Biomedical subjects
Allen J Wilcox
Publications and source records attributed to Allen J Wilcox.
Exploring the effects of methylenetetrahydrofolate reductase gene variants C677T and A1298C on the risk of orofacial clefts in 261 Norwegian case-parent triads.
Folic acid and the methylenetetrahydrofolate reductase (MTHFR) gene have both been implicated in the etiology of orofacial clefts. The authors selected 261 case-parent triads (173 cases with cleft lip with or without cleft palate (CL/P) and 88 cases with cleft palate only (CPO)) from a Norwegian population-based study of orofacial clefts (May 1996-1998). A case-parent triad design was used to examine whether MTHFR variants C677T and A1298C, and their haplotypes, are risk factors for orofacial clefts. Among CL/P cases, the child's genotype at C677T or A1298C did not influence the risk. However, children of mothers carrying the C677T variant allele had a lower risk of CL/P. For CPO, children carrying the C677T variant allele had about a twofold increased risk, whereas the mother's genotypes did not contribute to the risk. The haplotype-based transmission/disequilibrium test showed that except for 677T/1298A (p = 0.06), none of the other haplotypes showed evidence of excess transmission to the offspring. The authors also explored interaction of C677T with maternal use of folic acid among children with CPO. Surprisingly, the risk associated with the child's carrying either CT or TT was higher (fourfold) when the mother used folic acid. These findings suggest a possible role of MTHFR and folic acid in the causation of orofacial clefts, but the strength and direction of these effects remain to be clarified.
Subfecundity as a correlate of preeclampsia: a study within the Danish National Birth Cohort.
A long interpregnancy interval is associated with preeclampsia. If some women experiencing a long interval between births had difficulty conceiving, subfecundity and preeclampsia may share a common etiology. Therefore, the authors examined the association between subfecundity and preeclampsia. By using interview data collected during the second trimester of pregnancy (1998-2001) from women participating in the Danish National Birth Cohort, they identified 20,034 and 24,698 singleton livebirths to primiparous and multiparous women, respectively, for whom preeclampsia information was available from hospital birth records. Among women with no known hypertension, the authors estimated a higher risk of preeclampsia in those with longer times to pregnancy (TTPs), after adjustment for maternal age, prepregnancy body mass index, and smoking. Compared with primiparas who became pregnant right away (referent category), the risk of preeclampsia increased with TTP and then stabilized for women taking 6 months or longer to conceive, whose risk of preeclampsia increased by 50%. Multiparas also had an increased risk, but only those reporting a TTP longer than 12 months (odds ratio = 2.47, 95% confidence interval: 1.30, 4.69). The authors found that a long TTP was associated with preeclampsia, supporting the hypothesis that some factors delaying clinically recognized conception may also be in a causal pathway for preeclampsia.
Variants of developmental genes (TGFA, TGFB3, and MSX1) and their associations with orofacial clefts: a case-parent triad analysis.
We selected 262 case-parent triads from a population-based study of orofacial clefts in Norway, and examined variants of developmental genes TGFA, TGFB3, and MSX1 in the etiology of orofacial clefts. One hundred seventy-four triads of cleft lip cases (CL+/-P) and 88 triads of cleft palate only cases (CPO) were analyzed. There was little evidence for an association of any of these genes with CL+/-P. The strongest association was a 1.7-fold risk with two copies of the TGFB3-CA variant (95% CI=0.9-3.0). Among CPO cases, there was a 3-fold risk with two copies of the TGFA TaqI A2 allele, and no increase with one copy. Assuming this to be a recessive effect, we estimated a 3.2-fold risk among babies homozygous for the variant (95% CI=1.1-9.2). Furthermore, there was strong evidence of gene-gene interaction. While there was only a weak association of the MSX1-CA variant with CPO, the risk was 9.7-fold (95% CI=2.9-32) among children homozygous for both the MSX1-CA A4 allele and the TGFA A2 allele. No association of CPO with the TGFA variant was seen among the other MSX1-CA genotypes. In conclusion, no strong associations were found between CL+/-P and variants at these three genes. There was a possible recessive effect of the TGFA TaqI variant on the risk of CPO, with a 3-fold risk among children homozygous for the variant. The effect of this TGFA genotype was even stronger among children homozygous for the MSX1-CA A4 allele, raising the possibility of interaction between these two genes.
Cleft palate, transforming growth factor alpha gene variants, and maternal exposures: assessing gene-environment interactions in case-parent triads.
We have previously reported a threefold risk of cleft palate only (CPO) among children homozygous for the less common allele A2 at the TaqI marker site of the transforming growth factor alpha gene (TGFA) (Jugessur et al. [2003a] Genet. Epidemiol. 24:230-239). Here we assess possible interaction between the child's TGFA TaqI A2A2 genotype and maternal cigarette smoking, alcohol consumption, use of multivitamins and folic acid. This was done by comparing the strength of genetic associations between strata of exposed and unexposed case-parent triads. We also looked for possible gene-gene interaction with the polymorphic variant C677T of the folic acid-metabolizing gene MTHFR. We analyzed a total of 88 complete CPO triads selected from a population-based study of orofacial clefts in Norway (May 1996-1998). No evidence of interaction was observed with either smoking or alcohol use. The risk associated with two copies of the A2 allele at TGFA TaqI was strong among children whose mothers did not use folic acid (relative risk=4.5, 95% confidence interval=1.3-15.7), and was only marginal among children whose mothers reported using folic acid (RR=1.4, 95% CI=0.2-12.7). Although the interaction between the child's genotypes at TGFA TaqI and MTHFR-C677T was not statistically significant, the effect of the TGFA TaqI A2A2 genotype appeared to be stronger among children with either one or two copies of the T-allele at C677T (RR=4.0, 95% CI=1.1-13.9) compared to children homozygous for the C-allele (RR=1.7, 95% CI=0.2-15.7). In conclusion, we find little evidence of interaction between the child's genotypes at TGFA TaqI and various exposures for cleft palate, with the possible exception of folic acid intake.
Commentary: On the paradoxes of birthweight.
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Rescue of the corpus luteum in human pregnancy.
Rescue of the corpus luteum from its programmed senescence maintains progesterone production required for pregnancy. In primates, chorionic gonadotropin produced by the developing conceptus acts as the primary luteotrophic signal. The purpose of this research was to assess corpus luteum rescue by examining changes in daily urinary progesterone metabolite levels during the first week after implantation. We determined the variability in progesterone metabolite profiles and evaluated its relationship to early pregnancy loss in 120 naturally conceived human pregnancies, including 43 early pregnancy losses. In other primates, an abrupt increase in the progesterone metabolite occurs at the time of implantation. This pattern occurred in an estimated 45% of the pregnancies in the present study. In the remaining pregnancies, there was a delayed rise (18%), neither a rise or decline (22%), or a decline (15%) during the week after implantation. The estimated rate of early pregnancy loss increased across these categories (from 5% loss with an abrupt rise at implantation to 100% loss with progesterone metabolite decline). Low urinary hCG levels in early pregnancy were significant determinants of a decline in postimplantation progesterone metabolite. However, preimplantation steroid metabolite levels were not significant, suggesting no inherent problem with the corpus luteum. Examination of individual progesterone metabolite profiles in relation to hCG profiles also indicated that few losses were caused by corpus luteum failure. Delineating the functional importance of an abrupt progesterone rise at the time of implantation may provide new strategies for promoting successful implantation in assisted reproduction.
Maternal serum level of 1,1-dichloro-2,2-bis(p-chlorophenyl)ethylene and risk of cryptorchidism, hypospadias, and polythelia among male offspring.
1,1-Dichloro-2,2-bis(p-chlorophenyl)ethylene (p,p'-DDE) is a metabolite of the insecticide 2,2-bis(p-chlorophenyl)-1,1,1-trichloroethane (DDT) and is a ubiquitous environmental contaminant. Nearly everyone in the United States has a detectable serum level of DDE. DDE was recently found to inhibit binding of androgen to its receptor and to block androgen action in rodents. Normal development of male genitalia in mammals depends on androgen action. The authors used stored serum samples to examine the relation between maternal DDE levels during pregnancy and adjusted odds of cryptorchidism (n = 219), hypospadias (n = 199), and polythelia (extra nipples) (n = 167) among male offspring, using a nested case-control design with one control group (n = 552). Subjects were selected from the Collaborative Perinatal Project, a US birth cohort study begun in 1959-1966, when DDE levels were much higher than they are at present. Compared with boys whose mother's recovery-adjusted serum DDE level was less than 21.4 microg/liter, boys with maternal levels greater than or equal to 85.6 microg/liter had adjusted odds ratios of 1.3 (95% confidence interval (CI): 0.7, 2.4) for crypt-orchidism, 1.2 (95% CI: 0.6, 2.4) for hypospadias, and 1.9 (95% CI: 0.9, 4.0) for polythelia. For cryptorchidism and polythelia, the results were consistent with a modest-to-moderate association, but in no instance was the estimate very precise. The results were inconclusive.
The interval between pregnancies and the risk of preeclampsia.
BACKGROUND: The risk of preeclampsia is generally lower in second pregnancies than in first pregnancies, but not if the mother has a new partner for the second pregnancy. One explanation is that the risk is reduced with repeated maternal exposure and adaptation to specific antigens from the same partner. However, the difference in risk might instead be explained by the interval between births. A longer interbirth interval may be associated with both a change of partner and a higher risk of preeclampsia. METHODS: We used data from the Medical Birth Registry of Norway, a population-based registry that includes births that occurred between 1967 and 1998. We studied 551,478 women who had two or more singleton deliveries and 209,423 women who had three or more singleton deliveries. RESULTS: Preeclampsia occurred during 3.9 percent of first pregnancies, 1.7 percent of second pregnancies, and 1.8 percent of third pregnancies when the woman had the same partner. The risk in a second or third pregnancy was directly related to the time that had elapsed since the preceding delivery, and when the interbirth interval was 10 years or more, the risk approximated that among nulliparous women. After adjustment for the presence or absence of a change of partner, maternal age, and year of delivery, the odds ratio for preeclampsia for each one-year increase in the interbirth interval was 1.12 (95 percent confidence interval, 1.11 to 1.13). In unadjusted analyses, a pregnancy involving a new partner was associated with higher risk of preeclampsia, but after adjustment for the interbirth interval, the risk of preeclampsia was reduced (odds ratio for preeclampsia with a change of partner, 0.73; 95 percent confidence interval, 0.66 to 0.81). CONCLUSIONS: The protective effect of previous pregnancy against preeclampsia is transient. After adjustment for the interval between births, a change of partner is not associated with an increased risk of preeclampsia.
A prospective study of the onset of symptoms of pregnancy.
The objective of this study was to provide prospectively collected data on the onset of pregnancy symptoms. Two hundred twenty-one women attempting pregnancy kept daily records of the occurrence of symptoms of pregnancy. Among 136 women delivering live infants, half began experiencing symptoms by day 36 after their last menstrual period (LMP), and 89% by the end of the eighth week. Onset of symptoms occurred later in pregnancies that went on to miscarry. Among 48 women with biochemically detected pregnancy loss before 6 weeks LMP, symptoms were substantially reduced but not entirely absent. Women who smoked tobacco or marijuana tended to have delayed onset of symptoms. Nearly 90% of women with successful pregnancies experience symptoms within 8 weeks LMP. Even pregnancies lost very early (before 6 weeks) are sometimes symptomatic. The earliest symptoms do not begin until after key stages of embryogenesis, reinforcing the need for women to initiate sound health behaviors before pregnancy is apparent. Published by Elsevier Science Inc.
"State of the journal" - 2002.
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