RESUMO
Mounting evidence indicates that adverse activation of the complement system plays a role in the development of diabetic vascular complications. Plasma levels of the complement proteins mannan-binding lectin (MBL) and its associated serine proteases (MASP-1 and MASP-2) are elevated in diabetes. We hypothesized that single nucleotide polymorphisms (SNPs) in the MASP1 gene may contribute to altered plasma levels of the belonging gene products; MASP-1, MASP-3 and mannan-binding lectin-associated protein of 44 kDa (MAp44) in patients with type 2 diabetes. To investigate this, we compared plasma levels of MASP-1, MASP-3 and MAp44 in 100 patients with type 2 diabetes and 100 sex- and age-matched controls. Ten carefully selected SNPs were analysed using TaqMan® genotyping assay. Additionally, we included a streptozotocin-induced diabetes mouse model to directly examine the effect of inducing diabetes on MASP-1 levels. MASP-1 levels were significantly higher among patients with type 2 diabetes compared with healthy controls (P = 0·017). Five SNPs (rs874603, rs72549254, rs3774275, rs67143992, rs850312) in the MASP1 gene were associated with plasma levels of MASP-1, MASP-3 and MAp44. In the diabetes mouse model, diabetic mice had significantly higher MASP-1 levels than control mice (P = 0·003). In conclusion, MASP-1 levels were higher among patients with type 2 diabetes and diabetic mice. The mechanism behind this increase remains elusive.
Assuntos
Composição Corporal , Diabetes Mellitus Tipo 2/sangue , Lectina de Ligação a Manose/sangue , Serina Proteases Associadas a Proteína de Ligação a Manose/análise , Idoso , Animais , Glicemia , Estudos de Casos e Controles , Dinamarca , Diabetes Mellitus Experimental , Feminino , Genótipo , Humanos , Modelos Lineares , Masculino , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Camundongos , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , EstreptozocinaRESUMO
The human major histocompatibility complex class II isotype HLA-DR is currently used as an activation marker for T cells. However, whether an endogenous protein expression or a molecular acquisition accounts for the presence of HLA-DR on T cells remains undetermined and still controversial. To further characterize this phenomenon, we compared several aspects of the presence of the HLA-DR protein to the presence of associated mRNA (HLA-DRB1), focusing on human T cells from peripheral blood of healthy individuals. Using a flow cytometric approach, we determined that the HLA-DR observed on CD4(+) T cells was almost exclusively cell surface-associated, while for autologous CD19(+) B cells, the protein could be located in the plasma membrane as well as in the cytoplasm. Moreover, negligible expression levels of HLA-DRB1 were found in CD4(+) T cells, using an HLA-DRB1 allele-specific qPCR assay. Finally, the presence of HLA-DR was not confined to activated CD4(+) and CD8(+) T cells, as evaluated by the co-expression of CD25. The functional role of the HLA-DR molecule on T cells remains enigmatic; however, this study presents evidence of fundamental differences for the presence of HLA-DR on T cells from HLA-DR in the context of antigen-presenting cells, which is a well-known phenomenon. Although an inducible endogenous protein expression cannot be excluded for the T cells, our findings suggest that a re-evaluation of the HLA-DR as a T cells activation marker is warranted.
Assuntos
Linfócitos T CD4-Positivos/imunologia , Expressão Gênica/imunologia , Cadeias HLA-DRB1/imunologia , RNA Mensageiro/imunologia , Antígenos CD19/genética , Antígenos CD19/imunologia , Linfócitos B/citologia , Linfócitos B/imunologia , Linfócitos T CD4-Positivos/citologia , Membrana Celular/imunologia , Citoplasma/imunologia , Citometria de Fluxo , Cadeias HLA-DRB1/genética , Humanos , Imunofenotipagem , Subunidade alfa de Receptor de Interleucina-2/genética , Subunidade alfa de Receptor de Interleucina-2/imunologia , Ativação Linfocitária , Cultura Primária de Células , RNA Mensageiro/genéticaRESUMO
OBJECTIVE: Prenatal and postnatal RhD prophylaxis reduces the risk of RhD immunization in pregnancies of RhD-negative women. Based on the result from prenatal screening for the fetal RHD gene, prenatal RhD prophylaxis in Denmark is targeted to RhD-negative women who carry an RhD-positive fetus. Here, we present a 2-year evaluation of a nationwide prenatal RHD screening. METHODS: Blood samples were drawn from RhD-negative women in gestational week 25. DNA was extracted from maternal plasma and analyzed for the RHD gene. The prenatal RHD results were compared with the serological typing of newborns in 12,668 pregnancies. Early compliance was assessed for 690 pregnancies. RESULTS: The sensitivity for the detection of fetal RHD was 99.9% (95% CI: 99.7-99.9%). Unnecessary recommendation of prenatal RhD prophylaxis was avoided in 97.3% of the women carrying an RhD-negative fetus. Fetuses that were seropositive for RhD were not detected in 11 pregnancies (0.087%). The sample uptake percentage was 84.2%, and the compliance for prenatal anti-D administration was 93.2%. CONCLUSION: The high sensitivity, maintained over 2 years, underlines the reliability of routine prenatal fetal RHD screening in RhD-negative pregnant women, specifically at 25 weeks of gestation. The remaining challenges are logistical and are related to program compliance.
Assuntos
Proteínas Fetais/sangue , Testes para Triagem do Soro Materno/estatística & dados numéricos , Sistema do Grupo Sanguíneo Rh-Hr/sangue , Dinamarca , Feminino , Humanos , Recém-Nascido , GravidezRESUMO
The poor remodeling of placental spiral arteries seen in preeclampsia is also discussed to contribute to recurrent pregnancy loss (RPL) preceded by abnormal angiogenesis and excessive complement activation. Low levels of Mannose-binding-lectin (MBL), a pattern recognition molecule (PRM) of the lectin pathway, have been found in women with RPL. We propose that pregnancy loss is connected to defective angiogenesis with reperfusion damage in the placenta and decreased levels of PRM in the lectin pathway in women with RPL. In this cohort study, we investigate the angiogenic factors and the lectin complement pathway in early pregnancy and their time-dependent relationship with pregnancy outcomes in 76 women with secondary RPL (sRPL) who have at least four prior pregnancy losses and a live birth. We evaluated levels of Angiopoietin-1 (Ang-1), Angiopoietin-2 (Ang-2), Vascular Endothelial Growth Factor (VEGF), soluble fms-like tyrosine kinase-1 (sFlt-1), and the PRMs, MBL, ficolin-1, -2, -3 and an additional soluble PRM, Pentraxin-3, during the 5th, 6th, and 7th gestational weeks. Our results showed that, compared to live births, pregnancies that ended in loss were associated with elevated VEGF levels and decreased levels of the Ang-2/Ang-1 ratio. Also, increasing levels of ficolin-2 were significantly associated with pregnancy loss, with MBL showing no association. Our research suggests that women with sRPL may have inadequate placentation with impaired angiogenesis in pregnancies ending in a loss.
Assuntos
Aborto Habitual , Lectina de Ligação a Manose da Via do Complemento , Lectinas , Lectina de Ligação a Manose , Receptor 1 de Fatores de Crescimento do Endotélio Vascular , Humanos , Feminino , Gravidez , Adulto , Aborto Habitual/imunologia , Aborto Habitual/sangue , Lectina de Ligação a Manose da Via do Complemento/imunologia , Lectinas/metabolismo , Lectinas/sangue , Lectinas/imunologia , Lectina de Ligação a Manose/sangue , Lectina de Ligação a Manose/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/metabolismo , Receptor 1 de Fatores de Crescimento do Endotélio Vascular/sangue , Fator A de Crescimento do Endotélio Vascular/metabolismo , Fator A de Crescimento do Endotélio Vascular/sangue , Angiopoietina-2/metabolismo , Angiopoietina-2/imunologia , Angiopoietina-2/sangue , Proteína C-Reativa/metabolismo , Proteína C-Reativa/análise , Angiopoietina-1/sangue , Angiopoietina-1/metabolismo , Componente Amiloide P Sérico/metabolismo , Ficolinas , Estudos de Coortes , Placenta/imunologia , Placenta/metabolismo , Placenta/patologia , Resultado da Gravidez , Indutores da Angiogênese/metabolismo , Ativação do Complemento/imunologiaRESUMO
Immune system aberrations are suggested to be an important factor in the pathophysiology of unexplained secondary recurrent pregnancy loss (sRPL). The objective was to investigate if the sex ratio of the firstborn child in sRPL patients differs from the background population and whether the sex of the firstborn child has a negative impact on the pregnancy prognosis alone and/or in combination with carriage of male-specific minor histocompatibility (H-Y) restricting HLA class II alleles. From January 2016 to October 2022, 582 patients with unexplained RPL were admitted to the RPL Center of Western Denmark and continuously followed-up. HLA-DRB1 and -DQB1 typing was performed as part of the routine diagnostic work-up. In sRPL patients, a history of a firstborn boy was significantly more frequent than in the Danish background population and was associated with significantly lower odds of a successful reproductive outcome in the first pregnancy after admission compared to a firstborn girl (OR=0.41, 95% CI: 0.20-0.83, p = 0.014). The odds of a successful reproductive outcome were enhanced in patients carrying ≥ 1 H-Y-restricting HLA class II alleles with a first-born girl compared to a firstborn boy (OR=3.33, 95% CI: 1.40-7.88, p = 0.005), while no difference in successful reproductive outcome was seen in sRPL patients not carrying these alleles (OR=1.20, 95% CI: 0.33-4.43, p = 0.781). The sex ratio of children born after RPL was similar to the Danish background population. These findings confirm previous findings and suggests that a harmful immune response triggered by H-Y-antigen exposure during a previous pregnancy in preconditioned women may cause sRPL.
Assuntos
Aborto Habitual , Antígeno H-Y , Feminino , Humanos , Masculino , Gravidez , Alelos , Antígeno H-Y/genética , Histocompatibilidade , Cadeias HLA-DRB1/genética , Prognóstico , Antígenos de Histocompatibilidade Classe II/imunologiaRESUMO
In this study, we report a novel real time polymerase chain reaction (Q-PCR) method using TaqMan probes for human neutrophil antigens (HNA)-1, -3, -4, and -5 genotyping. The method was validated in a Caucasian Danish population, a Zambian population, and in clinical samples using three different methods: an in-house polymerase chain reaction with sequence-specific primers (PCR-SSP) method, a commercial available PCR-SSP kit and a novel Q-PCR method. We observed no discrepancy in the genotype frequencies determined by the PCR-SSP methods and the TaqMan assay in the populations studied. In tests of a family of Nigerian origin and in samples carrying the rare SLC44A2*1:2 genotype, different results were produced by the commercial PCR-SSP kit and the real-time TaqMan assay. The TaqMan-based genotyping method was rapid and reproducible, allowing high-throughput HNA-1, -3, -4, and -5 genotyping.
Assuntos
Frequência do Gene/genética , Isoantígenos/genética , Reação em Cadeia da Polimerase em Tempo Real/métodos , Taq Polimerase/metabolismo , Dinamarca/etnologia , Proteínas Ligadas por GPI/genética , Genética Populacional , Técnicas de Genotipagem , Humanos , Isoantígenos/imunologia , Polimorfismo de Nucleotídeo Único/genética , Receptores de IgG/genética , Zâmbia/etnologiaRESUMO
The risk of infection with Campylobacter jejuni/coli as well as complications may be related to host genetics. We assessed six single-nucleotide polymorphisms in inflammatory cytokine genes in 105 patients with Campylobacter jejuni/coli gastroenteritis. The population distribution of the genes was determined in healthy subjects. The patients responded to mailed questionnaires with regard to reactive arthritis (RA) and irritable bowel syndrome (IBS) in 6-month follow-up. The genotype INFG(+ 874A/A) was less frequent in patients than in controls (20% versus 33%; P = 0.015), whereas the distribution of the other five SNPs did not differ from controls. After 6 months, RA had developed in 15 subjects and IBS in 20 subjects. RA was significant more frequent in patients with IL-18(-137G/G) (22%) than IL-18(-137C/C) (0%), P = 0.03, with INFG(+874 T/T (32%) than INFG(+874A/A) (0%), P = 0.007, and with INFG(+2197 A/A) (22%) than INFG(+2197G/G) (0%), P = 0.02. The development of IBS was not linked to gene polymorphisms. In conclusion, the risk of acquiring clinical gastroenteritis with Campylobacter jejuni/coli is related to the INFG (+ 874A>T) of intron 1. Polymorphisms in IL-18 and INFG are linked to the risk of post-infectious reactive arthritis, but not to irritable bowel syndrome.
Assuntos
Infecções por Campylobacter/genética , Campylobacter coli , Campylobacter jejuni , Citocinas/genética , Gastroenterite/genética , Polimorfismo Genético , Infecções por Campylobacter/diagnóstico , Infecções por Campylobacter/imunologia , Citocinas/imunologia , Gastroenterite/diagnóstico , Gastroenterite/imunologia , Humanos , Prognóstico , Fatores de RiscoRESUMO
BACKGROUND AND AIM: Elevated CRP and matrix metalloproteinase-9 associate with increased risk of cardiovascular events, possibly because these plasma proteins mark vulnerable atherosclerotic plaques. We tested the hypothesis that levels of C-reactive protein (CRP) and matrix metalloproteinase-9 associate with prognosis in patients with stable coronary heart disease. METHODS AND RESULTS: We measured baseline plasma CRP and matrix metalloproteinase-9 in 1090 patients with stable coronary heart disease and as the primary composite endpoint detected incident unstable angina, myocardial infarction and any death during 15 years of follow-up. CRP above versus below the median of 3.0 mg/L was associated with an increased cumulative incidence of unstable angina, myocardial infarction and any death combined (log-rank p < 0.0001). CRP above versus below the median had a corresponding hazard ratio of 1.5(95% CI, 1.3-1.8) after age adjustment, of 1.4(1.2-1.6) after multifactorial adjustment, and of 1.4(1.2-1.6) after multifactorial adjustment including degree of coronary disease. In contrast, matrix metalloproteinase-9 above versus below the median was not associated with risk of unstable angina, myocardial infarction and death. CONCLUSIONS: Elevated CRP, but not elevated matrix metalloproteinase-9, associates with increased risk of unstable angina, myocardial infarction and death in patients with stable coronary heart disease.
Assuntos
Proteína C-Reativa/análise , Doença das Coronárias/sangue , Metaloproteinase 9 da Matriz/sangue , Idoso , Angina Instável/mortalidade , Biomarcadores/sangue , Causas de Morte , Distribuição de Qui-Quadrado , Doença das Coronárias/enzimologia , Doença das Coronárias/imunologia , Doença das Coronárias/mortalidade , Dinamarca/epidemiologia , Progressão da Doença , Feminino , Seguimentos , Humanos , Estimativa de Kaplan-Meier , Masculino , Pessoa de Meia-Idade , Infarto do Miocárdio/mortalidade , Prognóstico , Modelos de Riscos Proporcionais , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Fatores de Tempo , Regulação para CimaRESUMO
STUDY QUESTION: Are low or high plasma mannose-binding lectin (p-MBL) levels associated with recurrent pregnancy loss (RPL) and the reproductive and perinatal outcomes before and after RPL? SUMMARY ANSWER: The prevalence of low p-MBL levels was significantly higher in RPL patients, while high levels were significantly less prevalent. No association was found between p-MBL level and reproductive and perinatal outcomes before and after RPL. WHAT IS KNOWN ALREADY: Mannose-binding lectin (MBL) is an important component in the innate immune system. Low p-MBL levels have been associated with RPL, while the correlation with high levels has been poorly studied. Adverse perinatal outcomes are generally more frequent among RPL patients, but reports concerning the association between maternal p-MBL levels and perinatal outcomes, including birth weight (BW) and gestational age (GA), are conflicting. STUDY DESIGN SIZE DURATION: This study was a combined cross-sectional and cohort study of 267 RPL patients admitted to the RPL Center of Western Denmark between January 2016 and March 2020. RPL patients were followed until birth of a liveborn child or until end of follow-up, March 2021. A sample of 185 healthy female blood donors of reproductive age was used as a MBL reference group. PARTICIPANTS/MATERIALS SETTING METHODS: All RPL patients had ≥3 consecutive pregnancy losses, a regular menstrual cycle and no known significant chromosomal or uterine malformations. At the first consultation, routine blood samples including p-MBL measurement and detailed obstetrical and perinatal information were collected. p-MBL levels in RPL patients were compared to the MBL reference group. A logistic regression analysis adjusted for relevant confounders assessed the association between low p-MBL levels and an unsuccessful reproductive outcome in RPL patients in first pregnancy after admission. Perinatal outcomes before and after RPL were compared between RPL subgroups according to low (≤500 µg/l), intermediate (501-3000 µg/l) and high (>3000 µg/l) p-MBL levels. MAIN RESULTS AND THE ROLE OF CHANCE: Significantly more RPL patients had low p-MBL levels (prevalence proportion ratio (PPR): 1.79, 95% CI: 1.34-2.38) and fewer had high p-MBL levels (PPR: 0.56, 95% CI: 0.40-0.79) compared to the reference group, while the prevalence of intermediate p-MBL level was not different between the groups (PPR: 0.86, 95% CI: 0.69-1.08). In the prospective study, low p-MBL level was not a significant risk factor for a pregnancy loss in the first pregnancy after admission after adjustment for age, BMI and smoking. Neither before nor after the RPL diagnosis were maternal p-MBL levels significantly associated with BW or GA. LIMITATIONS REASONS FOR CAUTION: Only 161 (60.3%) patients had given birth after RPL during the follow-up period, which limited the possibility to detect clear associations between p-MBL levels and perinatal outcomes after RPL. WIDER IMPLICATIONS OF THE FINDINGS: In agreement with several previous studies, low p-MBL levels are strongly associated with RPL, while this study for the first time documents that high levels may play a protective role, which suggests a causal relationship. We suggest that larger prospective studies evaluate the association between p-MBL levels and RPL prognosis. STUDY FUNDING/COMPETING INTERESTS: No external funding was received. We acknowledge the Department of Obstetrics and Gynaecology at Aalborg University Hospital for financial support. U.S.K. has reported personal fees from Merck, consulting fees from IBSA Nordic, and a grant from Gedeon Richter, Merck and IBSA Nordic outside of the submitted work. TRIAL REGISTRATION NUMBER: ID from clinicaltrials.gov is NCT04017754.
RESUMO
Introduction: Accumulating evidence support that mannan-binding lectin (MBL) is a promising prognostic biomarker for risk-stratification of diabetic micro- and macrovascular complications. Serum MBL levels are predominately genetically determined and depend on MBL genotype. However, Type 1 diabetes (T1D) is associated with higher MBL serum levels for a given MBL genotype, but it remains unknown if this is also the case for patients with T2D. In this study, we evaluated the impact of MBL genotypes on renal function trajectories serum MBL levels and compared MBL genotypes in newly diagnosed patients with T2D with age- and sex-matched healthy individuals. Furthermore, we evaluated differences in parameters of insulin resistance within MBL genotypes. Methods: In a cross-sectional study, we included 100 patients who were recently diagnosed with T2D and 100 age- and sex-matched individuals. We measured serum MBL levels, MBL genotype, standard biochemistry, and DEXA, in all participants. A 5-year clinical follow-up study was conducted, followed by 12-year data on follow-up biochemistry and clinical status for the progression to micro- or macroalbuminuria for the patients with T2D. Results: We found similar serum MBL levels and distribution of MBL genotypes between T2D patients and healthy individuals. The serum MBL level for a given MBL genotype did not differ between the groups neither at study entry nor at 5-year follow-up. We found that plasma creatinine increased more rapidly in patients with T2D with the high MBL expression genotype than with the medium/low MBL expression genotype over the 12-year follow-up period (p = 0.029). Serum MBL levels did not correlate with diabetes duration nor with HbA1c. Interestingly, serum MBL was inversely correlated with body fat percentage in individuals with high MBL expression genotypes both at study entry (p=0.0005) and 5-years follow-up (p=0.002). Discussion: Contrary to T1D, T2D is not per se associated with increased MBL serum level for a given MBL genotype or with diabetes duration. Serum MBL was inversely correlated with body fat percentage, and T2D patients with the high MBL expression genotype presented with deterioration of renal function.
Assuntos
Diabetes Mellitus Tipo 1 , Diabetes Mellitus Tipo 2 , Lectina de Ligação a Manose , Humanos , Diabetes Mellitus Tipo 2/genética , Lectina de Ligação a Manose/genética , Seguimentos , Estudos Transversais , Genótipo , Rim/fisiologiaRESUMO
Mannan-binding lectin (MBL) and MBL-associated serine protease 2 (MASP-2) are key factors of the lectin pathway of complement activation. Polymorphisms of the MBL2 and MASP-2 genes affect serum levels of MBL and MASP-2. In patients with colorectal cancer (CRC), the MBL and MASP-2 serum levels are increased and high MASP-2 levels are associated with recurrence and poor survival, whereas low MBL levels predict post-operative pneumonia. It is not known whether these associations are genetically based. In this study, the MBL and MASP-2 genotypes are investigated in 593 patients with CRC and 348 healthy controls. The potential association between genetic profile and infections, recurrence and survival is evaluated. Four single-nucleotide polymorphisms (SNPs) of MBL2 were analysed using TaqMan assays, with characterization of MBL2 wildtype A, variants B, C and D and alleles H/L, Y/X and P/Q. The SNP D120G for MASP-2 was determined. Serum levels of MBL and MASP-2 were measured. The MBL2 and MASP-2 genotype distribution was similar among patients with CRC and healthy controls and MBL2 genotype significantly associated with MBL concentration in serum (P<0.0001). No significant association between MBL2/MASP-2 genotype and post-operative infectious complications (P=0.33 and 0.22), recurrent cancer or survival (P=0.74 and P=0.61 respectively) was found. Thus, the increased serum levels of MBL and MASP-2 found in patients with CRC are not explained for by genetic profiles. In contrast to what has been demonstrated for serum levels of MBL and MASP-2, the genotypes do not predict disease course of the CRC patients.
Assuntos
Neoplasias Colorretais/genética , Lectina de Ligação a Manose/genética , Serina Proteases Associadas a Proteína de Ligação a Manose/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Neoplasias Colorretais/sangue , Neoplasias Colorretais/tratamento farmacológico , Feminino , Genótipo , Humanos , Masculino , Lectina de Ligação a Manose/sangue , Serina Proteases Associadas a Proteína de Ligação a Manose/metabolismo , Pessoa de Meia-Idade , Resultado do TratamentoRESUMO
Many cases of recurrent pregnancy loss (RPL) defined as ≥3 consecutive pregnancy losses are suggested to be caused by an aberrant maternal immune response against the fetus or trophoblast. Human leukocyte antigen (HLA)-DRB1 and -DQB1 polymorphisms are associated with most autoimmune disorders and studies of HLA-DBB1 polymorphism in RPL patients are thus relevant. In previous studies, the HLA-DRB1*03 allele was found with increased prevalence in RPL patients. We wanted to clarify whether HLA-DRB1 alleles indeed were associated with RPL among women of Caucasian descent. A total of 1078 women with unexplained RPL and 2066 bone marrow donors were HLA-DRB1-typed and subsets were also HLA-DQB1 typed. All patients were initially HLA-DRB1-typed by DNA-based low-resolution techniques and subsets of patients and all controls were typed by high-resolution techniques. Among patients, the HLA-DRB1*07 allele frequency was significantly increased compared with controls; OR 1.29 (95 % CI 1.09-1.52), p < 0.0025; after correction for multiple comparisons pc = 0.031. The HLA-DRB1*07/*07 genotype was highly increased in patients with RPL compared with controls: OR 2.27 (1.31-3.93), p = 0.0027. The frequency of the HLA-DRB1*07 phenotype in RPL patients had increased significantly (p = 0.002) in three studies from our group published 1994-2021. The allele frequency of HLA-DRB1*03 was not increased in RPL patients compared with controls; OR 0.96 (0.83-1.12). In conclusion, the previous association between HLA-DRB1*03 and RPL could not be confirmed in our study whereas an association to HLA-DRB1*07 was detected for the first time. Since the latter association is a new finding, it should be confirmed in future studies.
Assuntos
Aborto Habitual/genética , Predisposição Genética para Doença , Cadeias HLA-DRB1/genética , Aborto Habitual/imunologia , Adolescente , Adulto , Estudos de Casos e Controles , Feminino , Frequência do Gene , Voluntários Saudáveis , Homozigoto , Humanos , Pessoa de Meia-Idade , Polimorfismo Genético , Gravidez , Adulto JovemRESUMO
BACKGROUND: The association among hereditary thrombophilia, recurrent pregnancy loss (RPL) and obstetric complications is yet uncertain. The objective of the study was to assess the prognostic value of the factor V Leiden (FVL) and prothrombin (PT) mutations for the subsequent chance of live birth for women with RPL. METHODS: Pregnancy outcome was recorded in a retrospective cohort of 363 women with a minimum of three consecutive pregnancy losses (early miscarriage, late miscarriage or stillbirth/neonatal death) who were not treated with anticoagulation therapy. RESULTS: Of the 363 women, 29 were FVL-mutation carriers and 6 were PT-mutation carriers. The unadjusted live birth rate was 45.7% in FVL/PT carriers versus 63.4% in FVL/PT non-carriers, P = 0.04. The adjusted odds ratio for live birth in FVL/PT carriers was 0.48 (95% CI = 0.23-1.01), P = 0.05. Among the obstetric complications, only excessive bleeding was found to be associated with FVL/PT mutations. CONCLUSIONS: In the unadjusted analysis, FVL and PT mutations have a negative prognostic impact on the live birth rate in women with RPL; however, when adjusting for significant covariates, the results no longer reach statistical significance. Strong conclusions on the association between obstetric complications and hereditary thrombophilia cannot be drawn from this study. Whether anticoagulation therapy would improve the prognosis in women with RPL and FVL/PT mutations remains to be documented in large randomized controlled trials.
Assuntos
Aborto Habitual/genética , Fator V/genética , Protrombina/genética , Trombofilia/genética , Aborto Espontâneo/epidemiologia , Adulto , Anticoagulantes/uso terapêutico , Estudos de Coortes , Dinamarca/epidemiologia , Feminino , Humanos , Mutação , Complicações do Trabalho de Parto/genética , Gravidez , Resultado da Gravidez/genética , Prognóstico , Estudos Retrospectivos , Natimorto/epidemiologia , Trombofilia/tratamento farmacológicoRESUMO
BACKGROUND: The chance of a live birth after a diagnosis of secondary recurrent miscarriage (SRM) is reduced in patients who, prior to the miscarriages, gave birth to a boy and carry HLA class II alleles that efficiently present male-specific (H-Y) antigens to the immune system. Information about obstetric complications in births prior and subsequent to the SRM diagnosis is limited. The relations between maternal carriage of H-Y-restricting HLA, fetal sex, obstetric complications and prognosis are unknown. METHODS: Women with unexplained SRM referred to the Danish Recurrent Miscarriage Clinic between 1986 and 2006 (n = 358) were included; 213 gave birth after the diagnosis. Controls, retrieved from the Danish National Birth Registry, were all women with singleton birth of parity 0, 1982-2005 (n = 608,068) and parity 1, 1986-2008 (n = 510,264). Cross-linkage to the National Discharge Registry identified birth complication diagnoses related to the relevant births among patients and controls. RESULTS: The sex ratio was 1.49 in births prior to SRM and 0.76 in birth after SRM (P < 0.0001). For SRM patients with only late miscarriages (>10 weeks gestation), the corresponding sex ratios were 2.31 and 0.21. Compared with the control groups, obstetric complications were more frequent both before (39% versus 24% P Assuntos
Aborto Habitual/imunologia
, Antígeno H-Y/imunologia
, Antígenos HLA/imunologia
, Histocompatibilidade Materno-Fetal/imunologia
, Complicações na Gravidez/imunologia
, Aborto Habitual/genética
, Alelos
, Dinamarca
, Feminino
, Antígeno H-Y/genética
, Antígenos HLA/genética
, Histocompatibilidade Materno-Fetal/genética
, Humanos
, Recém-Nascido
, Nascido Vivo
, Masculino
, Gravidez
, Complicações na Gravidez/genética
, Sistema de Registros
, Fatores de Risco
, Estatísticas não Paramétricas
RESUMO
BACKGROUND: The birth of a boy is significantly more common than a girl prior to secondary recurrent miscarriage (SRM) and is associated with a poorer chance of a subsequent live birth. Children born after SRM are more likely to be girls. High-titer antisera specific for male antigens (H-Y) have been shown to arrest development of male bovine embryos efficiently. We consequently questioned the role of H-Y antibodies in women with SRM. METHODS: Serum samples from patients with unexplained SRM (n = 84), unexplained primary recurrent miscarriage (PRM) (n = 12) and healthy women (n = 37) were obtained. The samples were taken during pregnancy (gestational weeks 4-5) for 77 (80%) of the patients. Enzyme-linked immunosorbent assay was used to detect immunoglobulin G antibodies that specifically recognized any of the five recombinant H-Y proteins (EIF1AY, RPS4Y1, ZFY, DDX3Y and UTY) and their H-X homologs. RESULTS: H-Y-specific antibodies were more frequent in SRM patients (46%) compared with female controls (19%, P = 0.004) and PRM patients (8%, P = 0.01). The presence of H-Y antibodies in early pregnancy was associated with a low male: female birth ratio among the subsequent live births, as only 12% of children born to H-Y antibody-positive patients were boys compared with 44% boys born to H-Y antibody negative patients (P = 0.03). CONCLUSIONS: The high frequency of H-Y antibody-positive SRM patients and the association between the presence of these antibodies in early pregnancy and the low number of male offspring, suggest that maternal immune responses against H-Y antigens can cause pregnancy losses. Further exploring these mechanisms may increase our understanding of unexplained SRM.
Assuntos
Aborto Habitual/imunologia , Antígeno H-Y/imunologia , Isoanticorpos/análise , Resultado da Gravidez , Adolescente , Adulto , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Masculino , Gravidez , Primeiro Trimestre da Gravidez , Razão de MasculinidadeRESUMO
BACKGROUND AND OBJECTIVES: Antibodies to antigens in the Kell blood group system, especially anti-KEL1, are involved in both haemolytic disease of the newborn and foetus and haemolytic transfusion reactions. Correct typing results are important and discrepancies between serologic and genetic typing must be resolved. Here, we describe the investigation of three healthy individuals who were initially phenotyped as KEL:1,-2. MATERIALS AND METHODS: Antigen typing was performed by standard serological techniques and by flow cytometric analysis. The KEL*01/02 polymorphism was tested by an allele-discrimination TaqMan assay as well as by PCR with allele-specific primers and PCR-RFLP. DNA sequencing of the KEL coding region was also performed. RESULTS: Two KEL*02N alleles with mutated splice sites around exon 8 were identified: intron 7 -1g>c (novel) and intron 8 +1g>t (previously reported in one case of K(0)). In the third sample, a missense mutation in exon 8, 787G>A (novel) predicting Gly263Arg, was detected on a KEL*02 allele and associated with dramatically weakened KEL2 antigen expression. CONCLUSION: Resolution of discrepant phenotype/genotype results identified silencing mutations in or around exon 8. A combination of molecular and serologic methods has the potential to improve the quality of test results and was required to ensure both the accurate KEL2 antigen status and KEL*01 zygosity of these individuals.
Assuntos
Alelos , Éxons , Sistema do Grupo Sanguíneo de Kell/genética , Feminino , Citometria de Fluxo , Genótipo , Humanos , Sistema do Grupo Sanguíneo de Kell/imunologia , Masculino , Fenótipo , Reação em Cadeia da Polimerase , Polimorfismo Genético , Polimorfismo de Fragmento de RestriçãoRESUMO
Hepatitis C virus (HCV) is a major cause of hepatic disease and of liver transplantation worldwide. Mannan-binding lectin (MBL), encoded by the MBL2 gene, can have an important role as an opsonin and complement activating molecule in HCV persistence and liver injury. We assessed the MBL2 polymorphism in 102 Euro-Brazilian patients with moderate and severe chronic hepatitis C, paired for gender and age with 102 HCV seronegative healthy individuals. Six common single nucleotide polymorphisms in the MBL2 gene, three in the promoter (H/L, X/Y and P/Q) and three in exon 1 (A, the wild-type, and B, C or D also known as O) were evaluated using real-time polymerase chain reaction with fluorescent hybridization probes. The concentration of MBL in plasma was measured by enzyme-linked immunosorbent assay. The frequency of the YA/YO genotype was significantly higher in the HCV patients compared with the controls (P = 0.022). On the other hand, the genotypes associated with low levels of MBL (XA/XA, XA/YO and YO/YO) were decreased significantly in the patients with severe fibrosis (stage F4), when compared with the patients with moderate fibrosis (stage F2) (P = 0.04) and to the control group (P = 0.011). Furthermore, MBL2 genotypes containing X or O mutations were found to be associated with non-responsiveness to pginterferon and ribavirin treatment (P = 0.023). MBL2 polymorphisms may therefore be associated not only with the development of chronic hepatitis C, but also with its clinical evolution and response to treatment.
Assuntos
Antivirais/uso terapêutico , Hepatite C Crônica/genética , Interferon-alfa/uso terapêutico , Cirrose Hepática/virologia , Lectina de Ligação a Manose/genética , Adulto , Feminino , Predisposição Genética para Doença , Genótipo , Hepatite C Crônica/sangue , Hepatite C Crônica/tratamento farmacológico , Humanos , Cirrose Hepática/genética , Masculino , Lectina de Ligação a Manose/sangue , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Índice de Gravidade de Doença , Resultado do TratamentoRESUMO
Lipoprotein lipase degrades triglycerides in plasma and as a byproduct produces HDL particles. Genetic variation in lipoprotein lipase may therefore affect cardiovascular risk. We tested 9,214 men and women from a general population sample and 948 patients with ischemic heart disease for the Asn291Ser substitution in lipoprotein lipase. The allele frequency in the general population was 0.024 and 0.026 for women and men, respectively. In comparison with noncarriers, female heterozygous probands had increased plasma triglycerides (delta = 0.23 mmol/liter), while HDL cholesterol was reduced in both female and male carriers (delta = 0.18 mmol/liter and delta = 0.11 mmol/liter, respectively). A similar phenotype was found in six homozygous carriers. On multiple logistic regression analysis, plasma triglycerides and HDL cholesterol were independent predictors of ischemic heart disease in both genders. On univariate analysis, odds ratios for ischemic heart disease in probands were 1.89 in women (95% CI: 1.19-3.01) and 0.90 in men (95% CI: 0.62-1.31), and on multivariate analysis were 1.98 in women (95% CI: 1.11-3.53) and 1.02 in men (95% CI: 0.65-1.60). This study demonstrates that a single common mutation in the lipoprotein lipase gene is associated with elevated plasma triglycerides and reduced HDL cholesterol levels, whereby carriers, in particular women, seem to be predisposed to ischemic heart disease. It cannot be excluded, however, that male carriers of this substitution may represent a subset of low-HDL individuals without raised triglycerides not predisposed to ischemic heart disease.
Assuntos
Lipase Lipoproteica/genética , Mutação , Isquemia Miocárdica/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , HDL-Colesterol/sangue , Feminino , Heterozigoto , Homozigoto , Humanos , Masculino , Pessoa de Meia-Idade , Isquemia Miocárdica/etiologia , Fenótipo , Triglicerídeos/sangueRESUMO
Severe infections related to treatment are common in patients with multiple myeloma (MM). Genetic polymorphisms of the immune system may influence the risk of infections. Mannan-binding lectin (MBL) is part of the innate immune system, and individuals homozygous for wild-type MBL encoding gene (MBL2) have a well-functioning MBL pathway of complement activation, in contrast to individuals carrying one or two variant alleles. We evaluated 113 courses of high-dose melphalan and autologous stem cell transplantation (ASCT) in patients with MM. Patients homozygous for wild-type MBL2 had a significantly reduced risk of septicaemia during the ASCT procedure compared with patients carrying variant MBL2: Odds Ratio (OR) 0.19 (95% CI: 0.04-0.77), (P=0.02) in multivariate analysis. The risk of Common Toxicity Criteria grade 3-4 infections in general was not affected by wild-type MBL2: OR 1.20 (95% CI: 0.52-2.78), (P=0.67). The findings indicate that MBL to some extent protects against the most severe infections during ASCT.
Assuntos
Transplante de Células-Tronco Hematopoéticas/efeitos adversos , Infecções/etiologia , Lectina de Ligação a Manose/genética , Melfalan/efeitos adversos , Mieloma Múltiplo/complicações , Polimorfismo Genético/imunologia , Adulto , Idoso , Feminino , Humanos , Imunidade/genética , Infecções/genética , Masculino , Lectina de Ligação a Manose/imunologia , Melfalan/administração & dosagem , Pessoa de Meia-Idade , Mieloma Múltiplo/genética , Estudos Retrospectivos , Risco , Transplante AutólogoRESUMO
BACKGROUND: Cholesteryl ester transfer protein (CETP) mediates the transfer of cholesteryl ester from HDL in exchange for triglycerides in apolipoprotein B-containing lipoproteins. METHODS AND RESULTS: We studied 2 common mutations in CETP, A373P and R451Q, in 8467 healthy women and men from the Danish general population and in 1636 Danish women and men with ischemic heart disease. The prevalence of 373P and 451Q was 0.10 and 0.07, respectively, for heterozygous carriers and 0.003 and 0.002, respectively, for homozygous carriers. All carriers of the 451Q allele also carried the 373P allele. HDL cholesterol in female noncarriers, heterozygotes, and homozygotes of 373P was 1.74+/-0.01 (mean+/-SE), 1.62+/-0.02, and 1.38+/-0.09 mmol/L, respectively (ANOVA, P:<0.001). In men, equivalent values were 1.40+/-0.01, 1.26+/-0.02, and 1.19+/-0.09 mmol/L, respectively (ANOVA, P:<0.001). HDL cholesterol decreased similarly as a function of 451Q genotypes and all 373P/451Q genotype combinations. Furthermore, apolipoprotein AI and the HDL cholesterol/apolipoprotein AI ratio was also lower in carriers of either of these mutations for both sexes. Finally, the CETP genotype was not associated with risk of ischemic heart disease unless we adjusted for HDL cholesterol: female heterozygous and homozygous carriers versus noncarriers had 36% lower risk of ischemic heart disease (95% CI 4% to 57%); in male carriers, we observed a similar trend. CONCLUSIONS: The A373P/R451Q polymorphism in CETP is associated with decreases in HDL cholesterol of 0.12 to 0.36 mmol/L in women and 0.14 to 0.21 mmol/L in men and possibly with a paradoxical 36% decrease in the risk of ischemic heart disease in women.