Association of HLA-DRB1*01 with Dupuytren's disease.

OBJECTIVES: To explore the human leucocyte antigen (HLA)-DRB1 allele frequency in Dupuytren's disease (DD). METHOD: HLA-DRB1 genotypes were analysed by sequence-specific primers (SSPs) in samples collected from 172 men participating in a nested case-control study on the clinical manifestations and progression of DD. Of those, 121 had signs of DD while 51 did not. Of the 121 men with DD, 49 had contracted fingers or had been operated on, while 72 had nodules or fibrous cords in the palms. Odds ratios (ORs) and 95% confidence interval (CIs) were used to evaluate the results. RESULTS: The HLA-DRB1*01 allele was observed in 26 of the 121 affected men (23.7%) but in only four of the controls (7.8%) (OR 3.22, 95% CI 1.06-9.75). The HLA-DRB1*01 allele frequency in those affected was 11%, while in the control group it was 4% (OR 3.07, 95% CI 1.05-9.03). CONCLUSIONS: This observation indicates a possible association of HLA-DRB1*01 with DD, but further studies are needed for confirmation.

Dupuytren's disease, alcohol consumption and alcoholism.

OBJECTIVE: To assess the relation between alcohol consumption and Dupuytren's disease. DESIGN: The participants were recruited from a previous study on Dupuytren's disease carried out in 1981-82 as part of a cohort study. Men with Dupuytren's disease in the former study and a control group were invited. The groups were matched for age and smoking habits. SETTINGS: The study took place at the Heart Preventive Clinic in Reykjavik. PATIENTS: Of 244 invited participants, 193 (79.1%) responded to the invitation; 137 had Dupuytren's disease and 56 were disease-free. Participants were examined for the presence of Dupuytren's disease and answered a questionnaire about alcohol habits. MAIN OUTCOME MEASURES: Alcoholism, alcohol consumption and signs of Dupuytren's disease. RESULTS: Of the Dupuytren's group, 19 (13.9%) had been treated for alcoholism or were heavy drinkers compared to 8 (14.3%) of those without Dupuytren's disease (NS). Little or moderate alcohol consumption was reported in 78.1% of the Dupuytren's patients compared to 73.2% of the controls (NS). Total abstainers from alcohol were 11 (8.0%) in the Dupuytren's group compared to 7 (12.5%) in the control group (NS). CONCLUSION: Our findings do not support a positive association between the use of alcohol and Dupuytren's disease.

MODY in Iceland is associated with mutations in HNF-1alpha and a novel mutation in NeuroD1.

AIMS/HYPOTHESIS: Five different types of maturity-onset diabetes of the young (MODY) have been identified until now but mutation screening suggests that more MODY genes exist. Mutations in genes encoding transcription factors essential for normal development and function of pancreatic beta cells has recently become important in studying the genetics of Type II (non-insulin-dependent) diabetes mellitus. Patients with MODY and their families in Iceland were screened for mutations in the transcription factor genes. METHODS: Clinical and biochemical information on individuals with MODY was collected and their family trees constructed. Linkage analysis was carried out on chromosomal regions known to harbour genes previously shown to be associated with MODY. Mutations were identified by direct sequencing. RESULTS: Three families were identified. Two of these showed linkage to chromosome 12 and carried mutations in exon 4 of the HNF-1alpha gene (290fsdelC and R272C). However, the third family showed no linkage to the previously described MODY genes but shared a novel mutation in the NeuroD1 gene on chromosome 2q32. This mutation, a glutamate to lysine substitution at codon 110, resides in the basic domain of the protein. CONCLUSION/INTERPRETATION: Mutations in MODY subjects have been identified in the Icelandic population. In addition this study identified the NeuroD1 gene as the gene responsible for the sixth type of MODY.

Polymorphisms in the tumor necrosis factor and lymphotoxin-alpha gene region and preeclampsia.

OBJECTIVE: To investigate potential association or linkage among nine polymorphisms in the genes encoding tumor necrosis factor (TNF) alpha or lymphotoxin (LT) alpha and preeclampsia. METHODS: Four di-allelic polymorphisms and five microsatellite markers in the genes encoding TNF-alpha (TNF) and LTalpha (LTA) and their haplotypes were studied in 150 Dutch families. These families contained sib-pairs of women affected with preeclampsia; eclampsia; the hemolysis, elevated liver enzymes, low platelets (HELLP) syndrome (strict criteria); or pregnancy-induced hypertension (mild criteria). Frequencies were compared with 98 healthy controls. Nonparametric affected sib-pair analyses for allele sharing among siblings were carried out for all nine markers. Each sibship was composed of an affected index woman and one or more affected sisters. RESULTS: Although we found a striking association with the TNF-I haplotype in 30 index women with (pre-)eclampsia or HELLP syndrome compared with controls (odds ratio [OR] 3.8; 95% confidence interval [CI] 1.6, 8.9), this association was not found in their 30 sisters meeting similar disease criteria. Analyses in all 150 families showed a similar TNF-I association in 122 index women meeting the strict criteria compared with controls (OR 1.9; 95% CI 1.1, 3.3), but, again, not in their 91 sisters meeting similar disease criteria. This association was stronger in a subgroup of 75 index women with preeclampsia only (OR 2.3; 95% CI 1.2, 4.2). No excess allele sharing for any marker was seen between the siblings. CONCLUSION: The nine polymorphisms studied in the TNF-LTA region did not show evidence for association or linkage with familial preeclampsia.

Eighteen years follow-up study of the clinical manifestations and progression of Dupuytren's disease.

OBJECTIVE: To evaluate the clinical manifestations and progression of Dupuytren's disease. METHODS: In 1981-82 a total of 1297 men were examined for Dupuytren's disease, and of these 19.2% had the disease. In 1999 those with signs of the disease in 1981-82 were invited for a follow-up study. As controls symptom free individuals from the study in 1981-82 were invited. RESULTS: A total of 53 individuals from the control group had developed Dupuytren's disease in 1999. Men with palmar nodules/fibrous cord in 1981-82 were more likely to develop contracted fingers than those without Dupuytren's disease. Patients with young age at disease onset more often required operations than those with later onset. Of the men who had been operated 70% still had finger contractures in 1999. CONCLUSION: The incidence of Dupuytren's disease is high in elderly men. Dupuytren's disease is progressive in nature and most operated patients have recurrent finger contractures.

Mutations in the gene for methylenetetrahydrofolate reductase, homocysteine levels, and vitamin status in women with a history of preeclampsia.

OBJECTIVE: This study was undertaken to assess frequencies of the methylenetetrahydrofolate reductase gene mutations cytosine-to-thymine substitution at base 677 (C677T) and adenine-to-cytosine substitution at base 1298 (A1298C) and their interactions with homocysteine and vitamin levels among Dutch women with preeclampsia. STUDY DESIGN: Mutations were studied in the following 5 groups: 47 consecutive women with preeclampsia, 49 women with preeclampsia and with hyperhomocysteinemia, 36 women with preeclampsia but without hyperhomocysteinemia, 127 women with familial preeclampsia (typed for C677T mutations only), and 120 control subjects. Plasma levels of homocysteine, folate, and vitamin B12 were measured. RESULTS: Although 10.6% of the consecutive women with preeclampsia had strictly defined hyperhomocysteinemia (values >97.5th percentile), neither mutation was found in excess relative to the control group. Women with preeclampsia who had mild hyperhomocysteinemia (values >75th percentile) had a significant excess of the TT genotype (homozygosity for C677T mutation) relative to the women with preeclampsia who did not have hyperhomocysteinemia (odds ratio, 8.2; 95% confidence interval, 1.8-39). They also had significantly lower vitamin levels. CONCLUSION: Hyperhomocysteinemia in women with preeclampsia was associated with mutations in the gene for methylenetetrahydrofolate reductase, but the high frequency of hyperhomocysteinemia itself cannot be explained by these mutations alone.

A genome-wide scan for preeclampsia in the Netherlands.

Preeclampsia, hallmarked by de novo hypertension and proteinuria in pregnancy, has a familial tendency. Recently, a large Icelandic genome-wide scan provided evidence for a maternal susceptibility locus for preeclampsia on chromosome 2p13 which was confirmed by a genome scan from Australia and New Zealand (NZ). The current study reports on a genome-wide scan of Dutch affected sib-pair families. In total 67 Dutch affected sib-pair families, comprising at least two siblings with proteinuric preeclampsia, eclampsia or HELLP-syndrome, were typed for 293 polymorphic markers throughout the genome and linkage analysis was performed. The highest allele sharing lod score of 1.99 was seen on chromosome 12q at 109.5 cM. Two peaks overlapped in the same regions between the Dutch and Icelandic genome-wide scan at chromosome 3p and chromosome 15q. No overlap was seen on 2p. Re-analysis in 38 families without HELLP-syndrome (preeclampsia families) and 34 families with at least one sibling with HELLP syndrome (HELLP families), revealed two peaks with suggestive evidence for linkage in the non-HELLP families on chromosome 10q (lod score 2.38, D10S1432, 93.9 cM) and 22q (lod score 2.41, D22S685, 32.4 cM). The peak on 12q appeared to be associated with HELLP syndrome; it increased to a lod score of 2.1 in the HELLP families and almost disappeared in the preeclampsia families. A nominal peak on chromosome 11 in the preeclampsia families showed overlap with the second highest peak in the Australian/NZ study. Results from our Dutch genome-wide scan indicate that HELLP syndrome might have a different genetic background than preeclampsia.

Dyslipoproteinaemia in postmenopausal women with a history of eclampsia.

OBJECTIVE: To test the hypothesis that postmenopausal women with a history of eclampsia manifest a more high risk lipid profile than postmenopausal women with a history of normal pregnancy. SETTING: The Department of Obstetrics and Gynaecology, National University Hospital, Reykjavik, Iceland, and the Magee-Womens Research Institute, Pittsburgh, Pennsylvania, USA. PARTICIPANTS: Thirty Icelandic women with a history of eclampsia, aged between 50 and 67 years at the time of re-examination (cases) were individually matched for current age, and for age and parity at index pregnancy, to 30 unrelated Icelandic women with a history of normal pregnancy (controls). METHODS: The participating women completed a health and family history questionnaire and underwent a physical examination. Fasting plasma low density lipoprotein diameter, serum lipids, insulin, and glucose were measured. RESULTS: Mean low density lipoprotein size was significantly smaller and apolipoprotein B concentration was higher in women with prior eclampsia. The percentage of cases receiving blood pressure medication (33%) was significantly greater than controls (6.7%). Thirteen cases had had hypertensive complications in at least one other pregnancy (recurrent subgroup); postmenopausally, these women displayed significantly increased diastolic blood pressures, smaller-sized low density lipoprotein, increased apolipoprotein B, decreased high density lipoprotein2 (HDL2) cholesterol, and increased total cholesterol: HDL cholesterol ratio compared with their controls. Fourteen cases were normotensive in all other pregnancies (nonrecurrent); these showed no differences from their controls. CONCLUSIONS: Dyslipoproteinaemia is more prevalent among postmenopausal women with prior eclampsia, especially with recurrent hypertension in pregnancy, than in postmenopausal women with prior normal pregnancies.

Epidemiology of Dupuytren's disease: clinical, serological, and social assessment. The Reykjavik Study.

Dupuytren's disease or palmar fibromatosis is a common disabling hand disorder, mainly confined to Caucasians of northwestern European origin. The prevalence of Dupuytren's disease and possible risk factors related to the disease were evaluated in a random sample of 1297 males and 868 females, aged 46 to 74 years. Blood samples were collected and biochemical parameters were evaluated. The possible relation between the disease and clinical, social, and biochemical parameters were estimated with age-adjusted univariate logistic regression analysis. Altogether 19.2% of the males and 4.4% of the female participants had clinical signs of Dupuytren's disease. The prevalence increased with age, from 7.2% among males in the age group 45-49 years up to 39.5% in those 70-74 years old. The more severe form of the disease, finger contractures, was found in 5.0% of the men and 1.4% had required operation, while this was rarely seen among women. In men elevated fasting blood glucose (P < 0.04), low body weight, and body mass index were significantly correlated with the presence of the disease (P < 0.001). Dupuytren's disease was common among heavy smokers (P = 0.02) and those having manual labor as occupation (P = 0.018). These results show that Dupuytren's disease is common in the Icelandic population and occupation and lifestyle seem to be related to the disease.

Prevalence of joint complaints amongst individuals with Dupuytren's disease--from the Reykjavík study.

It has been reported that Dupuytren's disease is very uncommon amongst patients with rheumatoid arthritis (RA). We investigated the prevalence of different joint complaints in a cohort of 1297 males, aged 46-74 years, participating in a prospective longitudinal health survey. Joint complaints were less frequently observed in men with Dupuytren's disease than in those who did not have any signs of this disease. When adjusted for age the Dupuytren's patients had less frequently history of morning stiffness (odds ratio (OR)=0.65; 95% confidence interval (CI)=0.44-0.98, P=0.04), joint swelling (OR=0.52; 95% CI=0.27-1.00, P=0.05), and attendance to doctors due to rheumatic disorders (OR=0.44; 95% CI=0.15-0.86, P=0.02) than those who did not have clinical signs of Dupuytren's disease. Furthermore, these associations were even stronger after adjustment for other potential confounding factors, such as smoking, lipids, diabetes, education, and occupation. The reason for a negative association between Dupuytren's disease and joint complaints is not clear but genetic and immunological factors may be important.

A genome-wide scan reveals a maternal susceptibility locus for pre-eclampsia on chromosome 2p13.

Pre-eclampsia is a common and serious disease and a major cause of maternal and infant mortality. Antenatal care systems world-wide screen for signs of the disease such as hypertension and proteinuria. Unlike most other human disorders it impacts two individuals, the mother and the child, both of whom can be severely affected. The pathophysiology of the disorder is incompletely understood, but familial clustering of the disease is apparent. Here we report the results of a genome-wide screen of Icelandic families representing 343 affected women. Including those patients with non-proteinuric pre-eclampsia (gestational hypertension), proteinuric pre-eclampsia and eclampsia, we detected a significant locus on 2p13 with a lod score of 4.70 (single point P < 3.49 x 10(-6)). This is the first reported locus for pre-eclampsia meeting the criteria for genome-wide significance.

Prediction of liability to orofacial clefting using genetic and craniofacial data from parents.

BACKGROUND: Cleft lip with or without cleft palate (CL(P)) and isolated cleft palate (CP) are separate clinical entities and for both polygenic multifactorial aetiology has been proposed. Parents of children with orofacial clefting have been shown to have distinctive differences in their facial shape when compared to matched controls. OBJECTIVE: To test the hypothesis that genetic and morphometric factors predispose to orofacial clefting and that these markers differ for CL(P) and CP. Methods-Polymorphisms at the transforming growth factor alpha (TGFalpha) locus in 83 parents of children with nonsyndromic orofacial clefts were analysed, and their craniofacial morphology was assessed using lateral cephalometry. RESULTS: Parents of children with CL(P) and CP showed an increased frequency of the TGFalpha/TaqI C2 allele (RR=4.10, p=0.009) relative to the comparison group. Also the TGFalpha/BamHI A1 allele was more prevalent in the CP parents. MULTIVARIATE STATISTICAL ANALYSIS: Using stepwise logistic regression analysis the TGFalpha/TaqI C2 polymorphism provides the best model for liability to orofacial clefting. To determine the type of clefting a model involving interaction between the parental TGFalpha/BamHI and TGFalpha/RsaI genotypes showed the best fit. Using genotype only to predict the clefting defect in the children according to parental genotype, 68.3% could be correctly classified. By adding information on craniofacial measurements in the parents, 76% of CP and 94% of CL(P) parents could be correctly classified. CONCLUSIONS: This study provides a model for prediction of liability to orofacial clefting. These findings suggest that different molecular aberrations at the TGFalpha locus may modify the risk for CP and CL(P).

T-and B-lymphocyte subsets in patients with Dupuytren's disease. Correlations with disease severity.

Previous reports have indicated that inflammatory mechanisms may be involved in the pathogenesis of Dupuytren's disease and it has even been suggested that this condition is a T-cell mediated autoimmune disorder. We investigated peripheral blood lymphocyte subsets from 21 patients with Dupuytren's disease and compared them with ten healthy blood donors. The Dupuytren's patients had an increase in DR+ T-cells compared with healthy controls. Furthermore, patients with both palmar and plantar involvement had a higher percentage of DR+ T-cells than those with only the palm affected. The percentage of circulating CD5+ B-cells was lower in the Dupuytren's patients compared with the control group; this feature was marginally significant for the whole group of Dupuytren's patients but was strongest in the group of patients with both palmar and plantar involvement. These findings support previous suggestions that immunological mechanisms, involving activated T-cells and probably also B-cells, are involved in the pathogenesis of Dupuytren's disease.

Evidence for a familial pregnancy-induced hypertension locus in the eNOS-gene region.

Pregnancy-induced hypertension may be regarded as a manifestation of endothelial-cell dysfunction. The role of the eNOS gene in the development of a familial pregnancy-induced hypertension was evaluated by analysis of linkage among affected sisters and in multiplex families (n = 50). Markers from a 4-cM region encoding the eNOS gene showed distortion from the expected allele sharing among affected sisters (P = .001-.05), and the statistic obtained from the multilocus application of the affected-pedigree-member method also showed distortion (T[f(P)=sqrt(P)] = 3.53; P < .001). A LOD score of 3.36 was obtained for D7S505 when a best-fitting model derived from genetic epidemiological data was used, and LOD scores of 2.54-4.03 were obtained when various other genetic models were used. Estimates of recombination rate, rather than maximum LOD-score values, were affected by changes in the genetic parameters. The transmission-disequilibrium test, a model-free estimate of linkage, showed strongest association and linkage with a microsatellite within intron 13 of the eNOS gene (P = .005). These results support the localization of a familial pregnancy-induced hypertension-susceptibility locus in the region of chromosome 7q36 encoding the eNOS gene.

A novel pattern of oculocerebral malformation.

AIMS/BACKGROUND: To report a novel pattern of oculocerebral malformation related to the group of diseases characterised by cobblestone lissencephaly. METHODS: By means of a case report with specialist descriptions of the novel neuropathological and ophthalmic pathology features. RESULTS: The patient, born to healthy consanguineous parents, presented in the neonatal period with jaundice, convulsions, and macrocephaly. Computed tomography demonstrated hydrocephalus and abnormal cerebral gyration. Ophthalmic examination revealed severe myopia and segments of retinal atrophy. Cytogenetic investigation revealed a balanced reciprocal translocation (46,XX,t(5p11;19q13.1)) that was inherited from the mother and was present in several normal relatives. Mild short stature and profound mental handicap were evident. The child died aged 7 years. At necropsy the brain showed 'cobblestone' (type II) lissencephaly. Cerebellar cortical architecture was abnormal and the brain stem lacked cerebral peduncles, basis pontis, and pyramids. Biopsies of skeletal muscles were normal. The ocular abnormalities included discrete sectors of retina of varying thickness with disordered neuronal lamination and gliosis. The optic nerve was gliotic and contained few nerve fibres. The anterior iris surface was studded with cellular stromal nodules which appear to be melanocytic in nature. CONCLUSION: Retinal dysgenesis occurs in the group of syndromes with 'cobblestone lissencephaly', the best known being Walker-Warburg syndrome. In this case, relatively long survival, lack of muscular dystrophy, and novel ocular pathology distinguish it from the other diagnoses in this group of syndromes. We suggest this child was affected by a distinct and novel oculocerebral syndrome.

Familial hemiplegic migraine in the west of Scotland: a clinical and genetic study of seven families.

OBJECTIVES: Clinical and genetic characterisation of families in the west of Scotland with familial hemiplegic migraine. METHODS: Families with familial hemiplegic migraine were identified via probands attending the regional paediatric neurology and child development centre. All available family members were assessed clinically and genetic linkage studies for the known familial hemiplegic migraine gene locus on chromosome 19 were carried out on three families. RESULTS: Seven unrelated kindreds with familial hemiplegic migraine were identified. Clinical information was obtained on 138 family members, 27 of whom fulfilled the International Headache Society criteria for familial hemiplegic migraine. Whereas the severity, duration, frequency, and temporal progression of acute hemiplegic migrainous attacks showed pronounced variability within and between families, and even in the same individual over time, no true clinical heterogeneity of the condition was apparent. Genetic linkage analysis gave results consistent with linkage to the familial hemiplegic migraine gene locus on chromosome 19p in one family. In the other two families, evidence against linkage was obtained. There was no significant clinical difference between these three families. CONCLUSIONS: This study provides characterisation of the clinical features of familial hemiplegic migraine in a British population. Significant variability was found in the frequency and character of migraine attacks within and between families, and no true clinical heterogeneity was identified. On the other hand, further evidence for genetic heterogeneity of the condition was found.

Death rates from ischemic heart disease in women with a history of hypertension in pregnancy.

BACKGROUND: Evidence about the influence of hypertension in pregnancy on later health and in particular the risk of cardiovascular disorders is conflicting, although a link has been suggested. In a population-based study with a long follow-up time the potential association between hypertension in pregnancy, preeclampsia and eclampsia with increased death rates from ischemic heart disease (IHD) was investigated. METHODS: All 7543 case records at the main maternity hospital in Iceland during 1931-1947 were reviewed to identify women with hypertension in pregnancy, subdivided by parity and severity of disease into those with eclampsia, preeclampsia and hypertension alone. Information on those who had died was obtained from death certificates, supplemented by autopsy reports and hospital records. Death rates from IHD were compared to population data from public health and census reports during corresponding periods and between study groups. RESULTS: Of 374 hypertensive women 177 had died. The death rate was slightly higher among women with any hypertension in pregnancy than in the reference population (RR = 1.20; 95% CI 1.01-1.42). About half of the increase was attributed to excess mortality from IHD with a relative risk of dying of 1.47 (95% CI 1.05-2.02). The relative risk of dying from IHD was significantly higher among eclamptic women (RR = 2.61; 95% CI 1.11-6.12) and those with preeclampsia (RR = 1.90; 95% CI 1.02-3.52) than those with hypertension alone. Parous women at the index pregnancy had a twofold higher risk of dying from IHD than primigravid women (RR = 2.05; 95% CI 1.19-3.55; p = 0.01). CONCLUSION: There is an indication of increased death rates among women with a history of hypertension in pregnancy, where ischemic heart disease may be more common than in the general population.

Falling population incidence of eclampsia. A case-control study of short term outcome.

BACKGROUND: Eclampsia remains a serious complication of pregnancy and childbirth and factors related to morbidity require continued evaluation. DESIGN: Retrospective case-control study on the incidence and outcome of eclampsia. SETTING: A defined total island population over 20 years. METHODS: All centrally collected birth registration returns in Iceland for the years 1972-1991 were reviewed to identify women with the diagnosis of eclampsia, selecting women delivering immediately before and after the eclamptic case as controls. Information from all places where women had delivered was obtained to ensure that no case was missed. Maternity records were reviewed to verify the diagnosis and obtain maternal and neonatal data. RESULTS: Forty women had eclampsia (0.046% of deliveries). The incidence diminished between the decades 1972-81 and 1982-91 (p < 0.05), as did the incidence of eclamptic convulsions before delivery. Eclamptic women were more often primiparous, younger and delivered earlier than controls. Preterm delivery and a low ponderal index were more common among offspring of the eclamptic mothers and the male/female ratio was lower. CONCLUSION: The incidence of eclampsia in the population is falling. Common features related to the condition were confirmed. Severe maternal illness is rare, but the babies often appear growth-retarded and are delivered preterm.