2026
Thesis:
INTERPRETABLE PREDICTIVE MODELLING FOR MULTI-DOMAIN HEALTHCARE OUTCOMES AND INSIGHTS.
Author: Muhammad Mursil
Doctoral Thesis Director: Murphy, M.
Defence date: 13/02/2026
Doctorate Programme: Computer engineering and security mathematics.
2025
Thesis:
MATERNAL FOLATE AND COBALAMIN STATUS AND GENE INTERACTIONS FROM EARLY PREGNANCY UNTIL BIRTH.
Author: Muhammad Mursil
Doctoral Thesis Director: Murphy, M.
Defence date: 04/07/2025
Doctorate Programme: Biomedicine
Thesis:
MATERNAL FOLATE AND COBALAMIN STATUS AND GENE INTERACTIONS FROM EARLY PREGNANCY UNTIL BIRTH.
Author: Luis A Santos-Calderón
Doctoral Thesis Director: Murphy, M.
Defence date: 04/07/2025
Doctorate Programme: Biomedicine
2022
Thesis:
PRENATAL GENE-NUTRIENT INTERACTIONS AND THEIR RELATIONSHIP WITH DEVELOPMENT AND HEALTH IN THE OFFSPRING.
Author: Alejandra Rojas Gomez
Doctoral Thesis Director: Murphy, M.
Defence date: 12/12/2022
Doctorate Program: Biomedicine
Thesis defended with mention of international doctorate
http://hdl.handle.net/10803/687506
ABSTRACT: Inadequate pregnancy cobalamin status has been associated with adverse offspring health in Asia but there are few studies in countries with low prevalence of cobalamin deficiency. Less is known regarding the association between the betaine-dimethylglycine pathway during pregnancy, foetal growth and mid-childhood health. The associations between pregnancy fasting plasma total homocysteine (tHcy), cobalamin status (cobalamin, holotranscobalamin (holoTC), methylmalonic acid (MMA)) and mid-childhood (6-8y) metabolic score (MetSco) (including fat mass index, homeostatic model assessment of insulin resistance and dyslipidemia) were studied in a prospective study of 293 mother–child dyads. Associations between pregnancy fasting plasma betaine, dimethylglycine (DMG)/betaine, c.716G>A BHMT genotype and foetal growth were investigated in a prospective study of 748 mother–neonate dyads. The association between pregnancy fasting plasma betaine and mid-childhood (7.5 y) MetSco was investigated in 213 mother–child dyads. Child plasma metabolite status was studied according to pregnancy 1C metabolism status and bivariate correlations between child plasma metabolites and anthropometric measurements in 238 children were studied to identify potential biomarkers associated with the metabolic syndrome. Moderately elevated pregnancy tHcy, low holoTC and high MMA were associated with increased mid-childhood MetSco in boys. Cord plasma betaine was inversely associated with foetal growth. Babies born to mothers with the BHMT c.716 AA genotype had a higher risk of small for gestational age (SGA) compared to GG, and GA+GG genotypes. The pregnancy betaine-DMG pathway was not associated with child MetSco. Plasma betaine was higher in children born to mothers in the lowest tertile of pregnancy plasma cobalamin compared to the mid-high tertiles, while plasma tryptophan was lowest in those born to mothers in the highest vs low-mid maternal pregnancy plasma tHcy tertiles. Child plasma betaine, cysteine, 3-hydroxyanthranilic acid, kynurenic acid, histidine and asymmetric dimethylarginine were positively correlated with adiposity while picolinic acid, trigonelline and neopterin were negatively associated.
Thesis:
THE ONE CARBON METABÒLIC NETWORK, THE L-ARGININE PATHWAY AND HYPERTENSION IN ADULTS AND DURING PREGNANCY.
Author: Carla Ramos Rodríguez
Doctoral Thesis Director: Murphy, M.
Defence date: 28/10/2022
Doctorate Program: Biomedicine
Thesis defended with mention of international doctorate
http://hdl.handle.net/10803/675952
ABSTRACT: Impaired One-Carbon metabolism (1CM) has been associated with hypertension and pregnancy-induced hypertension, although the mechanism is unknown. During homocysteine remethylation, S-adenosylmethionine donates methyl groups to methylate L-Arginine, creating ADMA and SDMA, which impair the conversion of L-Arginine to nitric oxide (NO) by eNOS. This has been associated with endothelial dysfunction, as NO is a vasodilator. In a representative population of 788 adults tHcy, but not the MTHFR C677T genotype, was associated with ADMA and SDMA. ADMA, the L-Arginine/ADMA Ratio and the NOS G894T genotype variant were associated with hypertension in adults over 50 years of age. In the Reus-Tarragona Birth Cohort, 810 mothers at <12 weeks of gestation were recruited. First-trimester maternal plasma concentrations of ADMA and SDMA were higher in the highest first-trimester tHcy tertile compared with the lowest, and lower in participants with the MTHFR TT versus CC genotype. The ADMA/SDMA Ratio in first- trimester maternal plasma was associated with an increased risk of pregnancy-induced hypertension. The 416 participating fathers with tHcy in the highest tertile had higher plasma ADMA and SDMA concentrations compared with the lowest tertiles. Paternal ADMA and SDMA concentrations did not differ between MTHFR C677T genotypes.
2020
Thesis:
GENETIC AND METABOLIC ALTERATIONS IN MATERNAL AND PATERNAL ONE CARBON METABOLISM AND DEVELOPMENT OF PREGNANCY COMPLICATIONS OF PLACENTAL ORIGIN.
Author: Júlia Haro Barceló
Doctoral Thesis Director: Murphy, M.
Defence date: 21/10/2020
Doctorate Program: Biomedicine
http://hdl.handle.net/10803/670244
ABSTRACT: Placental-derived pregnancy complications including pregnancy induced hypertension (PIH) and intrauterine growth retardation (IUGR) put maternal and foetal health at risk. Suboptimal maternal folate and one carbon (1C) metabolic status and unhealthy lifestyle can lead to adverse pregnancy outcomes. The common MTHFR 677C>T and SLC19A1 80G>A polymorphisms are associated with poor folate status and elevated fasting plasma total homocysteine (tHcy). Paternal factors can contribute to impaired placentation, due to poor trophoblast invasion and remodelling of the uterine spiral arteries but are rarely considered. Data on lifestyle, clinical history and fasting blood samples were collected from 773 mother-neonate dyads and 414 mother- father- neonate triads from the Reus- Tarragona Birth Cohort. Plasma and red blood cell folate, tHcy and B12 status and MTHFR 677 C>T and SLC19A1 80G>A genotype associations with impaired placentation, PIH and IUGR were investigated. Maternal and paternal MTHFR 677C>T genotypes were not associated with IUGR and maternal genotype was not associated with impaired placentation. Elevated paternal tHcy was associated with fivefold greater probability of an IUGR-affected pregnancy and increased risk of impaired placentation [OR 95% (CI) 2.7 (1.2, 6.0)]. Compared to CC genotype, paternal MTHFR 677CT and TT genotypes were associated with impaired placentation [OR 95% (CI)]: 4.0 (1.3, 12.6) and 7.1 (1.6, 32.8) respectively. Mothers with the MTHFR 677TT compared to CC genotype were threefold more likely to develop PIH. Maternal and paternal tHcy concentrations and paternal genotype were not associated with increased risk of PIH. Maternal and paternal SLC19A1 80G>A genotypes were not associated with increased risk of any of the outcomes. In conclusion, fathers with elevated versus normal tHcy or the variant MTHFR 677T allele versus CC genotype were more likely to father pregnancies affected by impaired placentation and IUGR. Mothers with the MTHFR 677TT versus CC genotype were at increased risk of developing PIH.
2019
Thesis:
A STUDY OF THE ASSOCIATION BETWEEN ONE CARBON METABOLISM AND BLOOD PRESSURE IN ADULTS AND TRANSGENERATIONALLY BETWEEN PREGNANT WOMEN AND THEIR CHILDREN.
Author: Gemma Ornosa Martín
Doctoral Thesis Director: Murphy, M.
Defence date: 25/10/2019
Doctorate Program: Biomedicine
Thesis defended with mention of international doctorate
http://hdl.handle.net/10803/668771
ABSTRACT: One carbon metabolism nutrients and the MTHFR 677 C>T polymorphism have been found to be associated with blood pressure and hypertension. and the mechanism associated is thoughtIt is possible that the underlying mechanism may involve to be fetal programming.. An adequate status of 1C metabolism nutrients has been proven to be beneficial for some health outcomes in adults population and also in pregnancy, from in utero development until later in life including childhood and adulthood. The aim of this thesis is to explore the associations between 1C metabolism nutrients, including B-vitamins and tHcy, as well as the MTHFR 677C>T polymorphism, and blood pressure and hypertension in two different populations, an adult population and a mother-child study with follow-up during pregnancy and children at 7.5 years. Seven hundred and eighty eight participants randomly selected from the population town halls’ registers participated in the population study. This population is unexposed to mandatory folic acid fortification and B vitamin supplement use. Being in the 3rd tertile of tHcy compared to the 1st increases the risk of having hypertension 1.8 times [OR=1.8 (1.0, 3.3)] in the total population. Stratifying for age, showed that the association in the >50 years group [OR= 2.5 (1.2, 5.4)] drives the overall result. only the people in the >50 years group showed an association with hypertension [OR= 2.5 (1.2, 5.4)]. Having the TT genotype increases the risk of having hypertension compared to the other genotypes in all models of people aged ≤ 50 years [OR= 8.2 (1.3, 53.9)]. In the Reus-Tarragona Birth Cohort two hundred and twelve mother-child dyads were followed up during pregnancy and children at 7.5 years. The prevalence of child hypertension was 6.2%. Child CT genotype increases the risk of having prehypertension/+hypertension 6.5 times [OR= 6.5 (1.0, 43.5)] in the office BP model. Maternal MTHFR 677 CT genotype increases the risk of having prehypertension/ hypertension and prehypertension 7.4 times [OR= 7.4 (1.0, 55.0)]. The association between the genotypes and prehypertension/ hypertension is maintained aftereven adjusting for classical other risk factors.
2017
Thesis:
PRENATAL ONE CARBON METABOLISM GENE INTERACTIONS, PLACENTA TRACE ELEMENT CONTENT AND THEIR EFFECT ON PREGNANCY OUTCOME.
Author: Jose María Colomina Muela
Doctoral Thesis Director: Murphy, M.
Defense date: 28/06/2017
Doctorate Program: Biomedicine
http://hdl.handle.net/10803/441746
ABSTRACT: One carbon metabolism and essential trace elements affect foetal development and pregnancy outcome. The effects of several highly prevalent one carbon metabolism polymorphisms (MTHFR c.665C>T, BHMT c.716G>A, SLC19A1 c.80G>A and MTRR c.66A>G) in pregnancy and their possible modulation by folate status, and which factors are associated with the placenta trace element concentrations (zinc, copper, selenium and iron), are unknown. These aspects of the aforementioned polymorphisms and trace elements were studied in 617 pregnancies of the Reus-Tarragona Birth Cohort and 218 placentas. With high erythrocyte folate status at ≤12 gestational weeks (GW) and with high plasma folate status from 15GW on, the homocysteine-enhancing effect of MTHFR c.665C>T was not observed. Lower plasma dimethylglycine in BHMT c.716 variant genotypes was found at mid-late pregnancy, and this was also true for early pregnancy if plasma folate status was high. MTRR c.66 variant homozygotes had higher plasma homocysteine concentration at early pregnancy, and after plasma folate status stratification this was not observed in the extreme tertiles. Placenta concentrations of zinc, copper and selenium were positively correlated, and negatively associated with birth weight. Smoking during pregnancy was associated with higher copper and selenium concentrations. Intake of these trace elements from food and/or supplements was not associated with their concentrations in placenta. Plasma cobalamin at ≤12GW and homocysteine at labour were negatively and positively, respectively, associated with placenta copper concentrations. MTHFR c.665 normal allele in the neonate and placenta copper concentration were positively associated with intrauterine growth restriction. These studied polymorphisms and their modulation by folate status, and the placenta trace elements, are associated with metabolic changes and pregnancy outcome.
2016
Thesis:
PRENATAL ONE CARBON METABOLISM AND IN UTERO PROGRAMMING OF GROWTH AND ADIPOSITY IN THE OFFSPRING.
Author:Pol Solé Navais
Doctoral Thesis Director: Murphy M & Fernández-Ballart JD,
Defence date: 28/06/2016
Doctorate Program: Biomedicine
http://hdl.handle.net/10803/401551
ABSTRACT: One carbon metabolism positively influences health in early and late stages of life (e.g. folic acid fortification reduced neural tube defect prevalence, homocysteine in adults and possiblystroke mortality). Whether the effects of in utero one carbon metabolism affect postnatal growth is unknown. Harmful effects of elevated folate status have been reported. We evaluated the interactions between prenatal folate and cobalamin and their effects during pregnancy and on offspring growth and adiposity at mid-childhood. 563 women from the Reus-Tarragona Birth Cohort were followed-up throughout pregnancy and 162 of their offspring until mid-childhood, when growth and adiposity were measured. Folate status did not modify the association between inadequate cobalamin and its metabolic or haematological indicators. Early pregnancy inadequate RBC folate, cobalamin or tHcy were associated with lower offspring height. Inadequate holoTC was also associated with higher offspring BMI. Maternal MTHFR 677C>T and TCN2 776C>T genetic variants were associated with higher and lower offspring BMI and height from birth to mid-childhood, respectively. Child MTRR 66A>G was associated with lower linear and ponderal growth. This endorses the safety of elevated folate status, and supports a role for prenatal one carbon metabolism on postnatal growth and adiposity.
2013
Thesis:
GENETIC-NUTRITIONAL REGULATION OF FOLATE STATUS IN AN ADULT POPULATION NOT EXPOSED TO PROPHYLACTIC FOLIC ACID AND DURING PREGNANCY. [REGULACIÓN GENÉTICO-NUTRICIONAL DEL ESTADO EN FOLATOS EN UNA POBLACIÓN ADULTA NO EXPUESTA A ÁCIDO FÓLICO PROFILÁCTICO Y DURANTE EL EMBARAZO].
Author:Olalla Bueno Fraile
Doctoral Thesis Director: Murphy M & Fernández-Ballart JD,
Defence date: 25/11/2013
Doctorate Program: Biomedicine
http://hdl.handle.net/10803/128921
ABSTRACT: Many polymorphisms involved in folate transport and metabolism can impair folate status, and the co-existence of certain polymorphisms with MTHFR 677 C>T could enhance the effect of this polymorphism on folate status. However, mandatory folic acid fortification of grain products in some countries could mask the effect of the genotype. A cross-sectional study with a representative sample of general population and a longitudinal pregnancy study were driven. We describe for the first time four couples of polymorphisms which are associated with higher risk of being in the low tertile of plasma or red cell folate and one polymorphism associated with lower risk of being in the low tertile of red cell folate. In pregnant women, we find that folic acid supplementation during the first trimester balances the deleterious effects of MTHFR 677TT genotype on red cell folate concentration.
Thesis:
CONTRIBUTION OF MATERNAL NUTRITIONAL STATUS AND PLACENTAR FUNCTION ON THE DEVELOPMENT OF INTRAUTERINE GROWTH RETARDATION. [CONTRIBUCIÓ DE L’ESTAT NUTRICIONAL MATERN I DE LA FUNCIÓ PLACENTÀRIA SOBRE EL DESENVOLUPAMENT DEL RETARD DE CREIXEMENT INTRAUTERÍ].
Author: Pere Cavallé-Busquets
Doctoral Thesis Director: Murphy, M.
Defence date: 08/11/2013
Doctorate Program: Research Methods in Cínical Sciences
http://hdl.handle.net/10803/128935
ABSTRACT: We investigated whether early pregnancy hyperhomocysteinemiais a biomarker of pathological fetoplacental Doppler or intrauterine growth retardation (IUGR). METHODS: A nested case-control study with a group of cases based onpopulation birthweightcurves (IUGR-Pop) and another group with customisedcurves(IUGR-Cus) was performed. RESULTS: 43 cases were matched with 161 controls in the IUGR-Pop group, and 145 cases with 63 controls in the group IUGR-Cus. Hyperhomocysteinemia was defined as plasma homocysteine above the 90th percentile and was associated with reduced birth weight, increased resistance of the uterine arteries, increased risk of pathological umbilical Doppler (OR = 3.1), IUGR-Poprisk (OR=8.2) andIUGR-Cus risk (OR=4.9). CONCLUSION : Early pregnancy hyperhomocysteinemiais associated with reduced birth weight, altered feto-placental Doppler function and increased IUGR risk in the two populations studied .
Thesis:
GENETIC-ENVIRONMENTAL REGULATION OF THE NUTRITIONAL STATUS OF VITAMIN B2 AND INFLUENCE ON THE METHIONINE CYCLE IN AN ADULT POPULATION AND IN PREGNANT PEOPLE. [REGULACIÓN GENÉTICO-AMBIENTAL DEL ESTADO NUTRICIONAL DE LA VITAMINA B2 E INFLUENCIA SOBRE EL CICLO DE LA METIONINA EN UNA POBLACIÓN ADULTA Y EN GESTANTES].
Author: Carlos Jesús Garcia-Minguillan del Campo
Doctoral Thesis Director: Murphy M & Fernández-Ballart JD,
Defence date: 05/11/2013
Doctorate Program: Nutrition & Metabolism
http://hdl.handle.net/10803/129176
ABSTRACT: MTHFR and MTRR, riboflavin dependent enzymes, participate in homocysteine metabolism. Their substrates,folate and cobalamin, respectively, are inversely associated with fasting plasma homocysteine (tHcy). Riboflavin status may also affect tHcy. We investigated whether riboflavin, folate and cobalamin status affect the association between the MTHFR 677 C>T, MTRR 66 A>G orMTRR 524 C>T polymorphisms and tHcy in an adult population and in pregnant women. Riboflavin status was inversely associated with tHcy in the presence of the MTHFR 677 TT genotype, independently of folate status. High riboflavin status was positively associated with tHcy in carriers of the MTRR 66 A>Gmutant allele but inversely associated with tHcy in MTRR 524 C>T mutant allele carriers when cobalamin status was low. High riboflavin combined with low cobalamin status was positively associated with tHcy in pregnant carriers of mutant alleles for either of the latter polymorphisms.
2012
Thesis:
CONTRIBUTION OF CHOLINE AND BETAINE TO HOMOCYSTEIN METABOLISM DURING GESTATION. [CONTRIBUCIÓN DE LA COLINA Y LA BETAÏNA AL METABOLISMO DE LA HOMOCISTEÏNA DURANTE LA GESTACIÓN].
Author: Sílvia Fernandez-Roig
Doctoral Thesis Director: Murphy M & Fernández-Ballart JD,
Defence date: 31/10/2012
Doctorate Program: Nutrition & Metabolism
http://hdl.handle.net/10803/96334
ABSTRACT: Choline is the main methyl group donor. Folate status might modify the role of choline. We investigated the contribution of the choline oxidation pathway to homocysteine metabolism during pregnancy and how folate status affects it. In the NUTCIR study six blood samples were collected from 497 pregnant women throughout pregnancy. Plasma choline increased from the second trimester, betaine decreased until mid pregnancy and dimethylglycine increased from 24-27 gestational weeks. Women with low folate status at 24-27 gestational weeks had lower betaine and higher dimethylglycine. These results suggest increasing activity of the choline oxidation pathway as pregnancy progresses and that it is further upregulated in response to low folate status. This shows that the choline oxidation pathway does contribute to homocysteine metabolism during pregnancy and more so when folate status is low.
Thesis:
METABOLIC AND GENETIC FACTORS IN THE REGULATION OF COBALAMIN STATUS, IN THE ADULT POPULATION AND DURING PREGNANCY. [FACTORS METABÒLICS I GENÈTICS EN LA REGULACIÓ DE L’ESTAT EN COBALAMINA, EN LA POBLACIÓ ADULTA I DURANT L’EMBARÀS].
Author: Judith Salat Batlle
Doctoral Thesis Director: Murphy M & Fernández-Ballart JD,
Defence date: 16/03/2012
Doctorate Program: Nutrition & Metabolism
http://hdl.handle.net/10803/80719
ABSTRACT: The worse cobalamin (Cbl) status during pregnancy is close to functional deficiency (increased plasma methylmalonic acid (MMA) and homocysteine (tHcy)) in pregnant women who start pregnancy with low Cbl status. Regular use of supplements containing 2 µg of cyanocobalamin is associated with higher plasma Cbl, HoloTC and HoloTC/Cbl throughout pregnancy and in cord. The MTRR 524TT, TCII 776CG and 776GG genotypes, in adults are associated with a reduction of holotranscobalamin (HoloTC). In pregnant women with low cobalamin status in early pregnancy, MTRR 524TT and 66GG genotypes are associated with increased MMA and tHcy, respectively. TCII 776GG genotype is associated with triple risk of intrauterine growth retardation. In adults with low cobalamin and high folate status, there is a positive relation between folate and tHcy. Furthermore the beginning of pregnancy with low cobalamin and high folate status is associated with higher plasma MMA.