Joanne T.E. Shaw

Linkage of Paget disease of bone to a novel region on human chromosome 18q23.

Paget disease of bone (PDB) is characterized by increased osteoclast activity and localized abnormal bone remodeling. PDB has a significant genetic component, with evidence of linkage to chromosomes 6p21.3 (PDB1) and 18q21-22 (PDB2) in some pedigrees. There is evidence of genetic heterogeneity, with other pedigrees showing negative linkage to these regions. TNFRSF11A, a gene that is essential for osteoclast formation and that encodes receptor activator of nuclear factor-kappa B (RANK), has been mapped to the PDB2 region. TNFRSF11A mutations that segregate in pedigrees with either familial expansile osteolysis or familial PDB have been identified; however, linkage studies and mutation screening have excluded the involvement of RANK in the majority of patients with PDB. We have excluded linkage, both to PDB1 and to PDB2, in a large multigenerational pedigree with multiple family members affected by PDB. We have conducted a genomewide scan of this pedigree, followed by fine mapping and multipoint analysis in regions of interest. The peak two-point LOD scores from the genomewide scan were 2.75, at D7S507, and 1.76, at D18S70. Multipoint and haplotype analysis of markers flanking D7S507 did not support linkage to this region. Haplotype analysis of markers flanking D18S70 demonstrated a haplotype segregating with PDB in a large subpedigree. This subpedigree had a significantly lower age at diagnosis than the rest of the pedigree (51.2+/-8.5 vs. 64.2+/-9.7 years; P=.0012). Linkage analysis of this subpedigree demonstrated a peak two-point LOD score of 4.23, at marker D18S1390 (straight theta=0), and a peak multipoint LOD score of 4.71, at marker D18S70. Our data are consistent with genetic heterogeneity within the pedigree and indicate that 18q23 harbors a novel susceptibility gene for PDB.

The relative risks of hyperglycaemia, obesity and dyslipidaemia in the relatives of patients with Type II diabetes mellitus.

Summary Type II (non-insulin-dependent) diabetes mellitus has a substantial genetic component; however, its molecular basis remains largely unknown. The mode of inheritance is likely to be polygenic, with penetrance influenced by environmental factors. Although the familial aggregation of Type II diabetes is acknowledged, there is little data concerning the prevalence of diabetes in the relatives of subjects with diabetes in comparison with the general population, and our objective was to address this question in the defined geographic region of Oxfordshire, England. We studied 139 first degree relatives of 90 probands with Type II diabetes who attended routine diabetes clinics in Oxfordshire and documented the fasting plasma glucose, triglyceride and HDL-cholesterol concentrations and BMI of these subjects. The probands were selected without regard to family history of diabetes. The control population data were derived from two large-scale Oxford community studies which documented the prevalences of known and newly diagnosed diabetes. The prevalences of newly diagnosed and known diabetes were calculated for each group. The mean BMI, and concentrations of fasting glucose, triglyceride and HDL-cholesterol were compared and prevalence ratios for obesity (defined as BMI > 30 kg/m2), hyperglycaemia (defined as fasting plasma glucose ≥ 6.1 mmol/l), and dyslipidaemia (defined as triglyceride > 2.0 mmol/l, HDL < 1.0 mmol/l) were calculated. There was a fourfold higher prevalence of hyperglycaemia in the first degree relatives of subjects with Type II diabetes compared with the control population: the prevalence ratio after adjustment for age, sex and BMI was 4.32 (95 % confidence interval 2.29–8.17). The relatives had a considerably higher fasting plasma glucose concentration than the control population (5.18 ± 0.67 mmol/l (mean ± 1 SD) vs 4.76 ± 1.59 mmol/l, p = 0.0001), and this difference remained statistically significant after adjustment for age, sex and obesity. The relatives were significantly more obese, had higher fasting plasma insulin concentrations and had lower HDL-cholesterol concentrations. In conclusion, there is a strong familial aggregation of hyperglycaemia and obesity in the relatives of subjects with Type II diabetes and these subjects have higher fasting plasma insulin concentrations and lower HDL-cholesterol than the general population. These data indicate the particular relevance of screening the first degree relatives of subjects with Type II diabetes, as intervention strategies which aim to improve the metabolic profile are indicated for a large proportion of these subjects. [Diabetologia (1999) 42: 24–27]

Familial Paget's disease of bone: nonlinkage to the PDB1 and PDB2 loci on chromosomes 6p and 18q in a large pedigree.

Pagets disease of bone is a common condition characterized by bone pain, deformity, pathological fracture, and an increased incidence of osteosarcoma. Genetic factors play a role in the pathogenesis of Pagets disease but the molecular basis remains largely unknown. Susceptibility loci for Pagets disease of bone have been mapped to chromosome 6p21.3 (PDB1) and 18q21.1‐q22 (PDB2) in different pedigrees. We have identified a large pedigree of over 250 individuals with 49 informative individuals affected with Pagets disease of bone; 31 of whom are available for genotypic analysis. The disease is inherited as an autosomal dominant trait in the pedigree with high penetrance by the sixth decade. Linkage analysis has been performed with markers at PDB1; these data show significant exclusion of linkage with log10 of the odds ratio (LOD) scores < −2 in this region. Linkage analysis of microsatellite markers from the PDB2 region has excluded linkage with this region, with a 30 cM exclusion region (LOD score < −2.0) centered on D18S42. These data confirm the genetic heterogeneity of Pagets disease of bone. Our hypothesis is that a novel susceptibility gene relevant to the pathogenesis of Pagets disease of bone lies elsewhere in the genome in the affected members of this pedigree and will be identified using a microsatellite genomewide scan followed by positional cloning.

The relationship between the insulin resistance syndrome and insulin sensitivity in the first-degree relatives of subjects with non-insulin dependent diabetes mellitus

Non-insulin dependent diabetes mellitus (NIDDM) has a substantial genetic component. Impaired insulin secretion, insulin insensitivity in muscle and adipose tissue, and elevated hepatic glucose production are the major pathophysiological features of NIDDM. Insulin insensitivity is also a feature of the insulin resistance syndrome, which describes the epidemiological association of glucose intolerance, upper body obesity, hyperinsulinaemia, hypertension, increased triglyceride levels and decreased high-density-lipoprotein (HDL)-cholesterol concentrations. Insulin insensitivity has been found to be a familial trait, and this raises the hypothesis that the insulin resistance syndrome may also occur as a familial trait in caucasian families in association with the development of NIDDM. The 90 first degree relatives of 50 caucasian subjects with NIDDM were studied with a continuous infusion glucose tolerance test to quantitate glucose tolerance, insulin sensitivity and beta-cell function. Body mass index (BMI), blood pressure, fasting triglyceride and HDL-cholesterol measurements were obtained, and the intercorrelations between these variables were examined. As a group the first degree relatives had a median insulin sensitivity of 65% (interquartile range 46-99%). Insulin sensitivity was univariately correlated with systolic and diastolic blood pressure, triglyceride and HDL-cholesterol. These associations were present in both the hyperglycaemic and the normoglycaemic relatives. The hyperglycaemic relatives were significantly more insulin insensitive than the normoglycaemic relatives, but this additional insulin insensitivity was not associated with significant differences in blood pressure, triglyceride or HDL-cholesterol concentrations. Our data indicate that the insulin insensitivity present in the first degree relatives of subjects with NIDDM is correlated with the cardiovascular risk factors which make up the insulin resistance syndrome, and that glycaemic status does not appear to be the major determinant of these associations. Interventions targeting obesity and insulin insensitivity in these subjects may reduce cardiovascular risk.

Association between anthropometric measures of obesity and cardiovascular risk markers in a self-selected group of indigenous Australians

Background Indigenous Australians have a high prevalence of obesity and an unacceptably high rate of cardiovascular disease. Methods We conducted a cross-sectional analysis of 93 high-risk indigenous Australians to assess how strongly three anthropometric measures correlated with known cardiovascular risk factors. Results Both waist circumference and body mass index were strongly associated with important risk factors. The waist: hip ratio was less useful. Waist circumference was the only measure that significantly correlated with the urine albumin creatinine ratio (ρ = 0.14; P =0.04). Conclusion Measuring the waist circumference is a cheap, effective way of monitoring cardiovascular risk.

Identification of an apolipoprotein(e) variant associated with type III hyperlipoproteinaemia in an indigenous Australian

As a result of testing for lipid and apolipoprotein(e) (apo E) phenotype status of an indigenous Australian community, an apo E variant associated with type III hyperlipoproteinaemia has been identified. Apo E phenotype was determined by analysis of VLDL by isoelectric focusing, and genotype on DNA amplified by polymerase chain reaction, using two different restriction enzyme isotyping assays. Phenotypes and genotypes were discordant in samples from two subjects and an abnormal-sized restriction fragment was also observed in their genotyping gel patterns. DNA sequencing studies revealed this was due to a single nucleotide deletion, 3817delC, at amino acid 136 on apo E. This resulted in a new reading frame and the premature termination of the apo E protein due to a stop codon (TGA) at nucleotide 4105. The variant apo E null allele showed a recessive mode of inheritance and, in combination with the E2 allele, resulted in the type III hyperlipoproteinaemic phenotype but when inherited with the E4 allele had no marked effect on plasma lipids.

Correlates of preclinical cardiovascular disease in Indigenous and Non-Indigenous Australians: a case control study.

BackgroundThe high frequency of premature death from cardiovascular disease in indigenous Australians is often attributed to the high prevalence of risk factors, especially type II diabetes mellitus (DM). We evaluated the relationship of ethnicity to atherosclerotic burden, as evidenced by carotid intima-media thickness (IMT), independent of risk factor status.MethodsWe studied 227 subjects (147 men; 50 ± 13 y): 119 indigenous subjects with (IDM, n = 54), and without DM (InDM, n = 65), 108 Caucasian subjects with (CDM, n = 52), and without DM (CnDM, n = 56). IMT was measured according to standard methods and compared with clinical data and cardiovascular risk factors.ResultsIn subjects both with and without DM, IMT was significantly greater in indigenous subjects. There were no significant differences in gender, body mass index (BMI), systolic blood pressure (SBP), or diastolic blood pressure (DBP) between any of the groups, and subjects with DM showed no difference in plasma HbA1c. Cardiovascular risk factors were significantly more prevalent in indigenous subjects. Nonetheless, ethnicity (β = -0.34; p < 0.0001), age (β = 0.48; p < 0.0001), and smoking (β = 0.13; p < 0.007) were independent predictors of IMT in multiple linear regression models.ConclusionEthnicity appears to be an independent correlate of preclinical cardiovascular disease, even after correction for the high prevalence of cardiovascular risk factors in indigenous Australians. Standard approaches to control currently known risk factors are vital to reduce the burden of cardiovascular disease, but in themselves may be insufficient to fully address the high prevalence in this population.

Ethnicity is an independent correlate of preclinical cardiovascular disease in indigenous Australians

We sought to determine the relative impact of myocardial scar and viability on post-infarct left ventricular (LV) remodeling in medically-treated patients with LV dysfunction. Forty patients with chronic ischemic heart disease (age 64±9, EF 40±11%) underwent rest-redistribution Tl201 SPECT (scar = 50% transmural extent), A global index of scarring for each patient (CMR scar score) was calculated as the sum of transmural extent scores in all segts. LV end diastolic volumes (LVEDV) and LV end systolic volumes (LVESV) were measured by real-time threedimensional echo at baseline and median of 12 months follow-up. There was a significant positive correlation between change in LVEDV with number of scar segts by all three imaging techniques (LVEDV: SPECT scar, r = 0.62, p 15%) was predicted bySPECTscars(AUC= 0.79),DbEscars(AUC= 0.76),CMR scars (AUC= 0.70), and CMR scar score (AUC 0.72). There were no significant differences between any of the ROC curves (Z score <0.74). Number of SPECT scars (p = 0.002), DbE scars (p = 0.01), CMR scars (p = 0.004), and CMR scar score (p = 0.03) were independent predictors of LVEDV. The extent of scar tissue can predict global LV remodeling irrespective of cardiac imaging technique but myocardial viability may not be protective against LV remodeling in medically-treated patients.Transmural extent of infarction (TME) may be an important determinant of functional recovery and remodeling. Recent animal data suggest that strain rate imaging (SRI) maybe able to identify subendocardial ischemia.We compared SRI and cyclic variation of integrated backscatter (CVIB) for predicting TME in the quantitative assessment of regional subepicardial function. Forty-nine (n = 49) postmyocardial infarct patients (61±10 years, EF 41±10%) underwent tissue Doppler echocardiography (TDE) and contrast enhanced magnetic resonance imaging (CMR). A15 mm×2mm sampling volume (tracked to wall motion) was placed over the long axis subepicardial region of each segment during TDE offline analysis to measure peak longitudinal systolic strain rate (SR), peak longitudinal systolic strain (PS), and CVIB. Findingswere compared with TME classified into two categories of scar thickness by CMR: Non-transmural (TME≤50%), and transmural (TME > 50%). Of 213 segments identified with resting wall motion abnormalities, 145 segments showed delayed hyperenhancement on CMR. SR, PS and CVIB were similar with no significant differences between transmural and non-transmural infarcts regardless of the echo modality.Revascularization (RVS) of scar segts does not lead to recovery of left ventricular (LV) function, but its effect on post-infarct remodeling is unclear. We examined the impact of RVS on regional remodeling in different transmural extents of scar (TME). Dobutamine echo (DbE) and contrast enhanced magnetic resonance imaging (ce- MRI) were performed in 72 pts post MI (age 63±10, EF 49±12%). Pts were selected for RVS (n = 31) or medical treatment (n = 41). Segts were classified as scar if there were no contractile reserve during lowdose DbE.TMEwas measured by ce-MRI; a cutoff of 75% was used to differentiate transmural (TM) from non-transmural (NT) scars. Regional end systolic (ESV) and end diastolic volumes (EDV) were measured at baseline and 12 months follow up.Of 218 segts identified as scar on DbE, 164wereNTand 54 were TM on ce-MRI. Revascularization was performed to 62 NT and 11 TM segts. In the RVS group, there was reverse remodeling with significant reduction in LV volumes in NT (ESV, 6.8±3.2 ml versus 5.8±3.7 ml, p = 0.002; EDV, 10.9±4.9 ml versus 9.8±5.6 ml, p = 0.02), but no significant change in volumes in TM (ESV, 6.9±3.7 ml versus 5.4±2.1 ml, p = 0.09; EDV, 10.2±4.4 ml versus 9.4±4.3 ml, p = 0.5). In the medically treated group, there were no changes in LV volumes in both NT (ESV, 12.0±11.9 ml versus 12.7±13.8 ml, p = 0.3; EDV, 12.5±7.8 ml versus 12.6±9.7 ml, p = 0.8) and TM (ESV, 8.0±3.8 ml versus 7.9±4.6 ml, p = 0.8; EDV, 10.3±4.8 ml versus 10.4±5.4 ml, p = 0.9). Despite absence of contractile reserve on DbE, NT benefit from coronary revascularization with regional reverse LV remodeling.Left ventricular (LV) volumes have important prognostic implications in patients with chronic ischemic heart disease. We sought to examine the accuracy and reproducibility of real-time 3D echo (RT-3DE) compared to TI-201 single photon emission computed tomography (SPECT) and cardiac magnetic resonance imaging (MRI). Thirty (n = 30) patients (age 62±9 years, 23 men) with chronic ischemic heart disease underwent LV volume assessment with RT-3DE, SPECT, and MRI. Ano vel semi-automated border detection algorithmwas used by RT-3DE. End diastolic volumes (EDV) and end systolic volumes (ESV) measured by RT3DE and SPECT were compared to MRI as the standard of reference. RT-3DE and SPECT volumes showed excellent correlation with MRI (Table). Both RT- 3DE and SPECT underestimated LV volumes compared to MRI (ESV, SPECT 74±58 ml versus RT-3DE 95±48 ml versus MRI 96±54 ml); (EDV, SPECT 121±61 ml versus RT-3DE 169±61 ml versus MRI 179±56 ml). The degree of ESV underestimation with RT-3DE was not significant.