHEUMATOID ARTHRITIS (RA) AND SYSTEMIC SCLEROSIS (SSC) ARE CHARACTERIZED BY A STRONG GENETIC SUSCEPTIBILITY FROM THE HUMAN LEUCOCYTE ANTIGEN (HLA) LOCUS. ADDITIONALLY, DISORDERS OF EPIGENETIC PROCESSES, IN PARTICULAR NON-RANDOM X CHROMOSOME INACTIVATION (XCI), HAVE BEEN REPORTED IN MANY FEMALE-PREDOMINANT AUTOIMMUNE DISEASES. HERE WE TEST THE HYPOTHESIS THAT WOMEN WITH RA OR SSC WHO ARE STRONGLY GENETICALLY PREDISPOSED ARE LESS SUSCEPTIBLE TO XCI BIAS. METHODS: USING METHYLATION SENSITIVE GENOTYPING OF THE ANDROGEN RECEPTOR (AR) GENE, XCI PROFILES WERE PERFORMED IN PERIPHERAL BLOOD MONONUCLEAR CELLS FROM 161 WOMEN WITH RA, 96 WOMEN WITH SSC AND 100 HEALTHY WOMEN. HLA-DRB1 AND DQB1 WERE GENOTYPED. PRESENCE OF SPECIFIC AUTOANTIBODIES WAS DOCUMENTED FOR PATIENTS. XCI SKEWING WAS DEFINED AS HAVING A RATIO >/= 80:20 OF CELLS INACTIVATING THE SAME X CHROMOSOME. RESULTS: 110 WOMEN WITH RA, 68 WOMEN WITH SSC, AND 69 CONTROLS WERE INFORMATIVE FOR THE AR POLYMORPHISM. AMONG THEM 40.9% OF RA PATIENTS AND 36.8% OF SSC PATIENTS HAD SKEWED XCI COMPARED TO 17.4% OF HEALTHY WOMEN (P = 0.002 AND 0.018, RESPECTIVELY). PRESENCE OF RA-SUSCEPTIBILITY ALLELES CODING FOR THE "SHARED EPITOPE" CORRELATED WITH HIGHER SKEWING AMONG RA PATIENTS (P = 0.002) AND SUCH CORRELATION WAS NOT OBSERVED IN OTHER WOMEN, HEALTHY OR WITH SSC. PRESENCE OF SSC-SUSCEPTIBILITY ALLELES DID NOT CORRELATE WITH XCI PATTERNS AMONG SSC PATIENTS. CONCLUSION: DATA DEMONSTRATE XCI SKEWING IN BOTH RA AND SSC COMPARED TO HEALTHY WOMEN. UNEXPECTEDLY, SKEWED XCI OCCURS MORE OFTEN IN WOMEN WITH RA CARRYING THE SHARED EPITOPE, WHICH USUALLY REFLECTS SEVERE DISEASE. THIS REINFORCES THE VIEW THAT LOSS OF MOSAICISM IN PERIPHERAL BLOOD MAY BE A CONSEQUENCE OF CHRONIC AUTOIMMUNITY. 2016 2 1419 31 DIFFERENT CLINICAL FORMS OF HEREDITARY TYROSINEMIA (TYPE I) IN PATIENTS WITH IDENTICAL GENOTYPES. HEREDITARY TYROSINEMIA TYPE I (HTI, MCKUSICK 276700) IS AN AUTOSOMAL RECESSIVE DISEASE CAUSED BY DEFICIENT FUMARYLACETOACETATE HYDROLASE (FAH, EC 3.7.1.2) ACTIVITY. HTI IS CHARACTERIZED BY PROGRESSIVE LIVER DYSFUNCTION WITH NODULAR CIRRHOSIS OFTEN LEADING TO HEPATOCELLULAR CARCINOMA. TWO EXTREMES OF THE CLINICAL PHENOTYPE HAVE BEEN DESCRIBED: THE "ACUTE" (SEVERE, EARLY ONSET AND DEATH) AND "CHRONIC" (DELAYED ONSET AND SLOW COURSE) PHENOTYPE. ALLELIC HETEROGENEITY AND/OR MUTATION REVERSION IN HEPATIC CELLS HAVE BEEN PROPOSED EARLIER TO EXPLAIN THE CLINICAL HETEROGENEITY. TWO PROBANDS (ONE "ACUTE," ONE "CHRONIC") FROM THE FRENCH-CANADIAN ISOLATE WHERE HTI IS PREVALENT WERE STUDIED. BOTH WERE HOMOZYGOUS (GERM LINE) FOR THE SEVERE SPLICE MUTATION IVS12 + 5G --> A; BOTH SHOWED LIVER MOSAICISM FOR FAH IMMUNOREACTIVITY WITH EVIDENCE FOR MUTATION REVERSION TO HETEROZYGOSITY (IVS12 + 5G --> A/+) IN FAH-STAINED NODULES AS SHOWN BY AMPLIFICATION OF DNA EXTRACTED FROM MICRODISSECTED NODULES. WESTERN BLOT ANALYSIS OF PROTEINS FROM A REVERTED FAH-EXPRESSING NODULE SHOWED 29 +/- 3% FAH IMMUNOREACTIVE MATERIAL AS COMPARED TO AN AVERAGE NORMAL LIVER. THIS WAS CONSISTENT WITH THE MEASURED FAA HYDROLYTIC ACTIVITY (25%) IN THIS LARGE REGENERATING NODULE. THESE FINDINGS SHOW THAT GENOTYPIC HETEROGENEITY IS NOT A SUFFICIENT EXPLANATION FOR CLINICAL HETEROGENEITY AND IMPLICATE EPIGENETIC AND OTHER FACTORS MODIFYING THE PHENOTYPE IN HTI. 1998 3 6815 25 [EVOLUTIONARY ONTOGENETIC ASPECTS OF PATHOGENETICS OF CHRONIC HUMAN DISEASES]. THIS ARTICLE IS A REVIEW OF SCIENTIFIC PUBLICATIONS, IN WHICH ISSUES OF PATHOGENETICS OF MULTIFACTORIAL DISEASES (MFDS) ARE CONSIDERED FROM THE VIEWPOINT OF EVOLUTION AND ONTOGENY. CONCEPTS EXPLAINING SIGNIFICANCE OF EVOLUTIONARY PROCESSES IN THE FORMATION OF GENETIC ARCHITECTURE OF HUMAN CHRONIC DISEASES ("THRIFTY" GENOMES AND PHENOTYPES, "DRIFTING GENES," DECANALIZATION) ARE ANALYZED. THE ROLES OF NATURAL SELECTION AND GENETIC DRIFT IN THE FORMATION OF HEREDITARY DIVERSITY OF GENES FOR SUSCEPTIBILITY TO MFDS ARE CONSIDERED. THE MODERN CONCEPT OF DISEASE ONTOGENY (SOMATIC MOSAICISM, LOSS OFHETEROZYGOSITY, PARADOMINANT INHERITANCE, EPIGENETIC VARIABILITY) IS DISCUSSED. IT IS DEMONSTRATED THAT THE EVOLUTIONARY AND ONTOGENETIC APPROACHES TO ANALYSIS OF GENIMUC AND OTHER "-OMIC" DATA ARE ESSENTIAL FOR UNDERSTANDING THE BIOLOGY OF DISEASES. 2011 4 3528 38 IL36G GENETIC VARIANT IS INDEPENDENTLY ASSOCIATED WITH SUSCEPTIBILITY, SEVERITY AND JOINT INVOLVEMENT IN PSORIASIS. PSORIASIS (PSO) IS A CHRONIC, IMMUNE-MEDIATED, INFLAMMATORY AND POLYGENIC DERMATOSIS ASSOCIATED WITH BOTH PHYSICAL AND PSYCHOLOGICAL BURDEN THAT CAN BE TRIGGERED BY INJURY, TRAUMA, INFECTIONS AND MEDICATIONS. THE ETIOLOGY OF PSO IS NOT FULLY ELUCIDATED BUT GENETIC, EPIGENETIC AND ENVIRONMENTAL FACTORS ARE ALL LIKELY TO PLAY A ROLE. A CASE-CONTROL STUDY WAS CARRIED OUT TO EVALUATE THE FREQUENCY OF THE IL36G C>T (RS13392494) AND THE IL36G A>G (RS7584409) VARIANTS AND THEIR ASSOCIATION WITH SUSCEPTIBILITY, JOINT INVOLVEMENT AND SEVERITY OF PSO. THE STUDY INCLUDED 154 PATIENTS WITH PSO AND 154 CONTROLS FROM BRAZILIAN POPULATION. THE SEVERITY OF PSO WAS ASSESSED BY THE PSORIASIS AREA AND SEVERITY INDEX (PASI). THE IL36G (RS13392494 AND RS7584409) VARIANTS WERE GENOTYPED BY ALLELIC DISCRIMINATION ASSAY USING THE REAL-TIME POLYMERASE CHAIN REACTION. THE ASSOCIATION BETWEEN THE IL36G GENETIC VARIANTS AND THE STUDY VARIABLES WAS ANALYZED IN ALLELIC, DOMINANT, CODOMINANT, OVERDOMINANT, RECESSIVE, AND HAPLOTYPE MODELS. THE MAIN RESULTS WERE THAT PSO PATIENTS WERE OLDER (P < 0.001) AND HAD HIGHER BODY MASS INDEX (P < 0.001) THAN CONTROLS; 95.8% OF THE PATIENTS HAD PLAQUE PSO, 16.1% HAD PSORIATIC ARTHRITIS (PSA), AND 27.9% HAD PASI > 10. THE IL36G RS1339294 VARIANT SHOWED NO ASSOCIATION WITH PSO IN ALL GENETIC MODELS WHILE THE IL36G RS7584409 VARIANT SHOWED A PROTECTIVE EFFECT IN PSO. HOWEVER, THE G ALLELE OF THE IL36G RS7584409 IN THE DOMINANT MODEL WAS POSITIVELY ASSOCIATED WITH PASI > 10 (P = 0.031). MOREOVER, PATIENTS WITH THE GG GENOTYPE OF THE IL36G RS7584409 VARIANT HAD ABOUT 5.0 TIMES MORE CHANCE OF PSA THAN THOSE WITH THE AA GENOTYPE (P = 0.014). REGARDING THE HAPLOTYPES, THE C/A IN A RECESSIVE MODEL (CACA VERSUS C/G AND T/A CARRIERS) WAS ASSOCIATED WITH PSO (P = 0.035) WHILE THE C/G HAPLOTYPE IN A DOMINANT MODEL (C/A CARRIERS VERSUS C/G AND T/A CARRIERS) SHOWED A PROTECTIVE EFFECT FOR PSO (P = 0.041). IN CONCLUSION, THE G ALLELE OF THE IL36G RS7584409 VARIANT WAS ASSOCIATED WITH PROTECTION TO PSO; HOWEVER, IN PATIENTS WITH PSO, THIS SAME ALLELE WAS ASSOCIATED WITH MODERATE TO SEVERE DISEASE AND PSA. THESE RESULTS SUGGEST THAT THE IL36G RS7584409 VARIANT MAY BE USED AS A POSSIBLE GENETIC BIOMARKER TO PREDICT SEVERITY AND JOINT INVOLVEMENT OF PSO. 2023 5 3574 39 IMPACT OF METHIONINE SYNTHASE REDUCTASE POLYMORPHISMS IN CHRONIC MYELOID LEUKEMIA PATIENTS. INTRODUCTION: METABOLISM METHIONINE AND OF FOLATE PLAY A VITAL FUNCTION IN CELLULAR METHYLATION REACTIONS, DNA SYNTHESIS AND EPIGENETIC PROCESS.HOWEVER, POLYMORPHISMS OF METHIONINE HAVE RECEIVED MUCH ATTENTION IN RECENT MEDICAL GENETICS RESEARCH. OBJECTIVES: TO ASCERTAIN WHETHER THE COMMON POLYMORPHISMS OF THE MTRR (METHIONINE SYNTHASE REDUCTASE) A66G GENE COULD PLAY A ROLE IN AFFECTING SUSCEPTIBILITY TO CHRONIC MYELOID LEUKEMIA (CML) IN SUDANESE INDIVIDUALS. METHODS: IN A CASE-CONTROLLED STUDY, WE EXTRACTED AND ANALYZED DNA FROM 200 CML PATIENTS AND 100 HEALTHY CONTROL SUBJECTS BY THE PCR-RFLP METHOD. RESULTS: WE FOUND NO SIGNIFICANT DIFFERENCE IN AGE ORGENDER BETWEEN THE PATIENT GROUP AND CONTROLS. THE MTRR A66G GENOTYPES WERE DISTRIBUTED BASED ON THE HARDY-WEINBERG EQUILIBRIUM (P > 0.05). THE VARIATION OF MTRR A66G WAS LESS SIGNIFICANTLY FREQUENT IN CASES WITH CML (68.35%) THAN IN CONTROLS (87%) (OR = 0.146, 95% CI = 0.162-0.662, P < 0.002). ADDITIONALLY, AG AND GG GENOTYPES AND G ALLELE WERE REDUCING THE CML RISK (ODDS RATIO [OR] = 0.365; 95% CI [0.179-0.746]; P = 0.006; OR = 0.292; 95% CI [0.145-0.590]; P = 0.001 AND OR = 0.146; 95% CI [0.162-0.662]; P = 0.002 AND OR = 2.0; 95% CI [1.3853-2.817]; RESPECTIVELY, (P = 0.000)). CONCLUSIONS: OUR DATA DEMONSTRATED THAT HETEROZYGOUS AND HOMOZYGOUS MUTANT GENOTYPES OF MTRR POLYMORPHISMS WERE ASSOCIATED WITH DECREASED RISK OF DEVELOPING CML IN THE SUDANESE POPULATION. 2022 6 553 12 AUTOINFLAMMATORY RETINOPATHY IN CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME. CHRONIC INFANTILE NEUROLOGICAL CUTANEOUS AND ARTICULAR (CINCA) SYNDROME IS A RARE AUTOSOMAL DOMINANT AUTOINFLAMMATORY DISEASE. WE REPORT THE CASES OF MONOZYGOTIC TWINS WITH CINCA SYNDROME WHOSE PREDOMINANT OCULAR MANIFESTATION WAS INFLAMMATORY ROD-CONE RETINAL DYSTROPHY. ATYPICALLY, THERE WERE SIGNIFICANT DIFFERENCES BETWEEN TWINS IN PHENOTYPE SEVERITY, SUGGESTIVE OF EPIGENETIC DIFFERENCES AND/OR INVOLVEMENT OF ENVIRONMENTAL FACTORS. 2016 7 5246 35 PROGNOSTIC SCORE INCLUDING GENE MUTATIONS IN CHRONIC MYELOMONOCYTIC LEUKEMIA. PURPOSE: SEVERAL PROGNOSTIC SCORING SYSTEMS HAVE BEEN PROPOSED FOR CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), A DISEASE IN WHICH SOME GENE MUTATIONS-INCLUDING ASXL1-HAVE BEEN ASSOCIATED WITH POOR PROGNOSIS IN UNIVARIABLE ANALYSES. WE DEVELOPED AND VALIDATED A PROGNOSTIC SCORE FOR OVERALL SURVIVAL (OS) BASED ON MUTATIONAL STATUS AND STANDARD CLINICAL VARIABLES. PATIENTS AND METHODS: WE GENOTYPED ASXL1 AND UP TO 18 OTHER GENES INCLUDING EPIGENETIC (TET2, EZH2, IDH1, IDH2, DNMT3A), SPLICING (SF3B1, SRSF2, ZRSF2, U2AF1), TRANSCRIPTION (RUNX1, NPM1, TP53), AND SIGNALING (NRAS, KRAS, CBL, JAK2, FLT3) REGULATORS IN 312 PATIENTS WITH CMML. GENOTYPES AND CLINICAL VARIABLES WERE INCLUDED IN A MULTIVARIABLE COX MODEL OF OS VALIDATED BY BOOTSTRAPPING. A SCORING SYSTEM WAS DEVELOPED USING REGRESSION COEFFICIENTS FROM THIS MODEL. RESULTS: ASXL1 MUTATIONS (P < .0001) AND, TO A LESSER EXTENT, SRSF2 (P = .03), CBL (P = .003), AND IDH2 (P = .03) MUTATIONS PREDICTED INFERIOR OS IN UNIVARIABLE ANALYSIS. THE RETAINED INDEPENDENT PROGNOSTIC FACTORS INCLUDED ASXL1 MUTATIONS, AGE OLDER THAN 65 YEARS, WBC COUNT GREATER THAN 15 X10(9)/L, PLATELET COUNT LESS THAN 100 X10(9)/L, AND ANEMIA (HEMOGLOBIN < 10 G/DL IN FEMALE PATIENTS, < 11G/DL IN MALE PATIENTS). THE RESULTING FIVE-PARAMETER PROGNOSTIC SCORE DELINEATED THREE GROUPS OF PATIENTS WITH MEDIAN OS NOT REACHED, 38.5 MONTHS, AND 14.4 MONTHS, RESPECTIVELY (P < .0001), AND WAS VALIDATED IN AN INDEPENDENT COHORT OF 165 PATIENTS (P < .0001). CONCLUSION: A NEW PROGNOSTIC SCORE INCLUDING ASXL1 STATUS, AGE, HEMOGLOBIN, WBC, AND PLATELET COUNTS DEFINES THREE GROUPS OF CMML PATIENTS WITH DISTINCT OUTCOMES. BASED ON CONCORDANCE ANALYSIS, THIS SCORE APPEARS MORE DISCRIMINATIVE THAN THOSE BASED SOLELY ON CLINICAL PARAMETERS. 2013 8 4571 32 MYELOMONOCYTIC SKEWING IN CHRONIC MYELOMONOCYTIC LEUKEMIA: PHENOTYPIC, MOLECULAR AND BIOLOGIC FEATURES AND IMPACT ON SURVIVAL. BACKGROUND: MYELOMONOCYTIC SKEWING IS CONSIDERED AS A KEY PATHOPHYSIOLOGIC PHENOMENON IN CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML), BUT ITS PREVALENCE AND POTENTIAL CORRELATION WITH PHENOTYPIC, GENOTYPIC, AND CLINICAL FEATURES ARE POORLY DEFINED. METHODS: SKEWED DIFFERENTIATION TOWARD THE MYELOMONOCYTIC OVER ERYTHROID COMMITMENT AS INDICATED BY AN INVERSE RATIO OF MYELOMONOCYTIC/ERYTHROID COLONIES WAS INVESTIGATED IN 146 PATIENTS WITH CMML BY SEMISOLID IN VITRO CULTURES. RESULTS: THERE WAS A HIGH PREVALENCE OF MYELOMONOCYTIC SKEWING IN PATIENTS WITH CMML (120/146, 82%); WHEREAS, THIS PHENOMENON WAS RARE IN NORMAL INDIVIDUALS (1/98, 1%). PATIENTS WITH CMML WITH MYELOMONOCYTIC SKEWING HAD HIGHER WHITE BLOOD CELL AND PERIPHERAL BLAST CELL COUNTS, AND LOWER PLATELET VALUES. THE NUMBER OF MUTATIONS IN GENES OF THE EPIGENETIC AND/OR SPLICING CATEGORY WAS HIGHER IN CMML PATIENTS WITH AS COMPARED WITH PATIENTS WITHOUT SKEWING. PATIENTS WITH MYELOMONOCYTIC SKEWING HAD MORE FREQUENTLY MUTATIONS IN RASOPATHY GENES AND HIGHER GROWTH FACTOR INDEPENDENT MYELOID COLONY FORMATION. INTERESTINGLY, THE LACK OF MYELOMONOCYTIC SKEWING DISCRIMINATED PATIENTS WITH CMML WITH A PARTICULARLY FAVORABLE PROGNOSIS (60 VS 19 MONTHS, P = .003) AND A MINIMAL RISK OF TRANSFORMATION. CONCLUSION: MYELOMONOCYTIC SKEWING AS DETERMINED BY SEMISOLID CULTURES CAN DISCRIMINATE SUBGROUPS OF PATIENTS WITH CMML WITH A DIFFERENT PHENOTYPE, A DIFFERENT GENOTYPE, AND A DIFFERENT PROGNOSIS. 2021 9 5639 43 SERUM MICRORNAS IN SYSTEMIC SCLEROSIS, ASSOCIATIONS WITH DIGITAL VASCULOPATHY AND LUNG INVOLVEMENT. BACKGROUND AND AIMS: SYSTEMIC SCLEROSIS (SSC) IS AN AUTOIMMUNE, RARE MULTISYSTEM CHRONIC DISEASE THAT IS STILL NOT WELL-UNDERSTOOD AETIOLOGICALLY AND IS CHALLENGING DIAGNOSTICALLY. IN THE LITERATURE, THERE ARE EVER-INCREASING ASSUMPTIONS REGARDING THE EPIGENETIC MECHANISMS INVOLVED IN SSC DEVELOPMENT; ONE OF THEM IS CIRCULATING MICRORNAS. MANY OF THEM REGULATE TLR PATHWAYS AND ARE SIGNIFICANT IN AUTOIMMUNE BALANCE. THE AIM OF THIS STUDY WAS TO DETERMINE PROFILE EXPRESSION OF SELECTED MICRORNAS IN SSC PATIENTS, INCLUDING MIR-126, -132, -143, -145, -155, -181A, -29A AND -3148, IN COMPARISON TO HEALTHY CONTROLS. METHODS: SERUM MICRORNAS WERE ISOLATED FROM 45 PATIENTS WITH SSC AND 57 HEALTHY DONORS (HC). ADDITIONALLY, SSC PATIENTS WERE CONSIDERED IN THE ASPECT OF DISEASE SUBTYPE, INCLUDING DIFFUSE SYSTEMIC SCLEROSIS (DCSSC) AND LIMITED SYSTEMIC SCLEROSIS (LCSSC). RESULTS: MIR-3148 WAS DETECTED NEITHER IN THE SERUM OF HC NOR IN SSC PATIENTS. ALL OF THE REST OF THE ANALYZED MICRORNAS, EXCLUDING MIR-126, MIR-29A AND MIR-181A, WERE SIGNIFICANTLY UPREGULATED IN SSC PATIENTS IN COMPARISON TO HC. HOWEVER, MIR-181A HAS BEEN REVEALED ONLY IN THE SERUM OF PATIENTS WITH LCSSC BUT NOT DCSSC. MODERATE POSITIVE CORRELATIONS BETWEEN THE TRANSFER FACTOR OF THE LUNG FOR CARBON MONOXIDE (TLCO) AND MIR-126 AND MIR-145 WERE OBSERVED. A SIGNIFICANT CORRELATION HAS BEEN FOUND BETWEEN SERUM MIR-143 LEVEL AND FORCED VITAL CAPACITY (FVC). SSC PATIENTS WITH FVC 0.05), DENOTING THAT (RS2251375) AND (RS3200401) ARE NOT IN LINKAGE DISEQUILIBRIUM. THERE IS NO ASSOCIATION BETWEEN H19 SNP (RS2251375) AND MALAT1 SNP (RS3200401) AND THE SUSCEPTIBILITY OF RA. HOWEVER, THERE IS AN ASSOCIATION BETWEEN H19 SNP (RS2251375) GENOTYPE CA AND MALAT1 SNP (RS3200401) GENOTYPE CC WITH RA HIGH DISEASE ACTIVITY. 2023 13 5665 30 SF3B1, RUNX1 AND TP53 MUTATIONS SIGNIFICANTLY IMPACT THE OUTCOME OF PATIENTS WITH LOWER-RISK MYELODYSPLASTIC SYNDROME. INTRODUCTION: PROGNOSIS OF PATIENTS WITH MYELODYSPLASTIC SYNDROME (MDS), PARTICULARLY THE GROUP WITH LOWER-RISK DISEASE (LR-MDS) IS VERY HETEROGENEOUS. SEVERAL STUDIES HAVE DESCRIBED THE PROGNOSTIC VALUE OF RECURRENT SOMATIC MUTATIONS IN MDS INCLUDING ALL RISK CATEGORIES. RECENTLY, THE INCORPORATION OF GENOMIC DATA TO CLINICAL PARAMETERS DEFINED THE NEW MOLECULAR INTERNATIONAL PROGNOSTIC SCORING SYSTEM (IPSS-M). MATERIALS AND METHODS: IN THIS STUDY, WE EVALUATED THE IMPACT OF MOLECULAR PROFILE IN A SERIES OF 181 PATIENTS WITH LR-MDS AND NON-PROLIFERATIVE CHRONIC MYELOMONOCYTIC LEUKEMIA. RESULTS: EPIGENETIC REGULATORS (TET2, ASXL1) AND SPLICING (SF3B1) WERE THE MOST RECURRENT MUTATED PATHWAYS. IN UNIVARIATE ANALYSIS, RUNX1 OR TP53 MUTATIONS CORRELATED WITH LOWER MEDIAN OVERALL SURVIVAL (OS). IN CONTRAST, SF3B1 MUTATION WAS ASSOCIATED WITH PROLONGED MEDIAN OS [95 MONTHS (95% IC, 32-157) VS. 33 MONTHS (95% CI, 19-46) IN UNMUTATED PATIENTS (P < 0.01)]. IN A MULTIVARIATE COX REGRESSION MODEL, RUNX1 MUTATIONS INDEPENDENTLY ASSOCIATED WITH SHORTER OS, WHILE SF3B1 MUTATION RETAINED ITS FAVORABLE IMPACT ON OUTCOME (HR: 0.24, 95% CI, 0.1-0.5; P = 0.001). IN ADDITION, TP53 OR RUNX1 MUTATIONS WERE IDENTIFIED AS PREDICTIVE COVARIATES FOR THE PROBABILITY OF LEUKEMIC PROGRESSION (P < 0.001). CONCLUSION: INCORPORATION OF MOLECULAR TESTING IN LR-MDS IDENTIFIED A SUBSET OF PATIENTS WITH EXPECTED POORER OUTCOME, EITHER DUE TO LOWER SURVIVAL OR PROBABILITY OF LEUKEMIC PROGRESSION. 2022 14 517 31 ASSOCIATION STUDY OF FOXO3A SINGLE-NUCLEOTIDE POLYMORPHISM AND BRONCHIAL ASTHMA IN EGYPTIAN CHILDREN. ASTHMA IS THE MOST COMMON CHRONIC ILLNESS IN CHILDREN AND IS A LEADING CAUSE OF CHILDHOOD HOSPITALIZATION AND SCHOOL ABSENTEEISM. ASTHMA PRESENTS WITH DIFFERENT PHENOTYPES DEPENDING ON AGE, GENDER, GENETIC BACKGROUND, ENVIRONMENTAL EXPOSURES AND EPIGENETIC FACTORS. FORKHEAD BOX O3 (FOXO3) IS A TRANSCRIPTION FACTOR INVOLVED IN THE PATHOGENESIS OF A NUMBER OF INFLAMMATORY AND RESPIRATORY DISEASES. THE STUDY AIMS TO INVESTIGATE THE ASSOCIATION BETWEEN THE SNP RS13217795 IN FOXO3 GENE AND PEDIATRIC ONSET ASTHMA IN THE EGYPTIAN POPULATION. NINETY ASTHMATICS AND 160 HEALTHY CONTROLS WERE SUBJECTED TO GENOTYPING OF FOXO3 SNP (RS13217795) USING THE PCR-RFLP METHOD. THE PROPORTION OF HOMOZYGOUS (CC) AND HETEROZYGOUS (CT) GENOTYPES WAS LOWER IN THE ASTHMATIC GROUP COMPARED TO THE CONTROL GROUP BUT STATISTICALLY INSIGNIFICANT; P > 0.05. ON THE OTHER HAND THE PROPORTION OF THE MUTANT HOMOZYGOUS (TT) GENOTYPE IN ASTHMATIC GROUP WAS HIGHER; 30 (33.3%) THAN THE CONTROL GROUP; 28(17.5%), THE DIFFERENCE WAS SIGNIFICANT IN RECESSIVE MODEL OF DISEASE PENETRANCE WITH ODDS RATIO OR (95% CI) OF 2.4(1 - 5.49) AND P=0.039. THIS ASSOCIATION WAS MORE PRONOUNCED IN MALE GENDER; OR AND 95% CI OF 5.3 (1.4- 19.3) AND P=0.01. IN CONCLUSIONS, EGYPTIAN CHILDREN CARRYING THE MUTANT (TT) GENOTYPE WERE AT HIGHER RISK TO DEVELOP ASTHMA WITH A HIGHER RISK IN MALE GENDER. 2020 15 2893 25 GAS5 RS2067079 AND MIR-137 RS1625579 FUNCTIONAL SNPS AND RISK OF CHRONIC HEPATITIS B VIRUS INFECTION AMONG EGYPTIAN PATIENTS. HEPATITIS B VIRUS (HBV) INFECTION IS A SIGNIFICANT HEALTH ISSUE WORLDWIDE.. WE ATTEMPTED TO FULFILL THE MOLECULAR MECHANISMS OF EPIGENETIC AND GENETIC FACTORS ASSOCIATED WITH CHRONIC HBV (CHBV). EXPRESSION LEVELS OF THE LNCRNA GROWTH ARREST-SPECIFIC 5 (GAS5) AND MIR-137 AND THEIR CORRESPONDING SNPS, RS2067079 (C/T) AND RS1625579 (G/T) WERE ANALYZED IN 117 CHBV PATIENTS AND 120 CONTROLS TO INVESTIGATE THE PROBABLE ASSOCIATION BETWEEN THESE BIOMARKERS AND CHBV PATHOGENESIS IN THE EGYPTIAN POPULATION. SERUM EXPRESSION LEVELS OF GAS5 AND MIR-137 WERE SIGNIFICANTLY DOWN-REGULATED IN CASES VS CONTROLS. REGARDING GAS5 (RS2067079), THE MUTANT TT GENOTYPE SHOWED AN INCREASED RISK OF CHBV (P < 0.001), WHILE THE DOMINANT CC WAS A PROTECTIVE FACTOR (P = 0.004). REGARDING MIR-137 RS1625579, THE MUTANT GENOTYPE TT WAS REPORTED AS A RISK FACTOR FOR CHBV (P < 0.001) AND THE NORMAL GG GENOTYPE WAS A PROTECTIVE FACTOR, P < 0.001. THE SERUM GAS5 WAS SIGNIFICANTLY HIGHER IN THE MUTANT TT GENOTYPE OF GAS5 SNP AS COMPARED TO THE OTHER GENOTYPES (P = 0.007). CONCERNING MIR-137 RS1625579, THE MUTANT TT GENOTYPE WAS SIGNIFICANTLY ASSOCIATED WITH A LOWER SERUM EXPRESSION LEVEL OF MIR-137 (P = 0.018). WE REVEALED THE DYSREGULATED EXPRESSION LEVELS OF GAS5 AND MIR-137 LINKED TO THEIR FUNCTIONING SNPS WERE ASSOCIATED WITH CHBV RISK AND MIGHT ACT AS POTENTIAL THERAPEUTIC TARGETS. 2021 16 6603 30 TWO SISTERS WITH FAMILIAL MEDITERRANEAN FEVER: LACK OF CORRELATION BETWEEN GENOTYPE AND PHENOTYPE? FAMILIAL MEDITERRANEAN FEVER (FMF) IS AN AUTOSOMAL RECESSIVE DISORDER CHARACTERIZED BY ATTACKS OF FEVER AND SEROSITIS. THE MOST IMPORTANT COMPLICATION OF FMF IS RENAL AMYLOIDOSIS, WHICH DETERMINES THE PROGNOSIS. THE GENE CODING THE DISEASE (MEFV) IS IDENTIFIED ON THE 16TH CHROMOSOME. THE MOST COMMON MEFV MUTATIONS ARE M694V, M680I, V726A AND M694I LOCATED ON EXON 10 AND E148Q LOCATED ON EXON 2. UNFORTUNATELY, GENOTYPE-PHENOTYPE CORRELATION IS NOT WELL ESTABLISHED AND THERE ARE UNEXPLAINED ETHNIC DIFFERENCES IN AMYLOIDOSIS RATES. WE REPORT TWO SISTERS WITH A COMMON GENOTYPE (M694V/M694V) PRESENTING WITH DIFFERENT PHENOTYPIC CHARACTERISTICS: ONE COMPLAINING OF INTERMITTENT ABDOMINAL PAIN, ARTHRITIS AND FEVER, WHILE THE OTHER WAS SUFFERING FROM INTERMITTENT PLEURITIS AND FEVER DURING ATTACKS. THE OBSERVATION OF DIFFERENT PHENOTYPIC PRESENTATIONS WITH A COMMON GENOTYPE IN TWO FAMILY MEMBERS SHOWS THAT DIFFERENT PHENOTYPES CANNOT BE EXPLAINED BY PARTICULAR MUTATIONS. TO UNDERSTAND THE CORRELATION BETWEEN GENOTYPIC AND PHENOTYPIC FMF VARIANTS THE EXISTENCE OF COMPLEX ALLELES, MODIFIER LOCI, GENETIC HETEROGENEITY AND POSSIBLE EPIGENETIC FACTORS SHOULD BE STUDIED EXTENSIVELY. 2006 17 4553 32 MUTATIONAL LANDSCAPE OF CHRONIC MYELOMONOCYTIC LEUKEMIA IN CHINESE PATIENTS. BACKGROUND: CHRONIC MYELOMONOCYTIC LEUKEMIA (CMML) IS A RARE AND HETEROGENEOUS HEMATOLOGICAL MALIGNANCY. IT HAS BEEN SHOWN THAT THE MOLECULAR ABNORMALITIES SUCH AS ASXL1, TET2, SETBP1, AND SRSF2 MUTATIONS ARE COMMON IN CAUCASIAN POPULATION. METHODS: WE RETROSPECTIVELY ANALYZED 178 CHINESE CMML PATIENTS. THE TARGETED NEXT GENERATION SEQUENCING (NGS) WAS USED TO EVALUATE 114 GENE VARIATIONS, AND THE PROGNOSTIC FACTORS FOR OS WERE DETERMINED BY COX REGRESSION ANALYSIS. RESULTS: THE CMML PATIENTS SHOWED A UNIQUE MUTATIONAL SPECTRUM, INCLUDING TET2 (36.5%), NRAS (31.5%), ASXL1 (28.7%), SRSF2 (24.7%), AND RUNX1 (21.9%). OF THE 102 PATIENTS WITH CLONAL ANALYSIS, THE ANCESTRAL EVENTS PREFERENTIALLY OCCURRED IN TET2 (18.5%), SPLICING FACTORS (16.5%), RAS (14.0%), AND ASXL1 (7.8%), AND THE SUBCLONAL GENES WERE MAINLY ASXL1, TET2, AND RAS. IN ADDITION, THE SECONDARY ACUTE MYELOID LEUKEMIA (SAML) TRANSFORMED FROM CMML OFTEN HAD MUTATIONS IN DNMT3A, ETV6, FLT3, AND NPM1, WHILE THE PRIMARY AML (PAML) DEMONSTRATED MORE MUTATIONS IN CEBPA, DNMT3A, FLT3, IDH1/2, NPM1, AND WT1. IT WAS OF NOTE THAT A SERIES OF CLONES WERE EMERGED DURING THE PROGRESSION FROM CMML TO AML, INCLUDING DNMT3A, FLT3, AND NPM1. BY UNIVARIATE ANALYSIS, ASXL1 MUTATION, INTERMEDIATE- AND HIGH-RISK CYTOGENETIC ABNORMALITY, CMML-SPECIFIC PROGNOSTIC SCORING SYSTEM (CPSS) STRATIFICATIONS (INTERMEDIATE-2 AND HIGH GROUP), AND TREATMENT OPTIONS (BEST SUPPORTIVE CARE) PREDICTED FOR WORSE OS. MULTIVARIATE ANALYSIS REVEALED A SIMILAR OUTCOME. CONCLUSIONS: THE COMMON MUTATIONS IN CHINESE CMML PATIENTS INCLUDED EPIGENETIC MODIFIERS (TET2 AND ASXL1), SIGNALING TRANSDUCTION PATHWAY COMPONENTS (NRAS), AND SPLICING FACTOR (SRSF2). THE CMML PATIENTS WITH DNMT3A, ETV6, FLT3, AND NPM1 MUTATIONS TENDED TO PROGRESS TO SAML. ASXL1 MUTATION AND THERAPEUTIC MODALITIES WERE INDEPENDENT PROGNOSTIC FACTORS FOR CMML. 2022 18 87 26 A PHASE 1 STUDY OF AZACITIDINE WITH HIGH-DOSE CYTARABINE AND MITOXANTRONE IN HIGH-RISK ACUTE MYELOID LEUKEMIA. IN THIS PHASE 1 STUDY, AZACITIDINE (AZA) WAS GIVEN BEFORE HIGH-DOSE CYTARABINE (HIDAC) AND MITOXANTRONE (MITO) BASED ON THE HYPOTHESIS THAT EPIGENETIC PRIMING WITH A HYPOMETHYLATING AGENT BEFORE CYTOTOXIC CHEMOTHERAPY WOULD IMPROVE RESPONSE RATES IN PATIENTS WITH HIGH-RISK ACUTE MYELOID LEUKEMIA (AML), INCLUDING RELAPSED/REFRACTORY DISEASE. THE PRIMARY OBJECTIVE WAS TO ESTABLISH THE RECOMMENDED PHASE 2 DOSE OF AZA GIVEN BEFORE STANDARD HIDAC/MITO. IN A DOSE ESCALATION SCHEME, 46 PATIENTS (MEDIAN AGE, 66 YEARS) RECEIVED AZA AT 37.5, 50, OR 75 MG/M2 SUBCUTANEOUSLY OR IV ONCE DAILY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10 (THE HIDAC/MITO DOSE WAS REDUCED 33% IN ELDERLY SUBJECTS). TWO DOSE-LIMITING TOXICITIES OCCURRED (BOTH IN THE SAME PATIENT): ACUTE LIVER FAILURE AND KIDNEY INJURY AT THE 50 MG/M2 DOSE. THE 30-DAY INDUCTION DEATH RATE WAS 2.2% (1 OF 46). THE OVERALL RESPONSE RATE, INCLUDING COMPLETE REMISSION AND COMPLETE REMISSION WITH INCOMPLETE COUNT RECOVERY, WAS 61% (28 OF 46). PREVIOUSLY UNTREATED PATIENTS AGED >/=60 YEARS WITH THERAPY-RELATED AML AND DE NOVO AML WERE MORE LIKELY TO RESPOND THAN UNTREATED PATIENTS WITH AML PROGRESSING FROM AN ANTECEDENT HEMATOLOGIC DISORDER (MYELODYSPLASTIC SYNDROME AND CHRONIC MYELOMONOCYTIC LEUKEMIA). PATIENTS WITH FAVORABLE EUROPEAN LEUKEMIA NETWORK RISK (P = .008), NPM1 MUTATIONS (P = .007), OR IDH2 MUTATIONS (P = .03) WERE MORE LIKELY TO RESPOND, AND THOSE WITH TP53 MUTATIONS (P = .03) WERE LESS LIKELY TO RESPOND. THE RECOMMENDED PHASE 2 DOSE OF AZA IS 75 MG/M2 PER DAY ON DAYS 1 TO 5 FOLLOWED BY HIDAC (3000 MG/M2) AND MITOXANTRONE (30 MG/M2) ONCE EACH ON DAYS 6 AND 10. THIS TRIAL WAS REGISTERED AT WWW.CLINICALTRIALS.GOV AS #NCT01839240. 2020 19 503 37 ASSOCIATION OF CHEMOKINE GENE VARIANTS WITH END STAGE RENAL DISEASE IN NORTH INDIAN POPULATION. BACKGROUND & AIM: THE PROGRESSION RATE OF CHRONIC KIDNEY DISEASE (CKD) TO ITS END-STAGE RENAL DISEASE (ESRD), AND THE DEVELOPMENT AND SEVERITY OF VARIOUS COMPLICATIONS, ARE INDIRECTLY INFLUENCED BY GENETIC AND EPIGENETIC FACTORS. CHEMOKINES ARE SMALL INDUCIBLE PRO-INFLAMMATORY CYTOKINES, WHICH ARE IMPLICATED IN MANY BIOLOGICAL PROCESSES LIKE MIGRATION OF LEUKOCYTES, ANGIOGENESIS, TUMOR GROWTH AND METASTASIS. WE TESTED ASSOCIATION OF FOUR SINGLE NUCLEOTIDE POLYMORPHISMS (SNPS) VIZ. CCL2I/D, CCL2A2518G, CXCL12G801A AND CXCR2(+1208)C/T AMONG INDIVIDUALS WITH ESRD (END STAGE RENAL DISEASE) AND NORMAL HEALTHY CONTROLS FROM NORTH INDIAN POPULATION. MATERIALS AND METHOD: CCL2I/D, CCL2A2518G, CXCL12G801A AND CXCR2(+1208)C/T WERE GENOTYPED IN BLOOD SAMPLES OF HOSPITAL-BASED CASE-CONTROL STUDY COMPRISING OF 200 ESRD CASES AND 200 HEALTHY CONTROLS USING RESTRICTION FRAGMENT LENGTH POLYMORPHISM (RFLP) AND ARMS (AMPLIFICATION REFRACTORY MUTATION SPECIFIC) PCR METHODOLOGY. RESULTS: A SIGNIFICANT ASSOCIATION WAS FOUND IN CXCL12G801A WITH ESRD RISK. IN CASE OF CXCL12G801A POLYMORPHISM HETEROZYGOUS (GA) GENOTYPE SHOWED SIGNIFICANT RISK (P=0.039; OR=1.55) WHEREAS A ALLELE CARRIER (GA+AA) ALSO EXHIBITED RISK WITH ESRD (P=0.045, OR=1.59). IN CXCR2(+1208)C/T POLYMORPHISM, THE HETEROZYGOUS GENOTYPE (CT) SHOWED SIGNIFICANT RISK FOR ESRD (P=0.028; OR=1.65) AND COMBINATION OF CT+TT DEMONSTRATED SIGNIFICANT HIGH RISK FOR ESRD (P=0.036; OR=1.52). IN CASE OF CCL2I/D, THE VARIANT GENOTYPE (D/D) SHOWED REDUCED RISK FOR ESRD PATIENTS. UPON ANALYZING THE GENE-GENE INTERACTION BETWEEN CXCR2 AND CXCL12, THE COMBINATION (CT-GA) SHOWED 2.65 FOLD RISK FOR ESRD (P=0.018). CONCLUSION: OUR RESULTS INDICATED THAT POLYMORPHISM IN CXCL12G801A AND CXCR2(+1208)C/T SHOWED HIGH RISK FOR ESRD IN NORTH INDIAN POPULATION. HOWEVER, CCL2I/D SHOWED REDUCED RISK AND CCL2A2518G EXHIBITED NO ASSOCIATION. STUDY WITH LARGE SAMPLE SIZE AND DIVERSE ETHNICITY IS REQUIRED TO VALIDATE THESE OBSERVATIONS. 2013 20 2205 47 EPIGENETIC MODIFICATION OF THE X CHROMOSOME INFLUENCES SUSCEPTIBILITY TO POLYCYSTIC OVARY SYNDROME. CONTEXT: THE CAUSE OF POLYCYSTIC OVARY SYNDROME (PCOS) IS UNKNOWN, ALTHOUGH GENETIC AND ENVIRONMENTAL INFLUENCES ARE CLEARLY IMPLICATED. SOME GENETIC STUDIES HAVE SUGGESTED THE INVOLVEMENT OF X-LINKED GENES IN PCOS, BUT THE INFLUENCE OF X CHROMOSOME INACTIVATION (XCI) ON MANIFESTATION OF THIS DISORDER HAS NOT PREVIOUSLY BEEN EXAMINED. OBJECTIVE: THE OBJECTIVE OF THE STUDY WAS TO TEST THE NULL HYPOTHESIS THAT XCI HAS NO INFLUENCE ON CLINICAL PRESENTATION OF PCOS. DESIGN: WE EXAMINED PATTERNS OF XCI BETWEEN SISTER PAIRS WITH THE SAME GENOTYPE AT A POLYMORPHIC LOCUS ON THE X CHROMOSOME IN FAMILIES WITH PCOS. SETTING: THE STUDY WAS CONDUCTED AT A PRIVATE PRACTICE. PARTICIPANTS: PCOS WAS DEFINED AS HYPERANDROGENEMIA WITH CHRONIC ANOVULATION. FORTY FAMILIES WERE STUDIED IN WHICH DNA WAS OBTAINED FROM AT LEAST ONE PARENT, THE PROBAND, AND ONE SISTER THAT COULD BE ACCURATELY DIAGNOSED AS BEING AFFECTED OR UNAFFECTED. MAIN OUTCOME MEASURE(S): RELATIVE EXPRESSION OF TWO X-LINKED ALLELES WAS DETERMINED, AND THE RATIO OF ONE TO THE OTHER REPRESENTED THE PATTERN OF XCI. RESULTS: THE STATISTICAL ODDS ON A DIFFERENT CLINICAL PRESENTATION BETWEEN SISTERS WAS APPROXIMATELY 29 TIMES HIGHER IN SISTER PAIRS WITH DIFFERENT PATTERNS OF XCI, COMPARED WITH SISTER PAIRS WITH THE SAME PATTERN OF XCI (ODDS RATIO 28.9; 95% CONFIDENCE INTERVAL 4.0-206; P = 0.0008). CONCLUSIONS: THIS STUDY PROVIDES EVIDENCE TO REFUTE THE NULL HYPOTHESIS AND PROPOSE A CLOSER INSPECTION OF X-LINKED GENES IN PCOS, ONE IN WHICH BOTH GENOTYPE AND EPIGENOTYPE ARE CONSIDERED. ENVIRONMENTAL DETERMINANTS OF PCOS MAY ALTER CLINICAL PRESENTATION VIA EPIGENETIC MODIFICATIONS, WHICH CURRENTLY REMAIN UNDETECTED IN TRADITIONAL GENETIC ANALYSES. 2006