Showing papers by "Mark Walker published in 2008"

Meta-analysis of genome-wide association data and large-scale replication identifies additional susceptibility loci for type 2 diabetes

Abstract: Genome-wide association (GWA) studies have identified multiple loci at which common variants modestly but reproducibly influence risk of type 2 diabetes (T2D). Established associations to common and rare variants explain only a small proportion of the heritability of T2D. As previously published analyses had limited power to identify variants with modest effects, we carried out meta-analysis of three T2D GWA scans comprising 10,128 individuals of European descent and approximately 2.2 million SNPs (directly genotyped and imputed), followed by replication testing in an independent sample with an effective sample size of up to 53,975. We detected at least six previously unknown loci with robust evidence for association, including the JAZF1 (P = 5.0 x 10(-14)), CDC123-CAMK1D (P = 1.2 x 10(-10)), TSPAN8-LGR5 (P = 1.1 x 10(-9)), THADA (P = 1.1 x 10(-9)), ADAMTS9 (P = 1.2 x 10(-8)) and NOTCH2 (P = 4.1 x 10(-8)) gene regions. Our results illustrate the value of large discovery and follow-up samples for gaining further insights into the inherited basis of T2D.

Clinical features, diagnosis and management of maternally inherited diabetes and deafness (MIDD) associated with the 3243A>G mitochondrial point mutation.

Abstract: Maternally inherited diabetes and deafness (MIDD) affects up to 1% of patients with diabetes but is often unrecognized by physicians. It is important to make an accurate genetic diagnosis, as there are implications for clinical investigation, diagnosis, management and genetic counselling. This review summarizes the range of clinical phenotypes associated with MIDD; outlines the advances in genetic diagnosis and pathogenesis of MIDD; summarizes the published prevalence data and provides guidance on the clinical management of these patients and their families.

Extreme phenotypic diversity and nonpenetrance in families with the LMNA gene mutation R644C.

Abstract: Mutations in the LMNA gene result in diverse phenotypes including Emery Dreifuss muscular dystrophy, limb girdle muscular dystrophy, dilated cardiomyopathy with conduction system disease, Dunnigan type familial partial lipodystrophy, mandibulo acral dysplasia, Hutchinson Gilford progeria syndrome, restrictive dermopathy and autosomal recessive Charcot Marie Tooth type 2. The c.1930C > T (R644C) missense mutation has previously been reported in eight unrelated patients with variable features including left ventricular hypertrophy, limb girdle muscle weakness, dilated cardiomyopathy and atypical progeria. Here we report on the details of nine additional patients in eight families with this mutation. Patients 1 and 2 presented with lipodystrophy and insulin resistance, Patient 1 having in addition focal segmental glomerulosclerosis. Patient 3 presented with motor neuropathy, Patient 4 with arthrogryposis and dilated cardiomyopathy with left ventricular non-compaction, Patient 5 with severe scoliosis and contractures, Patient 6 with limb girdle weakness and Patient 7 with hepatic steatosis and insulin resistance. Patients 8 and 9 are brothers with proximal weakness and contractures. Nonpenetrance was observed frequently in first degree relatives. This report provides further evidence of the extreme phenotypic diversity and low penetrance associated with the R644C mutation. Possible explanations for these observations are discussed.

Paternal age and adverse birth outcomes: teenager or 40+, who is at risk?

Abstract: Most previous studies on the effect of paternal age have focused on the association of advanced paternal age with congenital anomalies. The objective of this study was to determine whether paternal age is associated with the risk of adverse birth outcomes independent of maternal confounders. We carried out a retrospective cohort study of 2 614 966 live singletons born to married nulliparous women aged 20-29 years between 1995 and 2000 in the USA. Multiple logistic regressions were applied to estimate the independent effect of paternal age on adverse birth outcomes. Compared with infants born to fathers aged 20-29 years infants fathered by teenagers (less than 20 years old) had an increased risk of preterm birth [odds ratio (OR) = 1.15 95% confidence interval (CI): 1.10 1.20] low birth weight (OR = 1.13 95% CI: 1.08 1.19) small-for-gestational-age births (OR = 1.17 95% CI: 1.13 1.22) low Apgar score (OR = 1.13 95% CI: 1.01 1.27) neonatal mortality (OR = 1.22 95% CI: 1.01 1.49) and post-neonatal mortality (OR = 1.41 95% CI: 1.09 1.82). Advanced paternal age (greater than or equal to 40 years) was not associated with the risk of adverse birth outcomes. Teenage fathers carry an increased risk of adverse birth outcomes that is independent of maternal confounders whereas advanced paternal age is not an independent risk factor for adverse birth outcomes. (authors)

Age-related decline in mitochondrial DNA copy number in isolated human pancreatic islets

Abstract: Pancreatic beta cell function has been shown to decline with age in man. Depletion of mitochondrial DNA (mtDNA) copy number is associated with impaired insulin secretion in pancreatic beta cell lines, and decreased mtDNA copy number has been observed with age in skeletal muscle in man. We investigated whether mtDNA copy number decreases with age in human pancreatic beta cells, which might in turn contribute to the age-related decline in insulin secretory capacity. We quantified mtDNA copy number in isolated human islet preparations from 15 pancreas donors aged between 17 and 75 years. Islets (n = 20) were individually hand-picked and pooled from each donor isolate for the quantification of mtDNA copy number and deleted mtDNA (%), which were determined using real-time PCR methods. There was a significant negative correlation between mtDNA copy number and islet donor age (r = –0.53, p = 0.044). mtDNA copy number was significantly decreased in islet preparations from donors aged ≥50 years (n = 8) compared with those aged <50 years (n = 7) (median [interquartile range]: 418 [236–503] vs 596 [554–729] mtDNA copy number/diploid genome; p = 0.032). None of the islet preparations harboured high levels of deleted mtDNA affecting the major arc. Given the correlation between mtDNA content and respiratory chain activity, the age-related decrease in mtDNA copy number that we observed in human pancreatic islet preparations may contribute to the age-dependent decline in pancreatic beta cell insulin secretory capacity.

Exploring informed choice in the context of prenatal testing: findings from a qualitative study.

Abstract: Purpose This study explored whether and how a sample of women made informed choices about prenatal testing for foetal anomalies; its aim was to provide insights for future health policy and service provision. Methods We conducted semi-structured interviews with 38 mothers in Ottawa, Ontario, all of whom had been offered prenatal tests in at least one pregnancy. Using the Multi-dimensional Measure of Informed Choice as a general guide to analysis, we explored themes relevant to informed choice, including values and knowledge, and interactions with health professionals. Results Many, but not all, participants seemed to have made informed decisions about prenatal testing. Values and knowledge were interrelated and important components of informed choice, but the way they were discussed differed from the way they have been presented in scientific literature. In particular, ‘values’ related to expressions of women’s moral views or ideas about ‘how life should be lived’ and ‘knowledge’ related to the ways in which women prioritized and interpreted factual information, through their own and others’ experiences and in ‘thinking through’ the personal implications of testing. While some women described non-directive discussions with health professionals, others perceived testing as routine or felt pressured to accept it. Conclusions Our findings suggest a need for maternity care providers to be vigilant in promoting active decision making about prenatal testing, particularly around the consideration of personal implications. Further development of measures of informed choice may be necessary to fully evaluate decision support tools and to determine whether prenatal testing programmes are meeting their objectives.

Maternal exposure to folic acid antagonists and placenta-mediated adverse pregnancy outcomes

Abstract: Background: In previous studies, maternal exposure to folic acid antagonists was associated with increased risks of neural tube defects, cardiovascular defects, oral clefts and urinary tract defects. The objective of the current study was to assess the possible effects of using folic acid antagonists in pregnancy on placenta-mediated adverse outcomes of pregnancy. Methods: We used data from an administrative database to retrospectively compare the occurrence of placenta-mediated adverse pregnancy outcomes between pregnant women exposed to folic acid antagonists and women without exposure to these agents. Results: We included in the analysis a total of 14 982 women who had been exposed to folic acid antagonists and 59 825 women who had not been exposed. Sulfamethoxazole–trimethoprim was the most frequently prescribed dihydrofolate reductase inhibitor (a total of 12 546 exposures during the preconception period and all 3 trimesters), and phenobarbital was the most frequently prescribed among the other folic acid antagonists (a total of 1565 exposures). The risks of preeclampsia (adjusted odds ratio [OR] 1.52, 95% confidence interval [CI] 1.39–1.66), severe preeclampsia (OR 1.77, 95% CI 1.38–2.28), placental abruption (OR 1.32, 95% CI 1.12–1.57), fetal growth restriction defined as less than the 10th percentile (OR 1.07, 95% CI 1.01–1.13), fetal growth restriction defined as less than the 3rd percentile (OR 1.22, 95% CI 1.11–1.34) and fetal death (OR 1.35, 95% CI 1.07–1.70) were greater among mothers with exposure to folic acid antagonists. In general, the risks associated with exposure to other folic acid antagonists were higher than those associated with exposure to dihydrofolate reductase inhibitors. Supplementary analyses involving tight matching with propensity score, restriction of the analysis to women with exposure during the first and second trimesters and restriction of the analysis to specific categories of folic acid antagonists yielded similar results. Interpretation: Maternal exposure to folic acid antagonists appears to increase the risk of placenta-mediated adverse outcomes of pregnancy.

Variation in the ADIPOQ gene promoter is associated with carotid intima media thickness independent of plasma adiponectin levels in healthy subjects

Abstract: Aims The ADIPOQ gene encodes the protein adiponectin, and decreased circulating adiponectin levels have been observed in cardiovascular disease. We investigated the role of the ADIPOQ gene single-nucleotide polymorphisms (SNPs) A-11426G, G-11391A, C-11377G, and T45G with plasma adiponectin levels and common carotid artery intima media thickness (IMT) in a cohort of healthy subjects participating in the RISC (Relationship between Insulin Sensitivity and Cardiovascular disease) study. Methods and results Anthropometric and metabolic assessment and B-mode ultrasound of the carotid IMT were measured in 1306 subjects [589 men; 717 women, mean ± SD age 43.8 ± 8.3 years, BMI 25.5 ± 4.0 kg/m2] recruited from 19 centres in 14 European countries. Carriers of the −11426G allele and homozygous carriers of the −11391G allele had significantly lower plasma adiponectin levels. These relationships remained significant after adjusting for age, sex, recruitment centre, and BMI. Carriers of SNP −11377G allele had significantly greater IMT values compared with C allele homozygotes [geometric mean (interquartile range) 601 (543–665) vs. 590 (537–647) μm, P = 0.021]. This relationship became stronger after correcting for key covariates, including plasma adiponectin levels ( P = 0.011). Conclusion Variation within the ADIPOQ gene promoter is directly associated with carotid IMT in healthy subjects and is independent of circulating adiponectin levels.

Maternal characteristics associated with pregnancy exposure to FDA category C, D, and X drugs in a Canadian population.

Abstract: Purpose To estimate the frequency of exposure to prescription Food and Drug Administration (FDA) category C, D, and X drugs in pregnant women, and to analyze the maternal characteristics associated with such an exposure. Methods A 50% random sample of women who gave a birth in Saskatchewan between January 1, 1997 and December 31, 2000 was chosen for the study. The rate of exposure to FDA category C, D, or X drugs recorded in the pharmacist database was estimated. Associations of exposure to FDA category C, D, and X drugs with maternal characteristics were evaluated using multiple logistical regression, with adjusted odds ratios (ORs) and its 95% confidence intervals (CIs) as the association measures. Results A total of 18 575 women were included in this study. Among them, 3604 (19.4%) had exposure to one or more FDA category C, D, and X drugs during pregnancy. Category C drugs were the most frequently used drugs (15.8%), followed by D drugs (5.2%), and X drugs (3.9%). Women with chronic health conditions had fourfold at increased risk of exposure than women without. Regardless of health status, women who were <20 years of age, who had a parity ≥3, and who were on social assistance plan were at increased risk of pregnancy exposure to these drugs. Conclusions About 19.4% pregnant women are exposed to FDA C, D or X drugs during pregnancy. Women with chronic diseases, younger age, increased parity, and under social assistance are at increased risk of exposure to FDA C, D, or X drugs. Copyright © 2008 John Wiley & Sons, Ltd.

Beta cell glucose sensitivity is decreased by 39% in non-diabetic individuals carrying multiple diabetes-risk alleles compared with those with no risk alleles

Abstract: Aims/hypothesis Novel type 2 diabetes-susceptibility loci have been identified with evidence that individually they mediate the increased diabetes risk through altered pancreatic beta cell function. The aim of this study was to test the cumulative effects of diabetes-risk alleles on measures of beta cell function in non-diabetic individuals.

Influence of the ACE gene insertion/deletion polymorphism on insulin sensitivity and impaired glucose tolerance in healthy subjects

Abstract: OBJECTIVE —Recent studies suggested that the blockade of the renin-angiotensin system (RAS) may be associated with metabolic benefits. However, data about the potential influence of the ACE insertion/deletion (I/D) genotype on insulin resistance have been contradictory with studies of limited sample sizes. The purpose of this study was to investigate the relationship between the ACE gene I/D polymorphism and both insulin sensitivity and glucose intolerance in a large cohort of healthy subjects. RESEARCH DESIGN AND METHODS —A total of 1,286 participants in the Relationship Between Insulin Sensitivity and Cardiovascular Disease Risk Study had a 75-g oral glucose tolerance test and a hyperinsulinemic-euglycemic clamp to assess whole-body insulin sensitivity. RESULTS —Age, BMI, waist, fat-free mass (ffm), and physical activity did not differ by ACE genotype. Fasting glucose and insulin were similar among genotypes, but 2-h glucose levels were higher in DD than in ID and II subjects (DD: 5.9 ± 1.7; ID: 5.7 ± 1.5; II: 5.6 ± 1.5 mmol/l) ( P = 0.004). Participants with the DD genotype were more likely to have impaired glucose tolerance than those with the ID and II genotypes (13.1 vs. 8.7%; P = 0.02). Insulin sensitivity was lower in participants with the DD genotype than in those with the II genotype (136 ± 63 vs. 147 ± 65 μmol · min −1 · kg ffm −1 · mmol −1 · l −1 ; P = 0.02). The presence of the D allele was associated with a trend, albeit not significant, for reduced insulin secretion during the oral glucose tolerance test ( P = 0.07). CONCLUSIONS —The ACE I/D polymorphism is associated with whole-body insulin sensitivity and with impaired glucose tolerance in our healthy population. These findings confirm potential interactions between the RAS and glucose metabolism.

Population-Specific Risk of Type 2 Diabetes Conferred by HNF4A P2 Promoter Variants: A Lesson for Replication Studies

Abstract: OBJECTIVE—Single nucleotide polymorphisms (SNPs) in the P2 promoter region of HNF4A were originally shown to be associated with predisposition for type 2 diabetes in Finnish, Ashkenazi, and, more recently, Scandinavian populations, but they generated conflicting results in additional populations. We aimed to investigate whether data from a large-scale mapping approach would replicate this association in novel Ashkenazi samples and in U.K. populations and whether these data would allow us to refine the association signal. RESEARCH DESIGN AND METHODS—Using a dense linkage disequilibrium map of 20q, we selected SNPs from a 10-Mb interval centered on HNF4A. In a staged approach, we first typed 4,608 SNPs in case-control populations from four U.K. populations and an Ashkenazi population (n = 2,516). In phase 2, a subset of 763 SNPs was genotyped in 2,513 additional samples from the same populations. RESULTS—Combined analysis of both phases demonstrated association between HNF4A P2 SNPs (rs1884613 and rs2144908) and type 2 diabetes in the Ashkenazim (n = 991; P 0.5), and the estimate for the OR was much smaller (OR 1.04; [95%CI 0.91–1.19]). CONCLUSIONS—These data indicate that the risk conferred by HNF4A P2 is significantly different between U.K. and Ashkenazi populations (P < 0.00007), suggesting that the underlying causal variant remains unidentified. Interactions with other genetic or environmental factors may also contribute to this difference in risk between populations.

Patterns of pregnancy exposure to prescription FDA C, D and X drugs in a Canadian population

Abstract: To examine prescription Food and Drug Administration (FDA) C, D and X drugs in general obstetric population. Historical cohort study. A total of 18 575 women who gave a birth in Saskatchewan between January 1997 and December 2000 were included. Among them, 3604 (19.4%) received FDA C, D or X drugs at least once during pregnancy. The pregnancy exposure rates were 15.8, 5.2 and 3.9%, respectively, for category C, D and X drugs, and were 11.2, 7.3 and 8.2%, respectively, in the first, second and third trimesters. Salbutamol (albuterol), trimethoprim/sulfamethoxazole (co-trimoxazole), ibuprofen, naproxen and oral contraceptives were the most common C, D, X drugs used during pregnancy. About one in every five women uses FDA C, D and X drugs at least once during pregnancy, and the most common prescription drugs in pregnancy are antiasthmatic, antibiotics, nonsteroid anti-inflammation drugs, antianxiety or antidepressants and oral contraceptives.

The influence of the environment and other exogenous agents on spontaneous abortion risk.

Abstract: It is estimated that close to 30% of all pregnancies end in spontaneous abortion. Although about 60% of spontaneous abortions are thought to be due to genetic, infectious, hormonal, and immunological factors, the role of the environment remains poorly understood. Pregnancy involves a delicate balance of hormonal and immunological functions, which may be affected by environmental substances. Many toxic substances that are persistent in the environment and accumulate in the fatty tissues may disrupt this equilibrium. This overview addresses known risk factors for spontaneous abortions and examines the role, if any, that environmental factors (chemical and physical) may play in the etiology of this adverse health outcome.

Placenta previa: Its relationship with race and the country of origin among Asian women

Abstract: Objectives. To examine the association between placenta previa with maternal race and its variations by country of origin among Asian women. Study design. Retrospective cohort study. Methods. We analyzed data from a population-based retrospective cohort study of 16,751,627 pregnancies in the US. The data were derived from the national linked birth/infant mortality database for the period 1995–2000. Multiple logistic regressions were used to describe the relationship between placenta previa and race as well as country of origin among Asian women. Results. About 3.3 per 1,000 pregnancies were complicated with placenta previa among white women, while the corresponding figures for black women and women of other races were 3.0 and 4.5 per 1,000 pregnancies, respectively. The excess risk remained substantial and significant after adjustment for confounders for women of other races compared to white women. The frequencies of placenta previa among Chinese, Japanese, Filipino, Asian Indian, Korean, Vietnamese and ...

Effects of repeated courses of antenatal corticosteroids on somatic development in children 6 to 10 years of age.

Abstract: This study assessed the effects of repeated courses of antenatal corticosteroids on biometric characteristics, salivary cortisol, and heart function in children 6 to 10 years of age using a retrospective cohort study. Twenty-nine children whose mothers had received two or more courses of antenatal corticosteroids were identified from hospital charts. Eighty-seven children whose mothers did not receive antenatal corticosteroids were frequency matched with the exposed group by child's age, sex, and ethnicity. The body development, heart function, and salivary corticosteroid level were evaluated at 6 to 10 years of age. The percentiles of body measurements were calculated based on the 2000 Centers for Disease Control and Prevention growth charts. The general linear models were applied to assess the observed association. Decreased head circumference ( P = 0.017) and body mass index (BMI) ( P = 0.047) in children 6 to 10 years of age were associated with repeated courses of antenatal corticosteroids. Morning salivary cortisol level was lower in the exposed group than the unexposed group ( P = 0.048). No difference was found in height, weight, blood pressure, heart rate, and echocardiogram measurements between the two groups. Repeated courses of antenatal corticosteroid therapy are associated with decreased head circumference, BMI, and salivary cortisol level in children 6 to 10 years of age.

Does impaired mitochondrial function affect insulin signaling and action in cultured human skeletal muscle cells

Abstract: Insulin-resistant type 2 diabetic patients have been reported to have impaired skeletal muscle mitochondrial respiratory function. A key question is whether decreased mitochondrial respiration contributes directly to the decreased insulin action. To address this, a model of impaired cellular respiratory function was established by incubating human skeletal muscle cell cultures with the mitochondrial inhibitor sodium azide and examining the effects on insulin action. Incubation of human skeletal muscle cells with 50 and 75 μM azide resulted in 48 ± 3% and 56 ± 1% decreases, respectively, in respiration compared with untreated cells mimicking the level of impairment seen in type 2 diabetes. Under conditions of decreased respiratory chain function, insulin-independent (basal) glucose uptake was significantly increased. Basal glucose uptake was 325 ± 39 pmol/min/mg (mean ± SE) in untreated cells. This increased to 669 ± 69 and 823 ± 83 pmol/min/mg in cells treated with 50 and 75 μM azide, respectively (vs. untreated, both P < 0.0001). Azide treatment was also accompanied by an increase in basal glycogen synthesis and phosphorylation of AMP-activated protein kinase. However, there was no decrease in glucose uptake following insulin exposure, and insulin-stimulated phosphorylation of Akt was normal under these conditions. GLUT1 mRNA expression remained unchanged, whereas GLUT4 mRNA expression increased following azide treatment. In conclusion, under conditions of impaired mitochondrial respiration there was no evidence of impaired insulin signaling or glucose uptake following insulin exposure in this model system.