Pregnancy-associated plasma protein A, free human chorionic gonadotrophin and nuchal translucency as predictors of miscarriage.
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Abortion, Spontaneous↗
Biomedical subjects
M Ryynänen
Publications and source records attributed to M Ryynänen.
Maternal serum beta-HCG and alpha-fetoprotein concentrations in singleton pregnancies following assisted reproduction.
BACKGROUND: The reason for the elevated levels of HCG in assisted reproduction pregnancies remains unknown. Our hypothesis was that this increase is caused by the ovarian superovulation therapy. METHODS: We compared the beta-HCG and alpha-fetoprotein (AFP) multiples of the median (MoM) in singleton pregnancies after IVF or ICSI with those achieved by frozen embryo transfer (FET) in spontaneous cycles. RESULTS: The HCG and AFP MoMs (plus minus SEMs) of 59 FET pregnancies were compared with 144 IVF (including 48 ICSI) pregnancies. The maternal HCG of pregnancies following ovarian stimulation was 1.31 plus minus 0.08 MoM compared with 1.35 plus minus 0.12 MoM in the unstimulated ones. The values for AFP were 1.06 plus minus 0.05 versus 1.11 plus minus 0.05 respectively. No significant differences could be observed between pregnancies following stimulated IVF/ICSI and unstimulated FET cycles. CONCLUSIONS: Our results show that second trimester maternal serum HCG is also elevated in singleton pregnancies following spontaneous FET cycles. The increased maternal serum HCG in IVF pregnancies is thus not related to superovulation therapy. Because of the elevated maternal serum HCG levels, serum screening cannot be performed reliably in pregnancies following assisted reproduction technology. Ultrasonographic detection of the nuchal translucency is unaffected and should be used for this group of women undergoing assisted reproduction.
Chorionic Gonadotropin, beta Subunit, Human↗
Genome-wide linkage disequilibrium mapping of late-onset Alzheimer's disease in Finland.
BACKGROUND: AD is a complex neurodegenerative disorder comprising several disease-associated chromosome loci. To find novel susceptibility genes for late-onset AD, a population-based genome-wide search using linkage disequilibrium (LD) mapping approach has been performed. METHOD: Forty-seven patients with late-onset AD and 51 age-matched control subjects were carefully chosen from the same geographic area in eastern Finland, where the population is descended mainly from a small group of original founders. These subjects were initially genotyped with 366 polymorphic microsatellite markers, and a follow-up analysis was performed with additional microsatellite markers for those chromosome loci found to be associated with AD. RESULTS: Initial genome-wide screening revealed 21 chromosomal loci significantly associated with AD in addition to the 13q12 locus described previously. Subsequent comparison of single-allele frequencies of the microsatellite markers in the AD and control groups indicated the presence both of possible risk alleles (odds ratio [OR] > 1) and of possible protective alleles (OR < 1). Screening of the LD regions with additional microsatellite markers revealed seven chromosomal loci where more than one microsatellite marker was associated with AD (1p36.12, 2p22.2, 3q28, 4p13, 10p13, 18q12.1, and 19p13.3) in addition to the 13q12 locus. CONCLUSIONS: These genome-wide LD screening data suggest that several AD-associated chromosomal loci exist, which may encompass novel susceptibility genes for late-onset AD. Therefore, extensive screening of the genes located in the vicinity of these LD regions is necessary to elucidate their role in AD.
Age of Onset↗
Antenatal genetic screening for congenital nephrosis.
This study was undertaken to study the applicability of genetic antenatal screening for the Finnish type of congenital nephrosis (CNF), which is a recessive disorder leading to nephrotic syndrome from birth. At Kuopio University Hospital, a total of 1303 pregnant women were offered carrier screening for CNF at the time of first trimester nuchal fold translucency measurement when fetally derived alpha-fetoprotein is still produced by the yolk sac. Two mutations of the nephrin (NPHS 1) gene, accounting for approximately 95% of affected alleles, were tested by two PCR tests. Uptake of the gene test was 91.0% (n=1183). Altogether 38 female carriers were found; a population carrier frequency of 1 in 31. Their partners were tested and two of them were also found to be carriers. In these two pregnancies invasive prenatal diagnosis was offered and accepted, and the results indicated one carrier and one affected fetus. Carrier screening is an effective and well-accepted method for antenatal screening for fetal CNF. Direct mutation analysis involves markedly less invasive procedures compared with serum alpha-fetoprotein (AFP) screening, and the diagnosis was clear-cut. The results indicate that in single-gene disorders genetic testing is suitable for antenatal screening.
Alleles↗
First-trimester screening for Down's syndrome in in vitro fertilization pregnancies.
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Adult↗
Evaluation of first trimester maternal serum and ultrasound screening for Down's syndrome in Eastern and Northern Finland.
The current trend in prenatal diagnosis is that trisomy screening is being moved to the first trimester and ultrasonographic nuchal translucency measurement is included in risk calculation. It is likely that biochemical screening in the second trimester will gradually be given up. In Eastern and Northern Finland, during the year 1999 we offered first-trimester ultrasonographic and serum screening for trisomy 21, with measurements of maternal serum PAPP-A and beta-hCG. A total of 2515 pregnant women participated in the screening, yielding the detection of eight foetuses with Down's syndrome. Six affected foetuses (75%) were detected by means of first-trimester serum screening. Since we were in the phase of collecting data for the Finnish medians for PAPP-A and beta-hCG, the women were not given the estimates of risk for trisomy 21. Only 1602 of the 2515 enrolled women had the combination of first-trimester ultrasonographic and serum screening performed, and in that group there were five foetuses with Down's syndrome. The combination ultrasonographic and serum approach yielded a Down's syndrome detection rate of 80% (four out of five) with a 5% false positive rate, whereas in nuchal translucency based-screening the detection rate was 60%, with a 5% false positive rate.
Adult↗
Wide scope prenatal diagnosis at Kuopio University Hospital 1997-1998: integration of gene tests and fetal karyotyping.
OBJECTIVE: To investigate the applicability of carrier screening in women undergoing invasive prenatal diagnosis. DESIGN: Prospective study. SETTING: University-based clinic. PARTICIPANTS: Two hundred and fifty-six pregnant women. METHODS: Gene tests were offered for fragile X syndrome, aspartylglycosaminuria and infantile neuronal ceroid lipofuscinosis at the time of invasive prenatal testing. RESULTS: The overall uptake of the tests was 92%. Previously unrecognised carriership was found in 10 women: aspartylglycosaminuria (7); infantile neuronal ceroid lipofuscinosis (2) and fragile X (1). Fetal genotyping was carried out in one carrier of aspartylglycosaminuria whose partner was also a carrier, and in one woman who was found to have fragile X premutation. Both fetuses were unaffected. CONCLUSION: Carrier screening for single-gene disorders is feasible and well accepted among pregnant women undergoing invasive prenatal testing. The major benefit is that there is no need to consider extra invasive tests when carriership is detected. Incorporation of genetic testing into fetal karyotyping gives more security to future parents.
Cohort Studies↗
[Antenatal screening methods for chromosome 21 trisomy].
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Down Syndrome↗
Does apolipoprotein E genotype relate to BMD and bone markers in postmenopausal women?
OBJECTIVES: Bone mineral density (BMD) and development of osteoporosis are partly determined by genetic factors. The associations between one of suggested candidate, apolipoprotein E (apo E) genotype to bone mineral density (BMD) and bone biochemical markers was studied in 464 subjects recruited from a population-based group of early postmenopausal women (n = 13100). Additionally, the influence of apo E genotype on BMD changes during a 5-year follow-up with or without hormone replacement therapy (HRT) was investigated. METHODS: Participants were randomized into two treatment groups: HRT group: Sequential combination of 2 mg estradiol valerate and 1 mg cyproterone acetate with or without vitamin D3, 100-300 IU/day + calcium lactate, 500 mg/day (n = 232), and the non-HRT group: Calcium lactate, 500 mg/day alone or in combination with vitamin D3, 100-300 IU/day (n = 232). BMD was measured from the lumbar spine and proximal femur at baseline and after 5 years of treatment (n = 352). In a subgroup (n = 59), the serum concentrations of bone biochemical markers (intact osteocalcin (OC), bone-specific alkaline phosphatase (BAP) and type I collagen carboxy-terminal telopeptide (ICTP)) were measured at baseline and after 1 year of follow-up. RESULTS: At baseline, the BMDs were similar between the five apo E genotype groups (2/3, 2/4, 3/3, 3/4, 4/4). No significant differences in lumbar or femoral neck BMDs of women with the apo E4 allele were found compared with those without it. There was a statistically significant difference in 5-year BMD changes between the HRT and non-HRT groups. After 5 years, the BMD of the femoral neck had remained constant and the mean lumbar spine BMD had increased by 1.5% in the HRT group, whereas both BMDs had decreased by 4-5% in the non-HRT group. However, the apo E genotype did not modify the changes in BMD in either group. Additionally, the baseline concentrations of bone metabolic markers and their 1-year changes showed no genotype-related associations. CONCLUSIONS: The results of our population-based study indicate that apo E genotype does not modify lumbar or femoral neck BMDs or serum bone biochemical markers or their response to HRT in early postmenopausal Caucasian women.
Apolipoproteins E↗
Is the presenilin-1 E318G missense mutation a risk factor for Alzheimer's disease?
Nearly all of the presenilin-1 (PSEN-1) mutations are missense mutations leading to Alzheimer's disease (AD). The role of the mutation E318G (a substitution of glutamic acid to glycine) in the PSEN-1 is controversial. It has been found both in AD patients and in non-demented control individuals. Using the polymerase chain reaction and the restriction fragment length polymorphism method, we screened for E318G mutation in a total of 16 familial (FAD) cases, in 64 sporadic neuropathologically confirmed AD cases and in 270 non-demented controls including 35 neuropathologically confirmed individuals. We detected the E318G mutation in four FAD cases, seven sporadic AD cases and 10 control individuals with highly varying onset-ages. Odds ratios for carrying the mutation were 7.6 and 3 in FAD and sporadic AD cases, respectively. Our results suggest that this mutation could be a risk factor in the Finnish FAD and sporadic AD population. It may be in linkage disequilibrium with a pathogenic change somewhere else in the PSEN-1 gene or in close proximity to the PSEN-1 gene.
Aged↗
Prenatal diagnosis of fragile X syndrome and the risk of expansion of a premutation.
The aim of the present study was to evaluate prospectively the dynamics of the FMR1 gene. The risk of full mutation among pregnant women and the carriers, and the risk of expansion of a premutation allele to a full mutation were estimated. We identified 89 pregnant women with an expanded FMR1 gene seeking prenatal diagnosis. Amniocentesis or chorion villus sampling (CVS) was offered and a DNA test of the FMR1 gene was carried out in such pregnancies. The overall risk of full mutation among women (N = 21) with a repeat size between 60 and 80 was 4.8% (one fetus with mosaicism), and the risk of expansion of the premutation allele to a full mutation was 14% in those offspring to whom the premutation allele was transmitted. The risk of full mutation among the carriers (N = 13) with a repeat size between 81 and 100 was 61.5% (8/13), and the risk of expansion of a premutation allele to a full mutation was 89%. Only one case fell into the category of 101-200 repeats, and expansion to a full mutation was recorded. Fetuses of full mutation mothers inherited the larger allele in 64% (14/22) of the cases. The range of 40-59 repeats was safe: there were no fetal full mutations. The risk of full mutation was also low among the subjects with a repeat size between 60 and 80, whereas the risk increased significantly after 80 repeats. Maternal premutation size was positively correlated with the risk of having a full mutation offspring.
Adult↗
Multiple founder effects and geographical clustering of BRCA1 and BRCA2 families in Finland.
In the Finnish breast and ovarian cancer families six BRCA1 and five BRCA2 mutations have been found recurrently. Some of these recurrent mutations have also been seen elsewhere in the world, while others are exclusively of Finnish origin. A haplotype analysis of 26 Finnish families carrying a BRCA1 mutation and 20 families with a BRCA2 mutation indicated that the carriers of each recurrent mutation have common ancestors. The common ancestors were estimated to trace back to 7-36 generations (150-800 years). The time estimates and the geographical clustering of these founder mutations in Finland are in concordance with the population history of this country. Analysis of the cancer phenotypes showed differential ovarian cancer expression in families carrying mutations in the 5' and 3' ends of the BRCA1 gene, and earlier age of ovarian cancer onset in families with BRCA1 mutations compared with families with BRCA2 mutations. The identification of prominent and regional BRCA1 and BRCA2 founder mutations in Finland will have significant impact on diagnostics in Finnish breast and ovarian cancer families. An isolated population with known history and multiple local founder effects in multigenic disease may offer distinct advantages also for mapping novel predisposing genes.
Adult↗
Pregnancy outcome in carriers of fragile X.
OBJECTIVE: To evaluate pregnancy outcome in women who are carriers of fragile X. DESIGN: Cross-sectional case-control study. SETTING: Department of Obstetrics and Gynaecology, Kuopio University Hospital, Finland. SAMPLE: Sixty-three singleton pregnancies in carriers of fragile X who were referred for genetic counselling and prenatal diagnosis to Kuopio University Hospital. METHODS: Logistic regression analysis was used to compare pregnancy outcome in women who are fragile X carrier with outcome of the general obstetric population. RESULTS: Carriers of fragile X often experienced more bleeding in late pregnancy than did the reference group. Otherwise, the course and outcome of pregnancy were comparable in both groups. CONCLUSION: Pregnancy outcome in women who are carriers of fragile X is favourable. There is no need to initiate special fetal monitoring because of the fragile X status of the woman.
Adolescent↗
Etiology and outcome of second trimester non-immunologic fetal hydrops.
BACKGROUND: This investigation was undertaken to study the conditions resulting in midtrimester fetal hydrops and to evaluate its overall prognosis as regards counseling purposes. MATERIAL AND METHODS: The etiology of midtrimester non-immune fetal hydrops was retrospectively evaluated as regards cases detected in singleton pregnancies (n=58) from January 1987 through December 1996. The condition was diagnosed by way of routine biochemical and ultrasonographic screening of a pregnant population. RESULTS: The rate of diagnosed midtrimester fetal hydrops was 1 in 1700 pregnancies and the overall survival rate in this usually unexpected condition was less than 10%. Various chromosomal and fetal structural abnormalities dominated as a cause of fetal hydrops, representing 44.8% and 43.1% of the cases, respectively. Infection caused only 6.9%. The underlying etiology remained unknown in only three cases. However, in 78% the diagnosis was already known prenatally. DISCUSSION: Although the overall prognosis is poor, knowledge of the primary etiology is important to determine a rational therapeutic strategy. If the results of routine investigations rule out malformation and abnormal chromosomes, follow-up serial ultrasonographic assessment may indicate that the hydropic state is transient, carrying a somewhat better prognosis.
Female↗
Promoter polymorphism (-491A/T) in the APOE gene of Finnish Alzheimer's disease patients and control individuals.
Apolipoprotein E (APOE) epsilon4 allele is a major risk factor for the development of Alzheimer's disease (AD). It has been suggested that the quantitative expression of APOE alleles results from mutations in the promoter region of this gene. We studied the -491A/T promoter polymorphism and whether it is dependent on the APOE epsilon4 allele in clinic-based AD (n = 106) and community-based control (n = 123) samples. The -491A/T and APOE polymorphisms were analyzed using the polymerase chain reaction method and restriction fragment length polymorphism analysis. The APOE epsilon4 allele was strongly associated with AD when compared with controls, P < 0.001 (odds ratio 5.85, 95% CI 3.29- 10. 41). The genotype distribution of the -491A/T polymorphism did not significantly differ between the study groups (P = 0.063), and the -491A allele was not associated with any significant risk in the AD group when compared to controls (odds ratio 1.82, 95% CI 0.95-3.49). However, haplotype estimation analysis indicated linkage disequilibrium between APOE -491A/T polymorphism and the APOE epsilon4 allele. Our findings confirm APOE polymorphism still to be the most efficient predictor of risk in AD.
Aged↗
Linkage disequilibrium in the 13q12 region in Finnish late onset Alzheimer's disease patients.
Alzheimer's disease (AD) is a complex neurodegenerative disorder, for which several disease-associated loci have been located on different chromosomes. We have used a population-based linkage disequilibrium mapping approach in order to find potential AD-associated loci on chromosome 13. To avoid population stratification, late onset AD patients and age-matched controls were carefully chosen from the same geographical area in Eastern Finland, where the population is mainly descended from a small group of original founders. During the initial screening with chromosome 13-specific microsatellite markers, tetranucleotide marker D13S787 was found to be in linkage disequilibrium in the 13q12 region. Screening this region with additional microsatellite markers revealed that marker D13S292 was also significantly associated with AD. Stratification of the AD patients and controls into groups according to apolipoprotein E, sex, and familial/sporadic status indicated that the 13q12 locus was associated with female familial AD patients regardless of ApoE genotype. Based on the physical data from the region 13q12, markers D13S292 and D13S787 were estimated to reside in a 810kb long YAC clone 754h7 together with two infant brain-derived ESTs and the H,K-ATPase alpha-subunit protein gene (ATP1AL1). The localisation of these sequences at the linkage disequilibrium region suggests that they may be candidate genes involved in a sex-specific effect during development of AD.
Age of Onset↗
Is the response of serum lipids and lipoproteins to postmenopausal hormone replacement therapy modified by ApoE genotype?
Postmenopausal hormone replacement therapy (HRT) has favorable effects on the serum lipid profile, and it also decreases the risk of cardiovascular diseases. The apolipoprotein E genotype has influence on serum levels of lipids and lipoproteins; apoE allele epsilon4 (apoE4) is associated with high total and LDL cholesterol levels. Genotype also influences the lipid responses to treatment with diet and statins, but the effect of HRT in different apoE genotypes is unknown. We studied the effects of HRT on the concentrations of serum lipids in apoE4-positive early postmenopausal women (genotypes 3/4 and 4/4) compared with apoE4-negative women (genotypes 2/3 and 3/3) in a population-based, prospective 5-year study. In all, 232 early postmenopausal women were randomized into 2 treatment groups: an HRT group (n=116), which received a sequential combination of 2 mg estradiol valerate (E2Val) from day 1 to 21 and 1 mg cyproterone acetate (CPA) from day 12 to 21 (Climen), and a placebo group (n=116), which received 500 mg/d calcium lactate. Serum concentrations of total, LDL, and HDL cholesterol and triglycerides were measured at baseline and after 2 and 5 years of treatment. A total of 154 women completed the final analysis. During the follow-up period, serum total cholesterol and LDL cholesterol concentrations decreased in the HRT group in apoE4-negative women (8.1% and 17.1%, respectively; P<0.001) but did not change in the HRT group in apoE4-positive women or in the placebo group. Serum HDL cholesterol concentrations decreased in the placebo group (apoE4-negative, 3.9%, P=0.015; apoE4-positive, 8.1%, P=0.004) but did not change significantly in the HRT group. Serum triglyceride levels tended to increase in both study groups and genotypes (15.1% to 36.2%, P<0.038 to 0.001), but no differences were observed between the study groups or genotypes, respectively. Our finding was that in postmenopausal Finnish women LDL cholesterol levels in apoE4-negative subjects respond more favorably to HRT than those in apoE4-positive subjects. This finding has potential importance in postmenopausal women with hypercholesterolemia, if confirmed in other studies.
Apolipoprotein E4↗
The effects on fetal development of high alpha-fetoprotein and maternal smoking.
OBJECTIVES: This study determined the risk of impaired fetal growth resulting from the interaction between maternal smoking during pregnancy and unexplained elevated concentrations of maternal serum alpha-fetoprotein (MSAFP). METHODS: This observational study involved 123 pregnant smokers with unexplained second-trimester elevated concentrations of MSAFP, 827 smokers with normal levels, and 471 nonsmokers with raised levels. RESULTS: By logistic regression, coincident smoking and elevated MSAFP levels were found to be associated with increases in the low basic risks of prematurity, small-for-gestational-age births, low birthweight, and need for neonatal care. CONCLUSIONS: Maternal smoking has an adverse effect on fetal development in pregnancies with unexplained elevated MSAFP concentrations. Such pregnancies merit close surveillance.
Adult↗