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Biomedical subjects

James L Mills

Publications and source records attributed to James L Mills.

At least 19 recordsLinked to original sources
PubMed2006

The MTHFR 1298CC and 677TT genotypes have opposite associations with red cell folate levels.

Individuals homozygous for the thermolabile variant (677TT) of methylenetetrahydrofolate reductase exhibit reduced folate status as evidenced by a drop in the biomarker red cell folate (RCF) compared to those who carry at least one 677C allele. We now report that a different polymorphism in the same enzyme, namely 1298A>C, is associated with increased RCF levels. Thus, these two common polymorphisms change a metabolic phenotype in opposite directions suggesting that their cancer protective associations are by different mechanisms.

Biomarkers↗
PubMed2006

Confirmation of the R653Q polymorphism of the trifunctional C1-synthase enzyme as a maternal risk for neural tube defects in the Irish population.

The risk of neural tube defects (NTDs) is known to have a significant genetic component that could act through either the NTD patient and/or maternal genotype. The success of folic acid supplementation in NTD prevention has focused attention on polymorphisms within folate-related genes. We previously identified the 1958G>A (R653Q) polymorphism of the trifunctional enzyme MTHFD1 (methylenetetrahydrofolate-dehydrogenase, methenyltetrahydrofolate-cyclohydrolase, formyltetrahydrofolate synthetase; often referred to as 'C1 synthase') as a maternal risk for NTDs, but this association remains to be verified in a separate study to rule out a chance finding. To exclude this possibility, we genotyped an independent sample of mothers with a history of an NTD-affected pregnancy derived from the same Irish population. In this sample there was a significant excess of 1958AA homozygote mothers of NTD cases (n=245) compared to controls (n=770). The direction and magnitude of risk (odds ratio 1.49 (1.07-2.09), P=0.019) is consistent with our earlier finding. Sequencing of the MTHFD1 gene revealed that this association is not being driven by another common variant within the coding region. We have established that the MTHFD1 1958G>A polymorphism has a significant role in influencing a mother's risk of having an NTD-affected pregnancy in the Irish population.

Amino Acid Substitution↗
PubMed2006

Prospective identification of pregnant women drinking four or more standard drinks (> or = 48 g) of alcohol per day.

We aimed to identify drinking rates in a prospectively identified cohort of pregnant women, and subsequently, to identify the drinkers of 48 g or more alcohol/day among them, by using complementary methods for verifying self-reported drinking habits. A research team of social workers and health professionals at the Maipú Clinic, located in a lower middle class neighborhood of Santiago, Chile, conducted interviews of women attending a prenatal clinic between August 1995 and July 2000. Women whose interview responses met predefined criteria (identified in the text) were further evaluated by home visits. We interviewed 9,628 of 10,917 (88%) women receiving prenatal care. By initial interview, 42.6% of women reported no drinking, 57.4% some alcohol consumption, and 3.7% consuming at least one standard drink (15 mL of absolute alcohol) per day. Of the 887 women who had home visits, 101 were identified as consuming on average at least 4 drinks/day (48 g). To determine the best home visit questionnaire items for identifying those drinking at least 4 drinks per day, 48 women who openly admitted drinking this amount were compared with 786 women who were not considered drinkers after the home visit. The 48 self-reported 48 g/day drinkers were significantly more likely to get tipsy when drinking before (p = 0.01) or during (p < 0.0001) pregnancy, to have started drinking at a younger age (p = 0.007), or to exhibit signs of low self-esteem (p < 0.0001), sleep or appetite problems (p < 0.0001), bad interpersonal relationships (p < 0.0001) or having family members with fetal alcohol syndrome features (p < 0.009). In conclusion, using complementary methods of alcohol misuse ascertainment during pregnancy, we found that at least 1% of pregnant women in a Santiago, Chile, clinic population were drinking at levels that are clearly dangerous to the fetus (48 g/day or more). We identified specific interview questions that may help screen for alcohol use of 48 g/day or more in pregnant women.

Adolescent↗
PubMed2006

Circulating angiogenic factors and placental abruption.

OBJECTIVE: Abnormalities in circulating angiogenic factors have been reported in diseases of abnormal placentation, such as preeclampsia and intrauterine growth restriction. Our objective was to determine whether circulating angiogenic factors are altered in another placental vascular disease, abruptio placentae. METHODS: In a nested case-control study of nulliparous pregnancies, we examined levels of placental growth factor (PlGF) and soluble fms-like tyrosine kinase 1 (sFlt-1) in serum collected prospectively from 31 women who later developed placental abruption and from 31 normal control subjects. All serum specimens were collected before the onset of hypertension or abruption and before labor or delivery. Serum angiogenic factors were compared within 3 gestational age windows: early (20 weeks or less), middle (21-32 weeks), and late (33 weeks or more) pregnancy. RESULTS: During early pregnancy women who developed placental abruption had lower PlGF and higher sFlt-1 concentrations and higher sFlt-1/PlGF ratios than women with normal pregnancies. In mid-pregnancy these differences became greater, reaching statistical significance for PlGF concentration (431 versus 654 pg/mL, P<.01) and the sFlt-1/PlGF ratio (25.3 versus 2.5, P<.01). When the women with placental abruption were subdivided into those who did (n=10) and those who did not (n=21) develop preeclampsia or gestational hypertension, significant alterations in angiogenic factors were noted only in women who later developed hypertension in pregnancy. Among these women, PlGF concentrations were decreased in mid-pregnancy (160 versus 723 pg/mL, P<.001), and the mid-pregnancy sFlt-1/PlGF ratio was increased (70.1 versus 2.3, P=.001). CONCLUSION: Serum levels of the proangiogenic factor PlGF were decreased, and those of the antiangiogenic ratio sFlt-1/PlGF were increased in nulliparous women who subsequently developed hypertension and placental abruption.

Abruptio Placentae↗
PubMed2005

Reduced folate carrier polymorphisms and neural tube defect risk.

The reduced folate carrier (RFCI) is essential for folate transport into cells. Low folate is an important cause of neural tube defects (NTDs), and a single-nucleotide polymorphism (H27R) (80G-->A) in the RFCI gene has been reported to be a NTD risk factor. We investigated H27R and a 61 bp tandem repeat polymorphism as potential risk factors for NTDs, using a large homogeneous Irish population by case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and H27R in mothers [p = 0.23, odds ratio (OR) 0.87, 95% confidence interval (CI) 0.69-1.09], fathers (p = 0.11, OR 0.83, 95% CI 0.66-1.04), or cases (p = 0.36, OR 0.9, 95% CI 0.72-1.12) when compared to controls or through log-linear modeling for dominant or recessive effects or with the transmission disequilibrium test for preferential allele transmission. Using log-linear models, a significant protective case effect was seen for the 61 bp polymorphism (p = 0.0039, OR 0.21, 95% CI 0.05-0.85). When analyzed by genotype, individuals homozygous for a single copy of the 61 bp sequence were underrepresented in cases as compared to controls, although these results did not reach statistical significance (p = 0.081, OR 0.5, 95% CI 0.23-1.09, goodness of fit p = 0.42). We compared the frequencies of H27R and the 61 bp polymorphism in African-Americans and American-Caucasians. The frequencies of H27R polymorphism differed significantly between the two populations (p = 0.0001). This large study does not confirm previous reports that H27R is a risk factor for NTDs. The previously unstudied 61 bp tandem repeat, however, has a possible protective NTD effect in our Irish population. This requires confirmation in other studies.

Black or African American↗
PubMed2005

Screening for new MTHFR polymorphisms and NTD risk.

The enzyme, 5,10-methylenetetrahydrofolate reductase (MTHFR) plays a key role in cellular folate metabolism. The A222V (677C->T) polymorphism is a confirmed neural tube defect (NTD) risk factor within Irish and other populations. To search for other unknown single nucleotide polymorphisms (SNPs) that might play a role in the etiology of NTDs, we examined the entire MTHFR coding region in healthy individuals (n = 100). SNPs were identified using sequencing and database analysis and allele frequencies were determined in our Irish population. We identified P39P (116C->T; T allele frequency 0.13) and previously reported R594Q (1793G->A; Q allele frequency 0.07). We screened a large ethnically homogeneous Irish NTD cohort (n>1,300) for P39P and R594Q. A possible association between NTD cases and P39P (P = 0.034) was found but this was not confirmed by transmission disequilibrium testing. R594Q also showed some evidence of a NTD case association (P = 0.07). Further analysis indicated these observations are due to linkage disequilibrium with A222V (677C->T), and therefore these new SNPs are unlikely to be independent risk factors for NTDs. As rates of NTDs differ between ethnic groups, we examined allele and genotype frequencies of P39P and R594Q within African-American and American-Caucasian populations. This is the first NTD association study of both R594Q and the novel P39P. The association with NTD risk reported for these SNPs is driven by the linkage disequilibrium with the A222V (677C->T) NTD risk factor.

Base Sequence↗
PubMed2005

Folate-related genes and omphalocele.

Women who take folic acid in the periconceptional period greatly reduce their chances of having a child with a neural tube defect (NTD). Using multivitamins may also reduce the risk of having a child with an omphalocele. In this study, we tested single nucleotide polymorphisms in folate-related enzyme genes for association with omphalocele. Polymorphisms in methylenetetrahydrofolate reductase (MTHFR), methylenetetrahydrofolate dehydrogenase (MTHFD1), the reduced folate carrier (SLC19A1), and transcobalamin II (TCN2) were examined in 25 children with euploid omphalocele and 59 matched controls. Omphalocele cases were significantly more likely to carry the T allele of MTHFR 677C-->T, a known risk factor for NTDs (odds ratio 3.50, 95% confidence interval 1.07-11.47, P=0.035). The MTHFD1 R653Q, SLC19A1 R27H, and TCN2 P259R polymorphisms showed no significant association with omphalocele. In this small study, the thermolabile variant of MTHFR, 677C-->T, was associated with an increased risk for omphalocele. This variant causes reduced enzyme activity, thus suggesting a mechanism by which multivitamins with folic acid might prevent omphalocele. Additional investigation is required.

Adult↗
PubMed2005

Analysis of methionine synthase reductase polymorphisms for neural tube defects risk association.

Methionine synthase reductase (MTRR) regenerates methylated cobalamin levels from the oxidised cob(II)alamin form and in so doing plays a crucial role in maintaining the active state of methionine synthase (MTR). MTR is an essential enzyme catalyzing the conversion of homocysteine to methionine. Single nucleotide polymorphisms (SNPs) within the MTRR gene may potentially compromise MTR activity leading to elevated homocysteine levels, a known risk factor for neural tube defects (NTDs). We studied the MTRR polymorphisms I22M (66A-->G), S175L (524C-->T), and K350R (1049A-->G) as potential NTD risk factors in a large homogeneous Irish NTD population. Degree of risk was assessed via case/control comparison, log-linear analysis, and transmission disequilibrium testing. No association was found between NTDs and I22M in mothers (p = 0.16, OR1.14 [0.95-1.38], n = 447) or cases (p = 0.13, OR1.15 [0.96-1.38], n = 470) compared to controls (n = 476). A dominant I22M paternal effect was found through case/control comparison and log-linear modelling (p = 0.019) (goodness-of-fit p=0.91, OR 1.46 [1.10-1.93], n = 423). No significant NTD association was found with S175L or K350R in cases or their parents and no interactions were observed between these polymorphisms and the D919G variant of MTR or the A222V variant of 5,10-methylenetetrahydrofolate reductase (MTHFR). We also compared the frequencies of I22M, S175L, and K350R in African-Americans versus American-Caucasians. The frequencies of I22M and K350R differed significantly between the two groups (p = 0.0005 and p = 0.0001, respectively). Our findings do not support an important role for these MTRR variants in NTDs.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗
PubMed2005

MTHFD1 R653Q polymorphism is a maternal genetic risk factor for severe abruptio placentae.

This study examined the relationship between folate/homocysteine-related genetic polymorphisms: MTHFD1 1958G --> A (R653Q), MTHFR 677C --> T (A222V), MTHFR 1298A --> C (E429A), and risk of severe abruptio placentae. We genotyped 62 women with a pregnancy history complicated by severe abruptio placentae and 184 control pregnancies. Analysis of the MTHFD1 1958G --> A (R653Q) polymorphism showed increased frequency of the 'QQ' homozygote genotype in pregnancies affected by severe abruptio placentae compared to control pregnancies (odds ratio 2.85 (1.47-5.53), P = 0.002). In contrast to previous reports, the MTHFR polymorphisms 677C --> T (A222V) and 1298A --> C (E429A) were not associated with abruptio placentae risk in our cohort, when analyzed either independently or in combination. We conclude that women who are 'QQ' homozygote for the MTHFD1 1258G --> A (R653Q) polymorphism are almost three times more likely to develop severe abruptio placentae during their pregnancy than women who are 'RQ' or 'RR.'

Abruptio Placentae↗
PubMed2005

Evaluation of transcobalamin II polymorphisms as neural tube defect risk factors in an Irish population.

BACKGROUND: Decreased maternal folate levels are associated with having a child with a neural tube defect (NTD), and periconceptual folic acid supplementation reduces this risk by >50%. Vitamin B(12) (as methylcobalamin) is a cofactor for methionine synthase, an enzyme that plays a key role in folate metabolism. Alterations in vitamin B(12) metabolism may influence the development of NTDs. Low levels of maternal plasma vitamin B(12) and reduced binding of vitamin B(12) by transcobalamin II (TCII) are independent risk factors for NTDs. TCII levels are altered in the amniotic fluid of pregnancies affected by NTDs. Given this evidence, inherited variants in genes involved in vitamin B(12) trafficking such as TCII are candidate NTD risk factors. METHODS: We used case/control and family-based association methods to investigate whether six common polymorphisms in the TCII gene influence NTD risk. TCII genotypes were determined for more than 300 Irish NTD families and a comparable number of Irish controls. RESULTS: Allele and genotype frequencies for each polymorphism did not differ between family members and controls. CONCLUSIONS: These six TCII polymorphisms do not strongly influence NTD risk in the Irish population. The Supplementary Material for this article can be found on the Birth Defects Research (Part A) website: http://www.mrw.interscience.wiley.com/suppmat/1542-0752/suppmat/2005/73/v73.4.swanson.html

Alleles↗
PubMed2005

Choline and homocysteine interrelations in umbilical cord and maternal plasma at delivery.

BACKGROUND: Little is known about the interactions between choline and folate and homocysteine metabolism during pregnancy despite the facts that pregnancy places considerable stress on maternal folate and choline stores and that choline is a critical nutrient for the fetus. Choline, via betaine, is an important folate-independent source of methyl groups for remethylating homocysteine in liver. OBJECTIVES: Our aims were to examine the intermediates of choline oxidation in maternal and umbilical cord plasma and to determine the relations between this pathway and folate-dependent homocysteine remethylation. DESIGN: Blood samples were taken from 201 pregnant women and, at delivery, from the umbilical cord veins of their healthy, full-term infants. The blood samples were analyzed for plasma free choline, betaine, dimethylglycine, folate, vitamin B-12, total homocysteine (tHcy), and creatinine concentrations. RESULTS: Choline concentrations in umbilical cord plasma were approximately 3 times those in maternal plasma (geometric x: 36.6 and 12.3 micromol/L, respectively; P < 0.0001). Betaine and dimethylglycine concentrations were also significantly higher in umbilical cord than in maternal plasma. Choline was positively associated with tHcy (r = 0.34, P < 0.0001), betaine (r = 0.58, P < 0.0001), and dimethylglycine (r = 0.30, P < 0.0001) in maternal blood. Much weaker relations were seen in the fetal circulation. In a multiple regression model, choline was a positive predictor of maternal tHcy, whereas vitamin B-12 and betaine were negative predictors. CONCLUSIONS: The positive association between maternal choline and tHcy during pregnancy suggests that the high fetal demand for choline stimulates de novo synthesis of choline in maternal liver, with a resultant increase in tHcy concentrations. If this is confirmed, it may be appropriate to provide choline supplements during pregnancy to prevent elevated tHcy concentrations.

Betaine↗
PubMed2005

A polymorphism in the MTHFD1 gene increases a mother's risk of having an unexplained second trimester pregnancy loss.

Low maternal folate or vitamin B12 status has been implicated in numerous pregnancy complications including spontaneous abortion. The primary aim of this study was to test a polymorphism within the trifunctional folate enzyme MTHFD1 (5,10-methylenetetrahydrofolate dehydrogenase, 5,10-methenyltetrahydrofolate cyclohydrolase, 10-formyltetrahydrofolate synthetase) for an association with a mother's risk of having an unexplained second trimester pregnancy loss. We genotyped 125 women who had at least one unexplained spontaneous abortion or intrauterine fetal death between 13 and 26 weeks gestation and 625 control women with no history of prior pregnancy loss. Our study is the first to identify an association between the MTHFD1 1958G-->A (R653Q) polymorphism and the maternal risk of having an unexplained second trimester pregnancy loss. Women who are MTHFD1 1958AA homozygous have a 1.64-fold increased risk of having an unexplained second trimester loss compared to women who are MTHFD1 1958AG or 1958GG [OR 1.64 (1.05-2.57), P = 0.03]. It has been reported that polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR), 677C-->T (A222V), transcobalamin II (TCII), 776C-->G (P259R), are associated with pregnancy loss. Both variants were tested in this study. Neither showed evidence of significantly affecting the maternal risk of having a second trimester pregnancy loss. In conclusion, the MTHFD1 1958AA genotype may be an important maternal risk factor to consider during pregnancy.

Aborted Fetus↗
PubMed2005

Effects of folic acid fortification on twin gestation rates.

OBJECTIVE: Previous studies have reported an increase in twinning of as much as 40% associated with folic acid-containing supplements, and folic acid fortification of enriched cereal grains was authorized in 1996. The purpose of this study was to investigate whether twinning rates have increased since that time. METHODS: We used United States birth and fetal death records to calculate twin gestation rates from 1990 through 2000. To eliminate the influence of fertility treatments, our analysis was limited to nulliparous women aged 16-19. We compared time trends in twin gestation rates before and after folic acid fortification in 1996. RESULTS: A total of 25,065 twin and 3,362,245 singleton pregnancies were included. Twin gestation rates were stable from January 1990 through December 1996, at 7.2 per 1,000, and then began a steady increase, averaging 2.4% (95% confidence interval 0.1-4.2%, P = .006) per year, which continued through 2000 and reached 8.2 per 1,000. This translates to 2 additional twin pregnancies per 10,000 gestations per year. Twin rates continued to increase well beyond 1998, when the maximal fortification effect on folate status had been reached. CONCLUSION: Although twin gestation rates in women not using fertility treatments increased after food fortification with folic acid, they rose by much less than the 40% rate previously reported; the observed pattern of increase in twin gestation rates is not consistent with a folic acid fortification effect. LEVEL OF EVIDENCE: II-2.

Adolescent↗
PubMed2005

Elevated pregnancy losses at high and low extremes of maternal glucose in early normal and diabetic pregnancy: evidence for a protective adaptation in diabetes.

OBJECTIVE: Early pregnancy losses increase with marked hyperglycemia in diabetic pregnancy. However, mean loss rates do not differ from those of nondiabetic pregnancy. This observation might be explained by increased fetal losses at the extremes of glycemia in diabetic and nondiabetic pregnancy. To test this hypothesis, we examined relationships of proximate measures of prior glycemia, glycated protein and fructosamine, to pregnancy loss. RESEARCH DESIGN AND METHODS: A total of 389 diabetic and 429 nondiabetic pregnant subjects participated in the Diabetes In Early Pregnancy study. Glycated protein and fructosamine measurements were standardized as multiples of control values for each center (Z score). The logarithm of odds of pregnancy loss were plotted against Z scores and tested by logistic models. RESULTS: Mean pregnancy loss rates were 12% in diabetic and 13% in normal pregnancies. However, over six intervals of glycated protein in diabetic pregnancy, fetal loss rates at the upper and lower extremes (24 and 33%, respectively) were approximately threefold higher than the four intervening rates (8-14%). The odds ratio of pregnancy loss for these extreme intervals to the intervening intervals is 3.0 (P = 0.01). Nondiabetic losses showed a similar pattern. In confirmation, logit pregnancy losses were increased in a J-shaped curve at the glycemic extremes in normal (P < 0.019) and diabetic (P < 0.015) pregnancy. The upper glycemic extreme in diabetic pregnancy was two- to fivefold higher than in control pregnancy. CONCLUSIONS: Pregnancy losses are increased at the extremes of glycemia in both normal and diabetic pregnancy but at higher levels in diabetic pregnancy. The data suggest defensive adaptations against hyperglycemia in diabetic pregnancy.

Abortion, Spontaneous↗
PubMed2004

Neural tube defect rates before and after food fortification with folic acid.

BACKGROUND: Since 1998, enriched cereal grains sold in the United States have been fortified with folic acid, to reduce the incidence of neural tube defects (NTDs). The Centers for Disease Control and Prevention (CDC) recently reported that NTD rates have decreased 26% since fortification, but that additional effort is needed to achieve the national goal of a 50% reduction. However, accurate determination of NTD rates requires counting antenatally detected cases; the CDC study noted that the number of prenatally diagnosed cases was likely underestimated. METHODS AND RESULTS: We examined studies from the United States and Canada that compared rates of NTDs before and after very similar fortification programs were instituted in each country. U.S. studies had incomplete ascertainment of prenatally diagnosed NTD cases, and as a result, underreported the number of NTDs prevented. Canadian studies, in which ascertainment was more complete, showed decreases in NTD rates up to 54%. CONCLUSIONS: There is a strong correlation between the completeness of ascertainment and the percentage decrease in NTD rates. Studies that identify cases best show that folic acid fortification is preventing around 50% of NTDs. The percentage of NTDs that are folate-preventable in the United States is uncertain, but is probably 50-60%. Thus, we may be quite close to achieving the optimum level of protection at current fortification levels.

Female↗