Genetic determinants of serum bilirubin using inferred native American gene variants in Chilean adolescents.

Gene variants in the UGT1A1 gene are strongly associated with circulating bilirubin levels in several populations, as well as other variants of modest effect across the genome. However, the effects of such variants are unknown regarding the Native American ancestry of the admixed Latino population. Our objective was to assess the Native American genetic determinants of serum bilirubin in Chilean admixed adolescents using the local ancestry deconvolution approach. We measured total serum bilirubin levels in 707 adolescents of the Chilean Growth and Obesity Cohort Study (GOCS) and performed high-density genotyping using the Illumina-MEGA array (>1.7 million genotypes). We constructed a local ancestry reference panel with participants from the 1000 Genomes Project, the Human Genome Diversity Project, and our GOCS cohort. Then, we inferred and isolated haplotype tracts of Native American, European, or African origin to perform genome-wide association studies. In the whole cohort, the rs887829 variant and others near UGT1A1 were the unique signals achieving genome-wide statistical significance (b = 0.30; p = 3.34 × 10-57). After applying deconvolution methods, we found that significance is also maintained in Native American (b = 0.35; p = 3.29 × 10-17) and European (b = 0.28; p = 1.14 × 10-23) ancestry components. The rs887829 variant explained a higher percentage of the variance of bilirubin in the Native American (37.6%) compared to European ancestry (28.4%). In Native American ancestry, carriers of the TT genotype of this variant averaged 4-fold higher bilirubinemia compared to the CC genotype (p = 2.82 × 10-12). We showed for the first time that UGT1A1 variants are the primary determinant of bilirubin levels in Native American ancestry, confirming its pan-ethnic relevance. Our study illustrates the general value of the local ancestry deconvolution approach to assessing isolated ancestry effects in admixed populations.

Transcriptomic profiles reveal differences in zinc metabolism, inflammation, and tight junction proteins in duodenum from cholesterol gallstone subjects.

Cholesterol Gallstone Disease (GSD) is a common multifactorial disorder characterized by crystallization and aggregation of biliary cholesterol in the gallbladder. The global prevalence of GSD is ~10-20% in the adult population but rises to 28% in Chile (17% among men and 30% among women). The small intestine may play a role in GSD pathogenesis, but the molecular mechanisms have not been clarified. Our aim was to identify the role of the small intestine in GSD pathogenesis. Duodenal biopsy samples were obtained from patients with GSD and healthy volunteers. GSD status was defined by abdominal ultrasonography. We performed a transcriptome study in a discovery cohort using Illumina HiSeq. 2500, and qPCR, immunohistochemistry and immunofluorescence were used to validate differentially expressed genes among additional case-control cohorts. 548 differentially expressed genes between GSD and control subjects were identified. Enriched biological processes related to cellular response to zinc, and immune and antimicrobial responses were observed in GSD patients. We validated lower transcript levels of metallothionein, NPC1L1 and tight junction genes and higher transcript levels of genes involved in immune and antimicrobial pathways in GSD patients. Interestingly, serum zinc and phytosterol to cholesterol precursor ratios were lower in GSD patients. A significant association was observed between serum zinc and phytosterol levels. Our results support a model where proximal small intestine plays a key role in GSD pathogenesis. Zinc supplementation, modulation of proximal microbiota and/or intestinal barrier may be novel targets for strategies to prevent GSD.

Salmonella enterica serovar Typhi and gallbladder cancer: a case-control study and meta-analysis.

In Chile, where gallbladder cancer (GBC) rates are high and typhoid fever was endemic until the 1990s, we evaluated the association between Salmonella enterica serovar Typhi (S. Typhi) antibodies and GBC. We tested 39 GBC cases, 40 gallstone controls, and 39 population-based controls for S. Typhi Vi antibodies and performed culture and quantitative polymerase chain reaction for the subset with bile, gallstone, tissue, and stool samples available. We calculated gender and education-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for the association with GBC. We also conducted a meta-analysis of >1000 GBC cases by combining our results with previous studies. GBC cases were more likely to have high Vi antibody titer levels than combined controls (OR: 4.0, 95% CI: 0.9-18.3), although S. Typhi was not recovered from bile, gallstone, tissue, or stool samples. In our meta-analysis, the summary relative risk was 4.6 (95% CI: 3.1-6.8, Pheterogeneity =0.6) for anti-Vi and 5.0 (95% CI: 2.7-9.3, Pheterogeneity  = 0.2) for bile or stool culture. Our results are consistent with the meta-analysis. Despite differences in study methods (e.g., S. Typhi detection assay), most studies found a positive association between S. Typhi and GBC. However, the mechanism underlying this association requires further investigation.

The inflammatory inception of gallbladder cancer.

Gallbladder cancer is a lethal disease with notable geographical variations worldwide and a predilection towards women. Its main risk factor is prolonged exposure to gallstones, although bacterial infections and other inflammatory conditions are also associated. The recurrent cycles of gallbladder epithelium damage and repair enable a chronic inflammatory environment that promotes progressive morphological impairment through a metaplasia-dysplasia-carcinoma, along with cumulative genome instability. Inactivation of TP53, which is mutated in over 50% of GBC cases, seems to be the earliest and one of the most important carcinogenic pathways involved. Increased cell turnover and oxidative stress promote early alteration of TP53, cell cycle deregulation, apoptosis and replicative senescence. In this review, we will discuss evidence for the role of inflammation in gallbladder carcinogenesis obtained through epidemiological studies, genome-wide association studies, experimental carcinogenesis, morphogenetic studies and comparative studies with other inflammation-driven malignancies. The evidence strongly supports chronic, unresolved inflammation as the main carcinogenic mechanism of gallbladder cancer, regardless of the initial etiologic trigger. Given this central role of inflammation, evaluation of the potential for GBC prevention removing causes of inflammation or using anti-inflammatory drugs in high-risk populations may be warranted.

Effect of cholecystectomy on bile acid synthesis and circulating levels of fibroblast growth factor 19.

UNLABELLED: Background and rationale for the study. FGF19/15 is a gut-derived hormone presumably governing bile acid (BA) synthesis and gallbladder (GB) refilling. FGF19 mRNA is present in human GB cholangiocytes (hGBECs); however, the physiological significance of GB-derived FGF19 remains unknown. We investigated whether hGBECs secrete FGF19 and the effects of cholecystectomy on serum FGF19 ([FGF19]s) and BA synthesis. MATERIAL AND METHODS: FGF19 expression was assessed by qRT-PCRs and immunostaining in hGBECs and terminal ileum, and quantified in bile and serum by ELISA. Basal and BA (chenodexycholic acid, CDCA) induced FGF19 expression and secretion was analyzed in primary cultured hGBECs and GB-d1 cell line. Pre and postprandial serum changes in [FGF19]s, 7α-hydroxy-4-cholestene-3-one (C4, a marker of BA synthesis) and BA were evaluated in plasma of gallstone disease patients at baseline and after cholecystectomy. RESULTS: FGF19 mRNA levels were ~250-fold higher in hGBECs compared to distal ileum. GB bile contained ~23-fold higher FGF19 levels compared to serum (p < 0.0001). CDCA induced dose-dependent expression and secretion of FGF19 in hGBECs and GB-d1 cells. Cholecystectomy increased plasma BA synthesis ≥ 2-fold (p < 0.0001), and altered the diurnal rhythm and significantly reduced [FGF19]s noon peak. BA serum levels, serum cholesterol and triglyceride content remained unchanged. CONCLUSIONS: In conclusion human GB cholangiocytes constitutively express and secrete high levels of FGF19 in a process regulated by BA. Resection of this organ doubles BA synthesis concomitantly with changes in [FGF19]s. These findings suggest a potential connection between GB cholangiocytes-derived FGF19 and BA metabolism that could lead to metabolic dysregulation following cholecystectomy.

[Prevalence of metabolic syndrome in Mapuche individuals living in urban and rural environment in Chile]. / Prevalencia de síndrome metabólico en individuos de etnia Mapuche residentes en zonas rurales y urbanas de Chile.

BACKGROUND: Metabolic Syndrome (MS) increases the risk of diabetes and mortality associated with cardiovascular disease. However, the prevalence of MS could differ by ethnicity and lifestyle factors. AIM: To determine the prevalence of MS in Mapuche individuals living in urban and rural environments in Chile and to investigate whether the prevalence and risk of MS in urban and rural environments differs by sex, age and nutritional status. MATERIAL AND METHODS: A total of 1077 Mapuche participants were recruited from urban (MU = 288) and rural (MR = 789) settings. Body mass index, waist circumference and blood pressure were measured. A fasting blood sample was obtained to measure serum glucose, HDL cholesterol and triacylglycerol. The prevalence of MS was determined using the unified IDF and ATP-III criteria. RESULTS: An environment and sex interaction was found for the prevalence of MS (p = 0.042). The prevalence was significantly lower in male MR (13%) compared to other groups (22, 23 and 25% among female MR, female MU and male MU respectively). Also, the prevalence of central obesity and low HDL-cholesterol were significantly lower in male MR. MU are at an increased risk of developing MS compared to MR, with an odds ratio of 1.59 (95% confidence intervals 1.1 to 2.2). This risk increases along with age or body mass index of the population. CONCLUSIONS: The adoption of an urbanized lifestyle increases the risk of developing MS in Mapuche individuals. This risk is enhanced by age and nutritional status.

Prevalence of lactose intolerance in Chile: a double-blind placebo study.

BACKGROUND AND STUDY AIMS: Lactase non-persistence (LNP), or primary hypolactasia, is a genetic condition that mediates lactose malabsorption and can cause lactose intolerance. Here we report the prevalence of lactose intolerance in a double-blind placebo study. METHODS: The LCT C>T-13910 variant was genotyped by RT-PCR in 121 volunteers and lactose malabsorption was assessed using the hydrogen breath test (HBT) after consuming 25 g of lactose. Lactose intolerance was assessed by scoring symptoms (SS) using a standardized questionnaire following challenge with a lactose solution or saccharose placebo. RESULTS: The LNP genotype was observed in 57% of the volunteers, among whom 87% were HBT⁺. In the HBT⁺ group the median SS was 9 and in the HBT⁻ group the median SS was 3 (p < 0.001). No difference was observed in the SS when both groups were challenged with the placebo. The most common symptoms included audible bowel sounds, abdominal pain and meteorism. In the ROC curve analysis, an SS ≥ 6 demonstrated 72% sensitivity and 81% specificity for predicting a positive HBT. To estimate prevalence, lactose intolerance was defined as the presence of an SS ≥ 6 points after subtracting the placebo effect and 34% of the study population met this definition. CONCLUSIONS: The LNP genotype was present in more than half of subjects evaluated and the observed prevalence of lactose intolerance was 34%.

Prevalencia de síndrome metabólico en individuos de etnia Mapuche residentes en zonas rurales y urbanas de Chile / Prevalence of metabolic syndrome in Mapuche individuals living in urban and rural environment in Chile

Background: Metabolic Syndrome (MS) increases the risk of diabetes and mortality associated with cardiovascular disease. However, the prevalence of MS could differ by ethnicity and lifestyle factors. Aim: To determine the prevalence of MS in Mapuche individuals living in urban and rural environments in Chile and to investigate whether the prevalence and risk of MS in urban and rural environments differs by sex, age and nutritional status. Material and Methods: A total of 1077 Mapuche participants were recruited from urban (MU = 288) and rural (MR = 789) settings. Body mass index, waist circumference and blood pressure were measured. A fasting blood sample was obtained to measure serum glucose, HDL cholesterol and triacylglycerol. The prevalence of MS was determined using the unified IDF and ATP-III criteria. Results: An environment and sex interaction was found for the prevalence of MS (p = 0.042). The prevalence was significantly lower in male MR (13%) compared to other groups (22, 23 and 25% among female MR, female MU and male MU respectively). Also, the prevalence of central obesity and low HDL-cholesterol were significantly lower in male MR. MU are at an increased risk of developing MS compared to MR, with an odds ratio of 1.59 (95% confidence intervals 1.1 to 2.2). This risk increases along with age or body mass index of the population. Conclusions: The adoption of an urbanized lifestyle increases the risk of developing MS in Mapuche individuals. This risk is enhanced by age and nutritional status.

Prevalencia de síndrome de Gilbert y sus determinantes genéticas en población chilena / Prevalence of Gilbert syndrome and its genetic determinants in Chile

Background: In Europeans the TATA box TA7 repeat promoter variant in the UGT1A1 gene (UGT1A1*28) is the major determinant of bilirubin levels. Aim: To study the prevalence of Gilbert Syndrome (GS) and its genetic determinants in Chile. Material and Methods: Three different studies were conducted. The prevalence of GS in Chile was assessed in 991 subjects with normal liver tests (ALT and GGT) from the 2nd National Health Survey. We defined GS as a total bilirubin (TB) between 1.4-5mg/dL. The second study assessed the genotype prevalence of SNP rs6742078 (in LD with UGT1A1*28) and rs4149056 in 500 DNA samples of non-related Hispanics. Finally, a case-control study was designed to assess the phenotype-genotype correlation. UGT1A1*28 and rs4149056 variants were determined by direct sequencing and allelic discrimination assays (TaqMan), respectively. Results: Prevalence of GS in the general Chilean population was 2.6% (4.5% in males and 0.5% in female). No correlation with age, educational level or home location was found. Genotypes for UGT1A1*28 (TA6/6 50.5%, TA6/7 37.8%, TA7/7 11.7%) and rs4149056 (TT 74.1%, CT 22.8%, and CC 3.1%) variants were similar to Europeans. In the case-control study, most patients with GS were homozygotes for UGT1A1*28 (TA7/7, 74%). Of note, 44% of patients with intermediate TB levels were also TA7/7, compared to 7% in normal subjects. SLCO1B1 genotype was not correlated with TB levels. Conclusions: While the prevalence of GS was lower in Chile compared to Europeans (~5%), the prevalence of UGT1A1*28 homozygotes was similar (~12%). In Chilean Hispanics, the UGT1A1*28 variant explain 75% of GS phenotype.

[Prevalence of Gilbert syndrome and its genetic determinants in Chile]. / Prevalencia de síndrome de Gilbert y sus determinantes genéticas en población chilena.

BACKGROUND: In Europeans the TATA box TA7 repeat promoter variant in the UGT1A1 gene (UGT1A1*28) is the major determinant of bilirubin levels. AIM: To study the prevalence of Gilbert Syndrome (GS) and its genetic determinants in Chile. MATERIAL AND METHODS: Three different studies were conducted. The prevalence of GS in Chile was assessed in 991 subjects with normal liver tests (ALT and GGT) from the 2nd National Health Survey. We defined GS as a total bilirubin (TB) between 1.4-5mg/dL. The second study assessed the genotype prevalence of SNP rs6742078 (in LD with UGT1A1*28) and rs4149056 in 500 DNA samples of non-related Hispanics. Finally, a case-control study was designed to assess the phenotype-genotype correlation. UGT1A1*28 and rs4149056 variants were determined by direct sequencing and allelic discrimination assays (TaqMan), respectively. RESULTS: Prevalence of GS in the general Chilean population was 2.6% (4.5% in males and 0.5% in female). No correlation with age, educational level or home location was found. Genotypes for UGT1A1*28 (TA6/6 50.5%, TA6/7 37.8%, TA7/7 11.7%) and rs4149056 (TT 74.1%, CT 22.8%, and CC 3.1%) variants were similar to Europeans. In the case-control study, most patients with GS were homozygotes for UGT1A1*28 (TA7/7, 74%). Of note, 44% of patients with intermediate TB levels were also TA7/7, compared to 7% in normal subjects. SLCO1B1 genotype was not correlated with TB levels. CONCLUSIONS: While the prevalence of GS was lower in Chile compared to Europeans (~5%), the prevalence of UGT1A1*28 homozygotes was similar (~12%). In Chilean Hispanics, the UGT1A1*28 variant explain 75% of GS phenotype.

Loci from a genome-wide analysis of bilirubin levels are associated with gallstone risk and composition.

BACKGROUND & AIMS: Genome-wide association studies have mapped loci that are associated with serum levels of bilirubin. Bilirubin is a major component of gallstones so we investigated whether these variants predict gallstone bilirubin content and overall risk for gallstones. METHODS: Loci that were identified in a meta-analysis to attain a genome-wide significance level of a P value less than 1.0×10(-7) (UGT1A1, SLCO1B1, LST-3TM12, SLCO1A2) were analyzed in 1018 individuals with known gallstone composition. Gallstone risk was analyzed in 2606 German choleystecomized individuals and 1121 controls and was replicated in 210 cases and 496 controls from South America. RESULTS: By using the presence of bilirubin as a phenotype, variants rs6742078 (UGT1A1; P = .003), rs4149056 (SLCO1B1; P = .003), and rs4149000 (SLCO1A2; P = .015) were associated with gallstone composition. In regression analyses, only UGT1A1 and SLCO1B1 were independently retained in the model. UGT1A1 (rs6742078; P = .018) was associated with overall gallstone risk. In a sex-stratified analysis, only male carriers of rs6742078 had an increased risk for gallstone disease (P = 2.1×10(-7); odds ratio(recessive), 2.34; P(women) = .47). The sex-specific association of rs6742078 was confirmed in samples from South America (P(men) = .046; odds ratio(recessive), 2.19; P(women) = .96). CONCLUSIONS: The UGT1A1 Gilbert syndrome variant rs6742078 is associated with gallstone disease in men; further studies are required regarding the sex-specific physiology of bilirubin and bile acid metabolism. Variants of ABCG8 and UGT1A1 are the 2 major risk factors for overall gallstone disease, they contribute a population attributable risk of 21.2% among men.

Ezetimibe prevents cholesterol gallstone formation in mice.

BACKGROUND: Intestinal cholesterol absorption may influence gallstone formation and its modulation could be a useful therapeutic strategy for gallstone disease (GSD). Ezetimibe (EZET) is a cholesterol-lowering agent that specifically inhibits intestinal cholesterol absorption. AIMS: To test whether EZET can prevent gallstone formation in mice. METHODS/RESULTS: Gallstone-susceptible C57BL/6 inbred mice were fed control and lithogenic diets with or without simultaneous EZET administration. Lithogenic diet increased biliary cholesterol content and secretion, and induced sludge or gallstone formation in 100% of the animals. EZET administration reduced intestinal cholesterol absorption by 90% in control animals and by 35% in mice receiving the lithogenic diet. EZET prevented the appearance of cholesterol crystals and gallstones. In addition, mice fed the lithogenic diet plus EZET exhibited a 60% reduction in biliary cholesterol saturation index. Of note, EZET treatment caused a significant increase in bile flow (+50%, P<0.01) as well as bile salt, phospholipid and glutathione secretion rates (+60%, +44% and +100%, respectively, P<0.01), which was associated with a moderately increased expression of hepatic bile salt transporters. In addition, relative expression levels of Nieman-Pick C1 like 1 (NPC1L1) in the enterohepatic axis in humans were assessed. Expression levels of NPC1L1 were 15- to 30-fold higher in the duodenum compared with the liver at transcript and protein levels, respectively, suggesting preferential action of EZET on intestinal cholesterol absorption in humans. CONCLUSIONS: In a murine model of GSD, EZET prevented gallstone formation by reducing intestinal cholesterol absorption and increasing bile salt-dependent and -independent bile flow. EZET could be useful in preventing GSD disease in susceptible patients.

TP53 abnormalities are frequent and early events in the sequential pathogenesis of gallbladder carcinoma.

BACKGROUND: Gallbladder carcinoma (GBC) is a frequent neoplasm in Hispanic and native American populations. GBC is preceded by gallstones, chronic cholecystitis and dysplastic changes of the gallbladder epithelium. The knowledge of the molecular events involved in its pathogenesis is scarce. AIMS: We investigated the role of TP53 inactivation in the sequential pathogenesis of GBC. METHODS: Invasive tumor-, dysplastic- and histologically normal GB epithelial-cells were obtained from archival formalin-fixed tissues from GBC and GB from gallstone patients without GBC. Normal GB epithelia from 5 non-gallstone specimens were also studied. DNA extracted was examined for loss of heterozygosity (LOH) using 2 microsatellite markers and for TP53 mutations at exons 5 to 8. RESULTS: GBCs demonstrated a high frequency of LOH (81%) and mutation (67%), and both abnormalities indicating gene inactivation were detected in 52%. Similar frequency of TP53 abnormalities and gene inactivation (38%) were detected in their accompanying normal and dysplastic epithelia. Noteworthy, one third of normal and dysplastic epithelia obtained from GBs of gallstone patients without GBC demonstrated either TP53 allele loss or mutation, but gene inactivation was less frequent (11%). Most mutations affected exons 5 and 7, and they were more frequently missense point mutations. The same TP53 mutation was detected in only a subset (27%) of comparisons between non-malignant epithelia adjacent to GBCs, indicating that TP53 mutation occurs independently at several epithelial foci. CONCLUSIONS: These findings indicate that TP53 abnormalities are early and frequent events in the pathogenesis of GBC, starting from chronic cholecystitis.

Resultados del tratamiento quirúrgico en inercia colónica / Results of surgical treatment in colonic inertia

Introducción: Inercia colónica (IC) es un síndrome clínico que afecta principalmente a mujeres, caracterizado por constipación refractaria al tratamiento médico y tránsito colónico lento. El objetivo de este trabajo fue evaluar los resultados de la cirugía en pacientes con diagnóstico de IC. Material y Método: Se revisó en forma retrospectiva los pacientes con diagnósticos de IC refractorios al uso de laxantes, y operados en el Hospital Clínico de la Universidad Católica desde septiembre de 1994 hasta mayo de 2002. Resultados: Se evaluó 11 pacientes a los que se les practicó una colectomía total con anastomosis ileorrectal. Todos los pacientes fueron mujeres, con una edad promedio de 46,5 años (21-67 años). Todas las pacientes presentaban al menos 2 años de constipación refractaria al uso de laxantes. El 100 por ciento de las pacientes presentaba estudio de tránsito colónico alterado (20 por ciento o más de los marcadores distribuidos difusamente en el colon después de 5 días). A 9 pacientes se les realizó una manometría anorrectal preoperatoria, y a 2 pacientes se les realizó defecografía que fueron informados como normales descartando una patología del piso pélvico. Las 11 pacientes fueron sometidas a una colectomía total más ileorrectal anastomosis (9 en forma convencional y 2 en forma laparoscópica). Histológicamente ningún paciente presentaba ausencia de plexos neuroentéricos. La frecuencia defecatoria promedio postoperatorio con una media de seguimiento de 29,2 meses fue de 2,66 veces por día (vs 1,8 veces por semana en el preoperatorio). El 100 por ciento de las pacientes se encuentra satisfecha con el procedimiento: 9,2 (escala de 1-10). Conclusión: La colectomía total más anastomosis ileorrectal es una buena alternativa terapéutica en pacientes bien seleccionadas con IC confirmada, y asegurando que no existe obstrucción de salida fecal.

Evolución de la frecuencia de factores de riesgo cardiovascular en dos poblaciones chilenas / Changes in cardiovacular risk factors in two chilean populations

Objetivos: Establecer cambios en la frecuencia de factores de riesgo cardiovascular entre 1993 y 2001 en dos poblaciones étnicas chilenas. Materiales: En los años 1993 y 2001, se estudiaron 960 individuos adultos (625 mujeres y 335 hombres) de la comuna de la Florida (Santiago) y 113 habitantes (63 mujeres y 50 hombres) de la Isla Huapi (X región). Se estableció la frecuencia de: diabetes mellitus (DM): dos glicemias en ayuno ≥126 mg/dl o antecedente clínico de diabetes, obesidad: IMC ≥30 kg/mt², hipertensión arterial (HTA): PAS ≥140 y/o PAD ≥90 o tratamiento antihipertensivo, hipercolesterolemia: colesterol total ≥200 mg/dl y tabaquismo: consumo de al menos un cigarrillo en el último mes. Resultados: En el año 2001 en comparación a 1993, se detectó en la población de La Florida, un incremento significativo de la frecuencia de obesidad (13 por ciento), de DM (63 por ciento), de hipercolesterolemia (24 por ciento) y un leve pero significativo aumento de la HTA (3 por ciento). El tabaquismo disminuyó significativamente en un 8 por ciento. En la Isla Huapi se observó un incremento significativo de la frecuencia de obesidad (22 por ciento), de DM (105 por ciento) y de hipercolesterolemia (9 por ciento). No se detectaron cambios en la frecuencia de HTA. El tabaquismo disminuyó significativamente en alrededor de un 50 por ciento. Conclusiones: En los últimos años, la población chilena presenta un aumento progresivo de la frecuencia de obesidad, DM y dislipidemia, lo cual favorecería el aumento de la morbimortalidad cardiovascular.

GUTI: a new antigen in the Cromer blood group system.

BACKGROUND: The Cromer blood group system consists of seven high-incidence and three low-incidence antigens carried on decay-accelerating factor (DAF). This report describes the identification and characterization of a new Cromer high-incidence antigen, named GUTI. STUDY DESIGN AND METHODS: RT-PCR and sequence analysis were performed on cDNA prepared from a Chilean donor whose serum contained the alloantibody (anti-GUTI). Based on the observed point mutation, a PCR-RFLP assay using MaeII was developed. To map the epitope, DAF-deletion mutants were tested by immunoblotting with anti-GUTI. RESULTS: Sequence analysis revealed a substitution of 719G>A in DAF in the proband. The proband's parents and two daughters were heterozygotes for 719G>A, one sister whose RBCs typed GUTI- was homozygous for 719A, and one sister had the wild-type DAF (719G). Seven additional heterozygote samples were identified among 214 Chileans. No heterozygotes were found in 197 New York donors. Analysis using DAF-deletion mutants showed the antigenic determinant to be within short consensus repeat (SCR) 4. CONCLUSION: This study describes a novel high- incidence antigen (GUTI) in the Cromer blood group system characterized by the amino acid arginine at position 206 in SCR4 of DAF. The GUTI-negative proband has a substitution mutation that predicts for histidine at this position.

Registro de incidencia de hepatitis crónica: Asociación Chilena de Hepatología: período 1994-1996 / Chronic hepatitis incidence record: Chilean Hepatology Association (1994-1996)

La Asociación Chilena de Hepatología creó un registro de casos nuevos de hepatitis crónicas diagnosticadas con biopsia hepática entre los años 1994 y 1996. Se registran y clasifican de acuerdo a su etiología 106 pacientes altamente seleccionados con hepatitis crónica provenientes de la regiones metropolitana, quinta y segunda. De acuerdo a la etiología: 13 por ciento criptogénicas y 7 por ciento Virus B. La presencia de cirrosis al diagnóstico fue de 30 por ciento para las de origen viral C y 24 por ciento para las de origen autoinmune lo que podría afectar la respuesta a las alternativas terapéuticas. De acuerdo a estos resultados, deberíamos promover el diagnóstico más temprano en pacientes con alteraciones de laboratorio asintomáticas o notificando a los donantes de sangre en los que detecta alguna infección viral. En ausencia de otras instancias que realicen este tipo de evaluaciones, sugerimos repetir o mantener registros en lo posible de cobertura nacional, tanto para los pacientes con hepatitis crónica como para otras patologías hepáticas.