Durability and extent of protection of SARS-CoV-2 antibodies among patients with COVID-19 in Metro Manila, Philippines.

Introduction: Information on the magnitude and durability of humoral immunity against COVID-19 among specific populations can guide policies on vaccination, return from isolation and physical distancing measures. The study determined the durability of SARS-CoV-2 antibodies after an initial infection among Filipinos in Metro Manila, Philippines, and the extent of protection SARS-CoV-2 antibodies confer against reinfection. Methods: We conducted a cohort study to monitor the antibody levels of patients diagnosed with COVID-19. Receptor-binding domain (RBD)-specific antibodies were measured at Days 21, 90, 180, 270 and 360. Antibody levels were reported as geometric mean titers (GMT) with geometric standard deviation (GSD). Differences in GMT were tested using Friedman test and Kruskal Wallis test, with Bonferroni multiple comparisons procedure. Adjusted hazard ratios on the development of probable reinfection were estimated using Cox proportional models. Results: There were 307 study participants included in the study, with 13 dropouts. Study participants received SARS-CoV-2 vaccines at varying times, with 278 participants (90.5%) fully vaccinated by the end of study. The GMT of the study cohort increased over time, from 19.7 U/mL (GSD 11) at Day 21; to 284.5 U/mL (GSD 9.6) at Day 90; 1,061 U/mL (GSD 5.3) at Day 180; 2,003 U/mL (GSD 6.7) at Day 270; and 8,403 U/mL (GSD 3.1) at Day 360. The increase was statistically significant from Day 21 to Day 90 (p<0.0001), Day 90 to Day 180 (p=0.0005), and Day 270 to Day 360 (p<0.0001). Participants with more severe initial infection demonstrated significantly higher antibody levels compared to those with milder infection at Day 21. Sixty-four patients had probable COVID-19 reinfection (incidence of 20.8%, 95% CI 16.4, 25.8%). The GMT of these 64 patients was 411.8 U/mL (GSD 6.9) prior to the occurrence of the probable reinfection. Majority (87.5%) were fully vaccinated. Antibody titers significantly affected the risk of developing reinfection, with adjusted hazard ratio of 0.994, 95% CI 0.992-0.996, p<0.001. Conclusion: Antibody levels against SARS-CoV-2 increased over a one-year follow-up. Higher antibody levels were observed among those with more severe initial infection and those vaccinated. Higher antibody levels are associated with a lower risk of probable reinfection.

Isolated aniridia caused by a novel PAX6 heterozygous deletion mediated by multi-exon complex rearrangement.

PURPOSE: Mutations in PAX6 gene (chromosome 11p13) encoding a transcriptional regulator involved in oculogenesis mostly present with aniridia. Aniridia is not uncommon in the Philippines but only limited information is available as yet. The purpose of this study was to present a novel, deletion mediated by complex rearrangement in PAX6 gene causing an isolated aniridia in a Filipino girl. PATIENTS AND METHODS: The patient is an 8-year-old girl who came in due to leukocoria with associated nystagmus and esotropia. She presented with subnormal vision, nystagmus, aniridia, and cataractous lenses in both eyes. The family history reveals presence of the aniridia and cataract with the mother and a sibling. The patient underwent lens extraction without intraocular lens implantation bilaterally, where patient subsequently underwent intraocular lens implantation on her left eye. Systemic workup was performed including whole abdomen, renal ultrasound, blood chemistry, and urinalysis. Targeted cataract panel with WT1 and PAX6 genes revealed a novel, heterozygous PAX6-inherited mutation from the mother. This variant is a complex rearrangement in PAX6 involving partial deletions of exons 3-5, including the initiator codon. Deletions of PAX6 are part of a contiguous gene deletion syndrome - Wilms tumor, aniridia, genitourinary anomalies, and intellectual disability syndrome - and therefore evaluation of the WT1 gene was necessary to rule out this life-threatening syndrome. CONCLUSION: This rare, complex rearrangement of multiple exons and deletions in PAX6 causing an isolated aniridia phenotype is probably the first reported case. The patient was managed by a multidisciplinary team and the guardians were counseled regarding the prognosis and complications.

Evidence of TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism.

The molecular dysfunction in X-linked dystonia-parkinsonism is not completely understood. Thus far, only noncoding alterations have been found in genetic analyses, located in or nearby the TATA-box binding protein-associated factor 1 (TAF1) gene. Given that this gene is ubiquitously expressed and is a critical component of the cellular transcription machinery, we sought to study differential gene expression in peripheral models by performing microarray-based expression profiling in blood and fibroblasts, and comparing gene expression in affected individuals vs. ethnically matched controls. Validation was performed via quantitative polymerase chain reaction in discovery and independent replication sets. We observed consistent downregulation of common TAF1 transcripts in samples from affected individuals in gene-level and high-throughput experiments. This signal was accompanied by a downstream effect in the microarray, reflected by the dysregulation of 307 genes in the disease group. Gene Ontology and network analyses revealed enrichment of genes involved in RNA polymerase II-dependent transcription, a pathway relevant to TAF1 function. Thus, the results converge on TAF1 dysfunction in peripheral models of X-linked dystonia-parkinsonism, and provide evidence of altered expression of a canonical gene in this disease. Furthermore, our study illustrates a link between the previously described genetic alterations and TAF1 dysfunction at the transcriptome level.

New insights into the genetics of X-linked dystonia-parkinsonism (XDP, DYT3).

X-linked recessive dystonia-parkinsonism is a rare movement disorder that is highly prevalent in Panay Island in the Philippines. Earlier studies identified seven different genetic alterations within a 427-kb disease locus on the X chromosome; however, the exact disease-causing variant among these is still not unequivocally determined. To further investigate the genetic cause of this disease, we sequenced all previously reported genetic alterations in 166 patients and 473 Filipino controls. Singly occurring variants in our ethnically matched controls would have allowed us to define these as polymorphisms, but none were found. Instead, we identified five patients carrying none of the disease-associated variants, and one male control carrying all of them. In parallel, we searched for novel single-nucleotide variants using next-generation sequencing. We did not identify any shared variants in coding regions of the X chromosome. However, by validating intergenic variants discovered via genome sequencing, we were able to define the boundaries of the disease-specific haplotype and narrow the disease locus to a 294-kb region that includes four known genes. Using microarray-based analyses, we ruled out the presence of disease-linked copy number variants within the implicated region. Finally, we utilized in silico analysis and detected no strong evidence of regulatory regions surrounding the disease-associated variants. In conclusion, our finding of disease-specific variants occurring in complete linkage disequilibrium raises new insights and intriguing questions about the origin of the disease haplotype, the existence of phenocopies and of reduced penetrance, and the causative genetic alteration in XDP.

N-acetyltransferase2 genotype and its association with hepatitis among Filipino children treated with first line anti-tuberculosis drugs

RATIONALE: Among the first line antituberculosis (anti-TB) drugs, the major drug incriminated in the development of hepatotoxicity is isoniazid (INH). The human N-acetyl transferase2 (NAT2) gene is mainly responsible for INH metabolism. This gene exhibits a hereditarily determined polymorphism. There is presently no study on the predominant NAT2 genotype among Filipinos. There are also no Filipino studies on the incidence of hepatitis and other adverse effects of first line anti-TB drugs. OBJECTIVES: To determine the predominant NAT2 genotype and its association with the development of hepatitis among Filipino children given first line anti-TB drugs (INH, rifampicin and pyrazinamide) and to determine the incidence of hepatitis and other serious adverse reactions to these drugs. STUDY DESIGN: Prospective cohort study SETTING: Tertiary government hospital in Metro Manila STUDY POPULATION: Children on to 18 years old with pulmonary tuberculosis and normal liver function test at baseline. METHODS: Total bilirubin (TB), direct bilirubin (DB) and liver transaminases (AST and ALT) were checked routinely at baseline and at thow, four, eight and 12 weeks after starting treatment. Within the first month of treatment, blood was also taken for NAT2 genotyping. The identification of the three NAT2 polymorphisms that are associated with a slow acetylator status - 481C to T (NAT2*5), 950G to A (NAT2*6) and 857G to A (NAT2*7) was carried out by polymerase chain reaction-restriction fragment length polymorphism. All patients were followed up for a total of six months. The presense of any adverse effects like gastroinstestinal symptoms, rash, hepatitis or drug fever was also monitored. RESULTS: A total of 24 children [mean age: 5 years; 11 males] were included. Majority (96%) were diagnosed by passive detection and mean Z score was - 1.38 (1 to -3). No patient developed hepatotoxicity or any side effects to anti-TB drugs. In 23 patients who had NAT2 genotyping, 39% and 22% were alleles homozygous for the NAT2*6 and NAT2*7, respectively. There was a combination of alleles in only three (13%) subjects. CONCLUSION: NAT2*6 and NAT2*7 alleles associated with a slow acetylator status were detected among our patients although the presence of these variants did not lead to any hepatotoxicity nor any treatment-related side effects. A larger study with broader genotype analysis is needed to confirm the present findings.

Chromosomal structural abnormalities among Filipino couples with recurrent pregnancy losses

Introduction. Recurrent pregnancy loss is a devastating reproductive problem that affects 5% of couples trying to conceive. Majority of the cases are due to cytogenetic errors. This study determines the prevalence of chromosomal structural abnormalities in Filipino couples who presented with 2 or more pregnancy losses. Methods. Results from chromosomal analysis of couples referred for 2 or more miscarriages done at the Institute of Human Genetics-National Institutes of Health-University of the Philippines, Manila on peripheral blood samples from 1991 to 2010 were restrospectively reviewed. Results. There were 356 couples with a history of 2 or more miscarriages sent for chromosomal analysis from 1991-2010 included in this study. Among these 356 couples, 17 couples (4.8%) were found to be carriers of different chromosomal abnormalies. From a total of 18 cases, there were 13(3.6%) translocations, 1(0.3%) insertion, 2(0.6%) with marker chromosomes, 1(0.3%) pericentric inversion and 1(0.3%) deletion. Conclusion. The overall frequency of chromosomal structural abnormalities among patients with RPL in this study is 4.8% with translocations being the most common type detected. The results of this study are similar to that of previous large-scale studies which have demostrated that parental chromosomal abnormalities are associated with RPL.

Epidemiological risk factors for cancers of the lung, breast, colon-rectum and oral cavity: A case-control study in the Philippines

INTRODUCTION: In the Philippines, lung, breast, colon-rectum, and oral cavity cancers are among the top 10 most common cancers. This study evaluates the risk factors for these cancers among Filipinos. METHODS: This age-matched case-control study included incident primary cancers (histologically-diagnosed) of the lung, breast (also matched for sex), colon-rectum and oral cavity. Controls (clinically free and no history of cancer) were obtained from the same tertiary hospitals as the cases. Target sample size was 283 cases and 283 controls per cancer type. Conditional logistic regression was done. RESULTS: Exposure to cigarette/tobacco was a significant risk factor for lung (OR of current smoker compared to non-smoker [95% Confidence Interval]: 3.6 [1.6-7.9]) and oral cavity cancers (2.0 [1.2-3.3]); family history (1st degree) for lung (4.3 [1.314.2]) and breast cancers (3.0 [1.2-7.5]); every year increase in age at first pregnancy for breast cancer (1.06 [1.02-1.11]). Other risk factors for oral cavity were passive smoking (2.8 [1.6-5.1]), chewing tobacco (5.2[1.4-19.5]) and inverted cigarette smoking (3.2[1.3-8.1]). Fish sauce (patis) was found to be a protective factor for breast cancer (0.34 [0.22-0.51]) and oral cavity (0.44 [0.25-0.78]) and use of shrimp paste (bagoong) (0.48 [0.27-0.84]) for oral cavity. CONCLUSION AND RECOMMENDATIONS: Except for family history of cancer, the identified risk factors for lung, colon-rectum, and oral cavity cancers are preventable. Proper diet and lifestyle, avoidance of cigarettes and tobacco, and environmental safety in the workplace are key cancer prevention measures. Public awareness campaign and continuing healthcare provider education must always be part of a cancer prevention program.

Low incidence of alpha 1-antitrypsin deficiency among Filipinos with neonatal cholestatis.

AIM: Alpha 1-antitrypsin (AAT) deficiency is the most common genetic cause of liver disease in children. The Pi*S carrier rate among Filipinos is <1%. Its significance in Filipino infants with neonatal cholestasis has not been investigated. The aim of the study was to determine the incidence of AAT deficiency among Filipino infants presenting with neonatal cholestasis. METHODS: Genotype determination that detects Pi*S and Pi*Z alleles was performed using Elucigene AAT reagents (Cellmark Diagnostics, UK). AAT inclusions were identified by light microscopy using periodic acid-Schiff (PAS) stain. RESULTS: Ninety-six infants (mean age: 89 days, 48 males) with a history of jaundice since 2 weeks old and a direct bilirubin level>20% of the total were recruited. Only one patient (1 month old, male) was positive for Pi*S allele and 95 were negative for Pi*S and Pi*Z alleles, with an annual incidence of 0.7%. Of the 96, 49 infants underwent diagnostic percutaneous liver biopsy. All liver biopsy specimen were subjected to PAS stain and two infants, 2 and 4 months old, both with idiopathic neonatal hepatitis, had suspicious findings of AAT globules that was confirmed on immunostain. Both infants were negative for Pi*S alleles. The only patient positive for Pi*S allele was negative for PAS globule on liver biopsy. CONCLUSION: Our results showed a low incidence of AAT deficiency caused by the Pi*S and Pi*Z alleles among Filipino infants presenting with neonatal cholestasis, similar to the low carrier rate in the population.