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1.
PLoS Negl Trop Dis ; 16(5): e0010365, 2022 05.
Article in English | MEDLINE | ID: mdl-35507552

ABSTRACT

BACKGROUND: Characterising dengue virus (DENV) infection history at the point of care is challenging as it relies on intensive laboratory techniques. We investigated how combining different rapid diagnostic tests (RDTs) can be used to accurately determine the primary and post-primary DENV immune status of reporting patients during diagnosis. METHODS AND FINDINGS: Serum from cross-sectional surveys of acute suspected dengue patients in Indonesia (N:200) and Vietnam (N: 1,217) were assayed using dengue laboratory assays and RDTs. Using logistic regression modelling, we determined the probability of being DENV NS1, IgM and IgG RDT positive according to corresponding laboratory viremia, IgM and IgG ELISA metrics. Laboratory test thresholds for RDT positivity/negativity were calculated using Youden's J index and were utilized to estimate the RDT outcomes in patients from the Philippines, where only data for viremia, IgM and IgG were available (N:28,326). Lastly, the probabilities of being primary or post-primary according to every outcome using all RDTs, by day of fever, were calculated. Combining NS1, IgM and IgG RDTs captured 94.6% (52/55) and 95.4% (104/109) of laboratory-confirmed primary and post-primary DENV cases, respectively, during the first 5 days of fever. Laboratory test predicted, and actual, RDT outcomes had high agreement (79.5% (159/200)). Among patients from the Philippines, different combinations of estimated RDT outcomes were indicative of post-primary and primary immune status. Overall, IgG RDT positive results were confirmatory of post-primary infections. In contrast, IgG RDT negative results were suggestive of both primary and post-primary infections on days 1-2 of fever, yet were confirmatory of primary infections on days 3-5 of fever. CONCLUSION: We demonstrate how the primary and post-primary DENV immune status of reporting patients can be estimated at the point of care by combining NS1, IgM and IgG RDTs and considering the days since symptoms onset. This framework has the potential to strengthen surveillance operations and dengue prognosis, particularly in low resource settings.


Subject(s)
Dengue Virus , Dengue , Antibodies, Viral , Cross-Sectional Studies , Dengue/epidemiology , Diagnostic Tests, Routine , Fever , Humans , Immunoglobulin G , Immunoglobulin M , Point-of-Care Systems , Sensitivity and Specificity , Viral Nonstructural Proteins , Viremia
2.
Int J Neonatal Screen ; 8(1)2022 Jan 19.
Article in English | MEDLINE | ID: mdl-35225931

ABSTRACT

Newborn bloodspot screening (NBS) began as a research project in the Philippines in 1996 and was mandated by law in 2004. The program initially included screening for five conditions, with a sixth added in 2012. As screening technology and medical knowledge have advanced, NBS programs in countries with developed economies have also expanded, not only in the number of newborns screened but also in the number of conditions included in the screening. Various approaches have been taken regarding selection of conditions to be screened. With limited resources, low- and middle-income countries face significant challenges in selecting conditions for screening and in implementing sustainable screening programs. Building on expansion experiences in the U.S. and data from California on Filipinos born and screened there, the Philippine NBS program has recently completed its expansion to include 29 screening conditions. This report focuses on those conditions detectable through tandem mass spectrometry. Expanded screening was implemented in a stepwise fashion across the seven newborn screening laboratories in the Philippines. A university-based biochemical genetics laboratory provides confirmatory testing. Follow-up care for confirmed cases is monitored and provided through the NBS continuity clinics across the archipelago. Pre-COVID-19 pandemic, the coverage was 91.6% but dropped to 80.4% by the end of 2020 due to closure of borders between cities, provinces, and islands.

3.
Int J Neonatal Screen ; 9(1)2022 Dec 29.
Article in English | MEDLINE | ID: mdl-36648769

ABSTRACT

The COVID-19 pandemic has challenged healthcare systems worldwide. In the Philippines, long-term care for patients with conditions identified through newborn screening (NBS) is coordinated through Newborn Screening Continuity Clinics (NBSCCs). These clinics are integral to achieving optimal outcomes by providing follow-up oversight and assistance for individuals identified through screening. Continuity of NBSCC care for NBS during the COVID-19 pandemic was both challenging and necessary and was accomplished through innovative strategies of dedicated personnel. Following the discontinuation of the community quarantine, a situation assessment survey was completed by each NBSCC to better understand the challenges encountered and their effect on patient care. Performance data from each NBSCC were reviewed both before and after an extended community quarantine (2018-2021) to evaluate the impact of NBSCC disaster contingency plans in overcoming the resultant challenges (transportation, supply chain, etc.). Thematic analysis of the survey showed three primary challenges: Operations, communications, and safety. In 2018 and 2019, successful patient contacts were 70.6% and 70.2%, respectively. During the pandemic, successful contacts were 74.9% in 2020 and 76.8% in 2021, demonstrating that the contact approaches taken by the NBSCCs were sufficient to maintain (and even improve) patient contacts. The number of unresponsive patients decreased during the pandemic likely due to decreased mobility and improved follow-up actions from the NBSCCs.

4.
BMC Med ; 19(1): 217, 2021 09 30.
Article in English | MEDLINE | ID: mdl-34587957

ABSTRACT

BACKGROUND: Stratifying dengue risk within endemic countries is crucial for allocating limited control interventions. Current methods of monitoring dengue transmission intensity rely on potentially inaccurate incidence estimates. We investigated whether incidence or alternate metrics obtained from standard, or laboratory, surveillance operations represent accurate surrogate indicators of the burden of dengue and can be used to monitor the force of infection (FOI) across urban centres. METHODS: Among those who reported and resided in 13 cities across the Philippines, we collected epidemiological data from all dengue case reports between 2014 and 2017 (N 80,043) and additional laboratory data from a cross-section of sampled case reports (N 11,906) between 2014 and 2018. At the city level, we estimated the aggregated annual FOI from age-accumulated IgG among the non-dengue reporting population using catalytic modelling. We compared city-aggregated FOI estimates to aggregated incidence and the mean age of clinically and laboratory diagnosed dengue cases using Pearson's Correlation coefficient and generated predicted FOI estimates using regression modelling. RESULTS: We observed spatial heterogeneity in the dengue average annual FOI across sampled cities, ranging from 0.054 [0.036-0.081] to 0.249 [0.223-0.279]. Compared to FOI estimates, the mean age of primary dengue infections had the strongest association (ρ -0.848, p value<0.001) followed by the mean age of those reporting with warning signs (ρ -0.642, p value 0.018). Using regression modelling, we estimated the predicted annual dengue FOI across urban centres from the age of those reporting with primary infections and revealed prominent spatio-temporal heterogeneity in transmission intensity. CONCLUSIONS: We show the mean age of those reporting with their first dengue infection or those reporting with warning signs of dengue represent superior indicators of the dengue FOI compared to crude incidence across urban centres. Our work provides a framework for national dengue surveillance to routinely monitor transmission and target control interventions to populations most in need.


Subject(s)
Dengue , Cities/epidemiology , Dengue/epidemiology , Humans , Incidence , Laboratories , Philippines/epidemiology
5.
Viruses ; 13(8)2021 07 23.
Article in English | MEDLINE | ID: mdl-34452307

ABSTRACT

Zika virus (ZIKV) exposure across flavivirus-endemic countries, including the Philippines, remains largely unknown despite sporadic case reporting and environmental suitability for transmission. Using laboratory surveillance data from 2016, 997 serum samples were randomly selected from suspected dengue (DENV) case reports across the Philippines and assayed for serological markers of short-term (IgM) and long-term (IgG) ZIKV exposure. Using mixture models, we re-evaluated ZIKV IgM/G seroprevalence thresholds and used catalytic models to quantify the force of infection (attack rate, AR) from age-accumulated ZIKV exposure. While we observed extensive ZIKV/DENV IgG cross-reactivity, not all individuals with active DENV presented with elevated ZIKV IgG, and a proportion of dengue-negative cases (DENV IgG-) were ZIKV IgG-positive (14.3%, 9/63). We identified evidence of long-term, yet not short-term, ZIKV exposure across Philippine regions (ZIKV IgG+: 31.5%, 314/997) which was geographically uncorrelated with DENV exposure. In contrast to the DENV AR (12.7% (95%CI: 9.1-17.4%)), the ZIKV AR was lower (5.7% (95%CI: 3-11%)) across the country. Our results provide evidence of widespread ZIKV exposure across the Philippines and suggest the need for studies to identify ZIKV infection risk factors over time to better prepare for potential future outbreaks.


Subject(s)
Antibodies, Viral/blood , Zika Virus Infection/epidemiology , Zika Virus/immunology , Adolescent , Adult , Antibodies, Viral/immunology , Child , Cross Reactions , Dengue/epidemiology , Dengue/immunology , Dengue Virus/immunology , Female , Humans , Immunoglobulin G/blood , Immunoglobulin G/immunology , Immunoglobulin M/blood , Immunoglobulin M/immunology , Male , Philippines/epidemiology , Seroepidemiologic Studies , Young Adult , Zika Virus Infection/immunology
6.
Int J Neonatal Screen ; 7(2)2021 Jun 17.
Article in English | MEDLINE | ID: mdl-34204320

ABSTRACT

The Philippine newborn bloodspot screening (NBS) program began in 1996 with 24 hospitals and was formalized by legislation in 2004. The NBS panel was recently expanded to include a number of additional hereditary congenital conditions. Expertise and experiences from other NBS programs already screening for hemoglobinopathies were essential to its successful integration into the ongoing dried bloodspot NBS program in the Philippines. Building on clinical experiences and population data from Filipinos born in California, USA, hemoglobinopathies (including thalassemias) were selected for inclusion in the expanded screening panel. Hemoglobinopathy NBS, using high performance liquid chromatography, was implemented in a stepwise manner into the seven regional NBS screening laboratories. A central university laboratory provides confirmatory testing using both capillary electrophoresis and molecular methodologies. NBS results indicating carriers are followed up with educational fact sheets, while results of presumptive disease are referred for confirmatory testing and follow-up with a hematologist. Long-term care is provided through newborn screening continuity clinics across the country. Hemoglobinopathy NBS is now included in the national insurance package and screening uptake continues to increase nationally, exceeding 90% of all newborns in 7400+ hospitals and birthing centers nationwide prior to the COVID-19 pandemic.

7.
Mol Genet Metab Rep ; 27: 100745, 2021 Jun.
Article in English | MEDLINE | ID: mdl-33868929

ABSTRACT

Maple syrup urine disease (MSUD, MIM #248600) is an autosomal recessive metabolic disorder that results in elevation of the branched-chain amino acids (BCAA) leucine, isoleucine, and valine. Elevation of BCAA and certain alpha keto-acids is associated with a catabolic state and may result in neurological and developmental delays, feeding problems, and a urine and cerumen odor of maple syrup. Pregnancy is a period of multiple adaptations necessary to support fetal growth and development. Both the third trimester of pregnancy and the postpartum period present the possibility for catabolic states. We describe our treatment of an adolescent patient with intermittent MSUD and her resulting positive pregnancy outcome.

8.
Mol Genet Metab ; 132(2): 146-153, 2021 02.
Article in English | MEDLINE | ID: mdl-33485800

ABSTRACT

TRMU is a nuclear gene crucial for mitochondrial DNA translation by encoding tRNA 5-methylaminomethyl-2-thiouridylate methyltransferase, which thiolates mitochondrial tRNA. Biallelic pathogenic variants in TRMU are associated with transient infantile liver failure. Other less common presentations such as Leigh syndrome, myopathy, and cardiomyopathy have been reported. Recent studies suggested that provision of exogenous L-cysteine or N-acetylcysteine may ameliorate the effects of disease-causing variants and improve the natural history of the disease. Here, we report six infants with biallelic TRMU variants, including four previously unpublished patients, all treated with exogenous cysteine. We highlight the first report of an affected patient undergoing orthotopic liver transplantation, the long-term effects of cysteine supplementation, and the ability of the initial presentation to mimic multiple inborn errors of metabolism. We propose that TRMU deficiency should be suspected in all children presenting with persistent lactic acidosis and hypoglycemia, and that combined N-acetylcysteine and L-cysteine supplementation should be considered prior to molecular diagnosis, as this is a low-risk approach that may increase survival and mitigate the severity of the disease course.


Subject(s)
Leigh Disease/therapy , Liver Failure/therapy , Mitochondrial Proteins/genetics , Protein Biosynthesis , tRNA Methyltransferases/genetics , Acetylcysteine/administration & dosage , Acetylcysteine/metabolism , Acidosis/genetics , Acidosis/metabolism , Cysteine/administration & dosage , Cysteine/metabolism , DNA, Mitochondrial/genetics , Female , Humans , Infant , Leigh Disease/genetics , Leigh Disease/metabolism , Leigh Disease/pathology , Liver Failure/genetics , Liver Failure/metabolism , Liver Failure/pathology , Liver Transplantation/methods , Male , Mitochondria/enzymology , Mitochondrial Proteins/deficiency , RNA, Transfer/genetics , tRNA Methyltransferases/deficiency
9.
Int J Neonatal Screen ; 6(4)2020 Dec 11.
Article in English | MEDLINE | ID: mdl-33322257

ABSTRACT

Newborn Bloodspot Screening (NBS) has existed for over 60 years, having been initiated by Guthrie in the U.S. In the Philippines, NBS was introduced in 1996 and later was supported by legislation. The NBS program now includes 29 conditions, covering 91.6% of the newborn population in 2019. Program growth and expansion necessitated development of a formal performance evaluation and assessment scheme (PEAS) for monitoring performance and for continuously improving quality. This study's objective was to present the development, implementation, and results to date of the Philippine Performance PEAS (PPEAS). Using the comprehensive listing of laboratory and non-laboratory elements in the model PEAS system in the U.S., PPEAS tools were developed for critical Philippine NBS system components: regional Department of Health (national health agency, Philippines) (DOH) offices (CHDs), NBS laboratories (NSCs), NBS specimen submitters (NSFs), and long-term case management centers (NBSCCs). Data generated from the various PPEAS have been periodically reviewed and analyzed for NBS system impact. PPEAS were developed to facilitate quality improvement at various levels of the Philippine NBS system. PPEAS identified successes, gaps, and challenges to be addressed by NSCs, NSFs, CHDs, and NBSCCs with the assistance of the Newborn Screening Reference Center and the Department of Health.

10.
BMC Med ; 18(1): 364, 2020 11 27.
Article in English | MEDLINE | ID: mdl-33243267

ABSTRACT

BACKGROUND: In dengue-endemic countries, targeting limited control interventions to populations at risk of severe disease could enable increased efficiency. Individuals who have had their first (primary) dengue infection are at risk of developing more severe secondary disease, thus could be targeted for disease prevention. Currently, there is no reliable algorithm for determining primary and post-primary (infection with more than one flavivirus) status from a single serum sample. In this study, we developed and validated an immune status algorithm using single acute serum samples from reporting patients and investigated dengue immuno-epidemiological patterns across the Philippines. METHODS: During 2015/2016, a cross-sectional sample of 10,137 dengue case reports provided serum for molecular (anti-DENV PCR) and serological (anti-DENV IgM/G capture ELISA) assay. Using mixture modelling, we re-assessed IgM/G seroprevalence and estimated functional, disease day-specific, IgG:IgM ratios that categorised the reporting population as negative, historical, primary and post-primary for dengue. We validated our algorithm against WHO gold standard criteria and investigated cross-reactivity with Zika by assaying a random subset for anti-ZIKV IgM and IgG. Lastly, using our algorithm, we explored immuno-epidemiological patterns of dengue across the Philippines. RESULTS: Our modelled IgM and IgG seroprevalence thresholds were lower than kit-provided thresholds. Individuals anti-DENV PCR+ or IgM+ were classified as active dengue infections (83.1%, 6998/8425). IgG- and IgG+ active dengue infections on disease days 1 and 2 were categorised as primary and post-primary, respectively, while those on disease days 3 to 5 with IgG:IgM ratios below and above 0.45 were classified as primary and post-primary, respectively. A significant proportion of post-primary dengue infections had elevated anti-ZIKV IgG inferring previous Zika exposure. Our algorithm achieved 90.5% serological agreement with WHO standard practice. Post-primary dengue infections were more likely to be older and present with severe symptoms. Finally, we identified a spatio-temporal cluster of primary dengue case reporting in northern Luzon during 2016. CONCLUSIONS: Our dengue immune status algorithm can equip surveillance operations with the means to target dengue control efforts. The algorithm accurately identified primary dengue infections who are at risk of future severe disease.


Subject(s)
Dengue Virus/pathogenicity , Dengue/epidemiology , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , Female , Humans , Male , Philippines , Young Adult
11.
J Community Genet ; 11(3): 253-268, 2020 Jul.
Article in English | MEDLINE | ID: mdl-32415570

ABSTRACT

In an effort to explore new knowledge and to develop meaningful collaborations for improving child health, the First Pan African Workshop on Newborn Screening was convened in June 2019 in Rabat, Morocco. Participants included an informal network of newborn screening stakeholders from across Africa and global experts in newborn screening and sickle cell disease. Over 150 attendees, representing 20 countries, were present including 11 African countries. The agenda focused on newborn screening rationale, techniques, system development, implementation barriers, ongoing research, and collaborations both globally and across Africa. We provide an overview of the workshop and a description of the newborn screening activities in the 11 African countries represented at the workshop, with a focus on sickle cell disease.

12.
Curr Opin Pediatr ; 30(6): 734-739, 2018 12.
Article in English | MEDLINE | ID: mdl-30124582

ABSTRACT

PURPOSE OF REVIEW: We review newborn screening (NBS) publications from the developing countries to identify global progress in improving child health. RECENT FINDINGS: Many developing countries do not yet have national NBS. As infant mortality rates decline, NBS gains in public health priority. Local incidence and outcome data are used to persuade health officials to include screening in priority health spending. Congenital hypothyroidism is the most cost-effective screened condition in most countries. In sub-Saharan Africa, India and some parts of Asia, screening for hemoglobinopathies and glucose-6-dehydrogenase deficiency are also important. Expanded screening for metabolic conditions is most needed in areas of high consanguinity. Screening for hearing disorders and critical congenital heart defects is increasing globally. The largest birth cohorts are India and China, but only China has successful NBS. Reports from completed government research projects in India support initiation of NBS. SUMMARY: Government activities around NBS are increasing in India and there is increased emphasis on pilot programs for sickle cell NBS in sub-Saharan Africa. Genetic counseling training in Asia and Africa is increasing and will be helpful as part of NBS. To build successful screening programs, partnerships among health professionals, parents, policy makers and industry stakeholders are essential.


Subject(s)
Genetic Diseases, Inborn/diagnosis , Genetic Testing/trends , Infant Mortality/trends , Infant, Newborn, Diseases/diagnosis , Neonatal Screening , Public Health , Developing Countries , Genetic Counseling , Genetic Diseases, Inborn/genetics , Genetic Testing/statistics & numerical data , Humans , Infant , Infant, Newborn , Infant, Newborn, Diseases/genetics , Neonatal Screening/standards , Neonatal Screening/trends
13.
J Genet Couns ; 26(4): 763-775, 2017 Aug.
Article in English | MEDLINE | ID: mdl-27832511

ABSTRACT

Congenital adrenal hyperplasia (CAH), like other genetic conditions, is a relational disease from both the biological and psychosocial perspectives since the diagnosis gives rise to a variety of health, reproductive, and psychosocial implications. It is in these contexts that family communication of genetic information is important to study. Hence, this research aimed to explore genetic information communication in Filipino families affected with CAH. Using a qualitative descriptive design, families with a child affected with CAH were recruited through the CAH parent support group and were interviewed. Semi-structured interviews explored flow and content of genetic information communicated, the meanings the families attach to the communicated information, and the motivating and hindering factors in communication. Thematic analysis was used to analyze the findings. A total of five families participated, which included 11 individuals. Findings revealed that the diagnosis of CAH is not kept secret and it is openly shared with the family. The decision to communicate is influenced by several factors including the family's desire to seek further information about their family history. Initially, the focus of the communicated information is on the health implications and while communication about genetics occurs, this is almost always confined to the immediate family. The mother and grandmother serve as primary communicators in the family. The families have limited understanding of CAH especially its genetic implications including recurrence risk and carrier status. The findings can guide genetic counselors in supporting families in communicating information about CAH with the rest of the family.


Subject(s)
Adrenal Hyperplasia, Congenital/ethnology , Adrenal Hyperplasia, Congenital/genetics , Communication , Family/ethnology , Genetic Counseling/psychology , Adolescent , Adult , Female , Humans , Middle Aged , Philippines , Young Adult
14.
Mol Genet Genomic Med ; 4(5): 494-503, 2016 Sep.
Article in English | MEDLINE | ID: mdl-27652277

ABSTRACT

Genetics and genomic medicine in the Philippines.

15.
Otolaryngol Head Neck Surg ; 155(5): 856-862, 2016 11.
Article in English | MEDLINE | ID: mdl-27484237

ABSTRACT

OBJECTIVE: To identify genetic and environmental risk factors for otitis media in an indigenous Filipino population. STUDY DESIGN: Cross-sectional study. SETTING: Indigenous Filipino community. SUBJECTS AND METHODS: Clinical history and information on breastfeeding, tobacco smoke exposure, and swimming were obtained from community members. Heads of households were interviewed for family history and personal beliefs on ear health. Height and weight were measured. Otoscopic findings were described for the presence and character of perforation or discharge. An A2ML1 duplication variant that confers otitis media susceptibility was Sanger sequenced in all DNA samples. Co-occurrence of middle ear bacteria detected by 16S rRNA gene sequencing was determined according to A2ML1 genotype and social cluster. RESULTS: The indigenous Filipino population has a ~50% prevalence of otitis media. Young age was associated with otitis media (4 age strata; P = .004); however, age was nonsignificant as a bistratal or continuous variable. There was no association between otitis media and sex, body mass index, breastfeeding, tobacco exposure, or deep swimming. In multivariate analyses, A2ML1 genotype is the strongest predictor of otitis media, with an odds ratio of 3.7 (95% confidence interval: 1.3-10.8; P = .005). When otitis media diagnoses were plotted across ages, otitis media was observed within the first year of life, and chronic otitis media persisted up to adulthood, particularly in A2ML1-variant carriers. CONCLUSION: Among indigenous Filipinos, A2ML1 genotype is the primary risk factor for otitis media and main determinant of disease progression, although age, the middle ear microbiome, and social clusters might modulate the effect of the A2ML1 genotype.


Subject(s)
Environmental Exposure/adverse effects , Otitis Media/epidemiology , Otitis Media/genetics , alpha-Macroglobulins/genetics , Adolescent , Adult , Child , Child, Preschool , Cross-Sectional Studies , Female , Genetic Predisposition to Disease , Genotype , Humans , Male , Microbiota , Otitis Media/microbiology , Otoscopy , Philippines/epidemiology , Prevalence , Risk Factors
16.
JAMA Pediatr ; 170(8): 790-3, 2016 08 01.
Article in English | MEDLINE | ID: mdl-27366873

ABSTRACT

As the Sustainable Development Goals are adopted by United Nations member states, children with congenital disorders remain left behind in policies, programs, research, and funding. Although this finding was recognized by the creation and endorsement of the 63rd World Health Assembly Resolution in 2010 calling on United Nations member states to strengthen prevention of congenital disorders and the improvement of care of those affected, there has been little to no action since then. The Sustainable Development Goals call for the global health and development community to focus first and foremost on the most vulnerable and those left behind in the Millennium Development Goal era. To maximize the opportunity for every woman and couple to have a healthy child and to reduce the mortality and severe disability associated with potentially avoidable congenital disorders and their consequences for the children affected, their families and communities, and national health care systems, we propose priority measures that should be taken urgently to address this issue.


Subject(s)
Child Care , Congenital Abnormalities/prevention & control , Child , Congenital Abnormalities/rehabilitation , Data Collection/standards , Female , Food Contamination/prevention & control , Health Education , Health Priorities , Humans , Pregnancy , Pregnancy Complications/prevention & control , Prenatal Care/standards , Quality Improvement , Registries , Risk Assessment , Social Support
17.
Hum Mol Genet ; 25(13): 2862-2872, 2016 07 01.
Article in English | MEDLINE | ID: mdl-27033726

ABSTRACT

Orofacial clefts (OFCs), which include non-syndromic cleft lip with or without cleft palate (CL/P), are among the most common birth defects in humans, affecting approximately 1 in 700 newborns. CL/P is phenotypically heterogeneous and has a complex etiology caused by genetic and environmental factors. Previous genome-wide association studies (GWASs) have identified at least 15 risk loci for CL/P. As these loci do not account for all of the genetic variance of CL/P, we hypothesized the existence of additional risk loci. We conducted a multiethnic GWAS in 6480 participants (823 unrelated cases, 1700 unrelated controls and 1319 case-parent trios) with European, Asian, African and Central and South American ancestry. Our GWAS revealed novel associations on 2p24 near FAM49A, a gene of unknown function (P = 4.22 × 10-8), and 19q13 near RHPN2, a gene involved in organizing the actin cytoskeleton (P = 4.17 × 10-8). Other regions reaching genome-wide significance were 1p36 (PAX7), 1p22 (ARHGAP29), 1q32 (IRF6), 8q24 and 17p13 (NTN1), all reported in previous GWASs. Stratification by ancestry group revealed a novel association with a region on 17q23 (P = 2.92 × 10-8) among individuals with European ancestry. This region included several promising candidates including TANC2, an oncogene required for development, and DCAF7, a scaffolding protein required for craniofacial development. In the Central and South American ancestry group, significant associations with loci previously identified in Asian or European ancestry groups reflected their admixed ancestry. In summary, we have identified novel CL/P risk loci and suggest new genes involved in craniofacial development, confirming the highly heterogeneous etiology of OFCs.


Subject(s)
Cleft Lip/genetics , Cleft Palate/genetics , Asian People/genetics , Black People/genetics , Chromosomes, Human, Pair 17/genetics , Chromosomes, Human, Pair 19/genetics , Chromosomes, Human, Pair 2/genetics , Ethnicity , Female , Genetic Loci , Genetic Predisposition to Disease , Genome-Wide Association Study , Humans , Male , Polymorphism, Single Nucleotide/genetics , Risk Factors , White People/genetics
18.
Am J Hum Genet ; 98(4): 744-54, 2016 Apr 07.
Article in English | MEDLINE | ID: mdl-27018472

ABSTRACT

Cleft palate (CP) is a common birth defect occurring in 1 in 2,500 live births. Approximately half of infants with CP have a syndromic form, exhibiting other physical and cognitive disabilities. The other half have nonsyndromic CP, and to date, few genes associated with risk for nonsyndromic CP have been characterized. To identify such risk factors, we performed a genome-wide association study of this disorder. We discovered a genome-wide significant association with a missense variant in GRHL3 (p.Thr454Met [c.1361C>T]; rs41268753; p = 4.08 × 10(-9)) and replicated the result in an independent sample of case and control subjects. In both the discovery and replication samples, rs41268753 conferred increased risk for CP (OR = 8.3, 95% CI 4.1-16.8; OR = 2.16, 95% CI 1.43-3.27, respectively). In luciferase transactivation assays, p.Thr454Met had about one-third of the activity of wild-type GRHL3, and in zebrafish embryos, perturbed periderm development. We conclude that this mutation is an etiologic variant for nonsyndromic CP and is one of few functional variants identified to date for nonsyndromic orofacial clefting. This finding advances our understanding of the genetic basis of craniofacial development and might ultimately lead to improvements in recurrence risk prediction, treatment, and prognosis.


Subject(s)
Cleft Palate/genetics , DNA-Binding Proteins/genetics , Polymorphism, Single Nucleotide , Transcription Factors/genetics , Animals , Case-Control Studies , Cleft Palate/diagnosis , Disease Models, Animal , Ethnicity/genetics , Genetic Loci , Genome-Wide Association Study , Genotyping Techniques , Humans , Mutation, Missense , Risk Factors , Zebrafish/embryology , Zebrafish/genetics
19.
Acta Medica Philippina ; : 75-80, 2016.
Article in English | WPRIM (Western Pacific) | ID: wpr-632867

ABSTRACT

@#<p style="text-align: justify;">There is still a strong need for new treatment strategies that will maintain remission and prolong survival in patients with acute lymphoblastic leukemia (ALL). The glutathione-S-transferase (GST) enzymes, which are coded by highly polymorphic genes, have been associated with the risk of developing cancer and were found to regulate effect of cancer treatment drugs.<br /><strong>OBJECTIVES:</strong> The present study determines the association of GSTM1, GSTP1 and GSTT1 polymorphisms and treatment response in terms of occurrence of adverse events and relapse in ALL in Filipino children.<br /><strong>METHODS:</strong> This is a follow up study on the 2007 investigation done by Alcausin et al. which determined the association of the GST P1, M1, and T1 polymorphisms and occurrence of ALL. Four-year follow-up data were available for 46 out of the 50 patients from January 2007 to May 2011. Odds ratios (OR) as measures of association of GST M1, P1 and T1 gene polymorphisms with treatment outcomes were estimated at 95% confidence interval.<br /><strong>RESULTS:</strong> Results show a trend towards predisposition to elevation of liver enzymes in patients with GSTT1 and GSTP1 mutant genotypes showing an OR (95% Cl) of 2.0 (0.62-6.49). The presence of GSTM1 null genotype showed a trend towards protection from occurrence of relapse basing on both crude and adjusted ORs, 0.58 (0.16-2.07) and 0.23 (0.05-1.20), respectively. However, these results are not statistically significant.<br /><strong>CONCLUSION: </strong>The GSTP1 heterozygous genotype conferred increased predisposition to elevation of liver enzymes while the GSTT1 null genotype was shown to be a possible risk factor towards the occurrence of both infection and elevation of liver enzymes during chemotherapy. Furthermore, the GSTM1 null genotype appears to be protective from occurrence of relapse. It is recommended to do similar large-scale studies in the future to obtain more conclusive results.</p>


Subject(s)
Humans , Male , Female , Child , Child , Confidence Intervals , Follow-Up Studies , Genotype , Glutathione , Glutathione S-Transferase pi , Glutathione Transferase , Liver , Precursor Cell Lymphoblastic Leukemia-Lymphoma , Recurrence , Treatment Outcome
20.
Matern Child Health J ; 18(5): 1066-74, 2014 Jul.
Article in English | MEDLINE | ID: mdl-23963972

ABSTRACT

To test the utility of a preconception checklist tool in identifying preconception health needs of women in three countries; China, Lebanon and the Philippines. An academic medical center within each country participated in the development and testing of a preconception checklist tool, which was administered over a 6 month period to selected target groups in each country. The checklist provided valuable data on the preconception health of 6,530 women. Aggregated data identified common preconception health needs across all countries, including provision of modern contraceptives and adequate immunization coverage; HIV and STI screening; treatment for anemia; and counseling for maintenance of a healthy weight. A preconception checklist tool was found to be useful in distinct cultural settings. The study was a pilot. Future steps include validation and standardization of the checklist, data from which could be used to help shape preconception care policies and implementation strategies.


Subject(s)
Checklist , Health Services Needs and Demand , Preconception Care , Adult , China , Female , Humans , Lebanon , Philippines , Pregnancy , Risk Assessment
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