Exploring the role of the WNT5A rs566926 polymorphism and its interactions in non-syndromic orofacial cleft: a multicenter study in Brazil

Abstract Associations between the WNT5A rs566926 variant and non-syndromic orofacial cleft (NSOC) have been reported in different populations. Objective This study aimed to investigate the role of the rs566926 single nucleotide polymorphism (SNP) in WNT5A and its interactions with SNPs in BMP4, FGFR1, GREM1, MMP2, and WNT3 in the occurrence of NSOC in a Brazilian population. Methodology A case-control genetic association study was carried out involving participants from four regions of Brazil, totaling 801 patients with non-syndromic cleft lip with or without cleft palate (NSCL±P), 273 patients with cleft palate only (NSCPO), and 881 health volunteers without any congenital condition (control). Applying TaqMan allelic discrimination assays, we evaluated WNT5A rs566926 in an ancestry-structured multiple logistic regression analysis, considering sex and genomic ancestry as covariates. Interactions between rs566926 and variants in genes involved in the WNT5A signaling pathway (BMP4, FGFR1, GREM1, MMP2, and WNT3) were also explored. Results WNT5A rs566926 was significantly associated with an increased risk of NSCL±P, particularly due to a strong association with non-syndromic cleft lip only (NSCLO), in which the C allele increased the risk by 32% (OR: 1.32, 95% CI: 1.04-1.67, p=0.01). According to the proportions of European and African genomic ancestry, the association of rs566926 reached significant levels only in patients with European ancestry. Multiple interactions were detected between WNT5A rs566926 and BMP4 rs2071047, GREM1 rs16969681 and rs16969862, and FGFR1 rs7829058. Conclusion The WNT5A rs566926 polymorphism was associated with NSCL±P, particularly in individuals with NSCLO and high European ancestry. Epistatic interactions involving WNT5A rs566926 and variants in BMP4, GREM1, and FGFR1 may contribute to the risk of NSCL±P in the Brazilian population.

Genetic Polymorphisms in COL1A2 gene and the Risk of Tendinopathy: Case-Control Study / Polimorfismos genéticos no gene COL1A2 eo risco de tendinopatia: Estudo de caso-controle

Abstract Objective To evaluate the influence of polymorphisms on genes encoding type I collagen and the genetic susceptibility of tendinopathy. Methodology Case-control study involving 242 Brazilian athletes from different sports modalities (55 cases of tendinopathy and 187 controls). The polymorphisms COLIAI (rs1107946) and COLIA2 (rs412777, rs42524, and rs2621215) were analyzed by theTaqMansystem. Odds ratio(OR)withtheir 95% confidence intervals (CIs) were calculated using a nonconditional logistic regression model. Results The mean age was 24.0 ± 5.6 years old and 65.3% were men. Of the 55 cases of tendinopathy, 25.4% had > 1 affected tendon, the most frequent being patellar (56.3%), rotator cuff (30.9%) and elbow or hand flexors (30.9%). Age and amount of time of sports practice were associated with a higher chance of presenting tendinopathy (5 and 8 times, respectively). The frequency of variant alleles in control and case patients, respectively, was: COLIAI rs1107946 24.0 and 29.6%; COLIA2 rs412777 36.1 and 27.8%; rs42524 17.5 and 25.9%; and rs2621215 21.3 and 27.8%. After adjusting for confounding factors (age and years of sports practice), COLIA2 rs42524and rs2621215 polymorphisms were associated with increased risk of tendinopathy (OR = 5.5; 95% CI = 1.2-24.6 and OR = 3.9; IC95% = 1.1-13.5, respectively). The haplotype COLIA2 CGT was associated with low risk for disease development (OR = 0.5; 95%CI = 0.3-0.9). Conclusion Age (≥ 25 years old), time of sports practice (≥ 6years) and polymorphisms in the COLIA2 gene increased the risk of developing tendinopathy.

Resumo Objetivo Avaliar a influência de polimorfismos nos genes que codificam o colágeno tipo I e a suscetibilidade genética da tendinopatia. Metodologia Estudo caso-controle envolvendo 242 atletas brasileiros de diferentes modalidades esportivas (55 casos de tendinopatia e 187 controles). Os polimorfismos COL1A1 (rs1107946) e COL1A2 (rs412777, rs42524 e rs2621215) foram analisados pelo sistema TaqMan. As razões de chance (OR) com seus intervalos de confiança (IC) de 95% foram calculadas usando um modelo de regressão logística não-condicional. Resultados A média de idade foi de 24,0 ± 5,6 anos e 65,3% eram homens. Dos 55 casos de tendinopatia, 25,4% apresentaram mais de um tendão acometido, sendo os maisfrequentesopatelar(56,3%),omanguitorotador(30,9%)eodocotoveloou flexores das mãos (30,9%). A idade e o tempo de prática esportiva foram associados a uma maior chance de apresentar tendinopatia (5 e 8 vezes, respectivamente). A frequência dos alelos variantes nos controles e casos, respectivamente, foi: COL1A1 rs1107946 24,0 e 29,6%; COL1A2 rs412777 36,1 e 27,8%; rs42524 17,5 e 25,9%; e rs2621215 21,3 e 27,8%. Após ajuste pelos fatores de confundimento (idade e anos de práticas esportiva), os polimorfismos COL1A2 rs42524 e rs2621215 foram associados a um risco aumentado de tendinopatia (OR = 5,5; IC95% = 1,2-24,6 e OR = 3,9; IC95% = 1,1-13,5, respectivamente). O haplótipo COL1A2 CGT foi associado a um baixo risco para desenvolvimento da doença (OR = 0,5; IC95% = 0,3-0,9). Conclusão Aidade (> 25 anos), o tempo de prática esportiva (> 6 anos) e polimorfismos no gene COL1A2 aumentaram o risco de desenvolvimento da tendino-patia.

Human beta-defensin 1 circulating level and gene polymorphism in non-segmental vitiligo Egyptian patients

Abstract Background: Vitiligo is an acquired depigmented skin disorder. It has a genetic and autoimmune background. Human beta defensin-1(HBD-1) plus its gene polymorphism were linked to some autoimmune disorders. Objectives: To elucidate the possible role of HBD-1 in the pathogenesis of non-segmental vitiligo (NSV) through evaluation of HBD-1 serum levels and its single nucleotide polymorphism (SNP) in patients having NSV, in addition, to correlating the results with the extent of vitiligo in those patients. Methods: A current case-control study included 50 patients having NSV and 50 controls. The authors used Vitiligo Area Scoring Index (VASI) score to assess vitiligo severity and laboratory investigations to assess serum HBD-1 level using ELISA and defensin-beta1 (DEFB1) SNP using polymerase chain reaction-restriction fragment length polymorphism (PCR-RFLP). Results: There were significantly lower HBD-1 serum levels in NSV cases than in controls (p < 0.001). There was a significant predominance of GG DEFB1 genotype and G allele in NSV patients in comparison to controls (p < 0.001). The levels of serum HBD-1 and DEFB1 genotypes were not associated or correlated significantly with any of the personal and clinical parameters of vitiligo patients. Study limitations: The small sample size. Conclusions: DEFB1 gene polymorphism (GG genotype and G allele) may modulate vitiligo risk and contribute to vitiligo development in Egyptian populations. Decreased circulating HBD-1 levels might have an active role in vitiligo etiopathogenesis that could be mediated through its possible anti-inflammatory effects.

The role of IL10 and IL17 gene polymorphisms in treatment response in children and adolescents with severe asthma / O papel de polimorfismos dos genes IL10 e IL17 na resposta ao tratamento em crianças e adolescentes com asma grave

ABSTRACT Objective: To determine whether polymorphisms of the IL10 and IL17 genes are associated with severe asthma control and bronchodilator reversibility in children and adolescents with severe asthma. Methods: This was a cross-sectional study, nested within a prospective cohort study of patients with severe asthma. Two outcomes were evaluated: asthma control and bronchodilator reversibility. We extracted DNA from peripheral blood and genotyped three single nucleotide polymorphisms: rs3819024 and rs2275913 in the IL17A gene; and rs3024498 in the IL10 gene. For the association analyses, we performed logistic regression in three genetic models (allelic, additive, and dominant). Results: The rs3024498 C allele in the IL10 gene was associated with failure to achieve asthma control despite regular treatment (p = 0.02). However, the G allele of the IL17A rs3819024 polymorphism was associated with failure to respond to stimulation with a b2 agonist. The rs2275913 polymorphism of the IL17A gene showed no relationship with asthma control or bronchodilator reversibility. Conclusions: In pediatric patients with severe asthma, the IL10 polymorphism appears to be associated with failure to achieve clinical control, whereas the IL17A polymorphism appears to be associated with a worse bronchodilator response. Knowledge of the involvement of these polymorphisms opens future directions for pharmacogenetic studies and for the implementation of individualized therapeutic management of severe asthma in pediatric patients.

RESUMO Objetivo: Determinar se existe relação entre polimorfismos dos genes IL10 e IL17 e controle da asma grave e reversibilidade com broncodilatador em crianças e adolescentes com asma grave. Métodos: Estudo transversal, aninhado em um estudo prospectivo de coorte com pacientes com asma grave. Foram avaliados dois desfechos: controle da asma e reversibilidade com broncodilatador. Extraímos DNA do sangue periférico e genotipamos três polimorfismos de nucleotídeo único: rs3819024 e rs2275913 no gene IL17A e rs3024498 no gene IL10. Para as análises de associação, realizamos regressão logística em três modelos genéticos (alélico, aditivo e dominante). Resultados: O alelo C do polimorfismo rs3024498 do gene IL10 apresentou relação com asma que permaneceu descontrolada mesmo com tratamento regular (p = 0,02). No entanto, o alelo G do polimorfismo rs3819024 do gene IL17A apresentou relação com ausência de resposta ao estímulo com b2-agonista. O polimorfismo rs2275913 do gene IL17A não apresentou relação com controle da asma ou reversibilidade com broncodilatador. Conclusões: Em pacientes pediátricos com asma grave, o polimorfismo do gene IL10 parece estar relacionado com ausência de controle clínico, ao passo que o polimorfismo do gene IL17A parece estar relacionado com pior resposta ao broncodilatador. O conhecimento a respeito do envolvimento desses polimorfismos abre perspectivas futuras para estudos farmacogenéticos e para a implantação de manejo terapêutico individualizado da asma grave em pacientes pediátricos.

Investigation of allele frequencies of polymorphic variants in genes that are related to polycystic ovary syndrome

SUMMARY OBJECTIVE: Polycystic ovary syndrome is a hormonal disorder that normally affects women of reproductive age in the range of 18-44 years. This study aimed to investigate the allelic frequencies of two polymorphisms, IRS rs18012781 and INSR rs1799817, which are suspected to be involved in polycystic ovary syndrome. METHODS: The samples were obtained from the patients admitted to the Near East University Hospital, Department of Gynecology and Obstetrics. The samples were divided into two groups: control and polycystic ovary syndrome groups. Blood samples were collected from 55 women in the control group and 65 samples from the patient group. DNA from whole blood was obtained. The allelic frequencies of single-nucleotide polymorphisms were determined using real-time PCR. Results were presented as the heterozygous and homozygous state of the single-nucleotide polymorphisms. RESULTS: There were no significant differences in the allelic frequencies of the single-nucleotide polymorphisms between the patient and control groups. Further statistical analysis investigating the INSR Tm using the Mann-Whitney U test value revealed that there was no difference in the homozygous and heterozygous state of INSR rs1799817. The result of this study showed that there was no statistically significant difference between the allelic frequencies of IRS1 rs1801278 and INSR rs1799817 between the patient and control groups. CONCLUSION: These single-nucleotide polymorphisms do not seem to modify the risk of polycystic ovary syndrome, and they cannot be used as a marker in clinical circumstances to evaluate the possible occurrence of polycystic ovary syndrome.

Polymorphisms rs2010963 and rs833061 of the VEGF gene in polycystic ovary syndrome

SUMMARY OBJECTIVE: The polycystic ovary syndrome is the most common endocrine disorder, characterized by the dysregulation of ovarian angiogenesis. This alteration can be related to changes in the activities of the vascular endothelial growth factor (VEGF) gene. Single-nucleotide polymorphisms have been observed in the promoter, intronic, and untranslated regions of the VEGF gene, and several studies have suggested that these polymorphisms may be associated with the risk of polycystic ovary syndrome. This study aimed to investigate the association between rs2010963 and rs833061 polymorphisms and haplotypes of VEGF in the etiology of polycystic ovary syndrome. METHODS: A total of 210 women, 102 diagnosed with polycystic ovary syndrome and 108 controls, participated in this study. The genotyping of the samples was performed by PCR-RFLP and real-time PCR for rs2010963 and rs833061 polymorphisms, respectively. The statistical analyses were performed by the chi-square test and logistic regression model. RESULTS: The clinical characteristics of the patients showed that 75.8% of the patients did not become pregnant, 36.3% had a family history of polycystic ovary syndrome, 58.6% were obese, and about 60% had clinical characteristics of hyperandrogenism. There were no associations between the distribution of rs2010963 (OR 1.24; 95%CI 0.60-2.57; p=0.56) and rs833061 (OR 0.78; 95%CI 0.32-1.92; p=0.59) in patients and controls. CONCLUSIONS: The patients with polycystic ovary syndrome have similar rates of VEGF polymorphisms rs2010963 and rs833061 on the general population.

Thylenetetrahydrofolate reductase gene polymorphisms and susceptibility to esophageal cancer: a case-control study / Polimorfismos do gene metilenotetrahidrofolato redutase e suscetibilidade ao câncer de esôfago: estudo caso-controle

ABSTRACT BACKGROUND: The enzyme methylenetetrahydrofolate reductase is engaged in DNA synthesis through folate metabolism. Inhibiting the activity of this enzyme increases the susceptibility to mutations, and damage and aberrant DNA methylation, which alters the gene expression of tumor suppressors and proto-oncogenes, potential risk factors for esophageal cancer. AIMS: This study aimed to investigate the association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and susceptibility to esophageal cancer, by assessing the distribution of genotypes and haplotypes between cases and controls, as well as to investigate the association of polymorphisms with clinical and epidemiological characteristics and survival. METHODS: A total of 109 esophageal cancer patients who underwent esophagectomy were evaluated, while 102 subjects constitute the control group. Genomic DNA was isolated from the peripheral blood buffy coat followed by amplification by polymerase chain reaction and real-time analysis. Logistic regression was used to assess associations between polymorphisms and the risk of developing esophageal cancer. RESULTS: There was no association for methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and haplotypes, with esophageal cancer susceptibility. Esophageal cancer patients carrying methylenetetrahydrofolate reductase 677TT polymorphism had higher risk of death from the disease. For polymorphic homozygote TT genotype, the risk of death significantly increased compared to wild-type genotype methylenetetrahydrofolate reductase 677CC (reference) cases (p=0.045; RR=2.22, 95%CI 1.02-4.83). CONCLUSIONS: There was no association between methylenetetrahydrofolate reductase 677C>T and methylenetetrahydrofolate reductase 1298A>C polymorphisms and esophageal cancer susceptibility risk. Polymorphic homozygote genotype methylenetetrahydrofolate reductase 677TT was associated with higher risk of death after surgical treatment for esophageal cancer.

RESUMO RACIONAL: A enzima metilenotetrahidrofolato redutase está envolvida na síntese de DNA através do metabolismo do folato. A inibição da sua atividade aumenta a suscetibilidade a mutações, danos e metilação aberrante do DNA, o que altera a expressão gênica de supressores tumorais e proto-oncogenes, potenciais fatores de risco para câncer de esôfago. OBJETIVOS: Investigar a associação entre os polimorfismos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C e a suscetibilidade ao câncer de esôfago, avaliando a distribuição de genótipos e haplótipos entre casos e controles, bem como investigar a associação de polimorfismos com características clínicas, epidemiológicas e sobrevida. MÉTODOS: Avaliaram-se 109 pacientes com câncer de esôfago submetidos à esofagectomia, enquanto 102 indivíduos constituaram o grupo controle. O DNA genômico do sangue periférico foi isolado e submetido à amplificação por reação em cadeia da polimerase em tempo real. A associação entre os polimorfismos e o risco de desenvolver câncer de esôfago foi avaliada por regressão logística. RESULTADOS: Não houve associação dos polimorfismos e haplótipos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C com a suscetibilidade ao câncer de esôfago. Pacientes com câncer de esôfago portadores do polimorfismo metilenotetrahidrofolato redutase 677TT apresentaram maior risco de morte pela doença. Para o genótipo TT homozigoto polimórfico, o risco de morte aumentou significativamente em comparação com os casos do genótipo selvagem metilenotetrahidrofolato redutase 677CC (referência) (p=0,045; RR=2,22, IC95% 1,02-4,83). CONCLUSÕES: Não houve associação entre os polimorfismos metilenotetrahidrofolato redutase 677C>T e metilenotetrahidrofolato redutase 1298A>C e o risco de suscetibilidade ao câncer de esôfago. O genótipo homozigoto polimórfico metilenotetrahidrofolato redutase 677TT associou-se a um maior risco de óbito após tratamento cirúrgico para câncer de esôfago.

Is -94ins/delattg polymorphism in the nuclear factor kappa-b1 gene (nfkb1) associated with necrotizing enterocolitis? / Polimorfismo -94ins/delattg no gene do fator nuclear kappa-b1 (nfkb1) está associado à enterocolite necrosante?

ABSTRACT BACKGROUND: Abnormalities in the different stages of the intestinal maturation process cause metabolic and molecular changes. Among the genetic alterations associated with necrotizing enterocolitis, the -94ins/delATTG polymorphism in NFKB1 gene leads to unregulated activation of the NFKB protein due to an increase in the inherent pro-inflammatory state of the premature intestine. AIMS:To determine the prevalence of the -94ins/delATTG polymorphism in NFKB1 gene in neonates with and without necrotizing enterocolitis. METHODS:This is a case-control study, in which 25 neonates were evaluated as the case group and 50 neonates as the control group, of both genders. DNA was extracted from peripheral blood leukocytes, and the site encompassing the polymorphism was amplified by molecular techniques (polymerase chain reaction/polymorphism in restriction fragment length). RESULTS:Necrotizing enterocolitis was diagnosed in 25 (33%) neonates and, of these, 3 (12%) died. Male gender was more prevalent in both groups (p=0.1613): cases (52%) and controls (62%). Moderate and extreme preterm newborns were predominant in both groups: cases (80%) and controls (88%) (p=0.3036). Low birth weight and extremely low birth weight newborns were the most prevalent in cases (78%), and very low birth weight and extremely low birth weight were the most prevalent in controls (81%) (p=0.1073). Clinical treatment was successful in 72%, and hospital discharge was achieved in 88% of newborns with NEC. The -94ins/delATTG polymorphism in NFKB1 gene was not identified in all the 150 alleles analyzed (100%). CONCLUSIONS:The absence of the -94ins/delATTG polymorphism in NFKB1 gene in newborns with and without necrotizing enterocolitis does not rule out the possibility of alterations in this and/or in other genes in newborns with this condition, which reinforces the need for further research.

RESUMO RACIONAL:Anormalidades nas diferentes fases do processo de maturação intestinal causam alterações metabólicas e moleculares. Dentre as alterações genéticas associadas à enterocolite necrotizante, o polimorfismo -94ins/delATTG no gene NFKB1 leva à ativação desregulada da proteína NFKB devido ao aumento do estado pró-inflamatório inerente ao intestino prematuro. OBJETIVOS:Determinar a prevalência do polimorfismo -94ins/delATTG no gene NFKB1 em neonatos com e sem enterocolite necrotizante. MÉTODOS: Trata-se de um estudo caso-controle, no qual foram avaliados 25 neonatos como grupo caso e 50 neonatos como grupo controle, de ambos os sexos. O DNA foi extraído de leucócitos do sangue periférico e o sítio que engloba o polimorfismo foi amplificado por técnicas moleculares (reação em cadeia da polimerase/polimorfismo no comprimento do fragmento de restrição). RESULTADOS: Enterocolite necrosante foi diagnosticada em 25 (33%) neonatos e, destes, 3 (12%) foram a óbito. O gênero masculino foi mais prevalente em ambos os grupos (p=0,1613): casos (52%) e controles (62%). Os prematuros moderados e extremos foram predominantes em ambos os grupos: casos (80%) e controles (88%) (p=0,3036). Recém-nascidos de baixo peso e extremo baixo peso foram os mais prevalentes nos casos (78%) e de muito baixo peso e extremo baixo peso foram os mais prevalentes nos controles (81%) (p=0,1073). O tratamento clínico foi bem-sucedido em 72% e a alta hospitalar foi obtida em 88% dos recém-nascidos com enterocolite necrotizante. O polimorfismo -94ins/delATTG no gene NFKB1 não foi identificado em todos os 150 alelos analisados (100%). CONCLUSÕES: A ausência do polimorfismo -94ins/delATTG no gene NFKB1 em recém-nascidos com e sem enterocolite necrosante não afasta a possibilidade de alterações neste e/ou em outros genes em recém-nascidos com esta condição, o que reforça a necessidade de novas pesquisas.

Genetic Polymorphism of 16 X-STR Loci in Xinjiang Uygur Population / 法医学杂志

OBJECTIVES@#To study the genetic polymorphism and population genetic parameters of 16 X-STR loci in Xinjiang Uygur population.@*METHODS@#The Goldeneye® DNA identification system 17X was used to amplify 16 X-STR loci in 502 unrelated individuals (251 females and 251 males). The amplified products were detected by 3130xl genetic analyzer. Allele frequencies and population genetic parameters were analyzed statistically. The genetic distances between Uygur and other 8 populations were calculated. Multidimensional scaling and phylogenetic tree were constructed based on genetic distance.@*RESULTS@#In the 16 X-STR loci, a total of 67 alleles were detected in 502 Xinjiang Uygur unrelated individuals. The allele frequencies ranged from 0.001 3 to 0.572 4. PIC ranged from 0.568 8 to 0.855 3. The cumulative discrimination power in females and males were 0.999 999 999 999 999 and 0.999 999 999 743 071, respectively. The cumulative mean paternity exclusion chance in trios and in duos were 0.999 999 997 791 859 and 0.999 998 989 000 730, respectively. The genetic distance between Uygur population and Kazakh population was closer, and the genetic distance between Uygur and Han population was farther.@*CONCLUSIONS@#The 16 X-STR loci are highly polymorphic and suitable for identification in Uygur population, which can provide a powerful supplement for the study of individual identification, paternity identification and population genetics.

UGT1A1 gene polymorphisms in patients with Gilbert syndrome and Crigler-Najjar syndrome type Ⅱ / 临床肝胆病杂志

Objective To investigate the differences in UGT1A1 gene mutation sites, haplotypes, and diplotypes between patients with Gilbert syndrome (GS) and those with Crigler-Najjar syndrome type Ⅱ (CN-2). Methods A retrospective analysis was performed for the clinical data of 138 patients with GS or CN-2 who attended Beijing YouAn Hospital, Capital Medical University, from January 1, 2010 to December 31, 2019, with 109 patients in the GS group and 29 patients in the CN-2 group, and the differences in mutation sites were analyzed between the two phenotypes. The Mann-Whitney U test was used for comparison of continuous data between two groups, and the chi-square test or the Fisher's exact test was used for comparison of categorical data between groups. SNPStats software was used to perform linkage disequilibrium (LD) and haplotype analyses of mutation sites. Strong LD was defined as both | D ′| and r 2 > 0.8, and moderate LD was defined as | D ′| > 0.8 and r 2 > 0.4. Results UGT1A1 gene detection was performed for all patients, and mutations mainly included -3279T > G mutation (104 patients, 75.36%) and -3152G > A mutation (82 patients, 59.42%) in the upstream promoter PBREM region, a promoter TATA box TA insertion mutation (88 patients, 63.77%), and c.211G > A mutation in Exon 1 of the coding region (66 patients, 47.83%). Compared with the CN-2 group, the GS group had a significantly higher proportion of PBREM region -3279T > G mutation (82.57% vs 48.28%, χ 2 =14.508, P A mutation (68.81% vs 24.14%, χ 2 =18.955, P (TA) 7 mutation (72.48% vs 31.03%, χ 2 =17.027, P 0.8, r 2 > 0.8) between (TA) 6 > (TA) 7 and -3152G > A and moderate LD (| D ′| > 0.8, r 2 > 0.4) between (TA) 6 > (TA) 7 and -3279T > G, between -3152G > A and -3279T > G, between (TA) 6 > (TA) 7 and c.211G > A, and between -3279T > G and c.211G > A. Haplotype frequency analysis showed that compared with the CN-2 group, the GS group had a significantly higher frequency of haplotype -3279G—-3152A—(TA) 7 (45.72% vs 17.24%, χ 2 =7.833, P =0.005) and significantly lower frequencies of c.1456G (4.10% vs 16.48%, χ 2 =4.873, P =0.027) and c.211A—c.1456G (1.86% vs 24.90%, χ 2 =15.210, P < 0.001). The diplotype analysis showed that diplotypes consisting of haplotype c.1456G or c.211A—c.1456G were associated with a higher level of total bilirubin (TBil). Conclusion There are differences in common mutation sites and major haplotypes of the UGT1A1 gene between patients with GS and those with CN-2, and the common diplotypes of CN-2 correspond to a higher level of TBil.

Genetic polymorphisms and their effects on the severity of silicosis in workers exposed to silica in Brazil / Polimorfismos genéticos e seus efeitos na gravidade da silicose em trabalhadores expostos à sílica no Brasil

ABSTRACT Objective: Silicosis is a pneumoconiosis characterized by fibrosis of the lung parenchyma caused by inhalation of silica particles. Genetic factors might play a role in the severity silicosis. We sought to evaluate the influence of polymorphisms in the ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1, and TNF genes on the severity of silicosis. Methods: Nine polymorphisms were genotyped by PCR in a sample of 143 patients with silicosis in the state of Rio de Janeiro, Brazil. Results: Fifty-seven patients (40%) were classified as having simple silicosis and 86 (60%) were classified as having complicated silicosis. The TT genotype of rs1800469 in the TGFB1 gene showed a protective effect for complicated silicosis (OR = 0.35; 95% CI, 0.14-0.92; p = 0.028) when compared with the other two genotypes (CC+CT). The polymorphic T allele of rs763110 in the FASLG gene (OR = 0.56; 95% CI, 0.31-0.99; p = 0.047), as well as a dominant model for the T allele (TT+CT: OR = 0.37; 95% CI, 0.15-0.96; p = 0.037), also showed a protective effect. When patients with simple silicosis despite having been exposed to silica for a longer time (> 44,229 hours) were compared with patients with complicated silicosis despite having been exposed to silica for a shorter time, the T allele of rs763110 in the FASLG gene (OR = 0.20; 95% CI, 0.08-0.48; p < 0.0001), as well as dominant and recessive models (OR = 0.06; 95% CI, 0.00-0.49; p = 0.01 and OR = 0.22; 95% CI, 0.06-0.77; p = 0.014, respectively), showed a protective effect against the severity of silicosis. Conclusions: It appears that rs1800469 polymorphisms in the TGFB1 gene and rs763110 polymorphisms in the FASLG gene are involved in the severity of silicosis. Given the lack of studies relating genetic polymorphisms to the severity of silicosis, these results should be replicated in other populations.

RESUMO Objetivo: A silicose é uma pneumoconiose caracterizada por fibrose do parênquima pulmonar causada por inalação de partículas de sílica. Fatores genéticos podem desempenhar um papel na gravidade da silicose. Nosso objetivo foi avaliar a influência de polimorfismos dos genes ACE, FAS, FASLG, NOS2, IL1RN, FAM13A, TGFB1 e TNF na gravidade da silicose. Métodos: Nove polimorfismos foram genotipados por meio de PCR em uma amostra composta por 143 pacientes com silicose no estado do Rio de Janeiro, Brasil. Resultados: A silicose foi classificada em simples em 57 (40%) dos pacientes e em complicada, em 86 (60%). O genótipo TT do polimorfismo rs1800469 do gene TGFB1 teve efeito protetor contra a silicose complicada (OR = 0,35; IC95%: 0,14-0,92; p = 0,028) em comparação com os outros dois genótipos (CC+CT). O alelo T polimórfico do polimorfismo rs763110 do gene FASLG (OR = 0,56; IC95%: 0,31-0,99; p = 0,047) e um modelo dominante do alelo T (TT+CT: OR = 0,37; IC95%: 0,15-0,96; p = 0,037) também tiveram efeito protetor. Quando se compararam os pacientes que tinham silicose simples com um tempo maior de exposição à sílica (> 44.229 horas) àqueles que tinham silicose complicada com um tempo menor de exposição à sílica, o alelo T do polimorfismo rs763110 do gene FASLG (OR = 0,20; IC95%: 0,08-0,48; p < 0,0001) e modelos dominantes e recessivos (OR = 0,06; IC95%: 0,00-0,49; p = 0,01 e OR = 0,22; IC95%: 0,06-0,77; p = 0,014, respectivamente) tiveram efeito protetor contra a gravidade da silicose. Conclusões: Polimorfismos rs1800469 do gene TGFB1 e polimorfismos rs763110 do gene FASLG parecem estar envolvidos na gravidade da silicose. Como há poucos estudos que tenham estabelecido relações entre polimorfismos genéticos e a gravidade da silicose, esses resultados devem ser replicados em outras populações.

Determinantes do ganho rápido de peso e a sua influência no estado nutricional infantil / Determinants of rapid weight gain and its influence on child nutritional status

A ocorrência do ganho rápido de peso infantil (GRP) pode estar associado a desfechos de peso ao longo do ciclo de vida. Os fatores de risco para o GRP incluem preditores maternos, gestacionais, infantis e contextuais e reforça-se a importância de avaliar também a hipótese sobre a possível associação com polimorfismos genéticos. Objetivo: Testar a associação entre ganho rápido de peso na infância, polimorfismos genéticos e estado nutricional de crianças. Metodologia (Manuscrito 1): Estudo transversal com bases de dados de inquéritos populacionais em crianças com peso ao nascer adequado no Brasil, Bolívia, Colômbia e Peru para estimar a associação entre GRP e excesso de peso em crianças de 0 a 5 anos. Foram estimadas as prevalências, odds ratio e IC95% por regressão logística multivariada. Metodologia (Manuscrito 2): Estudo de coorte com crianças do PROLAC no município de Viçosa, Minas Gerais, do nascimento aos seis meses. Foi obtido material biológico por swab bucal para análises genéticas de polimorfismos dos genes FTO, MC4R e APOA5. Considerouse GRP quando a diferença (subtração) de escore-z de peso para idade (P/I) era >+0,67 entre duas avaliações. Na análise exploratória das curvas da taxa de incidência acumulada de GRP utilizou-se o estimador de Kaplan-Meier (failure), bem como o teste Log-Rank para realizar as comparações entre os grupos de interesse. Para estimar a razão de riscos utilizou-se o modelo semi-paramétrico de Cox e para verificar a qualidade do ajuste do modelo proposto foram utilizados os resíduos generalizados de Cox-Snell. Metodologia (Manuscrito 3): Estudo de coorte com 267 crianças. As crianças tinham que ter ao menos 3 avaliações antropométricas, ou seja, ao nascer, entre o nascimento e seis meses de vida e entre 4 e 7 anos de idade, e foram divididas em grupo de acordo com a presença ou ausência do GRP, diagnosticado se a diferença de escore-z de P/I peso para idade foi > +0,67 entre duas avaliações. Para analisar a trajetória da média de IMC infantil foi utilizada a função Longitudinal Analyses Data Plots, para comparação entre as médias de IMC dos grupos em cada tempo foi aplicado uma ANOVA de dois fatores e para as comparações múltiplas foi utilizado o teste Bonferroni. Resultados (Manuscrito 1): As chances de excesso de peso em crianças com GRP, ajustado por amamentação, foram de 6,1 vezes, 4,4 vezes, 6,7 vezes e 12,2 vezes quando comparado às crianças sem GRP no Brasil, Bolívia, Colômbia e Peru, respectivamente. Resultados 13 (Manuscrito 2): A porcentagem de crianças com GRP foi 31,84% ao longo do estudo e a taxa de incidência foi estimada em 2,31 casos/1000 pessoas-dia. Apresentaram maior risco de GRP as crianças que nasceram com peso <3000g e cujas mães que apresentaram sobrepeso ou obesidade pré-gestacional. Resultados (Manuscrito 3): As crianças com GRP apresentaram significativamente maiores níveis da média de IMC ao longo da trajetória. Conclusões: Não foi possível demostrar associação entre os polimorfismos genéticos e GRP pelo menos na infância, porém o peso ao nascer inadequado e o alto peso pré-gestacional materno se associaram significativamente ao GRP. O GRP foi associado a um maior risco de desfechos de peso aferidos por meio de índices de massa corporal. Dado o impacto do GRP na trajetória da média de IMC ao longo da infância e no excesso de peso infantil, faz-se importante os cuidados desde o pré-natal, pós-parto e puericultura nos primeiros anos de vida da criança.

The occurrence of rapid infant weight gain (RWG) may be associated with weight outcomes throughout the life cycle. Risk factors for RWG include maternal, gestational, infant and contextual predictors and the importance of also evaluating the hypothesis about the possible association with genetic polymorphisms is reinforced. Objective To test the association between RWG, genetic polymorphisms and children's nutritional status Methodology (Manuscript 1): Cross-sectional study with databases of population surveys in children with adequate birth weight in Brazil, Bolivia, Colombia and Peru to estimate the association between RWG and excess weight in children aged 0 to 5 years. Prevalence, odds ratio and 95%CI were estimated by multivariate logistic regression. Methodology (Manuscript 2): Cohort study with children from birth to six months of PROLAC in the municipality of Viçosa, Minas Gerais. Biological material was obtained by oral swab for genetic analysis of FTO, MC4R and APOA5 gene polymorphisms. RWG was considered when the difference of weight-for-age (W/A) z-score was >+0.67 between two evaluations. In the exploratory analysis of the curves of the cumulative incidence rate of RWG, the Kaplan-Meier estimator (failure) was used, as well as the Log-Rank test to make comparisons between the groups of interest. The hazard ratio was estimated using the Cox semi-parametric model. Methodology (Manuscript 3): Cohort study with 267 children. Children had to have at least 3 anthropometric assessments, that is, at birth, between birth and six months of life and between 4 and 7 years of age, and were divided into groups according to the presence or absence of RWG, diagnosed if the difference in weight-for-age (W/A) z-score was > +0.67 between two evaluations. The Longitudinal Analyzes Data Plots function was used to analyze the trajectory of the child's BMI mean, to compare the child's BMI mean of the groups at each time point a two-way ANOVA was applied and the Bonferroni test was used for multiple comparisons. Results (Manuscript 1): The odds of overweight in children with RWG, adjusted for breastfeeding, were 6.1 times, 4.4 times, 6.7 times, and 12.2 times in Brazil, Bolivia, Colombia and Peru, respectively, when compared to children without RWG. Results (Manuscript 2): The percentage of children with RWG was 31.84% throughout the study and the incidence rate was estimated at 2.31 cases/1000 person-days. Children who were born weighing <3000g and 15 whose mothers were overweight or obese pre-pregnancy presented a higher risk of RWG. Results (Manuscript 3): Children with GRP had significantly higher mean BMI levels along the trajectory. Conclusions: It was not possible to demonstrate an association between genetic polymorphisms and GRP, at least in childhood, but inadequate birth weight and high maternal pre-pregnancy weight were significantly associated with RWG. RWG was associated with a higher risk of weight outcomes measured using body mass index. Given the impact of RWG on the trajectory of child's BMI mean throughout childhood and on childhood excess weight, care from prenatal, postpartum and childcare in the first years of a child's life is important.

Association between beta-2 adrenergic receptor variants and clinical outcomes in children and adolescents with acute asthma

ABSTRACT Objective To investigate whether different genotypes of p.Arg16Gly, p.Gln27Glu, p.Arg19Cys and p.Thr164Ile variants interfere in response to treatment in children and adolescents with moderate to severe acute asthma. Methods This sample comprised patients aged 2 to 17 years with a history of at least two wheezing episodes and current moderate to severe asthma exacerbation. All patients received multiple doses of albuterol and ipratropium bromide delivered via pressurized metered-dose inhaler with holding chamber and systemic corticosteroids. Hospital admission was defined as the primary outcome. Secondary outcomes were changes in forced expiratory volume in the first second after 1 hour of treatment, and for outpatients, length of stay in the emergency room. Variants were genotyped by sequencing. Results A total of 60 patients were evaluated. Hospital admission rates were significantly higher in carriers of the genotype AA relative to those with genotype AG or GG, within the p.Arg16Gly variant (p=0.03, test χ2, alpha=0.05). Secondary outcomes did not differ between genotypes. Conclusion Hospital admission rates were significantly higher among carriers of the genotype AA within the p.Arg16Gly variant. Trial registration: ClinicalTrials.gov: NCT01323010

Influence of the presence of mannose-binding lectin polymorphisms on the occurrence of leishmaniasis: a systematic review and meta-analysis

Abstract Background Leishmaniasis is caused by an intracellular protozoan of the Leishmania genus. Mannose-binding lectin (MBL) is a serum complement protein and recognizes lipoprotein antigens in protozoa and the bacterial plasma membrane. Nucleotide variants in the promoter region and exon 1 of the MBL gene can influence its expression or change its molecular structure. Objective To evaluate, through a systematic review, case-control studies of the genetic association of variants in the MBL2 gene and the risk of developing leishmaniasis. Methods This review carried out a search in PubMed, Science Direct, Cochrane Library, Scopus and Lilacs databases for case-control publications with six polymorphisms in the mannose-binding Lectin gene. The following strategy was used: P = Patients at risk of leishmaniasis; I = Presence of polymorphisms; C = Absence of polymorphisms; O = Occurrence of leishmaniasis. Four case/control studies consisting of 791 patients with leishmaniasis and 967 healthy subjects (Control) are included in this meta-analysis. The association of variants in the mannose-binding Lectin gene and leishmaniasis under the allelic genetic model, -550 (Hvs. L), -221 (X vs. Y), +4 (Q vs. P), CD52 (A vs. D), CD54 (A vs. B), CD57 (A vs. C) and A/O genotype (A vs. O) was evaluated. International Prospective Register of Systematic Reviews (PROSPERO): CRD42020201755. Results The meta-analysis results for any allelic genetic model showed no significant association for the variants within the promoter, the untranslated region, and exon 1, as well as for the wild-type A allele and mutant allele O with leishmaniasis. Study limitations Caution should be exercised when interpreting these results, as they are based on a few studies, which show divergent results when analyzed separately. Conclusions This meta-analysis showed a non-significant association between the rs11003125, rs7096206, rs7095891, rs5030737, rs1800450, and rs1800451 polymorphisms of the Mannose-binding Lectin gene and leishmaniasis in any allelic and heterogeneous evaluation.

Analysis of GLT6D1 and CDKN2BAS gene polymorphisms in Brazilian patients with advanced periodontitis

Abstract Gene polymorphisms can predispose to periodontal disease, as demonstrated by the well-documented association between aggressive periodontitis and single nucleotide polymorphisms (SNPs) such as rs153745 in the GLT6D1 gene and rs3217992 in the CDKN2BAS gene. The purpose of this study was to evaluate the presence of these SNPs in Brazilian patients with advanced periodontitis (stages III/IV, Grade B/C) vs. healthy controls. A total of 100 patients with periodontitis (Group BC) were enrolled. Of these, 51 patients were classified as stage III and 49 patients were classified as stage IV, and 52 were Grade B (Group B) and 48 were Grade C (Group C). The control Group consisted of 61 healthy subjects. DNA samples extracted from buccal epithelial cells were used to genotype the SNPs rs1537415 (GLT6D1) and rs3217992 (CDKN2BAS) by real-time quantitative PCR. No significant differences in polymorphism frequency were found between the control Group and each of the patient groups (BC, B, or C), and Group B did not differ from Group C. In conclusion, the evaluated SNPs had no significant influence on the prevalence of periodontal disease in the sampled Brazilian population.

Detección del polimorfismo p.K952L en pacientes cubanos con la enfermedad de Wilson

RESUMEN Fundamento La enfermedad de Wilson es una entidad rara con patrón de herencia autosómico recesivo, a causa de las mutaciones en el gen ATP7B, lo cual provoca la acumulación de cobre en tejidos y órganos. En la literatura se informan más de 800 polimorfismos. Objetivo identificar el polimorfismo p.K952L en los pacientes cubanos con diagnóstico clínico presuntivo de enfermedad de Wilson. Métodos se realizó un estudio descriptivo, en el Centro Nacional de Genética Médica y el Instituto Nacional de Gastroenterología, que incluyó 35 pacientes con diagnóstico clínico de la enfermedad de Wilson. La extracción del ADN fue por la técnica de precipitación salina; y la amplificación del fragmento de interés, mediante la técnica de Reacción en Cadena de la Polimerasa. Además, se empleó la técnica de Polimorfismo Conformacional de Simple Cadena para la determinación de los cambios conformacionales y la presencia del polimorfismo p.K952L. Resultados en el exón 12 se identificaron los cambios conformacionales denominados b y c, que correspondieron al polimorfismo p.K952L en estado heterocigótico y homocigótico, respectivamente. La frecuencia alélica del polimorfismo p.K952L fue de 38,6 %. Las manifestaciones más frecuentes en los pacientes que presentaron este polimorfismo fueron las hepáticas. Conclusión Se identificó el polimorfismo p.K952L en 21 pacientes cubanos con diagnóstico clínico de enfermedad de Wilson, lo cual posibilita ampliar los estudios moleculares por métodos indirectos.

ABSTRACT Background Wilson's disease is a rare entity with an autosomal recessive inheritance pattern, due to mutations in the ATP7B gene, which causes the accumulation of copper in tissues and organs. More than 800 polymorphisms are reported in the literature. Objective to identify the p.K952L polymorphism in Cuban patients with a presumptive clinical diagnosis of Wilson's disease. Methods a descriptive study was carried out at the Medical Genetics National Center and the Gastroenterology National Institute, which included 35 patients with a Wilson's disease clinical diagnosis. DNA extraction was by saline precipitation technique; and the amplification of the fragment of interest, by means of the Polymerase Chain Reaction technique. In addition, the Simple Chain Conformational Polymorphism technique was used to determine the conformational changes and the presence of the p.K952L polymorphism. Results in exon 12 the conformational changes called b and c were identified, which corresponded to the polymorphism p.K952L in the heterozygous and homozygous state, respectively. The allelic frequency of the p.K952L polymorphism was 38.6%. The most frequent manifestations in patients with this polymorphism were liver. Conclusion The p.K952L polymorphism was identified in 21 Cuban patients with a clinical diagnosis of Wilson's disease, which makes it possible to extend molecular studies by indirect methods.

Association of VDR gene Apal polymorphism with obesity in Iranian population / Asociación del polimorfismo Apal del gen receptor de vitamina D con la obesidad en una población iraní

Abstract | Introduction: Identifying obesity risk factors as a health problem facing communities is crucial given its complexity. The vitamin D receptor gene has been reported as a possible cause of this disease. Objective: To study the association of the VDR gene ApaI, BsmI, and Ta qI polymorphisms with obesity in an Iranian population. Materials and methods: We analyzed the genotypes of 348 obese (BMI≥30 kg/m2) and 320 non-obese people (BMI: 18.5-24.9 kg/m2) using PCR-RFLP. We measured FBS, TG, total cholesterol, and HDL and LDL cholesterol levels in an automatic biochemical analyzer. Results: We found significantly higher BMI, FBS, and TG levels in the obese group compared to the control. In the obese individuals, the frequency of genotype AA was 47.1% and that of the combined Aa+aa genotype, 52.9% while in the control group they were 30% and 70%, respectively (p=0.024, 95% confidence interval (CI)=1.100-3.933, odds ratio (OR)=2.08). A and a alleles frequencies for the ApaI polymorphism were statistically significant in the two groups (allele A vs. a; p=0.017). No significant relationship was observed between Ta qI genotypes and alleles in the control and obese subjects. Conclusion: We found that VDR ApaI (rs7975232 C/A) polymorphism appeared to be a risk factor for obesity. Especially, the A allele and the AA genotype in ApaI were associated with the obesity phenotypes.

Resumen | Introducción. La determinación de los factores de riesgo de la obesidad en la población iraní como problema de salud de la comunidad es crucial dada su complejidad. El gen receptor de la vitamina D (VDR) se ha mencionado como posible causante de dicha enfermedad. Objetivo. El objetivo del estudio fue investigar la asociación de los polimorfismos Apal, Bsml y Ta ql, con el gen VDR y la obesidad en una población iraní. Materiales y métodos. Se analizaron genotipos de 348 individuos obesos (BMI≥30 kg/m²) y 320 no obesos (BMI: 18,5-24,9 kg/m²) mediante reacción en cadena de la polimerasa y polimorfismos de longitud de fragmentos de restricción (PCR-RFLP). Para medir los niveles de glucemia en ayunas, tiroglobulina (TG), colesterol total, colesterol HDL y colesterol LDL, se utilizó un analizador bioquímico automático. Resultados. Los índices de masa corporal, glucemia en ayunas y TG fueron significantemente más elevados en el grupo de los obesos que en el de control. En los individuos obesos, la incidencia del genotipo AA fue de 47,1 % y la del genotipo combinado Aa+aaa fue de 52,9 %, en tanto que en el grupo de control estas cifras fueron, respectivamente, de 30 y 70 % (p=0,024; IC95% 1,100-3,933; la razón de probabilidades (OR) fue de 2,08. La frecuencia de los alelos "A" y "a" para el polimorfismo Apal en ambos grupos fue estadísticamente significativa (alelo A Vs. A; p=0,017). No se observó ninguna relación significativa entre los genotipos Ta ql y los alelos en los sujetos obesos y, tampoco, en los controles. Conclusión. El polimorfismo Apal del gen VDR (rs 7975232C/A) sería un factor de riesgo para la obesidad. El alelo y el genotipo AA en dicho polimorfismo se asociaron con los fenotipos de obesidad.

Expression of Vitamin D Receptor and Vitamin D Receptor Gene Polymorphisms (BsmI, FokI, and TaqI) in Patients with Pterygium / Expressão do gene do receptor da vitamina D e de seus polimorfismos (BsmI, FokI e TaqI) em pacientes com pterígio

ABSTRACT Purpose: This study aimed to determine the role of vitamin D receptor in the pathogenesis of pterygium. The vitamin D receptor eexpression levels in pterygium tissue, blood vitamin D levels, and frequency of selected vitamin D receptor gene polymorphisms (BsmI, FokI, and TaqI) were compared between patients with pterygium and healthy participants. Methods: The study included patients with pterygiumeee (n=50) and healthy volunteers (n=50). The serum vitamin D levels were measured for both groups. Immunohistochemical staining for vitamin D receptor ewas performed on sections obtained from the pterygium and adjacent healthy conjunctival tissues of the same individuals. The genomic existence of vitamin D receptor epolymorphisms (BsmI, FokI, and TaqI) were analyzed in DNA obtained from venous blood of participants using polymerase chain reaction and restriction fragment length polymorphism methods. Results: There was no difference found between the serum vitamin D levels of patients with pterygium and healthy controls. However, tissue expression of vitamin D receptor was higher in the pterygium endothelial cells of micro-vessels (p=0.002), subepithelial stromal (p=0.04), and intravascular inflammatory cells (p=0.0001), in comparison with the adjacent healthy conjunctival tissue. Moreover, while the BBtt haplotype was 2-fold higher, the bbTt haplotype was 2.5-fold lower, and the BbTT haplotype was 2.25-fold lower in the control group than in the pterygium group (p<0.001). Conclusions: Vitamin D serum levels did not differ between the healthy and pterygium groups. Vitamin D receptor expression was increased in the pterygium tissue versus the adjacent healthy tissue. However, vitamin D receptor polymorphism analysis in patients with pterygium did not reveal any significant difference in BsmI, FokI, or TaqI polymorphisms in comparison with the healthy volunteers.(AU)

RESUMO Objetivo: Determinar o papel do receptor da vitamina D na patogênese do pterígio. Os níveis de expressão do receptor da vitamina D no tecido do pterígio, os níveis sanguíneos de vitamina D e a frequência de alguns polimorfismos do gene do receptor da vitamina D (BsmI, FokI e TaqI) foram comparados entre pacientes com pterígio e participantes saudáveis. Métodos: Foram incluídos pacientes com pterígio (n=50) e voluntários saudáveis (n=50). Os níveis séricos de vitamina D foram medidos em ambos os grupos. Foi feita uma coloração imuno-histoquímica para o receptor da vitamina D em cortes obtidos do pterígio e dos tecidos conjuntivais saudáveis adjacentes dos mesmos indivíduos. A existência de polimorfismos do receptor da vitamina D (BsmI, FokI e TaqI) no genoma foi analisada em DNA obtido do sangue venoso dos participantes, usando métodos de Polymerase chain reaction (PCR) e RFLP. Resultados: Não foi observada nenhuma diferença entre os níveis séricos de vitamina D dos pacientes com pterígio e os dos controles saudáveis. Entretanto, a expressão tissular do receptor da vitamina D foi maior nas células endoteliais dos microvasos do pterígio (p=0,002), nas células estromais sub-epiteliais (p=0,04) e nas células inflamatórias intravasculares (p=0,0001), quando comparada à expressão no tecido conjuntival saudável adjacente. Além disso, embora o haplótipo BBtt tenha sido duas vezes mais frequente, o haplótipo bbTt foi 2,5 vezes menos frequente e o haplótipo BbTT foi 2,25 vezes menos frequente no grupo de controle do que no grupo com pterígio (p<0,001). Conclusões: Os níveis séricos de vitamina D não apresentaram diferenças entre o grupo de pessoas saudáveis e o com pterígio. A expressão do receptor da vitamina D mostrou-se maior no grupo com pterígio do que no tecido saudável adjacente. Entretanto, a análise dos polimorfismos do receptor da vitamina D nos pacientes com pterígio não revelou qualquer diferença significativa nos polimorfismos BsmI, FokI ou TaqI em comparação com os voluntários saudáveis.(AU)

Association between the L55M and Q192R polymorphisms of the paraoxonase-1 gene and age-related macular degeneration: a meta-analysis / Associação entre os polimorfismos L55M e Q192R do gene da paraoxonase1 e a degeneração macular relacionada à idade: uma meta-análise

ABSTRACT Purpose: Paraoxonase-1 activity is associated with age-related macular degeneration. Two polymorphisms (L55M and Q192R) were shown to increase paraoxonase-1 activity and have been implicated in the development of age-related macular degeneration. The results of studies that have examined these polymorphisms are conflicting, showing no effect, as well as increased or decreased risk. Therefore, this meta-analysis was conducted to determine the effect of these polymorphisms on age-related macular degeneration. Methods: PubMed, EBSCO, LILACS, and Scopus databases, as well as and the retrieved bibliographies of publications were searched for case-control studies that examined for paraoxonase-1 polymorphisms and age-related macular degeneration. Data were analyzed using the Comprehensive Meta-Analysis Version 2.2 and the NCSS Statistical Version 2020 software. Genotype distributions were extracted and, depending on the level of heterogeneity, fixed effects or random effects models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (95% CIs) for the heterozygous, homozygous, dominant, recessive, and allelic genetic models. Results: Overall, for the L55M polymorphism, none of the genetic models demonstrated a significant association. However, for non-Asian populations, a significant association was determined for the heterozygous and dominant genetic models (ORrange=1.24-1.27, p<0.05). For the Asian population, the heterozygous, dominant, and allelic genetic models demonstrated a benefit/protective factor (ORrange=0.29-0.35, p<0.05). For the Q192R polymorphism, none of the genetic models demonstrated a significant association. However, when the cohort was grouped by ethnicity, a significant association was determined in the Asian population for the recessive and allelic genetic models (ORrange=1.63-2.08, p<0.05). However, for the non-Asian population, there was no association observed. Also, there was no identifiable risk when the cohort was stratified into exudative and non-exudative cases. Conclusions: The paraoxonase-1L55M polymorphism increases the risk of developing age-related macular degeneration in non-Asian populations, whereas in Asian populations, the polymorphism exerts a protective effect. However, for the paraoxonase-1 Q192R polymorphism, only the Asian population demonstrated a risk of developing age-related macular degeneration.(AU)

RESUMO Objetivo: A atividade da paraoxonase1 está associada à degeneração macular relacionada à idade. Dois polimorfismos (L55M e Q192R) mostraram aumentar a atividade da paraoxonase1 e foram implicados no desenvolvimento da degeneração macular relacionada à idade. Os estudos que examinaram esses polimorfismos apresentaram resultados conflitantes: nenhum efeito, risco aumentado ou diminuído. Assim, esta meta-análise foi realizada para determinar o efeito desses polimorfismos na degeneração macular relacionada à idade. Métodos: Foi feita uma busca nos bancos de dados PubMed, EBSCO, LILACS e SCOPUS, bem como nas bibliografias compiladas das publicações, buscando-se estudos caso-controle que tivessem analisado os polimorfismos da paraoxonase1 e a degeneração macular relacionada à idade. Os dados foram analisados com software Comprehensive Meta-Analysis, versão 2.2, e NCSS Statistical, versão 2020. As distribuições de genótipos foram extraídas e, dependendo do nível de heterogeneidade, modelos de efeitos fixos ou aleatórios foram utilizados para calcular razões de probabilidade (RPs) combinadas, com intervalos de confiança de 95% (IC 95%) para os modelos genéticos heterozigoto, homozigoto, dominante, recessivo e alélico. Resultados: Em geral, nenhum dos modelos genéticos demonstrou associação significativa para o polimorfismo L55M. Entretanto, em populações não asiáticas, foi determinada uma associação significativa para os modelos genéticos heterozigoto e dominante (RPfaixa=1,24-1,27, p<0,05). Para a população asiática, os modelos heterozigoto, dominante e alélico mostraram um fator benéfico ou protetor (RPfaixa=0,29-0,35, p<0,05). Para o polimorfismo Q192R, nenhum dos modelos genéticos demonstrou qualquer associação significativa. Porém, quando a coorte foi agrupada por etnia, determinou-se uma associação significativa na população asiática para os modelos genéticos recessivo e alélico (RPfaixa=1,63-2,08, p<0,05). Contudo, nenhuma associação foi observada para a população não asiática. Não houve risco identificável quando a coorte foi estratificada em exsudativa e não exsudativa. Conclusões: Determinamos que o polimorfismo L55M da paraoxonase1 de fato aumenta o risco de desenvolvimento de degeneração macular relacionada à idade em populações não asiáticas, enquanto que em populações asiáticas, esse polimorfismo tem um efeito protetor. Porém, para o polimorfismo Q192R da paraoxonase1, apenas a população asiática demonstrou risco de desenvolver degeneração macular relacionada à idade.(AU)