Progress 07/01/16 to 06/30/21
Outputs
Target Audience:Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects. Changes/Problems:Work progress was slowed by the COVID-19 pandemic. What opportunities for training and professional development has the project provided?Training activities have included mentoring of junior colleagues and students, presentation of the study background, analyses, and results in undergraduate and graduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included work with colleagues at several U.S. and international institutions to develop further grant proposals for the study of gestational diabetes and orofacial clefts. How have the results been disseminated to communities of interest?Results have been disseminated via classroom teaching to USU undergraduates and graduate students, non-governmental organizations that serve patient populations affected by orofacial clefts (Operation Smile and The Smile Train), via workshops and websites sponsored by the World Health Organization, the European Science Foundation, the U.S. National Institute for Dental and Craniofacial Research, and the scientific meetings listed above. What do you plan to do during the next reporting period to accomplish the goals?Project has been completed. Additional analyses will be conducted during 2021-2022 with other sources of funding available to Dr. Munger.
Impacts
What was accomplished under these goals?
1) Major activities completed: We analyzed data from a state-wide case-control study of orofacial cleft (OFC) birth defects conducted by Dr. Munger. Cases were children born during the period 1995-2005 with an isolated cleft lip or cleft palate or both. Controls were unaffected children randomly selected from birth certificates. Mothers of case and control children had been interviewed and physical examinations and blood collections were completed in clinical visits 10 years (mean) after the index birth. Laboratory assays of maternal biomarkers related to metabolic syndrome (MS) and gestational diabetes mellitus (GDM) were completed. Logistic regression analyses estimated risk for OFCs while adjusting for the potential confounding effects of maternal age and smoking.We analyzed genetic data related to gestational diabetes (GDM) from the International Genetic Epidemiology study of Oral Clefts, a part of the Gene-Environment Association Studies Initiative (GENEVA) of the National Institutes of Health, a multi-center, international study of samples from Europe, the U.S., China, Taiwan, Singapore, Korea, and the Philippines. We expanded our collaborations with colleagues at the University of Iowa College of Dentistry (Dr. Azeez Butali) and the University of Puerto Rico School of Dental Medicine (Dr. Carmen Buxo Martinez). Dr. Butali has led genotyping efforts at Iowa with additional DNA specimens from our Utah studies, Puerto Rico, and Iowa. We completed biomarker assays of vitamin B12 status in samples from our case-control study in India and found associations between poor B12 status and risk of orofacial clefts. The COVID-19 pandemic severely affected activities related to the presentation of results at international conferences, laboratory assays of Utah samples, and site visits to collaborative sites. Dr. Munger presented results of this study at the online virtual conference of the International Association for Dental Research on 21 July 2021. Another consequence of suspended travel was the cancellation of Dr. Munger's visit to Dr. Adebowale Adeyemo's laboratory at NHGRI/NIH in Washington D.C. Dr. Adeyemo is Deputy Director, Center for Research on Genomics and Global Health, and Associate Investigator, National Human Genome Research Institute, National Institutes of Health. Dr. Adeyemo has offered to assay stored Utah specimens for adipokines related to maternal diabetes for the cost of kits only. Due to the pandemic, analytical work in Dr. Adeyemo's laboratory has been paused until 2021. Dr. Munger shipped the samples to Dr. Adeyemo's lab at NIH in June, 2021. The analytical work on the samples in Dr. Adeyemo's lab are continuing after the June 30th, 2021, termination of the project and the cost of the analyses will be covered by other research funds available to Dr. Munger. The plans for further genotyping of the Utah samples in the laboratory of Dr. Azeez Butali of the University of Iowa College of Dentistry, have also been paused due to the pandemic but the samples have been shipped to Dr. Butali's lab in June, 2021. Dr. Butali will cover the cost of the genotyping and his students will be involved in the analysis of data and manuscript preparation. With the cancellation of in-person and laboratory work Dr Munger has focused on manuscript preparation, further data analyses of existing data, literature reviews, and preparation of grant proposals. Dr. Munger has worked with Dr. Butali (PI) and colleagues on preparation of a new NIH UO1 proposal to further study the role of maternal metabolic syndrome and gestational diabetes in orofacial clefts with a comprehensive approach including novel nutritional biomarkers, environmental exposures, and genomic analyses of populations in Utah, Puerto Rico, Europe, Africa, and Asia; submission is expected in mid-2021. Dr. Munger retired from his position as Professor on June 30th, 2021, and is now continuing active research with colleagues as Professor Emeritus in the Department of Nutrition, Dietetics, and Food Sciences. 2) Specific objectives met: These analyses address Objectives 1, 2, 4, and 5 in the original project proposal. 3) Significant results achieved: Maternal obesity increased risk of both non-isolated and isolated OFCs (adjusted odds ratios (aOR): 1.41, 95%CI: 1.07-1.87 and aOR: 1.23, 95% confidence interval (CI): 1.01-1.50, respectively). Pre-existing diabetes increased risk of all OFCs (aOR: 2.19, 95% CI: 1.18-4.09) with a larger effect for non-isolated OFCs (aOR: 3.83, 95%CI: 1.71-8.58) vs isolated OFCs (aOR: 1.54, 95%CI: 0.70-3.41). Mediation analysis indicated that obesity had a direct effect of increasing the risk of OFCs without the mediating effect of known maternal diabetes. Mothers of children with OFCs had higher mean levels of plasma glucose, insulin, triglycerides, waist circumference and systolic blood pressure, and lower HDL cholesterol. Similarly, mean plasma leptin and IL-8 levels were higher among mothers of OFC cases compared to controls. Elevated leptin level (highest vs. lowest tertile) was associated with OFCs. The International Diabetes Federation (IDF) index of metabolic syndrome biomarkers was associated with OFCs (OR = 1.64, 95% CI: 1.04-2.59) Mothers having GDM in any pregnancy had an increased risk of OFCs (OR = 3.05, 95% CI: 1.61-5.80) and this was consistent for each specific type of OFC. We found associations of note between OFCs and genes known to be associated with gestational diabetes (GDM) including ADIPOQ (adiponectin) and LEP. A recent meta-analysis has provided evidence of significant associations between impaired vitamin B12 status and gestational diabetes. We recently completed biomarker assays of vitamin B12 status in samples from our case-control study in India. We concluded found that mothers of OFC children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL+P, and whether poor vitamin B12 status interacts with GDM or GDM-related genes to increase the risk of orofacial clefts. 4) Key impacts: OFCs occur at a higher rate in Utah than any other state and the reasons are unknown. We found that obese mothers have an increased risk of all types of OFCs and that both pre-existing and gestational diabetes were associated with risk. We also found that mothers of OFC children have abnormal values for biomarkers that define metabolic syndrome, a precursor to gestational diabetes and later post-pregnancy diabetes, and that elevated levels of leptin, a signaling molecule produced both by fat tissue and by placenta tissues, may be important as an early biomarker of maternal metabolic abnormalities in early pregnancy, before the detection of overt GDM. The impact of our research has been extended by discovering evidence of associations between adipokine genes known to be associated with GDM (adiponectin and leptin) and the possibility that impaired vitamin B12 status may increasing with risk of both GDM and OFCs, hence strengthening the evidence for a causal association between GDM and risk of OFCs. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
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Progress 10/01/19 to 09/30/20
Outputs
Target Audience:Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects Changes/Problems:Work progress has been slowed by the COVID-19 pandemic. It is anticipated that with increases in vaccination and decline in the prevalence of COVID-19 by Spring 2021 that site visits and laboratory collaborations with NIH will resume. What opportunities for training and professional development has the project provided?Training activities have included mentoring of junior colleagues and students, presentation of the study background, analyses, and results in undergraduate and graduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included work with colleagues at several U.S. and international institutions to develop further grant proposals for the study of gestational diabetes and orofacial clefts. How have the results been disseminated to communities of interest?Results have been disseminated via classroom teaching to USU undergraduates and graduate students, non-governmental organizations that serve patient populations affected by orofacial clefts (Operation Smile and The Smile Train), via workshops and websites sponsored by the World Health Organization, the European Science Foundation, the U.S. National Institute for Dental and Craniofacial Research, and the scientific meetings listed above. What do you plan to do during the next reporting period to accomplish the goals?During 2021 we anticipate that the reduction of the COVID-19 pandemic due to widespread vaccination will allow us to continue our investigations of GDM and risk of OFCs using genetic and environmental data with Dr. Adeyemo at NIH, with Dr. Butali at the University of Iowa School of Dentistry, and with Dr Martinez at the University of Puerto Rico School of Dental Medicine. We will continue to develop grant proposals to be submitted to the U.S. NIH and the U.K and European Union funding agencies to extend our studies of GDM and OFCs to populations in Puerto Rico, Nigeria and other African countries. We will continue analyses of existing data and preparation of manuscripts.
Impacts
What was accomplished under these goals?
1) Major activities completed: The COVID-19 pandemic has severely affected activities related to the presentation of results at international conferences, laboratory assays of Utah samples, and site visits to collaborative sites. Dr. Munger was scheduled to present results of this study in an oral presentation at the meetings of the International Association for Dental Research in Washington, D.C. in March 2020, however this meeting was cancelled due to the pandemic. Another consequence of suspended travel was the cancellation of Dr. Munger's visit to Dr. Adebowale Adeyemo's laboratory at NHGRI/NIH in Washington D.C. Dr. Adeyemo is Deputy Director, Center for Research on Genomics and Global Health, and Associate Investigator, National Human Genome Research Institute, National Institutes of Health. Dr. Adeyemo has offered to assay stored Utah specimens for adipokines for the cost of kits only. Due to the pandemic, analytical work in Dr. Adeyemo's laboratory has been paused. The plans for further genotyping of the Utah samples in the laboratory of Dr. Azeez Butali of the University of Iowa College of Dentistry, have also been paused due to the pandemic. Dr. Munger has expanded collaborations with Dr. Carmen Buxo Martinez at the University of Puerto Rico School of Dental Medicine, but his planned site visit in 2020 was cancelled due to pandemic travel restrictions. Dr. Munger has continued to correspond with Dr. Martinez in developing a case-control study of orofacial clefts in Puerto Rico using biomarker methods developed in his Utah studies. With the cancellation of in-person and laboratory work Dr Munger has focused on manuscript preparation, further data analyses of existing data, literature reviews, and preparation of grant proposals. Dr. Munger led the preparation and submission of the manuscript "Maternal vitamin B12 status and risk of cleft lip and cleft palate birth defects in Tamil Nadu state, India" which has been accepted for publication in the Cleft Palate-Craniofacial Journal.Dr. Munger contributed as a co-investigator to the preparation of a grant proposal entitled "Folate and vitamin B12 and global health - evaluation of policies informed by integrated assessment of health effects" submitted to the Canadian Institutes of Health Research. Dr. Munger has worked with Dr. Butali (PI) and colleagues on preparation of a new NIH UO1 proposal to further study the role of maternal metabolic syndrome and gestational diabetes in orofacial clefts with a comprehensive approach including novel nutritional biomarkers, environmental exposures, and genomic analyses of populations in Utah, Puerto Rico, Europe, Africa, and Asia; submission is expected in mid-2021. 2) Specific objectives met: Analyses addressed Objective 4 in the original project proposal related to genetic analyses to investigate the association between gestational diabetes and risk of orofacial clefts. 3) Significant results achieved: As reported earlier, we found associations of note between orofacial clefts and genes known to be associated with gestational diabetes (GDM) including ADIPOQ (adiponectin) which is exclusively expressed in adipose tissue and is an important adipokine involved in the control of insulin sensitivity and fat metabolism with direct anti-diabetic activity and LEP (leptin) an adipokine made by adipose cells and enterocytes primarily known for involvement in regulating energy balance and hunger but recently found to be made by the placenta and to have important functions in pregnancy and to be expressed in the fetus during development. Recent publications have provided further evidence of significant associations between impaired vitamin B12 status and gestational diabetes. Our recently accepted manuscript reports on our completed biomarker assays of vitamin B12 status in samples from our case-control study in India which found associations between poor B12 status and risk of orofacial clefts. We concluded that mothers of CL+P children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. We are developing further studies in populations with diverse nutritional backgrounds to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL+P, and whether poor vitamin B12 status interacts with GDM or GDM-related genes to increase the risk of orofacial clefts. 4) Key impacts: OFCs occur at a higher rate in Utah than any other state and the reasons are unknown. We previously found that obese mothers have an increased risk of all types of OFCs and that both pre-existing and gestational diabetes were associated with risk. We also found previously that mothers of OFC children have abnormal values for biomarkers that define metabolic syndrome, a precursor to gestational diabetes and later post-pregnancy diabetes, and that elevated levels of leptin, a signaling molecule produced both by fat tissue and by placenta tissues, may be important as an early biomarker of maternal metabolic abnormalities in early pregnancy, before the detection of overt GDM. The impact of our research has been extended by discovering evidence of associations between adipokine genes known to be associated with GDM (adiponectin and leptin) and the possibility that impaired vitamin B12 status may increasing with risk of both GDM and OFCs, hence strengthening the evidence for a causal association between GDM and risk of OFCs. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
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Progress 10/01/18 to 09/30/19
Outputs
Target Audience:Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects. Changes/Problems:No Changes of program delays anticipated. What opportunities for training and professional development has the project provided?Training activities have included mentoring of junior colleagues and students, presentation of the study background, analyses, and results in undergraduate and graduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included work with colleagues at several U.S. and international institutions to develop further grant proposals for the study of gestational diabetes and orofacial clefts. How have the results been disseminated to communities of interest?Results have been disseminated via classroom teaching to USU undergraduates and graduate students, non-governmental organizations that serve patient populations affected by orofacial clefts (Operation Smile and The Smile Train), via workshops and websites sponsored by the World Health Organization, the European Science Foundation, the U.S. National Institute for Dental and Craniofacial Research, and the scientific meetings listed above. What do you plan to do during the next reporting period to accomplish the goals?During 2020 we will extend our investigations of GDM and risk of OFCs using genetic and environmental data from new collaborative projects with the University of Iowa School of Dentistry and the University of Puerto Rico School of Dental Medicine and continuing collaborations with the International Cleft Consortium, and the medical records obtained via collaboration with Intermountain Health Care, the University of Utah Health Care System, the Utah Department of Health and the Utah Population Data Base of the University of Utah. We will develop grant proposals to be submitted to the U.S. National Institutes of Health and the U.K and European Union funding agencies to extend our studies of GDM and OFCs to populations in Puerto Rico, Nigeria and other African countries. A new colleague in our NIH proposal development is Dr. Adebowale Adeyemo, Deputy Director, Center for Research on Genomics and Global Health, and Associate Investigator, National Human Genome Research Institute, National Institutes of Health. Dr. Adeyemo has offered to assay stored Utah specimen for adipokines for the cost of kits only and Co-PI on our NIH proposal, Dr. Azeez Butali of the University of Iowa College of Dentistry, has offered to genotype the Utah specimens for adipokine genes. Dr. Munger will share results of this study in an oral presentation at the meetings of the International Association for Dental Research in Washington, D.C. in March 2020. During these meetings in Washington Dr. Munger will convene research planning meetings with Drs. Butali, Martinez, and Adeyemo at NHGRI/NIH.
Impacts
What was accomplished under these goals?
1) Major activities completed. We have continued analyses of genetic data related to gestational diabetes (GDM) from the International Genetic Epidemiology study of Oral Clefts, a part of the Gene-Environment Association Studies Initiative (GENEVA) of the National Institutes of Health. As described previously, this study is a multi-center, international study of samples from Europe, the U.S., China, Taiwan, Singapore, Korea, and the Philippines. The study design is based on trios of children with an isolated orofacial cleft and their mothers and fathers using genome-wide association (GWA) data. We have expanded our collaborations with colleagues at the University of Iowa College of Dentistry (Dr. Azeez Butali) and the University of Puerto Rico School of Dental Medicine (Dr. Carmen Buxo Martinez). Dr. Butali is leading the genotyping efforts at Iowa with additional DNA specimens from our Utah studies, Puerto Rico, and Iowa. Dr. Munger is assisting Dr. Martinez in developing a case-control study of orofacial clefts in Puerto Rico using biomarker methods developed in his Utah studies. A recent meta-analysis has provided evidence of significant associations between impaired vitamin B12 status and gestational diabetes. While we are broadly interested the associations between orofacial cleft birth defects and genes known to be associated with gestational diabetes, we have developed a primary focus on leptin and adiponectin genes and potential interactions with impaired vitamin B12 status and other nutrients in folate-related one-carbon metabolism. We recently completed biomarker assays of vitamin B12 status in samples from our case-control study in India and found associations between poor B12 status and risk of orofacial clefts. 2) Specific objectives met: Analyses addressed Objective 4 in the original project proposal related to genetic analyses to investigate the association between gestational diabetes and risk of orofacial clefts. 3) Significant results achieved: Associations of note between orofacial clefts and genes known to be associated with gestational diabetes (GDM) in the GENEVA study sample include, among European trios, ADIPOQ (adiponectin, C1Q and collagen domain containing; for cleft palate w/o cleft lip) which is exclusively expressed in adipose tissue and is an important adipokine involved in the control of insulin sensitivity and fat metabolism with direct anti-diabetic activity. Also among the European trios, LEP (leptin; associated with cleft lip, w/o cleft palate via interaction with maternal smoking), an adipokine made by adipose cells and enterocytes primarily known for involvement in regulating energy balance and hunger but recently found to be made by the placenta and to have important functions in pregnancy and to be expressed in the fetus during development. A recent meta-analysis has provided evidence of significant associations between impaired vitamin B12 status and gestational diabetes. We recently completed biomarker assays of vitamin B12 status in samples from our case-control study in India and found associations between poor B12 status and risk of orofacial clefts. In this study case-mothers of children with cleft lip, with or without cleft palate (CL/P) (n=47) and control-mothers of unaffected children (n=50) were recruited an average of 1.4 years after birth of the index child and plasma vitamin B12, methylmalonic acid (MMA), total homocysteine (tHcy), and folate were measured at that time. Logistic regression analyses estimated associations between nutrient biomarkers and case-control status. Odds ratios (ORs) contrasting biomarker levels showed associations between case-mothers and low vs. high plasma vitamin B12 (OR=2.48, 95% CI 1.02, 6.01) and high vs. low plasma MMA, an indicator of poor B12 status (OR=3.65 95% CI 1.21, 11.05). Case-control status was not consistently associated with folate or tHCY levels. Low vitamin B12 status, when defined by a combination of both plasma vitamin B12 and MMA levels, had an even stronger association with case-mothers (OR=6.54, 95% CI 1.33, 32.09). We concluded that mothers of CL+P children in southern India were 6.5 times more likely to have poor vitamin B12 status, defined by multiple biomarkers, compared to control-mothers. Further studies in populations with diverse nutritional backgrounds are required to determine whether poor maternal vitamin B12 or folate levels or their interactions are causally related to CL+P, and whether poor vitamin B12 status interacts with GDM or GDM-related genes to increase the risk of orofacial clefts. 4) Key impacts: OFCs occur at a higher rate in Utah than any other state and the reasons are unknown. We previously found that obese mothers have an increased risk of all types of OFCs and that both pre-existing and gestational diabetes were associated with risk. We also found previously that mothers of OFC children have abnormal values for biomarkers that define metabolic syndrome, a precursor to gestational diabetes and later post-pregnancy diabetes, and that elevated levels of leptin, a signaling molecule produced both by fat tissue and by placenta tissues, may be important as an early biomarker of maternal metabolic abnormalities in early pregnancy, before the detection of overt GDM. In the past year the impact of our research has been extended by discovering evidence of associations between adipokine genes known to be associated with GDM (adiponectin and leptin) and the possibility that impaired vitamin B12 status may increasing with risk of both GDM and OFCs, hence strengthening the evidence for a causal association between GDM and risk of OFCs. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
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Progress 10/01/17 to 09/30/18
Outputs
Target Audience:Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects Changes/Problems:No Changes of program delays anticipated What opportunities for training and professional development has the project provided?Training activities have included mentoring of students, presentation of the study background, analyses, and results in undergraduate and graduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included oral presentations of research findings by Dr. Munger at the 75th annual meeting of the American Cleft Palate Craniofacial Association in Pittsburgh, the 45th annual meeting of the International Clearinghouse for Birth Defects Surveillance and Research in Prague, and an invited lecture at Lagos University Medical School in Lagos, Nigeria. Dr. Munger has assembled a team of epidemiologists, clinicians, and geneticists to develop grant proposals for related research in Nigeria and other African countries. How have the results been disseminated to communities of interest?Results have been disseminated via classroom teaching to USU undergraduates and graduate students, non-governmental organizations that serve patient populations affected by orofacial clefts (Operation Smile and The Smile Train), via workshops and websites sponsored by the World Health Organization, the European Science Foundation, the U.S. National Institute for Dental and Craniofacial Research, and the scientific meetings listed above. What do you plan to do during the next reporting period to accomplish the goals?During 2019 we will extend our investigations of GDM and risk of OFCs using genetic and environmental data from the International Cleft Consortium, and the medical records obtained via collaboration with Intermountain Health Care, the University of Utah Health Care System, the Utah Department of Health and the Utah Population Data Base of the University of Utah. We will develop grant proposals to be submitted to the U.S. National Institutes of Health and the U.K and European Union funding agencies to extend our studies of GDM and OFCs to populations in Nigeria and other African countries. A new colleague in our NIH proposal development is Dr. Adebowale Adeyemo, Deputy Director, Center for Research on Genomics and Global Health, and Associate Investigator, National Human Genome Research Institute, National Institutes of Health. Dr. Adeyemo has offered to assay stored Utah specimen for adipokines for the cost of kits only and Co-PI on our NIH proposal, Dr. Azeez Butali of the University of Iowa College of Dentistry, has offered to genotype the Utah specimens for adipokine genes. We will submit a request to the AES for supplemental funding in the amount of $16,000 to cover the costs of the adipokine kits and genotyping. The completion of this collaborative work would enhance the prospects of NIH funding of our grant proposal.
Impacts
What was accomplished under these goals?
1. Major activities completed. We have conducted analyses of genetic data related to gestational diabetes (GDM) from the International Genetic Epidemiology study of Oral Clefts, a part of the Gene-Environment Association Studies Initiative (GENEVA) of the National Institutes of Health. This study is a multi-center, international study of samples from Europe, the U.S., (including Utah with samples from Dr. Munger's NIH-funded case-control study of orofacial clefts), China, Taiwan, Singapore, Korea, and the Philippines. The study design is based on trios of children with an isolated orofacial cleft and their mothers and fathers using genome-wide association (GWA) data. Families were recruited from treatment centers or population-based registries. Research protocols were reviewed and approved by institutional review boards of each participating institutions and parents provided informed consent. Principal Components Analysis (PCA) was used to document ancestral population affiliation. OFC cases were examined by either a clinical geneticist or an experienced clinician to minimize misclassification of the OFCs. All cases with cleft palate with or without cleft lip (CP/L) were analyzed together based on evidence that maternal obesity and diabetes have a specific effect on palate development. Trios having CL/P and CP/L were analyzed in this study separately. 2. Specific objectives met: Analyses addressed Objective 4 in the original project proposal related to genetic analyses to investigate the association between gestational diabetes and risk of orofacial clefts. 3. Significant results achieved: Genetic data from the GENEVA study of orofacial clefts (OFCs) include trios of 892 cleft lip with or without cleft palate cases (CL/P) and 910 cleft palate with or without cleft lip (CP/L) cases of Asian ancestry and 665 CL/P and 644 CP/L cases of European ancestry. Twenty GDM-related genes were selected for analysis of association with OFCs. Genotypic transmission disequilibrium tests (gTDT) were used to analyze genetic effects and gene-environment (GxE) interactions with periconceptional maternal multivitamin use (PCMV), smoking, and environmental tobacco smoke (ETS). GDM genetic associations of note include the following: (1) SLC30A8 was associated with CL/P and HNF1B was associated with CP/L in Asian trios. (2) In Europeans, ADRB3 and TNF-α were associated with both CL/P and CP/L; ABCC8 was associated with CL/P only and ADIPOQ and HNF1 were associated with CP/L only. (3) Considering interactions with PCMV, associations were found for ABCC8 and CDKAL1 in Europeans. (4) Considering interactions with maternal smoking, associations were found for CDKN2A/2B in Asian and for LEP in Europeans. (5) In Asians, FTO, HHEX, and PPARG had associations with OFCs when considering interaction with ETS. In conclusion several genes related to GDM were associated with risk of isolated CL/P and CP/L through genotypic effects alone and gene-environment interactions with PCMV, maternal smoking, and ETS. These associations do not point to a single major GDM gene associated with OFCs, but support the hypothesis that GDM may be causally related to OFCs via multiple GDM susceptibility genes and interactions with environmental factors. 4. Key impacts: OFCs occur at a higher rate in Utah than any other state and the reasons are unknown. We previously found that obese mothers have an increased risk of all types of OFCs and that both pre-existing and gestational diabetes were associated with risk. We also found previously that mothers of OFC children have abnormal values for biomarkers that define metabolic syndrome, a precursor to gestational diabetes and later post-pregnancy diabetes, and that elevated levels of leptin, a signaling molecule produced both by fat tissue and by placenta tissues, may be important as an early biomarker of maternal metabolic abnormalities in early pregnancy, before the detection of overt GDM. In the past year the impact of our research has been extended by discovering evidence of associations between genes known to be associated with GDM and risk of OFCs, hence strengthening the evidence for a causal association between GDM and risk of OFCs. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2018
Citation:
Presentations
Munger, R. G., African Craniofacial Anomalies Network Meeting, "Development of studies of maternal nutritional and genetic factors related to cleft lip and palate in Nigeria," Lagos University Medical School, Lagos, Nigeria. (July 2, 2018 - July 6, 2018)
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2018
Citation:
Presentations
Maneerattansuporn, T. (Author Only), Munger, R. G. (Presenter & Author), Feldkamp, M. (Author Only), Nance, A. (Author Only), American Cleft Palate Craniofacial Association 75th Annual Meeting, "Gestational diabetes and maternal metabolic syndrome biomarkers are associated with risk of orofacial clefts," American Cleft Palate Craniofacial Association, Pittsburgh, Pennsylvania. (April 10, 2018 - April 14, 2018)
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Progress 10/01/16 to 09/30/17
Outputs
Target Audience:Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects Changes/Problems:No Changes of program delays anticipated What opportunities for training and professional development has the project provided?Training activities have included mentoring of PhD candidate Tiwaporn Maneerattansuporn and presentation of the study background, analyses, and results in undergraduate and graduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included an invited honorary lecture, The Fenton Braithwaite Oration, by Dr. Munger at the 13th International Cleft Congress and the 16th Annual Meeting of the India Society of Cleft Lip and Palate, held 8-11 February 2017 in Chennai, India. How have the results been disseminated to communities of interest?Results have been disseminated via classroom teaching to USU undergraduates and graduate students, non-governmental organizations that serve patient populations affected by orofacial clefts (Operation Smile and The Smile Train), via workshops and websites sponsored by the World Health Organization, the European Science Foundation, the U.S. National Institute for Dental and Craniofacial Research, and the scientific meetings of the India Society of Cleft Lip and Palate, and the American Cleft Palate Craniofacial Association. What do you plan to do during the next reporting period to accomplish the goals?During 2018 we will extend our investigations of gestational diabetes and risk of orofacial clefts using data from the International Cleft Consortium, and the medical records obtained via collaboration with Intermountain Health Care, the University of Utah Health Care System, the Utah Department of Health and the Utah Population Data Base of the University of Utah.
Impacts
What was accomplished under these goals?
1) Major activities completed. We have conducted analyses of data from a state-wide case-control study of orofacial cleft (OFC) birth defects conducted by Dr. Munger. Cases were children born during the period 1995-2005 with an isolated cleft lip or cleft palate or both. Controls were unaffected children randomly selected from birth certificates. Mothers of case and control children were interviewed and physical examinations and blood collections were completed in clinical visits 10 years (mean) after the index birth. Laboratory assays of maternal biomarkers related to metabolic syndrome (MS) and gestational diabetes mellitus (GDM) were completed. Logistic regression analyses estimated risk for OFCs while adjusting for the potential confounding effects of maternal age and smoking. 2) Specific objectives met: These analyses address Objectives 1, 2, and 5 in the original project proposal. 3) Significant results achieved: Analyses were based on data from 268 case-mothers and 344 control-mothers. Obese mothers (body mass index ≥ 30 kg/m2 ) had a higher risk of OFCs compared to normal weight (18.5-24.9 kg/m2) mothers (odds ratio (OR) = 1.45, 95% confidence interval (CI): 0.99, 2.13). Mothers of children with cleft palate, with or without cleft lip (CP/L), compared to controls, had higher mean levels of plasma glucose, insulin, triglycerides, waist circumference and systolic blood pressure, and lower HDL cholesterol; these associations were not seen for mothers of children with cleft lip only (CLO). Similarly, mean plasma leptin and IL-8 levels were higher among mothers of CP/L cases compared to controls; this association was not found among mothers of CLO cases. Elevated leptin level (highest vs. lowest tertile) was associated with CP/L (OR = 2.21, 95% CI: 1.28-3.81; p-trend 0.004) but was not associated with CLO (OR = 1.07; 95% CI: 0.54, 2.12). The International Diabetes Federation (IDF) index of MS biomarkers was associated with CP/L (OR = 1.64, 95% CI: 1.04-2.59) but not with CLO (OR = 1.16, 95% CI: 0.62, 2.17). Mothers having GDM in any pregnancy had an increased risk of OFCs (OR = 3.05, 95% CI: 1.61-5.80) and this was consistent for each specific type of OFC. From these data analyses we conclude that metabolic abnormalities underlying elevated MS biomarkers and GDM may contribute to the risk of OFCs. Elevated metabolic syndrome biomarkers and the IDF MS index, measured many years after the index births, were associated with risk of CP/L but not CLO. GDM was associated with all types of OFCs. Palate development may be more susceptible to disruption by milder MS abnormalities than lip development while the more severe abnormality of GDM appears sufficient to disrupt both palate and lip development. Leptin and IL-8 biomarkers of systemic inflammation may provide insight into metabolic abnormalities in the periconceptional period linked to OFCs. Evaluation of MS biomarkers during the period of palate and lip formation is needed in future studies. 4) Key impacts: Oral clefts occur at a higher rate in Utah than any other state and the reasons are unknown. Our previous findings based solely on Utah birth certificates, without direct interviews or the collection of biomarker data, provided evidence that obese mothers have an increased risk of all types of orofacial clefts and that both pre-existing and gestational diabetes were associated with orofacial cleft risk. In the past year of our study the impacts of our research have been extended by providing evidence from biomarker studies that mothers of cleft children have abnormal values for biomarkers that define metabolic syndrome, a precursor to gestational diabetes and later post-pregnancy diabetes. Our findings regarding elevated levels of leptin, a signaling molecule produced both by fat tissue and by placenta tissues, may be important as early biomarker of maternal metabolic abnormalities in early pregnancy, before the detection of overt gestational diabetes. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2017
Citation:
Munger, R. G., 13th International Congress of Cleft Lip and Palate and Related Craniofacial Anomalies, "Maternal nutrition, social justice, and the prevention of orofacial clefts," International Confederation of Cleft Lip and Palate and Related Craniofacial Anomalies, Chennai, India. (2017 - February 11, 2017)
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2017
Citation:
Munger, R. G., 13th International Congress of Cleft Lip and Palate and Related Craniofacial Anomalies, "Maternal Obesity, Gestational Diabetes, and the Prevention of Orofacial Clefts," International Confederation of Cleft Lip and Palate and Related Craniofacial Anomalies, Chennai, India. (2017 - February 9, 2017)
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2017
Citation:
Munger, R. G., 13th International Congress of Cleft Lip and Palate and Craniofacial Anomalies, "Co-Chair, Session on Research in Clefts and Craniofacial Anomalies," International Consortium for Cleft Lip and Palate and Craniofacial Anomalies, Chennai, India. (February 9, 2017)
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Progress 07/01/16 to 09/30/16
Outputs
Target Audience:Target Audience Academic researchers in areas of nutrition, public health, and birth defects; non-governmental organizations providing services to families affects by birth defects; families affected by birth defects Changes/Problems:Changes/Problems No Changes or program delays anticipated What opportunities for training and professional development has the project provided?Opportunities Training activities have included mentoring of PhD candidate Tiwaporn Maneerattansuporn and presentation of the study background, analyses, and results in undergraduate courses in nutrition, public health, and epidemiology taught by Dr. Munger. Professional development activities have included (1) an invited lecture by Dr. Munger at the University of Dundee, Scotland, Workshop on Orofacial Clefts sponsored by the European Science Foundation (1 July 2016) and (2) an invited lecture by Dr. Munger at the Workshop on Gene-Environment Interactions and Orofacial Clefts sponsored by the Institute of Dental and Craniofacial Research of the U.S. National Institutes of Health (6-8 Sept 2016). How have the results been disseminated to communities of interest?Dissemination Results have been disseminated via classroom teaching to undergraduates, non-governmental organizations that serve patient populations affected by orofacial clefts, and via workshops and websites sponsored by the World Health Organization, the European Science Foundation, and the U.S. National Institutes of Health What do you plan to do during the next reporting period to accomplish the goals?Plan of Work During 2017 we will extend our investigations of gestational diabetes and risk of orofacial clefts using linked medical records obtained via collaboration with the Utah Department of Health and the Utah Population Data Base of the University of Utah
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed. We have conducted analyses of Utah birth certificates of children born with orofacial clefts identified by the Utah Birth Defects Network of the Utah Department of Health. Birth certificates of randomly selected children without orofacial clefts were analyzed as controls in a case-control study maternal pre-pregnancy weight and history of gestational diabetes and risk of orofacial clefts. 2) Specific objectives met: These analyses address Objectives 1, 2, and 5 in the original project proposal. 3) Significant results achieved: Cases of orofacial clefts born to Utah resident mothers during 1995-2011 were ascertained by the state-wide Utah birth defects registry. Birth certificates of unaffected Utah children were randomly selected as controls at a ratio of 4:1 to cases, matched by birth month and year. Case records were linked to Utah birth certificates by the Utah Population Data Base of the University of Utah. Odds ratios (ORs) and 95% confidence intervals (CIs) were calculated to estimate the relative risk for orofacial cleft subtypes associated with maternal pre-pregnancy weight and maternal gestational diabetes (GDM). Multiple logistic regression analysis was used to adjust for the potential confounding effects of maternal age, education, body mass index (BMI), and depression. Pre-existing diabetes, gestational diabetes mellitus (GDM), and all diabetes were evaluated as mediating variables in the association between maternal obesity and risk of OFCs. Results are based on 1,451 live-born cases with registry diagnoses, reflected a successful linkage of 99 percent of the orofacial cleft cases to birth certificates. Obesity increased risk of both non-isolated and isolated OFCs (adjusted odds ratios (aOR): 1.41, 95%CI: 1.07-1.87 and aOR: 1.23, 95% confidence interval (CI): 1.01-1.50, respectively). Underweight mothers had a reduced risk of cleft lip only (CLO) (aOR: 0.46, 95%CI: 0.24-0.88), and an increased risk of cleft palate only (CPO) (aOR: 1.50, 95%CI: 1.04-2.16). Maternal depression increased risk of all OFCs (aOR: 1.31, 95%CI: 1.00-1.73). Pre-existing diabetes increased risk of all OFCs (aOR: 2.19, 95% CI: 1.18-4.09) with a larger effect for non-isolated OFCs (aOR: 3.83, 95%CI: 1.71-8.58) vs isolated OFCs (aOR: 1.54, 95%CI: 0.70-3.41). GDM mothers had an increased risk of all OFCs (aOR: 1.48, 95%CI: 1.05-2.09) with a larger effect for non-isolated OFCs (aOR: 2.29, 95%CI: 1.41-3.72) vs isolated OFCs (aOR: 1.15, 95%CI: 0.75-1.77). Mediation analysis indicated that obesity had a direct effect of increasing the risk of OFCs without the mediating effect of known maternal diabetes. 4) Key impacts: Oral clefts occur at a higher rate in Utah than any other state and the reasons are unknown. Our results have an important impact because they suggest that extremes of maternal pre-pregnancy weight are associated with risk of orofacial clefts with obese mothers having an increased risk of all types of orofacial clefts, while underweight mothers having a decreased risk of cleft lip only and an increased risk of cleft palate only. Maternal depression was also associated with OFC risk and merits further investigation. Both pre-existing and gestational diabetes were associated with orofacial cleft risk, with strongest effects for non-isolated orofacial clefts. Both stratification and mediation analyses suggest an effect of obesity on orofacial clefts apart from known maternal diabetes. The growing epidemics of obesity and diabetes and the challenge of early detection and treatment of GDM underscore the public health importance of further research in this area More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses nutrition education, the early detection and treatment of gestational diabetes, and measures to reduce the risk of gestational diabetes including the reduction of obesity.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2016
Citation:
Kutbi, H., Wehby, G. L., Moreno Uribe, L. M., Romitti, P. A., Carmichael, S., Shaw, G. M., Olshan, A. F., DeRoo, L., Rasmussen, S., Murray, J. C., Wilcox, A., Lie, R. T., Munger-Corresponding Author, R. (2016). Maternal underweight and obesity and risk of orofacial clefts in a large international consortium of population-based studies. Int J Epidemiol. http://www.ncbi.nlm.nih.gov/pubmed/27215617
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2016
Citation:
Presentations
Munger, R. G., NIDCR-NIH Workshop on Gene-Environment Interaction in Orofacial Clefting, "Overview of diet, maternal obesity, and micronutrients and risk of orofacial clefts," U.S. National Institutes of Health - Institute for Dental and Craniofacial Research, Bethesday, Maryland. (September 6, 2016 - September 7, 2016)
- Type:
Conference Papers and Presentations
Status:
Other
Year Published:
2016
Citation:
Presentations
Munger, R. G., EUROCLeftNet Research Conference on Genetics, Environment and Prevention of Orofacial Clefts, "Biomarkers of maternal exposures and metabolic abnormalities and risk of ororfacial clefts," European Science Foundation and The University of Dundee, Dundee, Scotland. (June 30, 2016 - July 1, 2016)
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