Genetic variants in ATP2B2 as risk factors for mortality in patients unrelated but not associated with families with severe COVID-19.

Introduction: The severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is the causative agent of Coronavirus Disease 2019 (COVID-19). The disease has a wide range of clinical manifestations, from asymptomatic to severe. Ancestral contribution, sex, immune response, and genetic factors influence the presentation of the disease. The objective of the present study was to validate these genetic variants in patients with severe COVID-19 who died and in survivor patients. Methods: Single nucleotide variants (SNVs) in six genes: ATPase plasma membrane Ca2+ transporting 2 (ATP2B2), transmembrane serine protease 2 (TMPRSS2), dedicator of cytokinesis 2 (DOCK2), (interferon alpha and beta receptor subunit 2) IFNAR2, tumor necrosis factor receptor superfamily, member 1A (TNFRSF1A), and tumor necrosis factor receptor superfamily, member 1B (TNFRSF1B), were explored in two groups: the first consisted of severe COVID-19-related patients (familial cases from 58 families, n = 130), and the second group of unrelated severe COVID-19 patients (n = 1045). In each study group, death was evaluated as the outcome. Results: In non-related patients with severe COVID-19, carriers of GG genotype (rs2289274) in the ATP2B2 gene showed a high-risk probability of non-surviving (OR = 1.43). Survival analysis to 75 days indicates that carriers of GG have a higher risk than GA or AA genotypes (p = 0.0059). The haplotype GG (rs2289273-rs2289274) in ATP2B2 was found to be associated with a high risk of death in severe non-related COVID-19 patients. No significant associations were found between severe COVID-19-related patients and SNVs in ATP2B2, TMPRSS2, DOCK2, IFNAR2, TNFRSF1A, or TNFRSF1B. Conclusions: Unrelated patients with severe COVID-19 that carry the GG genotype (rs2289274) in ATP2B2 showed a high death risk. Survival analysis to 75 days indicates that carriers of GG have a higher risk of non-survival compared to GA or AA genotypes.

ROLE OF GENETIC SUSCEPTIBILITY IN NICOTINE ADDICTION AND CHRONIC OBSTRUCTIVE PULMONARY DISEASE.

Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

Role of genetic susceptibility in nicotine addiction and chronic obstructive pulmonary disease

Abstract Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality in developed countries. Although cigarette smoking is the major risk factor, only 10-20% of smokers develop COPD. The extent of cigarette smoking (pack-years and smoking duration) accounts for only 15% of the variation in lung function, indicating that differences in susceptibility to COPD must exist. We provide an overview of the complexity of nicotine addiction and COPD, with special attention to the involvement of genetic factors. The following aspects are discussed in the present article: (1) epidemiology in Mexico and (2) a review of the published literature on genetic association studies using the National Center for Biotechnology Information database of the United States as a search tool. COPD is unique among complex genetic diseases where an environmental risk factor is known and the level of exposure can be documented with some precision. The high morbidity and mortality associated with COPD and its chronic and progressive nature has prompted the use of molecular genetic studies to identify susceptibility factors for the disease. Biomedical research has a remarkable set of tools to aid in the discovery of genes and polymorphisms. We present a review of the most relevant genetic associations in nicotine addiction and COPD.

Natural infection of Lutzomyia neivai with Leishmania spp. in northwestern Argentina.

The natural infection of Lutzomyia neivai with Leishmania in the endemic area of American cutaneous leishmaniasis (ACL) in northwestern Argentina was analyzed by the polymerase chain reaction (PCR)-hybridization technique. Phlebotominae sand flies were captured in the provinces of Tucumán and Salta between 1999 and 2003. From a sample of 440 Lu. neivai females analysed for the detection of the Leishmania (Viannia) and Leishmania (Leishmania) subgenera, 9.1% of the samples resulted infected with a parasite of the subgenus Viannia and none with the Leishmania. This is the first report of naturally infected sand flies in Argentina besides the first report of infected Lu. neivai sensu strictu. Our results contributed to further incrimination of this specie as vector of leishmaniasis in the area and the identification of the main circulating parasite as belonging to the Leishmania (Viannia) subgenera.

Detection of Leishmania braziliensis in human paraffin-embedded tissues from Tucumán, Argentina by polymerase chain reaction

American cutaneous leishmaniasis (ACL) is an endemic disease in Northern Argentina. We applied the polymerase chain reaction (PCR) followed by a hybridization labelled probe to 21 paraffin embedded human skin biopsies, already analyzed histologically, from leishmaniasis endemic areas in the province of Tucumán, Argentina. We used primers previously designed to detect a Leishmania-specific 120-base-pair fragment of kinetoplast DNA minicircle, other two primer pairs that amplify kDNA minicircles belonging to the L. braziliensis and L. mexicana complexes respectively, and specific oligonucleotide primers to detect L. (V.) braziliensis which amplify the sequence of the ribosomal protein L-14 of this species. The PCR-hybridization showed a sensitivity of 90.5 percent when compared to the histopathology test which was 61.9 percent. Five of the total samples analyzed were positive for the L. braziliensis complex whilst none was positive for the L. mexicana complex. The specific primers for L. (V.) braziliensis detected the parasite in four samples. These results are consistent with those reported for close endemic areas and demonstrate that the causative agent of human leishmaniasis in the analyzed cases was L. (V.) braziliensis. PCR should be used as a diagnostic tool for tegumentary leishmaniasis, especially in the mucosal form, and as a valuable technique for the identification of the Leishmania species that causes the disease in certain areas.

Phlebotominae fauna in the province of Tucumán, Argentina.

American Tegumentary Leishmaniasis is endemic in the province of Tucumán since 1916 where the first Argentinian case of leishmaniasis was reported. An epidemic outbreak took place in the province during 1986-1988, after that the number of cases increased gradually again between 1991-1996. Since October of 1999 sand flies captures were performed at different places associated with current and past transmission or sites identified as risky ones. The collections were carried out with CDC mini light trap and modified Shannon trap. In this study 2338 Phlebotominae were captured being prevalent Lutzomyia neivai (Lu intermedia complex) (97.7%), followed by Lu. migonei. We report Lu. shannoni for the first time in the province. Phlebotominae was abundant in the warm and humid months and showed a peak before the summer rains. Lutzomyia neivai showed a pattern (peridomestic prevalence, anthropophilia, abundance in secondary forest) consistent with other outbreak studies. Thus, the results reinforce this species incrimination as vector of leishmaniasis in the area. Domestic animals close to houses increase its abundance, and so the probable associated risk of human-Phlebotominae contact. Further studies should be done to understand the role of each Phlebotominae species in the transmission of leishmaniasis in Tucumán in order to design entomological surveillance strategies.

Phlebotominae fauna in the province of Tucuman, Argentina

American Tegumentary Leishmaniasis is endemic in the province of Tucumán since 1916 where the first Argentinian case of leishmaniasis was reported. An epidemic outbreak took place in the province during 1986-1988, after that the number of cases increased gradually again between 1991-1996. Since October of 1999 sand flies captures were performed at different places associated with current and past transmission or sites identified as risky ones. The collections were carried out with CDC mini light trap and modified Shannon trap. In this study 2338 Phlebotominae were captured being prevalent Lutzomyia neivai (Lu intermedia complex) (97.7 percent), followed by Lu. migonei. We report Lu. shannoni for the first time in the province. Phlebotominae was abundant in the warm and humid months and showed a peak before the summer rains. Lutzomyia neivai showed a pattern (peridomestic prevalence, anthropophilia, abundance in secondary forest) consistent with other outbreak studies. Thus, the results reinforce this species incrimination as vector of leishmaniasis in the area. Domestic animals close to houses increase its abundance, and so the probable associated risk of human-Phlebotominae contact. Further studies should be done to understand the role of each Phlebotominae species in the transmission of leishmaniasis in Tucumán in order to design entomological surveillance strategies

Leishmaniosis tegumentaria en un area con niveles epidemicos de transmision, Salta, Argentina, 1998 / Tegumentary leismaniasis in an area with epidemic levels of transmission, Salta, Argentina

En un área próxima a Orán, provincia de Salta, en octubre de 1997 se registró un aumento significativo de la incidencia de leishmaniosis tegumentaria. En junio de 1998 se realizó un estudio epidemiológico y entomológico de dicho brote epidémico en dos sitios que presentaron alta incidencia de leishmaniosis, el Paraje Las Carmelitas y Río Blanco. La prevalencia de infección (intradermoreacción de Montenegro reactiva) fue de 171/1000 habitantes en Paraje Las Carmelitas y 790/1000 en Río Blanco, mientras la tasa de leishmaniosis (lesiones activas) fue de 72/1000 y 790/1000 respectivamente. Las diferencias de prevalencia entre sexos y grupos etarios no fue significativa. Las características clínicas y epidemiológicas fueron compatibles con lo observado en la zona para Leishmania (Viannia) braziliensis. Lutzomyia intermedia fue la especie más abundante (96 percent) entre los 2577 Phlebotominae colectados, capturándose también Lu. shannoni, Lu. cortelezzii y Lu. migonei. Los resultados obtenidos de distribución etaria de prevalencia y distribución espacial de vectores sugieren una hipótesis de transmisión relacionada a la deforestación y la vegetación primaria residual. Así, los brotes epidémicos en Salta, generados por deforestación extensiva, pueden ser sostenidos y amplificados si los asentamientos humanos se localizan en la proximidad de pequeños remanentes de bosque primario. En estos casos, el riesgo de contacto humano-vector se incrementa por las actividades de subsistencia o recreación realizadas en el bosque secundario de transición, y la presencia de corrales alrededor de las viviendas. Los resultados se discuten en el marco de una posible estrategia de control. (Au)

Leishmaniosis tegumentaria en un area con niveles epidemicos de transmision, Salta, Argentina, 1998 / Tegumentary leismaniasis in an area with epidemic levels of transmission, Salta, Argentina

En un área próxima a Orán, provincia de Salta, en octubre de 1997 se registró un aumento significativo de la incidencia de leishmaniosis tegumentaria. En junio de 1998 se realizó un estudio epidemiológico y entomológico de dicho brote epidémico en dos sitios que presentaron alta incidencia de leishmaniosis, el Paraje Las Carmelitas y Río Blanco. La prevalencia de infección (intradermoreacción de Montenegro reactiva) fue de 171/1000 habitantes en Paraje Las Carmelitas y 790/1000 en Río Blanco, mientras la tasa de leishmaniosis (lesiones activas) fue de 72/1000 y 790/1000 respectivamente. Las diferencias de prevalencia entre sexos y grupos etarios no fue significativa. Las características clínicas y epidemiológicas fueron compatibles con lo observado en la zona para Leishmania (Viannia) braziliensis. Lutzomyia intermedia fue la especie más abundante (96 percent) entre los 2577 Phlebotominae colectados, capturándose también Lu. shannoni, Lu. cortelezzii y Lu. migonei. Los resultados obtenidos de distribución etaria de prevalencia y distribución espacial de vectores sugieren una hipótesis de transmisión relacionada a la deforestación y la vegetación primaria residual. Así, los brotes epidémicos en Salta, generados por deforestación extensiva, pueden ser sostenidos y amplificados si los asentamientos humanos se localizan en la proximidad de pequeños remanentes de bosque primario. En estos casos, el riesgo de contacto humano-vector se incrementa por las actividades de subsistencia o recreación realizadas en el bosque secundario de transición, y la presencia de corrales alrededor de las viviendas. Los resultados se discuten en el marco de una posible estrategia de control.