Showing papers by "Mark Walker published in 2007"

Genome-wide association study of 14,000 cases of seven common diseases and 3,000 shared controls

Abstract: There is increasing evidence that genome-wide association ( GWA) studies represent a powerful approach to the identification of genes involved in common human diseases. We describe a joint GWA study ( using the Affymetrix GeneChip 500K Mapping Array Set) undertaken in the British population, which has examined similar to 2,000 individuals for each of 7 major diseases and a shared set of similar to 3,000 controls. Case-control comparisons identified 24 independent association signals at P < 5 X 10(-7): 1 in bipolar disorder, 1 in coronary artery disease, 9 in Crohn's disease, 3 in rheumatoid arthritis, 7 in type 1 diabetes and 3 in type 2 diabetes. On the basis of prior findings and replication studies thus-far completed, almost all of these signals reflect genuine susceptibility effects. We observed association at many previously identified loci, and found compelling evidence that some loci confer risk for more than one of the diseases studied. Across all diseases, we identified a large number of further signals ( including 58 loci with single-point P values between 10(-5) and 5 X 10(-7)) likely to yield additional susceptibility loci. The importance of appropriately large samples was confirmed by the modest effect sizes observed at most loci identified. This study thus represents a thorough validation of the GWA approach. It has also demonstrated that careful use of a shared control group represents a safe and effective approach to GWA analyses of multiple disease phenotypes; has generated a genome-wide genotype database for future studies of common diseases in the British population; and shown that, provided individuals with non-European ancestry are excluded, the extent of population stratification in the British population is generally modest. Our findings offer new avenues for exploring the pathophysiology of these important disorders. We anticipate that our data, results and software, which will be widely available to other investigators, will provide a powerful resource for human genetics research.

A common variant in the FTO gene is associated with body mass index and predisposes to childhood and adult obesity

Abstract: Obesity is a serious international health problem that increases the risk of several common diseases. The genetic factors predisposing to obesity are poorly understood. A genome-wide search for type 2 diabetes-susceptibility genes identified a common variant in the FTO (fat mass and obesity associated) gene that predisposes to diabetes through an effect on body mass index (BMI). An additive association of the variant with BMI was replicated in 13 cohorts with 38,759 participants. The 16% of adults who are homozygous for the risk allele weighed about 3 kilograms more and had 1.67-fold increased odds of obesity when compared with those not inheriting a risk allele. This association was observed from age 7 years upward and reflects a specific increase in fat mass.

Replication of Genome-Wide Association Signals in UK Samples Reveals Risk Loci for Type 2 Diabetes

Abstract: The molecular mechanisms involved in the development of type 2 diabetes are poorly understood. Starting from genome-wide genotype data for 1924 diabetic cases and 2938 population controls generated by the Wellcome Trust Case Control Consortium, we set out to detect replicated diabetes association signals through analysis of 3757 additional cases and 5346 controls and by integration of our findings with equivalent data from other international consortia. We detected diabetes susceptibility loci in and around the genes CDKAL1, CDKN2A/CDKN2B, and IGF2BP2 and confirmed the recently described associations at HHEX/IDE and SLC30A8. Our findings provide insight into the genetic architecture of type 2 diabetes, emphasizing the contribution of multiple variants of modest effect. The regions identified underscore the importance of pathways influencing pancreatic beta cell development and function in the etiology of type 2 diabetes.

Association scan of 14,500 nonsynonymous SNPs in four diseases identifies autoimmunity variants

Abstract: We have genotyped 14,436 nonsynonymous SNPs (nsSNPs) and 897 major histocompatibility complex (MHC) tag SNPs from 1,000 independent cases of ankylosing spondylitis (AS), autoimmune thyroid disease (AITD), multiple sclerosis (MS) and breast cancer (BC). Comparing these data against a common control dataset derived from 1,500 randomly selected healthy British individuals, we report initial association and independent replication in a North American sample of two new loci related to ankylosing spondylitis, ARTS1 and IL23R, and confirmation of the previously reported association of AITD with TSHR and FCRL3. These findings, enabled in part by increased statistical power resulting from the expansion of the control reference group to include individuals from the other disease groups, highlight notable new possibilities for autoimmune regulation and suggest that IL23R may be a common susceptibility factor for the major 'seronegative' diseases.

Teenage pregnancy and adverse birth outcomes: a large population based retrospective cohort study

Abstract: Results All teenage groups were associated with increased risks for pre-term delivery, low birth weight and neonatal mortality Infants born to teenage mothers aged 17 or younger had a higher risk for low Apgar score at 5min Further adjustment for weight gain during pregnancy did not change the observed association Restricting the analysis to white married mothers with ageappropriate education level, adequate prenatal care, without smoking and alcohol use during pregnancy yielded similar results Conclusions Teenage pregnancy increases the risk of adverse birth outcomes that is independent of important known confounders This finding challenges the accepted opinion that adverse birth outcome associated with teenage pregnancy is attributable to low socioeconomic status, inadequate prenatal care and inadequate weight gain during pregnancy

Localization of type 1 diabetes susceptibility to the MHC class I genes HLA-B and HLA-A

Abstract: The major histocompatibility complex (MHC) on chromosome 6 is associated with susceptibility to more common diseases than any other region of the human genome, including almost all disorders classified as autoimmune. In type 1 diabetes the major genetic susceptibility determinants have been mapped to the MHC class II genes HLA-DQB1 and HLA-DRB1 (refs 1-3), but these genes cannot completely explain the association between type 1 diabetes and the MHC region. Owing to the region's extreme gene density, the multiplicity of disease-associated alleles, strong associations between alleles, limited genotyping capability, and inadequate statistical approaches and sample sizes, which, and how many, loci within the MHC determine susceptibility remains unclear. Here, in several large type 1 diabetes data sets, we analyse a combined total of 1,729 polymorphisms, and apply statistical methods-recursive partitioning and regression-to pinpoint disease susceptibility to the MHC class I genes HLA-B and HLA-A (risk ratios >1.5; P(combined) = 2.01 x 10(-19) and 2.35 x 10(-13), respectively) in addition to the established associations of the MHC class II genes. Other loci with smaller and/or rarer effects might also be involved, but to find these, future searches must take into account both the HLA class II and class I genes and use even larger samples. Taken together with previous studies, we conclude that MHC-class-I-mediated events, principally involving HLA-B*39, contribute to the aetiology of type 1 diabetes.

Common variants in WFS1 confer risk of type 2 diabetes

Abstract: We studied genes involved in pancreatic beta cell function and survival, identifying associations between SNPs in WFS1 and diabetes risk in UK populations that we replicated in an Ashkenazi population and in additional UK studies. In a pooled analysis comprising 9,533 cases and 11,389 controls, SNPs in WFS1 were strongly associated with diabetes risk. Rare mutations in WFS1 cause Wolfram syndrome; using a gene-centric approach, we show that variation in WFS1 also predisposes to common type 2 diabetes.

Common Variants of the Novel Type 2 Diabetes Genes CDKAL1 and HHEX/IDE Are Associated With Decreased Pancreatic β-Cell Function

Abstract: OBJECTIVE— Type 2 diabetes is characterized by impaired pancreatic β-cell function and decreased insulin sensitivity. Genome-wide association studies have identified common, novel type 2 diabetes susceptibility loci within the FTO , CDKAL1 , CDKN2A/CDKN2B , IGF2BP2 , HHEX/IDE , and SLC30A8 gene regions. Our objective was to explore the relationships between the diabetes-associated alleles and measures of β-cell function and whole-body insulin sensitivity. RESEARCH DESIGN AND METHODS— A total of 1,276 healthy subjects of European ancestry were studied at 19 centers. Indexes of β-cell function (including 30-min insulin response and glucose sensitivity) were derived from a 75-g oral glucose tolerance test, and whole-body insulin sensitivity (M/I) was assessed by hyperinsulinemic-euglycemic clamp. Genotype/phenotype relationships were studied by linear trend analysis correcting for age, sex, and recruitment center. RESULTS— CDKAL1 and HHEX/IDE diabetes-associated alleles were both associated with decreased 30-min insulin response (both P = 0.0002) and decreased pancreatic β-cell glucose sensitivity ( P = 9.86 × 10 −5 and 0.009, respectively), and these relationships remained after correction for M/I. The FTO susceptibility allele showed a weak but consistent association with increased adiposity, which in turn was linked to a decrease in M/I. However, none of the other novel diabetes susceptibility alleles were associated with insulin sensitivity. CONCLUSIONS— CDKAL1 and HHEX/IDE diabetes-associated alleles are associated with decreased pancreatic β-cell function, including decreased β-cell glucose sensitivity that relates insulin secretion to plasma glucose concentration. We confirmed the association between the FTO allele and increased adiposity, but none of the other novel susceptibility alleles were associated with whole-body insulin sensitivity.

Evaluation of Common Variants in the Six Known Maturity-Onset Diabetes of the Young (MODY) Genes for Association With Type 2 Diabetes

Abstract: An important question in human genetics is the extent to which genes causing monogenic forms of disease harbor common variants that may contribute to the more typical form of that disease. We aimed to comprehensively evaluate the extent to which common variation in the six known maturity-onset diabetes of the young (MODY) genes, which cause a monogenic form of type 2 diabetes, is associated with type 2 diabetes. Specifically, we determined patterns of common sequence variation in the genes encoding Gck, Ipf1, Tcf2, and NeuroD1 (MODY2 and MODY4–MODY6, respectively), selected a comprehensive set of 107 tag single nucleotide polymorphisms (SNPs) that captured common variation, and genotyped each in 4,206 patients and control subjects from Sweden, Finland, and Canada (including family-based studies and unrelated case-control subjects). All SNPs with a nominal P value P values P value −6 in >15,000 samples. We combined these results with our previous studies on HNF4α and TCF1 and explicitly tested for gene-gene interactions among these variants and with several known type 2 diabetes susceptibility loci, and we found no genetic interactions between these six genes. We conclude that although rare variants in these six genes explain most cases of MODY, common variants in these same genes contribute very modestly, if at all, to the common form of type 2 diabetes.

Insulin resistance, insulin response, and obesity as indicators of metabolic risk.

Abstract: Context: Insulin resistance (IR) and obesity, especially abdominal obesity, are regarded as central pathophysiological features of a cluster of cardiovascular risk factors (CVRFs), but their relative roles remain undefined. Moreover, the differential impact of IR viz. insulin response has not been evaluated. Objective: The objective of this study was to dissect out the impact of obesity, abdominal obesity, and IR/insulin response on CVRF. Design: This was a cross-sectional study. Setting: The study was conducted at 21 research centers in Europe. Subjects: The study included a cohort of 1308 nondiabetic subjects [718 womenand590men,age30–60yr,bodymassindex(BMI)17–44kgm 2 ]. Main Outcome Measures: We measured IR (by a standardized euglycemic insulin clamp), waist girth, insulin response to an oral glucose tolerance test, and major CVRF, and analyzed their associations by multivariate models and factor analysis. Results: BMI was positively related to all CVRFs. Waist circumferencewasrelatedtohigherbloodpressureandserumtriglyceridesand lower high-density lipoprotein-cholesterol, IR to reduced glucose tolerance, higher free fatty acids, triglyceride and low-density lipoprotein-cholesterol, and lower high-density lipoprotein-cholesterol, and insulin response to higher heart rate, blood pressure and fasting glucose, and the same dyslipidemic profile as IR (P 0.05 for all). By factor analysis, three main factors (related to IR, age, and fatness, respectively) appeared to underlie this pattern of associations. Each of BMI, waist girth, IR, and insulin response was independently associated with total CVRF load (all P 0.001). Conclusions: When IR, fat mass and distribution, and insulin response are measured simultaneously in a large cohort, no one factor stands out as the sole driving force of the CVRF cluster, each being associated with one or more physiological pathways according to known cause-effect relationships. (J Clin Endocrinol Metab 92: 2885–2892, 2007)

Environmental Hazards: Evidence for Effects on Child Health

Abstract: The human fetus, child, and adult may experience adverse health outcomes from parental or childhood exposures to environmental toxicants. The fetus and infant are especially vulnerable to toxicants that disrupt developmental processes during relatively narrow time windows. This review summarizes knowledge of associations between child health and development outcomes and environmental exposures, including lead, methylmercury, polychlorinated biphenyls (PCBs), dioxins and related polyhalogenated aromatic hydrocarbons (PHAHs), certain pesticides, environmental tobacco smoke (ETS), aeroallergens, ambient air toxicants (especially particulate matter [PM] and ozone), chlorination disinfection by-products (DBPs), sunlight, power-frequency magnetic fields, radiofrequency (RF) radiation, residential proximity to hazardous waste disposal sites, and solvents. The adverse health effects linked to such exposures include fetal death, birth defects, being small for gestational age (SGA), preterm birth, clinically overt cognitive, neurologic, and behavioral abnormalities, subtle neuropsychologic deficits, childhood cancer, asthma, other respiratory diseases, and acute poisoning. Some environmental toxicants, notably lead, ionizing radiation, ETS, and certain ambient air toxicants, produce adverse health effects at relatively low exposure levels during fetal or child developmental time windows. For the many associations supported by limited or inadequate epidemiologic evidence, major sources of uncertainty include the limited number of studies conducted on specific exposure-outcome relationships and methodologic limitations. The latter include (1) crude exposure indices, (2) limited range of exposure levels, (3) small sample sizes, and (4) limited knowledge and control of potential confounders. Important knowledge gaps include the role of preconceptual paternal exposures, a topic much less studied than maternal or childhood exposures. Large longitudinal studies beginning before or during early pregnancy are urgently needed to accurately measure and assess the relative importance of parental and childhood exposures and evaluate relatively subtle health outcomes such as neuropsychologic and other functional deficits. Large case-control studies are also needed to assess the role of environmental exposures and their interactions with genetic factors in relatively uncommon outcomes such as specific types of birth defects and childhood cancers. There is also an urgent need to accelerate development and use of biomarkers of exposure and genetic susceptibility in epidemiologic studies. This review supports the priority assigned by international agencies to relationships between child health and air quality (indoor and outdoor), lead, pesticides, water contaminants, and ETS. To adequately address such priorities, governments and agencies must strengthen environmental health research capacities and adopt policies to reduce parental and childhood exposures to proven and emerging environmental threats.

Paternal age and birth defects: how strong is the association?

Abstract: BACKGROUND: Although the association between maternal age and the risks of birth defects has been well studied, the evidence from population data linking paternal age with birth defects was limited and inconsistent. METHODS: We conducted a population-based retrospective cohort study of 5 213 248 subjects from the 1999-2000 birth registration data of the USA. Multiple logistic regressions were used to estimate the independent effect of paternal age on all birth defects and 21 specific defects groups after adjusting for potential confounding of maternal age, race, education, marital status, parity, prenatal care initiation, maternal smoking and alcohol drinking during pregnancy. RESULTS: A total of 77 514 (1.5%) birth defects were recorded in the study cohort. The adjusted odds ratios were 1.04 (1.01, 1.06), 1.08 (1.04, 1.12), 1.08 (1.02, 1.14) and 1.15 (1.06, 1.24), respectively, for infants born to fathers 30-35, 40-44, 45-49 and over 50 years (test for trend, P = 0.0155), when compared with those infants born to fathers aged 25-29 for any birth defect. Advanced paternal age was associated with increased risks of heart defects, tracheo-oesophageal fistulaoesophageal atresia, other musculoskeletal/integumental anomalies, Down's syndrome and other chromosomal anomalies. Fathers under 25 years of age were also at increased risks of spina bifida/meningocele, microcephalus, omphalocele/ gastroschisis and other musculoskeletal/integumental anomalies. CONCLUSIONS: Infants born to older fathers have a slightly increased risk of birth defects. Young paternal age is also associated with slightly increased risk of several selected birth defects in their offspring. However, given the weak association, paternal age appears to play a small role in the aetiology of birth defects.

DNA damage induces Chk1‐dependent centrosome amplification

Abstract: Centrosomal abnormalities are frequently observed in cancers and in cells with defective DNA repair. Here, we used light and electron microscopy to show that DNA damage induces centrosome amplification, not fragmentation, in human cells. Caffeine abrogated this amplification in both ATM (ataxia telangiectasia, mutated)- and ATR (ATM and Rad3-related)-defective cells, indicating a complementary role for these DNA-damage-responsive kinases in promoting centrosome amplification. Inhibition of checkpoint kinase 1 (Chk1) by RNA-mediated interference or drug treatment suppressed DNA-damage-induced centrosome amplification. Radiation-induced centrosome amplification was abrogated in Chk1−/− DT40 cells, but occurred at normal levels in Chk1−/− cells transgenically expressing Chk1. Expression of kinase-dead Chk1, or Chk1S345A, through which the phosphatidylinositol-3-kinase cannot signal, failed to restore centrosome amplification, showing that signalling to Chk1 and Chk1 catalytic activity are necessary to promote centrosome overduplication after DNA damage.

Adequacy of prenatal care and neonatal mortality in infants born to mothers with and without antenatal high-risk conditions.

Abstract: Background: Previous studies have found that inadequate prenatal care was associated with increased neonatal mortality in the general pregnant women. Aims: To examine the association between adequacy of prenatal care and neonatal mortality in the presence and absence of antenatal high-risk conditions. Methods: We conducted a retrospective cohort study of infants based on 1995–2000 vital statistics data in the USA. The relative risk for neonatal death associated with adequacy of prenatal care was estimated by multivariate logistic regressions with adjustment of confounding factors. Results: Inadequate prenatal care was associated with increased neonatal mortality when pregnancies were complicated by anaemia, cardiac disease, lung disease, chronic hypertension, diabetes, renal disease, pregnancy-induced hypertension, and previous preterm/small-for-gestational-age birth. The observed association also existed in the absence of these antenatal high-risk conditions. Overutilisation of prenatal care was associated with increased risk of neonatal deaths in both the presence and the absence of antenatal high-risk conditions. When gestational age at delivery and birthweight were further adjusted, the observed association between inadequate prenatal care and neonatal mortality was not significant in pregnancies with various high-risk conditions. Conclusions: Inadequate prenatal care is associated with increased neonatal death in both the presence and the absence of antenatal high-risk conditions. The observed association between inadequate prenatal care and neonatal mortality may be mediated by increased risk of preterm delivery and low birthweight in these pregnancies. Overutilisation of prenatal care is associated with potential risks for fetal and neonatal development, leading to increased neonatal mortality.

Teenage pregnancy and congenital anomalies: which system is vulnerable?

Abstract: BACKGROUND: Teenage pregnancy may be associated with some forms of congenital anomalies. The objective of this study was to identify the types of congenital anomalies associated with teenage pregnancy. METHODS: We carried out a retrospective cohort study of 5 542 861 nulliparous pregnant women younger than 35 years of age with a live singleton birth between 1995 and 2000 in the USA. RESULTS: Compared with adult pregnancy (20–34 years old), and after adjustment for confounding variables, teenage pregnancy (13–19 years old) was associated with increased risk of central nervous system anomalies [odds ratio (OR) 1.08; 95% confidence interval (CI): 1.01, 1.16], gastrointestinal anomalies (OR: 1.39; 95% CI: 1.31, 1.49) and musculoskeletal/integumental anomalies (OR: 1.06; 95% CI: 1.03, 1.10). The teenage pregnancy associated increase in risk for central nervous system anomalies was mainly attributable to anomalies other than anencephalus, spina bifida/meningocele and hydrocephalus and microcephalus; for gastrointestinal anomalies the risk was mainly attributable to omphalocele/gastroschisis; and for musculoskeletal/integumental anomalies the risk was mainly attributable to cleft lip/palate and polydactyly/syndactyly/adactyly. No increased risk was found for circulatory/respiratory anomalies, urogenital anomalies, or Down’s syndrome. CONCLUSIONS: Teenage pregnancy increases the risks of congenital anomalies in central nervous, gastrointestinal and musculoskeletal/integumental systems.

Association between the T-381C polymorphism of the brain natriuretic peptide gene and risk of type 2 diabetes in human populations

Abstract: Brain natriuretic peptide (BNP/NPPB) is a member of the natriuretic family involved in the regulation of blood pressure and blood volume as well as lipolysis control in human fat cells. Thus BNP may play a role in energy metabolism and metabolic diseases. We therefore assessed the association between the BNP promoter T-381C polymorphism and risk of type 2 diabetes and metabolic and BNP expression traits in several population samples. In French population-based samples (n = 3216), we found that individuals bearing the -381CC genotype had lower (P = 0.005) fasting glucose levels than -381TC or -381TT individuals. Moreover, the -381CC genotype was less frequent in individuals with type 2 diabetes (n = 280, 13.6%) or with impaired fasting glucose (n = 248, 12.9%) compared with normoglycaemic individuals (n = 2485, 17.8%). The adjusted odds ratio (OR) (95% CI) of type 2 diabetes for -381CC individuals was 0.69 (0.47-1.00), P = 0.05, when compared with -381T allele bearers. We replicated this association in four additional case-control studies for type 2 diabetes. The overall OR (95% CI) of type 2 diabetes was 0.85 (0.76-0.96), P = 0.008, (under a recessive model) (3593 cases and 6646 controls in total). We also found that the -381C allele was associated with higher plasma BNP concentrations (P = 0.015, n = 634) and higher BNP promoter activity in reporter gene assays. Collectively, these data suggest that relatively high BNP expression may protect against type 2 diabetes in humans.

Prevalence and progression of diabetes in mitochondrial disease.

Abstract: The aims of this study were (1) to determine the prevalence and rate of progression in diabetes secondary to mitochondrial DNA (mtDNA) mutations; and (2) to determine whether percentage heteroplasmy predicts clinical outcome in patients carrying the m.3243A>G mutation. We prospectively assessed 242 patients attending a specialist neuromuscular clinic using a validated mitochondrial disease rating scale. Retrospective clinical data on these patients from up to 25 years of follow-up were also included. Percentage heteroplasmy in blood, urine and muscle was determined for the m.3243A>G group and correlated against clinical features. Patients carrying the m.3243A>G mutation formed the largest group of patients with diabetes (31/81 patients). The highest prevalence of diabetes was in the m.12258C>A group (2/2 patients), the lowest in the multiple mtDNA deletions group (3/43 patients). The earliest age of onset was in the m.3243A>G group (37.9 years) with the highest age of presentation in the multiple deletion group (56.3 years). Of patients presenting with m.3243A>G, 12.9% required insulin; an additional 32.3% progressed to insulin requirement over a mean of 4.2 years after presentation. Percentage heteroplasmy in blood, urine or muscle did not predict progression of diabetes or risk of developing complications. Early age of presentation with diabetes did predict poor clinical outcome. Although patients carrying the m.3243A>G mutation account for the majority of cases of diabetes secondary to mtDNA mutations, several other genotypes are also associated with the development of diabetes, some with high penetrance. All show a gradual progression to insulin requirement. Percentage heteroplasmy is a poor predictor of severity of diabetes in the m.3243A>G group.

Semen quality in a residential, geographic and age representative sample of healthy Chinese men

Abstract: Population-based study of semen quality is rare in literature. Healthy men aged 20-60 years from six Chinese provinces were invited to participate in the study between December 2000 and November 2002. Posters were distributed in the participating counties to enroll 200 subjects from each province. Medians percentiles and proportions below lower threshold of the WHO criteria for semen parameters were calculated. Generalized linear models were used to examine the determinants of semen quality. Semen samples from 1191 healthy Chinese men were collected and analysed. The medians (5th and 95th percentiles) were 2.3 ml (1.0-4.5) for semen volume 65 x 10/6/ml (20-150) for semen concentration 154 x 10/6/ejection (29-421) for sperm count 19% (5-32) for rapid progressive motility 46% (29-66) for progressive motility 67% (47-81) for total motile spermatozoa 70% (48-88) for sperm viability and 39% (23-76) for normal morphology. Many healthy Chinese men had semen parameter values below the lower threshold of the WHO criteria. Region age abstinence duration and season were important determinants of semen quality. Chinese men have lower values of semen parameters according to WHO standard and a lower threshold for normal semen parameters for Chinese men should be considered. (authors)

Mitochondrial DNA haplogroups and type 2 diabetes: a study of 897 cases and 1010 controls

Abstract: Mitochondria play a central role in the secretion of insulin by pancreatic beta-cells, and pathogenic mutations of mitochondrial DNA (mtDNA) can cause diabetes. The aetiology of type 2 diabetes has a strong genetic component, raising the possibility that genetic variants of mtDNA alter the risk of developing the disorder. Recent studies have produced conflicting results. By studying 897 UK cases of type 2 diabetes and 1010 population-matched controls, it is shown that European mtDNA haplogroups are unlikely to play a major role in the risk of developing the disorder.

Hypertensive disorders of pregnancy and long-term risk of hypertension: what do Ontario prenatal care providers know, and what do they communicate?

Abstract: Objectives The objective of this study was to ascertain the knowledge base of Ontario maternity care providers (family physicians, obstetrician-gynaecologists, and midwives) regarding the future health risks of gestational hypertension and preeclampsia and the practices with respect to communication of these risks. Methods In 2004, all obstetricians (639) and midwives (249) in Ontario and a random sample of 600 Ontario family physicians were mailed a survey and a reminder. Non-responders were also sent a second, and in some cases, a third copy of the survey. The survey addressed areas of knowledge, reported practices, and both patient and interprofessional communication. Descriptive analysis was used for the responses. Results The overall response rate was 42%. The majority of respondents were familiar with the long-term risks of gestational hypertension and preeclampsia. Although maternity care providers stated that they inform women with these conditions about their subsequent risks and recommend follow-up, only 36% usually inform the women’s primary care providers about that subsequent risk. Only 58% of family physicians reported that they are usually informed by the maternity care providers about their patients who developed hypertension in pregnancy, compared with the 83% of maternity care providers who reported that they usually communicate this information to family physicians. Conclusion We have identified weaknesses in knowledge base and communication amongst Ontario maternity care providers that suggest that the identification and follow-up of women with hypertensive disorders of pregnancy is not occurring. These deficiencies would be amenable to directed educational activities, including reviews, presentations, and the development and implementation of guidelines.

Common Variation in the LMNA Gene (Encoding Lamin A/C) and Type 2 Diabetes: Association Analyses in 9,518 Subjects

Abstract: Mutations in the LMNA gene (encoding lamin A/C) underlie familial partial lipodystrophy, a syndrome of monogenic insulin resistance and diabetes. LMNA maps to the well-replicated diabetes-linkage region on chromosome 1q, and there are reported associations between LMNA single nucleotide polymorphisms (SNPs) (particularly rs4641; H566H) and metabolic syndrome components. We examined the relationship between LMNA variation and type 2 diabetes (using six tag SNPs capturing >90% of common variation) in several large datasets. Analysis of 2,490 U.K. diabetic case and 2,556 control subjects revealed no significant associations at either genotype or haplotype level: the minor allele at rs4641 was no more frequent in case subjects (allelic odds ratio [OR] 1.07 [95% CI 0.98-1.17], P = 0.15). In 390 U.K. trios, family-based association analyses revealed nominally significant overtransmission of the major allele at rs12063564 (P = 0.01), which was not corroborated in other samples. Finally, genotypes for 2,817 additional subjects from the International 1q Consortium revealed no consistent case-control or family-based associations with LMNA variants. Across all our data, the OR for the rs4641 minor allele approached but did not attain significance (1.07 [0.99-1.15], P = 0.08). Our data do not therefore support a major effect of LMNA variation on diabetes risk. However, in a meta-analysis including other available data, there is evidence that rs4641 has a modest effect on diabetes susceptibility (1.10 [1.04-1.16], P = 0.001).

UXT interacts with the transcriptional repressor protein EVI1 and suppresses cell transformation.

Abstract: The EVI1 transcriptional repressor is critical to the normal development of a variety of tissues and participates in the progression of acute myeloid leukaemias. The repressor domain (Rp) was used to screen an adult human kidney yeast two-hybrid library and a novel binding partner designated ubiquitously expressed transcript (UXT) was isolated. Enforced expression of UXT in Evi1-expressing Rat1 fibroblasts suppresses cell transformation and UXT may therefore be a negative regulator of Evi1 biological activity. The Rp-binding site for UXT was determined and non-UXT-binding Evi1 mutants (Evi1Δ706–707) were developed which retain the ability to bind the corepressor mCtBP2. Evi1Δ706–707 transforms Rat1 fibroblasts, showing that the interaction is not essential for Evi1-mediated cell transformation. However, Evi1Δ706–707 produces an increased proportion of large colonies relative to wild-type, showing that endogenous UXT has an inhibitory effect on Evi1 biological activity. Exogenous UXT still suppresses Evi1Δ706–707-mediated cell transformation, indicating that it inhibits cell proliferation and/or survival by both Evi1-dependent and Evi1-independent mechanisms. These observations are consistent with the growth-suppressive function attributed to UXT in human prostate cancer. Our results show that UXT suppresses cell transformation and might mediate this function by interaction and inhibition of the biological activity of cell proliferation and survival stimulatory factors like Evi1.