Progress 07/01/11 to 06/30/16
Outputs
Target Audience:Target Audience Clinicians involved in caring for children with cleft and cleft palate birth defects, researchers investigating causes of clefts, staff and constituents of non-governmental organizations involved in medical care for patients with oral clefts. Changes/Problems:Changes/Problems During the last project year, we discovered that folate assays conducted by colleagues using radioimmunoassay kits were likely flawed. We resolved this problem by analyzing additional aliquots using microbiologic assays for folate and B12 at the laboratory of Dr. Anne Molloy, Trinity College, Dublin, Ireland, and using mass spectrometry methods in the laboratory of Dr. Per Ueland, Bergen University, Norway. We are satisfied that the update folate results are valid and confirmed that the previous B12 results from India are in close agreement with the findings from the Ireland and Norway laboratories. What opportunities for training and professional development has the project provided?Opportunities Two PhD students of Dr. Munger, Ms. Meo La and Ms. Hebah Kutbi completed and successfully defended their dissertations during this project. A third PhD student, Ms. Tiwaporn Maneerattansuporn, completed data collection for her dissertation research on this project and is scheduled to finished writing her PhD dissertation in later 2016. Dr. Munger has collaborated with colleagues at the University of Iowa College of Medicine, Sri Ramachandra Medical School in Chennai, India, St. Johns University, Bangalore, India, Trinity College, Dublin, Ireland, University of Bergen, Bergen, Norway, and University of Dundee, Dundee, Scotland and has learned new research methods and discovered new opportunities at these institutions for mentoring and research. Dr. Munger has presented research findings from this project to the Division of Medical Genetics and to the Department of Obstetrics and Gynecology at the University of Utah, Sri Ramachandra Medical School in Chennai, India, The European Science Foundation and Dundee University, Scotland, and the U.S. National Institutes of Dental Research, U.S. National Institutes of Health, Bethesda, Maryland. How have the results been disseminated to communities of interest?Dissemination Dr. Munger and Ms. Maneerattansuporn have each presented findings at the USU graduate seminar in Epidemiology, Biostatistics, and Public Health 2015. Dr. Munger has conducted regular workshops and Skype conference calls on research methods in nutrition and epidemiology and oral clefts with colleagues at the Sri Ramachandra Medical University, Chennai, India. Dr. Munger hosted the visit to USU of a doctoral researcher from India, Ms. Rajarajeswari Kuppuswamy, during 13-27 May, 2015 for training in collaborative studies of orofacial cleft birth defects. Dr. Munger presented an invited seminar on 11 March 2015 at the Division of Medical Genetics, Department of Pediatrics and the University of Utah. On 13 August 2015 Dr. Munger presented a seminar at the Department of Obstetrics and Gynecology at the University of Utah. Dr. Munger's research group gave an oral presentation of results at the 7th International Conference on Birth Defects and Disabilities in the Developing World, Dar-es-Salam, Tanzania, 21-24 September 2015; Ms. Kuppuswamy gave the oral presentation. Dr. Munger gave an invited seminar and workshop for the Craniofacial Research Group at the University Iowa College of Medicine on 11 Sept 2015. Dr. Munger presented findings as a speaker at an invited workshop at Sri Ramachandra University, Chennai, India during 26-27 June 2016. Dr. Munger also gave an invited lecture on this work at the EuroCleftNet Meeting on the Genetics of Orofacial Clefts, Sponsored by the European Science Foundation, at the University of Dundee, Scotland, during 29-30 June, 2016. What do you plan to do during the next reporting period to accomplish the goals?Plan of Work The project has been completed. This is the final report.
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed: We have extended analyses of folate-related biomarkers, genes, gene x biomarker interactions, folic acid and multivitamin use in association with risk of cleft lip and cleft palate birth defects. 2) Specific objectives met: Analyses and reports meeting objectives 1-4 outlined in our Methods section. 3) Significant results achieved: We previously reported lower plasma and red cell folate in Utah mothers of orofacial cleft (OFC) cases compared to controls based on the microbiologic assay (MA) and case-control differences in dose-response curves by level of folic acid intake. We re-analyzed plasma aliquots from the same subjects using ls-ms/ms platforms to identify specific folate forms including 5-methyltetrahydrofolate (5mTHF), unmetabolized free folic acid (FFA), 4-a-hydroxy-5-methyl-dihydrofolate (4hmDHF), para-aminobenzoyl-glutamate (pABGlu), acetamidobenzoyl-glutamate (apABG), and sum of the analytes (SUM). We found higher mean levels in controls compared to cases for FFA (+65%, p=0.04) and apABG (+9%, p=0.001), but no significant differences for 5mTHF, 4hmDHF, pABG, or SUM. The ratio of lc-ms/ms vs. MA total plasma folate was 136% for cases and 112% for controls (p<0.001); these findings suggest that the ls-ms/ms and MA assays detect different folate forms and that the distribution of folate forms may differ between cases and controls. In our most recent review of the literature, completed during 2016 we learned that other investigators have generally found that the microbiologic assays of plasma and red cell folate appear to capture data that more accurately define biological activity of folate forms, as opposed to lc/msms methods; our findings seem to confirm this view because we find stronger associations between the microbiologic measures and cleft risk compared to the ls/msms measures of folates. Using genome-wide data from the collaborative NIH-support GENEVA study, which include our Utah samples and numerous other populations of European and Asian ancestry, we evaluated genotypes of maternal folate-related one-carbon metabolism (1CM) genes and gene-nutrient interations; we found genotypic associations with OFC risk for FUT6, gene-vitamin intake interactions for CBS in the Asian sample and MMAA and MTHFR in the European sample. Five OCM genes (FUT6, MMAA, MMACHC, MTHFD1, and MTHFR) showed evidence of gene-environment interactions with maternal 1CM-related biomarker in influencing risk to OFC in the Utah sample, the only sample with plasma nutrient biomarkers. These findings support the hypothesis that multiple genes and nutrients in the 1CM pathway are associated with risk of OFCs. We also completed a pilot case-control study of 50 mothers of children with OFCs and 50 mothers of unaffected children in Thiruvallur District, Tamil Nadu, India. Blood samples were collected from mothers at 1.4 years (median) after delivery, rapidly processed, and stored at -80 until analysis. We re-analyzed folate samples using labs at Trinity College, Dublin, Ireland, (microbiologic assays) and University of Bergen, Norway, and found that our previous folate assays using radioimmunoassay kits in India were flawed; this re-assessment found no evidence of a plasma folate-cleft association in contrast to the previous report. Our re-evaluation B12 related biomarkers confirmed the previous findings from India of a reduced risk of OFCs among mothers with high vs. low plasma vitamin B12 (OR = O.51, 95% CI 0.22, 1.14). Analysis of methylmalonic acid provided additional evidence for the involvement of poor vitamin B12 status (p = 0.028). Folate levels of case mothers declined with increasing time after delivery but levels of control mothers were stable. Our pilot study results in India indicate persistent, impaired B12 status is associated with risk of OFCs and are being used to scope a larger-scale study involving all nutrients involved in one-carbon metabolism and other potential environmental risk factors; these findings are consistent with our Utah results. Biomarker studies with common protocols are needed in diverse populations to provide a stronger scientific foundation for the prevention of OFCs. 4) Key impacts or other accomplishments realized: Oral clefts occur at a higher rate in Utah than any other state and the reasons are unknown. Rates are also high in developing countries and we have expanded our studies to India. Our results have an important impact because they suggest that maternal multivitamin use alone is unlikely to reduce the risk of oral clefts-- a combination however of maternal folic acid supplementation, perhaps at a level above the usual 400 ug/day dose and a healthy DASH dietary pattern with high intakes of fruits and vegetables, low-fat dairy products, reduced saturated fat and red meat intake, increased poultry and fish intake, and reduced intake of sweetened beverages and added sugars may reduce the risk by 50 percent. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses multivitamin use and nutrition education. Further we have found that mothers of cleft children in Utah have a lower plasma folate response to folic acid supplementation and we have found genetic associations that may partially explain the impaired response to folic acid supplementation. However, the nutritional background in India is quite different with B12 status being perhaps a more important modifier of one-carbon metabolism than folate status. Further studies of multiple nutrients and genes involved in one-carbon metabolism and risk of clefts is needed in diverse global populations to further our understanding of the causes and prevention of oral facial cleft birth defects.
Publications
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Progress 10/01/14 to 09/30/15
Outputs
Target Audience:Target Audience Clinicians involved in caring for children with cleft and cleft palate birth defects, researchers investigating causes of clefts, staff and constituents of non-governmental organizations involved in medical care for patients with oral clefts. Changes/Problems:Changes/Problems No major changes or problems. What opportunities for training and professional development has the project provided?Opportunities Two PhD students of Dr. Munger, Ms. Meo La and Ms. Hebah Kutbi completed and successfully defended their dissertations in 2014. A third PhD student, Ms. Tiwaporn Maneerattansuporn, is now completing her dissertation research on this project and is contributing to data analyses. Dr. Munger has collaborated with colleagues at the University of Iowa College of Medicine, Sri Ramachandra Medical School in Chennai, India, St. Johns University, Bangalore, India, Trinity College, Dublin, Ireland, University of Bergan, Bergan, Norway, and University of Dundee, Dundee, Scotland and has learned new research methods and discovered new opportunities at these institutions for mentoring and research. Dr. Munger has been invited to present findings to the Division of Medical Genetics and to the Department of Obstetrics and Gynecology at the University of Utah and in currently involved in discussions with these colleagues regarding additional collaborative studies. How have the results been disseminated to communities of interest?Dissemination Dr. Munger and Ms. Maneerattansuporn have each presented findings at the USU graduate seminar in Epidemiology, Biostatistics, and Public Health 2015. Dr. Munger has conducted regular workshops and Skype conference calls on research methods in nutrition and epidemiology and oral clefts with colleagues at the Sri Ramachandra Medical University, Chennai, India. Dr. Munger hosted the visit to USU of a doctoral researcher from India, Ms. Rajarajeswari Kuppuswamy, during 13-27 May, 2015 for training in collaborative studies of orofacial cleft birth defects. Dr. Munger presented an invited seminar on 11 March 2015 at the Division of Medical Genetics, Department of Pediatrics and the University of Utah. On 13 August 2015 Dr. Munger presented a seminar at the Department of Obstetrics and Gynecology at the University of Utah. Dr. Munger's research group gave an oral presentation of results at the 7th International Conference on Birth Defects and Disabilities in the Developing World, Dar-es-Salam, Tanzania, 21-24 September 2015; Ms. Kuppuswamy gave the oral presentation. Dr. Munger gave an invited seminar and workshop for the Craniofacial Research Group at the University Iowa College of Medicine on 11 Sept 2015. What do you plan to do during the next reporting period to accomplish the goals?Plan of Work During 2016 we will extend our investigation of folate-related genes, folate-related biomarkers, dietary intake and risk of orofacial clefts. This plan of work addresses objectives 3 and 4 listed in the Methods section.
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed: We have extended analyses of folate-related biomarkers, genes, gene x biomarker interactions, folic acid and multivitamin use in association with risk of cleft lip and cleft palate birth defects. 2) Specific objectives met: Analyses and reports meeting objectives 1-4 outlined in our Methods section. 3) Significant results achieved: We previously reported lower plasma and red cell folate in mothers of orofacial cleft (OFC) cases compared to controls based on the microbiologic assay (MA) and case-control differences in dose-response curves by level of folic acid intake. We re-analyzed plasma aliquots from the same subjects using ls-ms/ms platforms to identify specific folate forms including 5-methyltetrahydrofolate (5mTHF), unmetabolized free folic acid (FFA), 4-a-hydroxy-5-methyl-dihydrofolate (4hmDHF), para-aminobenzoyl-glutamate (pABGlu), acetamidobenzoyl-glutamate (apABG), and sum of the analytes (SUM). We found higher mean levels in controls compared to cases for FFA (+65%, p=0.04) and apABG (+9%, p=0.001), but no significant differences for 5mTHF, 4hmDHF, pABG, or SUM. The ratio of lc-ms/ms vs. MA total plasma folate was 136% for cases and 112% for controls (p<0.001); these findings suggest that the ls-ms/ms and MA assays detect different folate forms and that the distribution of folate forms may differ between cases and control. We evaluated genotypes for maternal folate-related genes and found associations with OFC risk for MTRR, MTR, NNMT, MTHFR, GART; only DHFR was associated with folate-related biomarkers. We completed a piloted case-control study of 50 mothers of children with OFCs and 50 mothers of unaffected children in Thiruvallur District, Tamil Nadu, India. Blood samples were collected from mothers at 1.4 years (median) after delivery, rapidly processed, and stored at -80 until analysis. Evaluation of odds ratios (ORs) for biomarker levels above and below the median, provided evidence of reduced risk of OFCs among mothers with high vs. low plasma folate (OR = 0.12, 95% CI 0.05-0.30) and high vs. low plasma vitamin B12 (OR = O.51, 95% CI 0.22, 1.14). Analysis of methylmalonic acid provided additional evidence for the involvement of poor vitamin B12 status (p = 0.028). Folate levels of case mothers declined with increasing time after delivery but levels of control mothers were stable. Our pilot study results in India indicate persistent, impaired maternal folate and B12 status are associated with risk of OFCs and are being used to scope a larger-scale study involving all nutrients involved in one-carbon metabolism and other potential environmental risk factors; these findings are consistent with our Utah results. Biomarker studies with common protocols are needed in diverse populations to provide a stronger scientific foundation for the prevention of OFCs. 4) Key impacts or other accomplishments realized: Oral clefts occur at a higher rate in Utah than any other state and the reasons are unknown. Rates are also high in developing countries and we have expanded our studies to India. Our results have an important impact because they suggest that maternal multivitamin use alone is unlikely to reduce the risk of oral clefts-- a combination however of maternal folic acid supplementation, perhaps at a level above the usual 400 ug/day dose and a healthy DASH dietary pattern with high intakes of fruits and vegetables, low-fat dairy products, reduced saturated fat and red meat intake, increased poultry and fish intake, and reduced intake of sweetened beverages and added sugars may reduce the risk by 50 percent. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses multivitamin use and nutrition education. Further we have found that mothers of cleft children have a lower plasma folate response to folic acid supplementation and we have found genetic associations that may partially explain the impaired response to folic acid supplementation. We have also found that underweight and obese mothers, and those with gestational diabetes have a higher risk of having a child with an oral cleft.
Publications
- Type:
Other
Status:
Published
Year Published:
2015
Citation:
Refereed Journal Articles
Botto, L. D., Krikov, S., Carmichael, S. L., Munger, R. G., Shaw, G. M., Feldkamp, M. L. (2015). Lower rate of selected congenital heart defects with better maternal diet quality: a population-based study. Archives of Disease in Childhood-Fetal and Neonatal Edition, 101(1), 43-9.
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Progress 10/01/13 to 09/30/14
Outputs
Target Audience: Target Audience Clinicians involved in caring for children with cleft and cleft palate birth defects, researchers investigating causes of clefts, staff and constituents of non-governmental organizations involved in medical care for patients with oral clefts. Changes/Problems: Changes/Problems No Major changes or problems What opportunities for training and professional development has the project provided? Opportunities The project has provided training for two PhD students of Dr. Munger, Ms. Meo La and Ms. Hebah Kutbi. Both of these students completed their PhD dissertations in 2014. Dr. Munger has collaborated with colleagues at Sri Ramachandra Medical School in Chennai, India, and University of Dundee, Scotland, and has learned new research methods and discovered new opportunities there for mentoring and research. How have the results been disseminated to communities of interest? Dissemination Ms. Kutbi, Ma. La, and Dr. Munger have presented findings at the USU Epidemiology Seminars in 2014. Dr. Munger conducted a workshop on research methods in nutrition and epidemiology and oral clefts at Sri Ramachandra Medical University, Chennai, India, during December 10-16, 2014. What do you plan to do during the next reporting period to accomplish the goals? Plan of Work During 2015 we will begin investigation of associations between genes related to gestational diabetes and oral clefts and will extend our investigation of folate-related genes, folate-related biomarkers, and biomarkers of metabolic syndrome (glucose, insulin, lipids, blood pressure) related to obesity. We will also investigate associations between biomarkers of metabolic syndrome and systemic inflammation and risk of oral clefts. This plan of work addresses objectives 3 and 4 listed in the Methods section.
Impacts
What was accomplished under these goals?
Accomplishments 1) Major activities completed: We have extended analyses of folate-related genes, gene x nutrient interactions, maternal dietary patterns, multivitamin use, folate-related blood biomarkers, body mass index, and diabetes history in association with risk of cleft lip and cleft palate birth defects. 2) Specific objectives met: Analyses and reports meeting objectives 1-4 outlined in our Methods section. 3) Significant results achieved: Ms. Meo La completed her PhD dissertation in 2014 and three manuscripts reporting results of this study: (1) Dietary patterns and risk of oral clefts: the combination of periconceptional multivitamin use and a healthy DASH dietary pattern was associated with a 55% reduction in risk of isolated oral clefts, evidence that prevention of oral clefts may require attention to both periconceptional multivitamin use and improving maternal diets. (2) Blood folate levels related to folic acid intake: Mothers of cleft children had lower plasma folate levels at each level of folic acid intake compared to controls, evidence that higher folate intake levels may be required for mothers with a history of a cleft -affected pregnancy. (3) Folate-related one-carbon metabolism genes and risk of oral clefts: FUT6 and TCN2, both known to be associated with vitamin B12, were associated with cleft risk. . Gene by maternal multivitamin use interaction revealed six genes associated with cleft risk: CBS, MTHFD2L, DHFR, MMAA, MTR, and TCN2. In the Utah samples with measured maternal blood biomarkers, GART, MUT, and TCN1 were associated with cleft risk through gene-biomarker interaction. Ms. Hebah Kutbi completed her PhD dissertation in 2014 and three manuscripts reporting results of this study: (1) Maternal body-mass index and risk or oral clefts: maternal obesity (pre-pregnancy BMI >30), compared to normal weight (18.5<BMI>25), was associated with an increased risk of cleft palate with or without cleft lip (CP/L), after adjusting for maternal age, multivitamin use, smoking during pregnancy, alcohol use, and education level. A marginal association was found between maternal underweight and CP/L. Cleft lip only was not associated with underweight or obesity. (2) Case-control study of maternal diabetes and risk of oral clefts in Utah: gestational diabetes mellitus and hypertension were associated with oral clefts suggesting a possible existence of underlying abnormalities related to metabolic syndrome prior to pregnancy. (3) International consortium case-control study of maternal diabetes and oral clefts: in a sample of 5000 mothers of children with cleft lip and/or cleft palate (CL-P) and 10,800 mothers of unaffected children from Europe and North America, maternal diabetes mellitus was significantly associated with an elevated risk of all types of OFCs. The elevated risk among diabetics only occurred among underweight, overweight, and obese mothers. 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 maternal multivitamin use alone is unlikely to reduce the risk of oral clefts-- a combination however of maternal multivitamin use and a healthy dietary pattern with high intakes of fruits and vegetables, low-fat dairy products, reduced saturated fat and red meat intake, increased poultry and fish intake, and reduced intake of sweetened beverages and added sugars may reduce the risk by 50 percent. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses multivitamin use and nutrition education. Further we have found that mothers of cleft children have a lower plasma folate response to folic acid supplementation and we have found genetic associations that may partially explain the impaired response to folic acid supplementation. We have also found that underweight and obese mothers, and those with gestational diabetes have a higher risk of having a child with an oral cleft.
Publications
|
Progress 01/01/13 to 09/30/13
Outputs
Target Audience: Clinicians involved in caring for children with cleft and cleft palate birth defects, researchers investigating causes of clefts, staff and constituents of non-governmental organizations involved in medical care for patients with oral clefts. Changes/Problems:
Nothing Reported
What opportunities for training and professional development has the project provided? The project has provide training for two PhD students of Dr. Munger, Ms. Meo La and Ms. Hebah Kutbi. Both of these students participated, along with Dr. Munger, in the 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies in Orlando, Florida. Dr. Munger has collaborated with colleagues at Sri Ramachandra Medical School in Chennai, India, and has learned new research methods and discovered new opportunities there for mentoring and research. How have the results been disseminated to communities of interest? Ms. Kutbi (PhD student presented results of analyses of maternal obesity and risk of oral clefts presentation at the 5-10 May, 2013, 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies in Orlando, Florida. Ms. La presented findings on maternal dietary patterns, multivitamin use and risk of oral clefts at the 5-10 May, 2013, 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies in Orlando, Florida. Dr. Munger conducted a week-long workshop on research methods in nutrition and epidemiology and oral clefts at Sri Ramachandra Medical University, Chennai, India, during December 9-14, 2013. What do you plan to do during the next reporting period to accomplish the goals? During 2014 we will deepen our investigation of the statistical associations between genetic polymorphisms in folate-related genes, folate-related biomarkers, and biomarkers of metabolic syndrome (glucose, insulin, lipids, blood pressure) related to obesity. This plan of work addresses objectives 3 and 4 listed in the Methods section.
Impacts
What was accomplished under these goals?
1) Major activities completed: We have completed analyses of maternal dietary patterns, multivitamin use, folate-related blood biomarkers, and body mass index in association with risk of cleft lip and cleft palate birth defects. 2) Specific objectives met: completed analyses meeting objectives 1-3 outlined in our Methods section. 3) Significant results achieved: Analyses of dietary patterns and their relationship to folate-related biomarkers, risk of oral clefts, and interactions with folate-pathway genes have been conducted by Ms. Meo La, PhD student. Ms. La presented findings on maternal dietary patterns, multivitamin use and risk of oral clefts at the 12th International Congress on Cleft Lip/Palate and Related Cranifacial Anomalies. In this analysis the combination of maternal multivitamin use combined with a higher score reflecting the ideal DASH diet, with high intakes of fruits and vegetables, low-fat dairy products, whole grains, poultry, fish and nuts, and low intakes of red meat, saturated fat, and sweetened desserts and beverages, was associated with a 50% reduction in risk of isolated oral clefts. Ms. La’s further analyses have shown that mothers of cleft children appear to have a lower plasma folate response to multivitamin supplementation, suggesting that at-risk mothers have an inherited or acquired inability to utilize folic acid in comparison to control mothers of unaffected children. Ms. La is investigating the genetic basis of this finding in collaboration with Dr. Munger and Dr. Terri Beaty of Johns Hopkins University. Candidate single nucleotide polymorphisms in genes related to folate metabolism have been selected from a literature review and data on genotyped and imputed SNPs have been obtained from the NIH GENEVA database, which includes our Utah samples. The Utah samples have measured folate-related biomarkers and we are investigating gene-nutrient interactions in association with cleft risk. Ms. Hebah Kutbi has investigated the relationship between obesity and metabolic syndrome risk factors and genes and risk of oral clefts. Ms. Kutbi presented results of analyses of maternal obesity and risk of oral clefts presentation at the 5-10 May, 2012, 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies in Orlando, Florida. This is a result of an expanded collaboration with a large international consortium of studies from the U.S. (three separate studies from Iowa, Utah, and the U.S. National Birth Defects Prevention Study-NBDPS), Denmark, and Norway. The combined sample includes ~ 15,800 women including 5000 mothers of children with cleft lip and/or cleft palate (CL-P) and 10,800 mothers of unaffected children. When combining all datasets, Ms. Kutbi found that both maternal underweight and obesity were associated with an increased risk specific to cleft palate (but not cleft lip). A significant interaction was found with educational status—the elevated risk was only found among less educated mothers but not among college educated mothers. Thus abnormal maternal weight appears to be an indirect measure of risk and further studies must examine the underlying metabolic states (such as insulin resistance and components of metabolic syndrome). 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 maternal multivitamin use alone is unlikely to reduce the risk of oral clefts-- a combination however of maternal multivitamin use and a healthy dietary pattern with high intakes of fruits and vegetables, low-fat dairy products, reduced staturated fat and red meat intake, increased poultry and fish intake, and reduced intake of sweetened beverages and added sugars may reduce the risk by 50 percent. More attention is thus needed for pre-conceptional education and pregnancy planning for mothers-to-be that stresses multivitamin use and nutrition education. Further we have found that mothers of cleft children have a lower plasma folate response to folic acid supplementation, suggesting an inherited or acquired difference in folate metabolism. We have also found that underweight and obese mothers have a higher risk of having a child with an oral cleft, but this risk appears to be modified by factors related to maternal education.
Publications
- Type:
Journal Articles
Status:
Published
Year Published:
2013
Citation:
Patel, P., Beaty, T.H., Ruczinski, I., Murray, J.C., Marizita, M.L., Munger, R. G., Hetmanski, J.B., Wu, T., Murray, T., Rose, M., Redditt, R.J., Jin, S., Lie, R., Wu-Chou, Y., Wang, H., Ye, X., Yeow, V., Chong, S., Jee, S., Shi, B., Scott, A.F. (2013). X-linked markers in the Duchenne muscular dystrophy gene associated with oral clefts. European Journal of Oral Science, 121(2), 63-8.
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Progress 01/01/12 to 12/31/12
Outputs
OUTPUTS: Mentoring outputs include supervision of two PhD candidates by Dr. Munger. Ms. Meo La is conducting research on dietary patterns and their relationship to folate-related biomarkers, risk of oral clefts, and interactions with folate-pathway genes. Ms. Hebah Kutbi is conducting research on the relationship between obesity and metabolic syndrome risk factors and genes and risk of oral clefts. We have completely initial analyses of maternal dietary patterns, multivitamin use and risk of oral clefts. Our paper has been accepted for oral presentation at the May, 2012, 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies to be held in Orlando, Florida, and will be presented by Ms. La. In this analysis the combination of maternal multivitamin use a higher score reflecting the ideal DASH diet, with high intakes of fruits and vegetables, low-fat dairy products, whole grains, poultry, fish and nuts, and low intakes of red meat, saturated fat, and sweetened desserts and beverages, was associated with a 50% reduction in risk of isolated oral clefts. We have also studied maternal obesity which has been associated with an increased risk of oral clefts in some studies but the magnitude of effect has varied across studies. The role of maternal underweight is relatively unstudied. Obesity is a leading global public health problem. While underweight is a lesser problem in industrialized countries, better understanding of the role of underweight may lead to a better understanding of the causes of oral clefts. We are collaborating with a large international consortium of population-based case-control data from the U.S. (three separate studies from Iowa, Utah, and the U.S. National Birth Defects Prevention Study-NBDPS), Denmark, and Norway. The combined sample includes ~ 15,800 women including 5000 mothers of children with cleft lip and/or cleft palate (CL-P) and 10,800 mothers of unaffected children. Data were available on pre-pregnancy maternal weight and height; data were also available on other perinatal and demographic factors which are used as covariates to control for potential confounding. Body-mass index (BMI) was computed as weight (kgs)/height (M2) and used to define body weight categories as underweight (BMI<18.5), normal weight (18.5-<25), overweight (25-<30) and obese (≥30). Logistic regression was used to model the effects of body weight on CL-P risk. When combining all datasets, CL-P risk was eighteen% greater (OR=1.18, 95% CI = 1.07-1.3) among obese compared to normal weight mothers. CL-P risk with underweight was significant in NBDPS (OR=1.21, 95% CI = 1.02-1.45) and was 16% greater in the combined analysis (OR= 1.16, 95% CI= 1.003-1.35) relative to normal weight. Analyses by cleft type are ongoing and will be presented. Our paper on maternal obesity has been accepted for oral presentation at the May, 2012, 12th International Congress on Cleft Lip/Palate and Related Craniofacial Anomalies to be held in Orlando, Florida, and will be presented by Ms. Kutbi. PARTICIPANTS: Dr. Ronald Munger, Principal Investigator. Ms Meo La, Graduate Research Assistant. Ms. Hebah Kutbi, Graduate Research Assistant. Partner organizations include the Utah Birth Defect Network and the Utah Department of Health. TARGET AUDIENCES: Families of children with oral cleft birth defects and health care workers that provide care and support for affected children. PROJECT MODIFICATIONS: Nothing significant to report during this reporting period.
Impacts
Cleft lip and cleft palate are among the most common birth defects in the United States and Utah has the highest rate of clefts in the U.S, but the reasons for this are unknown. Analysis of dietary patterns and risk of oral clefts and neural tube defects were conducted in the U.S. National Birth Defects Prevention Study. This analysis revealed that healthy dietary patterns defined by the Mediterranean Diet and the Diet Quality Index for Pregnancy was associated with a reduced risk of birth defects. Some Utah case and controls were included in this analysis and we are extending this analyses to our larger Utah case control study of oral clefts that was not a part of our published paper. Previous dietary studies have focused on the role of single nutrients and the risk of oral clefts. Our current approach of examining whole dietary patterns in relation to risk of cleft lip and palate is significant in that it may lead to dietary advice based on whole foods and dietary patterns that are effective and easily understood and implemented.
Publications
- Murray, T., Taub, M., Ruczinski, I., Scott, A., Hetmanski, J., Schwender, H., Patel, P., Zhang, T., Munger, R. G., Wilcox, A., Ye, X., Wang, H., Wu, T., Wu-Chou, Y., Shi, B., Jee, S., Chong, S., Yeow, V., Murray, J., Marizita, M., & Beaty, T., (2012). Examining markers in 8q24 to explain differences in evidence for association with cleft lip with/without cleft palate between Asians and Europeans: Genetic Epidemiology, 36(4): 392-399. (Published).
- Shi, M., Murray, J., Marizita, M., Munger, R. G., Ruczinski, I., Hetmanski, J., Wu, T., Ye, X., Yeow, V., Chong, S., Shi, B., Christensen, K., Scott, A., Patel, P., Cheah, F., & Beaty, T., (2012). Genome-wide study of maternal and parent-of-origin effects on the etiology of orfacial clefts.: American Journal of Medical Genetics, 158A(4): 784-94. (Published).
- Patel, P., Beaty, T., Ruczinski, I., Murray, J., Marizita, M., Munger, R. G., Hetmanski, J., Wu, T., Rose, M., Redett, R., Jin, S., Lie, R., Wu-Chou, Y., Wang, H., Ye, X., Yeow, V., Chong, S., Jee, S., Shi, B., & Scott, A. 2012. X-linked genetic variants in DMD associated with oral clefts: European Journal of Oral Science. (Accepted).
- Carmichael, S., Ma, C., Feldkkamp, M., Munger, R. G., Olney, R., Botto, L., Shaw, G., & Correa, A.. 2012. Nutritional factors and hypospadias risks: Paediatric and Perinatal Epidemiology, 26(4): 353-360. (Published).
- Wu, T., Fallin, M., Shi, M., Ruczinski, I., Liang, K., Hetmanski, J., Wang, H., Ingersoll, R., Huang, S., Ye, X., Wu-Chou, Y., Chen, P., Jabs, E., Shi, B., Redett, R., Scott, A., Murray, J., Marizita, M., Munger, R. G., & Beaty, T., (2012). Evidence of gene-environment interaction for the RUNX2 gene and environmental tobacco smoke in controlling the risk of cleft lip with/without cleft palate: Birth Defects Research A: Clinical and Molecular Teratology, 94(2): 76-83. (Published).
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Progress 01/01/11 to 12/31/11
Outputs
OUTPUTS: Mentoring outputs include supervision of two PhD candidates by Dr. Munger. Ms. Meo La is conducting research on dietary patterns and their relationship to folate-related biomarkers, risk of oral clefts, and interactions with folate-pathway genes. Ms. Hebah Kutbi is conducting research on the relationship between obesity and metabolic syndrome risk factors and genes and risk of oral clefts. Dr. Munger presented a paper at the 5th International Conference on Birth Defects in Developing Countries in September, 2011, in Lodz, Poland, on the work being done on maternal metabolic factors related to risk of oral clefts as a part of this project. A genetic database of Utah participants in an international genome-wide association study (GWAS) has been obtained from Dr. Terri Beaty, Johns Hopkins University, and is being analyzed by Ms. Meo La. Candidate single nucleotide polymorphisms in genes related to folate metabolism, obesity, and diabetes are being cataloged and will be evaluated in this database. A brochure for potential participants in the Utah oral cleft study has been produced and a website for participants is under development. The intended audience for the brochure and website are family members of children born with oral clefts and the family members of unaffected controls that are being recruited in this study. Dietary data are being analyzed and being used to define dietary pattern definitions that will be evaluated in relation to oral cleft risk and level of folate-related biomarkers. PARTICIPANTS: Dr. Ronald Munger, Principal Investigator. Ms Meo La, Graduate Research Assistant. Ms. Hebah Kutbi, Graduate Research Assistant. Partner organizations include the Utah Birth Defect Network and the Utah Department of Health. TARGET AUDIENCES: Families of children with oral cleft birth defects and health care workers that provide care and support for affected children. PROJECT MODIFICATIONS: Not relevant to this project.
Impacts
Cleft lip and cleft palate are among the most common birth defects in the United States and Utah has the highest rate of clefts in the U.S, but the reasons for this are unknown. Analysis of dietary patterns and risk of oral clefts and neural tube defects were conducted in the U.S. National Birth Defects Prevention Study. This analysis revealed that healthy dietary patterns defined by the Mediterranean Diet and the Diet Quality Index for Pregnancy was associated with a reduced risk of birth defects. Some Utah case and controls were included in this analysis and we are extending this analyses to our larger Utah case control study of oral clefts that was not a part of our published paper. Previous dietary studies have focused on the role of single nutrients and the risk of oral clefts. Our current approach of examining whole dietary patterns in relation to risk of cleft lip and palate is significant in that it may lead to dietary advice based on whole foods and dietary patterns that are effective and easily understood and implemented.
Publications
- UTAO+1053 Carmichael, S., Yang, W., Feldkamp, M., Munger, R. G., Siega-Riz, A.-M., Botto, L., & Shaw, G., (2012). Reduced Risks of Neural Tube Defects and Orofacial Clefts With Higher Diet Quality: Archives of Pediatric and Adolescent Medicine, 166(2): 121-126. (Published).
- UTAO+1053 Beaty, T., Ruczinski, I., Murray, J., Marizita, M., Munger, R. G., Hetmanski, J., Murray, T., Redett, R., Fallin, M., & Liang, K., (2011). Evidence for gene-environment interaction in a genome wide study of nonsyndromic cleft palate: Genetic Epidemiology, 35(6): 469-478. (Published).
- UTAO+1053 Mossey, P., Shaw, W., Munger, R. G., Murthy, J., & Little, J., (2011). Global oral health inequalities: challenges in the prevention and management of orofacial clefts and potential solutions.: Advances in Dental Research, 23(2): 247-258. (Published).
- UTAO+1053 Munger, R. G., Tamura, T., Johnston, K., Felkkamp, M., Pfister, R., Cutler, R., Murtaugh, M., & Carey, J., (2011). Oral clefts and maternal biomarkers of folate-dependent one-carbon metabolism in Utah: Birth Defects Researc A: Clinical and Molecular Teratology, 91(3): 153-161. (Published).
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