Biomedical subjects

R T Lie

Publications and source records attributed to R T Lie.

At least 19 recordsLinked to original sources

PubMed2025

Genetic-epigenetic interactions (meQTLs) in orofacial clefts etiology.

OBJECTIVES: Nonsyndromic orofacial clefts (OFCs) involve complex genetic and environmental factors, with over 60 risk loci accounting for only a minority of estimated heritability and residing in non-coding regions with unclear functional relevance. We hypothesize that some genetic variants alter orofacial cleft risk by modifying DNA methylation (DNAm) at regulatory sequences essential for craniofacial development, acting as methylation quantitative trait loci (meQTLs). METHODS: We analyzed 10 well-established OFC-associated SNPs against genome-wide DNAm profiles in 409 cases and 456 controls, identifying 23 potential meQTLs. We validated findings using 358 cleft-discordant sibling pairs analyzed with quantitative MethyLight assays. Cross-referencing with the mQTL Database assessed temporal patterns across human development. Functional annotation used GeneHancer and craniofacial enhancer databases. RESULTS: Nine meQTLs were successfully replicated, including the highly significant rs987525 (8q24) - cg16561172 (MYC) association (P = 9.610E-6). This association mapped to a mesendoderm-active enhancer upstream of MYC, providing mechanistic explanation for the longstanding 8q24 cleft locus. Additional validated associations involved MAFB-PLCG1, NOG-PPM1E, FOXE1-FRZB, and SPRY2-LGR4 interactions. Independent differential methylation analysis revealed significant differences between discordant siblings at three CpG sites. Cross-referencing confirmed concordance with population-level methylation effects, with childhood representing the critical developmental window for most associations. CONCLUSIONS: This systematic meQTL characterization in OFCs demonstrates that genetic variants influence disease risk through epigenetic mechanisms. The 8q24-MYC regulatory pathway evidence provides crucial mechanistic insight into a major OFC risk locus. These findings bridge genetic associations with functional consequences, address missing heritability challenges, and suggest potential biomarkers and therapeutic targets for OFC prevention and treatment.

Journal Article↗

PubMed1999

Consanguinity and recurrence risk of birth defects: a population-based study.

Recurrence risks give insight into the causes of birth defects and are useful in genetic counseling. There are few population-based studies of recurrence of birth defects for subsequent sibs with consanguineous parents. The aim of this study was to estimate and compare the recurrence risk of birth defects for offspring of first cousins and nonconsanguineous parents. The study population consisted of all single births with a previous sib born in Norway between 1967 and 1995. Altogether 660,398 children had nonconsanguineous parents, and 3,583 had parents who were first cousins. For nonconsanguineous parents the risk of a birth defect for the subsequent sib was 15 per 1,000 births (95% confidence interval: 14.5-15.1) if the previous child did not have a birth defect and 33 (95% confidence interval: 30-37) if the previous child had a birth defect. For parents who were first cousins the risk of a birth defect for the subsequent sib was 36 per 1,000 (95% confidence interval: 30-42) if the previous child did not have a birth defect and 68 (95% confidence interval: 33-122) if the previous child had a birth defect. The risk of recurrence of birth defects is higher for subsequent sibs with first-cousin parents than for those with nonconsanguineous parents. This difference indicates the degree to which the increased homozygosity among offspring of consanguineous parents influences the risk of recurrence of birth defects.

Age Factors↗

PubMed1999

Causes of death in patients with peptic ulcer perforation: a long-term follow-up study.

BACKGROUND: Survival is lower in ulcer perforation patients than in the general population. This study assesses the causes of death in patients treated for peptic ulcer perforation. METHODS: Cause-specific mortality in a population-based cohort of 817 patients treated for ulcer perforation in western Norway during the period 1962-1990 was compared with cause-specific population death rates. Analyses were based on observed and expected mortality curves for major causes of death and on standardized mortality rates (SMRs). Cox regression models were used to analyse possible differences on the basis of sex, birth cohort, surgical procedure, and ulcer location. RESULTS: Ulcer perforation patients experienced increased mortality from neoplasms (SMR = 1.8; 95% confidence interval (CI) = 1.4-2.1), lung cancer (SMR = 3.6; 95% CI = 2.3-4.9), circulatory diseases (SMR = 1.3; 95% CI = 1.1-1.6), ischaemic heart disease (SMR = 1.3; 95% CI = 1.03-1.6), and respiratory diseases (SMR = 1.9; 95% CI = 1.3-2.6). Postoperative deaths accounted for 38% of all excess deaths. Death from recurrent peptic ulcer was increased also in subjects who survived the 1st year after the perforation (SMR = 5.8; 95% CI = 1.2-10.4) but accounted for only a few deaths. The increase in mortality from lung cancer was higher in subjects born after 1910 than in patients of older generations. Excess mortality from lung cancer and from circulatory diseases was higher in male than in female patients. CONCLUSIONS: Increased mortality in ulcer perforation patients could mainly be attributed to smoking-related diseases. This is indirect evidence that smoking may be an important aetiologic factor for ulcer perforation.

Cardiovascular Diseases↗

PubMed1998

Distinguishing the effects of maternal and offspring genes through studies of "case-parent triads".

A gene variant that increases disease risk will be overrepresented among diseased persons, even compared with their own biologic parents. This insight has led to tests based solely on the asymmetric distribution of a variant allele among cases and their parents (e.g., the transmission/disequilibrium test). Existing methods focus on effects of alleles that operate through the offspring genotype. Alleles can also operate through the mother's genotype, particularly for conditions such as birth defects that have their origins in fetal life. An allele working through the mother would have higher frequency in case-mothers than in case-fathers. The authors develop a log-linear method for estimating relative risks for alleles in the context of case-parent triads. This method is able to detect the effects of genes working through the offspring, the mother, or both. The authors assume Mendelian inheritance, but Hardy-Weinberg equilibrium is unnecessary. Their approach uses standard software, and simulations demonstrate satisfactory power and confidence interval coverage. This method is valid with a self-selected or hospital-based series of cases and helps to protect against misleading inference that can result when cases and controls are randomly sampled from a population not in Hardy-Weinberg equilibrium.

5,10-Methylenetetrahydrofolate Reductase (FADH2)↗

PubMed1998

Influence of consanguinity and maternal education on risk of stillbirth and infant death in Norway, 1967-1993.

To analyze the influence of consanguinity and maternal education on stillbirth and infant death for children born in Norway between 1967 and 1993, the authors studied 7,274 children of ethnic Pakistani origin and 1,431,055 children of Norwegian ethnic origin. Of these children, 31.0% of the Pakistani children and 0.1% of the Norwegian children had parents who were first cousins. Consanguinity increased the relative risk of stillbirth (odds ratio (OR) = 1.3, 95% confidence interval (CI) 1.0-1.6) and infant death (OR = 2.4, 95% CI 2.0-3.0), after adjustment for maternal education, maternal age, parity, and year of birth. In 1985-1993, 29% (95% CI 13-45) of stillbirths and infant deaths among the Pakistani group were attributable to consanguinity. In the Norwegian group, 17% (95% CI 13-21) of the deaths were attributable to factors associated with low maternal education, while in the Pakistani group, the corresponding estimate was nonsignificant. The risks of stillbirth and infant death were similar for children with non-consanguineous parents in both populations. This is an important observation considering the differences in socioeconomic status between the two groups. The authors conclude that consanguinity influenced stillbirth and infant death independent of maternal education, and that a large proportion of deaths could be attributed to consanguinity in the Pakistani group due to high frequencies of consanguinity.

Consanguinity↗

PubMed1998

Expected survival compared with survival of peptic ulcer patients.

In analyses of patient survival it is often desirable to compare observed survival curves with expected survival curves based on information obtained from the general population. However, current methods of calculating expected survival curves are difficult to interpret and are often poorly documented. We discuss an alternative formulation of the so-called direct method which we recommend for general use. By simulation, we show that the expected survival curve obtained from this method represents the expectation of a Kaplan-Meier curve for a set of random population controls. Thus, the term expected survival does not refer to the expectation of patient survival, but rather to the expected survival curve for a random set of controls. The alternative methods are discussed, and we illustrate the methods in an analysis of long time survival of a population-based sample of peptic ulcer patients.

Age Factors↗

PubMed1998

Fetal and maternal contributions to risk of pre-eclampsia: population based study.

OBJECTIVE: To use familial patterns of recurrence of pre-eclampsia to investigate whether paternal genes expressed in the fetus contribute to the mother's risk of pre-eclampsia and whether mother's susceptibility to pre-eclampsia is related to maternal inheritance by mitochondrial DNA. DESIGN: Linked data on pregnancies of different women who had children with the same father, and subsequently linked data on pregnancies of half sisters who either had same mother and different fathers or had same father and different mothers. SETTING: Population based data from the Medical Birth Registry of Norway covering all births since 1967 (about 1.7 million) and the Norwegian Central Population Register. MAIN OUTCOME MEASURES: Relative risk of pre-eclampsia after a previous pre-eclamptic pregnancy in the family. Relative risks approximated by odds ratios. RESULTS: If a woman becomes pregnant by a man who has already fathered a pre-eclamptic pregnancy in a different woman her risk of developing pre-eclampsia is 1.8 (95% confidence interval 1.2 to 2.6). If the woman has a half sister who had pre-eclampsia and with whom she shares the same mother but different fathers the risk of pre-eclampsia is 1.6 (0.9 to 2.6). If the two sisters have the same father but different mothers the risk is 1.8 (1.01 to 2.9). CONCLUSIONS: Both the mother and the fetus contribute to the risk of pre-eclampsia, the contribution of the fetus being affected by paternal genes. Mitochondrial genes, which are transmitted by mothers, do not seem to contribute to the risk.

Fathers↗

PubMed1998

A log-linear approach to case-parent-triad data: assessing effects of disease genes that act either directly or through maternal effects and that may be subject to parental imprinting.

We describe a log-linear method for analysis of case-parent-triad data, based on maximum likelihood with stratification on parental mating type. The method leads to estimates of association parameters, such as relative risks, for a single allele, and also to likelihood ratio chi2 tests (LRTs) of linkage disequilibrium. Hardy-Weinberg equilibrium need not be assumed. Our simulations suggest that the LRT has power similar to that of the chi2 "score" test proposed by Schaid and Sommer and that both can outperform the transmission/disequilibrium test (TDT), although the TDT can perform better under an additive model of inheritance. Because a restricted version of the LRT is asymptotically equivalent to the TDT, the proposed test can be regarded as a generalization of the TDT. The method that we describe generalizes easily to accommodate maternal effects on risk and, in fact, produces powerful and orthogonal tests of the contribution of fetal versus maternal genetic factors. We further generalize the model to allow for effects of parental imprinting. Imprinting effects can be fitted by a simple, iterative procedure that relies on the expectation-maximization algorithm and that uses standard statistical software for the maximization steps. Simulations reveal that LRT tests for detection of imprinting have very good operating characteristics. When a single allele is under study, the proposed method can yield powerful tests for detection of linkage disequilibrium and is applicable to a broader array of causal scenarios than is the TDT.

Computer Simulation↗

PubMed1997

Birth defects and parental consanguinity in Norway.

The study compares frequencies of birth defects between immigrant groups and the rest of the Norwegian population in Norway and estimates the influence of consanguinity and socioeconomic factors on these frequencies. The authors studied all 1.56 million births in Norway from 1967 to 1993. Of these, 7,494 children had two Pakistani parents, 84,688 had one Norwegian and one immigrant parent, and 25,891 had two immigrant parents from countries other than Pakistan. The risk of birth defects relative to the Norwegian group was 0.98 (95% confidence interval 0.92-1.03) in the group with one foreign and one Norwegian parent, 1.39 (95% confidence interval 1.22-1.60) in the group with two Pakistani parents, and 1.04 (95% confidence interval 0.95-1.14) in the group with two parents from other foreign countries; 0.1% of the Norwegian and 30.1% of the Pakistani children had parents who were first cousins. There was no difference in risk between children of nonconsanguineous Pakistani parents and the other groups. The relative risk of birth defects among children whose parents were first cousins was about 2 in all groups. Among the Pakistani, 28% of all birth defects could be attributed to consanguinity. Low paternal educational level was associated with a slightly increased risk in the Norwegian group, while independent effects of parental educational levels were not found in any other groups.

Confidence Intervals↗

PubMed1997

[Congenital hip dislocation. Ultrasonic screening of newborn infants].

Despite the introduction of clinical screening and early treatment of congenital dislocation of the hip (CDH), the prevalence of subluxated/luxated hips in later infancy is still reported to be as high as 1-3 per 1,000 infants. Using ultrasound, it is possible to evaluate both hip morphology and hip stability. Hip morphology is best evaluated using Graf's coronal section through the deepest part of the acetabulum. Classification of the hips into different categories can then be based on measuring the angle of inclination of the acetabulum (alpha-angle) or femoral had coverage. Hip stability can be assessed by a Barlow-equivalent provocation test during the ultrasound examination. In the Norwegian newborn population approximately 85% of the infants have morphologically normal hips (based on the alpha-angle) while 12% have immature and 3% dysplastic hips. About 80-90% of infants with dysplastic acetabula show only minor changes, and many of the hips may normalize without treatment. Several studies indicate that universal ultrasound screening might reduce the occurrence of late diagnosed congenital dislocation of the hip.

Hip Dislocation, Congenital↗

PubMed1997

Environmental epidemiology at the Medical Birth Registry of Norway; strengths and limitations.

A national registry of all pregnancy-outcomes was started in Norway. in 1967 to facilitate epidemiological surveillance. One aim was to detect increases in birth detect prevalences that was caused by new harmful exposures. Over the years several studies of unexpected time-trends and regional differences have been performed, but specific harmful exposures have so far not been detected. In a study of possible effects of the Chernobyl fallout, the registry enabled a detailed investigation of a possible increase in prevalence of birth detects that occurred specifically in the most exposed areas of Norway. The strength of this approach was the population coverage of the registry, while important limitations were incomplete reporting (outcome misclassification) and crude exposure information (exposure misclassification). While still taking advantage of the population coverage of the medical birth registry, a new generation of studies with more complete case ascertainment and individual exposure information are being prepared. One particularly interesting new option is to use molecular genetic tools to identity susceptible mothers or children. Collection and storage of biological specimens on a large scale is challenging, but in the search for gene-environment interactions, population-based studies are particularly attractive.

Congenital Abnormalities↗

PubMed1997

Prediction of fetal growth based on maternal serum concentrations of human chorionic gonadotropin, human placental lactogen and estriol.

BACKGROUND: The purpose was to determine the usefulness of maternal serum concentrations of human chorionic gonadotropin (hCG), human placental lactogen (hPL) and estriol as predictors of fetal growth. METHOD: From a large cohort serum obtained serially at 17, 25, 33 and 37 weeks of gestation were analyzed for randomly selected pregnancies resulting in small for gestational age (SGA, n = 102) and non-SGA (n = 112) infants. RESULTS: There were no significant correlations between birthweight ratio (ratio of birthweight to mean weight for gestational age) and hCG, but between birthweight ratio on one hand and estriol for all stages of pregnancy (r = 0.19-0.38, p < 0.01 - p < 0.001) and hCL except at 33 weeks (r = 0.11-0.40, p ns-p < 0.001) on the other. There were statistically significant, but small median differences and substantial overlaps between the SGA and non-SGA infants for hCG at 17 and 37 weeks, for hPL at 17, 33 and 37 weeks, and for estriol at all the stages of pregnancy. The sensitivity and positive predictive value of low hormone concentrations (below the 10th percentile) in predicting the birth of an SGA infant were in the range of 6-26% and 17-39%, respectively. The corresponding specificity and prediction of a non-SGA infant from normal levels were 91-93% and 85-88%. CONCLUSIONS: HPL and estriol, but not hCG concentrations, are positively related to the size of the fetus, but the relationships are too weak to be of predictive value in an unselected population.

Adult↗

PubMed1997

Cell division in placentas of appropriate and small-for-gestational-age infants. A flow cytometry study.

BACKGROUND: The purpose of this study was to examine if placentas of small- for-gestational-age (SGA) and non-SGA infants differ with respect to proliferative cell activity. METHOD: Cell cycle distribution was studied in placentas from 181 SGA (birthweight < 10th percentile) and 528 non-SGA births by flow cytometry measurements of relative DNA content. RESULTS: The fraction of cells in various cell cycle phases (G1-, S- and G2-phases) did not differ with gestational age from 30 to 43 weeks in either of the groups. The placentas of the SGA infants had a significantly lower mean (+/-1 SEM) growth fraction than placentas of non-SGA infants (S-phase 5.2 +/- 0.2 vs 5.5 +/- 0.1, p = 0.05, and G2-fraction 5.4 +/- 0.2 vs 6.3 +/- 0.1, p < 0.001), but the overlaps of the distributions were large. Thus sensitivity, specificity and predictive values of low fractions did not differ substantially-from a purely random prediction of SGA. CONCLUSIONS: Cell division in the placenta is maintained until and beyond term. Placentas of SGA infants have on average, lower proliferative activity than placentas of non-SGA infants, but the difference is too small to be of predictive value in identifying intrauterine growth retardation.

Adult↗

PubMed1996

[Maternal diabetes--normalized perinatal mortality, but still high fetal growth].

Studies suggest that maternal diabetes can cause both placental insufficiency and exaggerated foetal growth. Pregnant mothers with diabetes have suffered high risk of losing their child. Data from the Medical Birth Registry of Norway show a decrease in the still birth rate from 16th week of gestation from 115.7 per 1,000 in 1967-75 to 12.8 in 1986-92 in the diabetes groups. The relative risks were 7.8 and 1.4 respectively for the two time periods. The early neonatal mortality rate decreased correspondingly. The proportion of Caesarean sections in mothers with diabetes, and the proportion of children with low birth weight or born prematurely also increased in the diabetes group. However, children in the diabetes group were on average still as big at gestational age in the most recent period as in the first period. Our data suggest that the improved metabolic control of maternal diabetes has reduced the occurrence and degree of placental insufficiency, with inherent decreases in mortality and risk of complications, but without reducing the foetal growth-stimulating effect of maternal diabetes.

Birth Weight↗

PubMed1996

Plasma brain natriuretic peptide as an indicator of left ventricular systolic function and long-term survival after acute myocardial infarction. Comparison with plasma atrial natriuretic peptide and N-terminal proatrial natriuretic peptide.

BACKGROUND: Elevated plasma levels of atrial natriuretic peptide (ANP) and the N-terminal fragment of the ANP prohormone (N-ANP) are associated with decreased left ventricular function and decreased long-term survival after acute myocardial infarction (AMI). Previous data suggest that plasma brain natriuretic peptide (BNP) may increase proportionally more than plasma ANP after AMI and in chronic heart failure. The diagnostic and prognostic value of plasma BNP as an indicator of left ventricular dysfunction and long-term survival after AMI, relative to that of ANP and N-ANP, remain to be established. METHODS AND RESULTS: Venous blood samples for analysis of ANP, N-ANP, and BNP were obtained on day 3 after symptom onset from 131 patients with documented AMI. Left ventricular ejection fraction was determined by echocardiography in a subsample of 79 patients. Twenty-eight cardiovascular and 3 noncardiovascular deaths occurred during the follow-up period (median, 1293 days). All three peptides proved to be powerful predictors of cardiovascular mortality by univariate Cox proportional hazards regression analyses (ANP: P < .0001; N-ANP: P = .0002; BNP: P < .0001). In a multivariate model, plasma BNP (P = .021) but not ANP (P = .638) or N-ANP (P = .782) provided additional prognostic information beyond left ventricular ejection fraction. Logistic regression analysis showed that ANP (P = .003) and N-ANP (P = .027) but not BNP (P = .14) were significantly associated with a left ventricular ejection fraction < or = 45%. CONCLUSIONS: These results suggest that plasma BNP determination provides important, independent prognostic information after AMI. Although plasma ANP appears to be a better predictor of left ventricular dysfunction, plasma BNP may have greater potential to complement standard prognostic indicators used in risk stratification after AMI because of its strong, independent association with long-term survival, enhanced in vitro stability, and simplicity of analysis.

Aged↗

PubMed1996

Developmental dysplasia of the hip: prevalence based on ultrasound diagnosis.

The prevalence of sonographically normal, immature and dysplastic hips, the association between hip morphology and gender, and known risk factors for developmental dysplasia of the hip (DDH) were determined for 3613 randomly selected, healthy newborns. Hip morphology was determined according to a modified Graf's method, and stability was evaluated using a Barlow equivalent maneuver. A higher proportion of girls than boys had immature hips [16.9 % vs 9.3 %; relative risk (RR) = 2.0, 95 % confidence interval (CI) = 1.6-2.4], minor dysplasia (4.5 % vs 1.0 %; RR = 4.8, 95 % CI = 2.9-8.1), and major dysplasia (1.2 % vs 0.2 %; RR = 5.5, 95 % CI = 1.9-16.2). An increased risk was associated with having a sibling or parent with DDH (RR = 2.2, 95 % CI = 1.0-4.6 and RR = 3.6, 95 % CI = 1.1-12.5 for girls and boys, respectively), but not with DDH in more distant relatives. Breech delivery represented a significant risk factor only for the girls (RR = 2.2, 95 % CI = 1.1-4.4). There was a strong association between hip morphology and sonographic stability (gamma = 0.98).

Female↗

PubMed1996

Survival after peptic ulcer perforation: a time trend analysis.

The survival of 1098 patients with ulcer perforation in Norway during the period 1952-1990 was compared with expected survival. Cox regression models incorporating population mortality rates, were used to analyse effects of sex, age, year of birth, and year at risk on excess mortality. Survival was lower in patients than in the general population through a follow-up period of 38 years. Relative survival was lower in women as compared to men, due to more delayed treatment. Long-term survival was lower after praepyloric perforations than after the other perforation types. Relative survival was higher in patients treated 1952-1970 than in those treated more recently. However, adjustment for year of birth revealed a decline in short-term mortality with calendar time, which is in accordance with improved management during the study period. Relative mortality, particularly long-term mortality, was higher in younger birth cohorts, suggesting a shift towards more serious etiologies.

Cohort Effect↗

PubMed1996

Developmental dysplasia of the hip. A population-based comparison of ultrasound and clinical findings.

Clinical and ultrasound findings were compared in 3613 newborns examined for developmental dysplasia of the hip (DDH) within 48 hours of delivery. Clinical and sonographic hip stability was described as stable, borderline unstable, dislocatable or dislocated, and the morphology on ultrasound as normal, immature or dysplastic. Persistent clinical or sonographic dislocatability or dislocation, major dysplasia or minor dysplasia combined with an unstable femoral head were indications for early treatment. A total of 123 (3.4%) infants were subjected to early treatment, of which 55 (45%) fulfilled the criteria for treatment on both clinical and ultrasound examinations, 52 (42%) were treated on the basis of ultrasound findings alone, and 16 (13%) on the basis of clinical findings alone. Thirty per cent of the infants with clinically dislocated or dislocatable hips were judged to have stable or just borderline unstable hips on the first clinical examination. Of 486 (13.5%) infants with sonographically immature or minor dysplastic but stable hips, 472 (97%) normalized spontaneously, while treatment was initiated in 14 (3%) of them at 1-3 months of age because of lack of sonographic improvement. Only one infant presented with late DDH during an observation period of 3 years. Accepting sonographic dysplasia as a criterion for early splinting may result in a treatment rate which is almost twice the rate based on clinical criteria, but late dislocation may be virtually eliminated.

Cross-Sectional Studies↗