Gaps in the Care of Familial Hypercholesterolaemia in Australia: First Report From the National Registry.

BACKGROUND: Familial hypercholesterolaemia (FH) is under-diagnosed and under-treated worldwide, including Australia. National registries play a key role in identifying patients with FH, understanding gaps in care and advancing the science of FH to improve care for these patients. METHODS: The FH Australasia Network has established a national web-based registry to raise awareness of the condition, facilitate service planning and inform best practice and care services in Australia. We conducted a cross-sectional analysis of 1,528 FH adults enrolled in the registry from 28 lipid clinics. RESULTS: The mean age at enrolment was 53.4±15.1 years, 50.5% were male and 54.3% had undergone FH genetic testing, of which 61.8% had a pathogenic FH-causing gene variant. Only 14.0% of the cohort were family members identified through cascade testing. Coronary artery disease (CAD) was reported in 28.0% of patients (age of onset 49.0±10.5 years) and 64.9% had at least one modifiable cardiovascular risk factor. The mean untreated LDL-cholesterol was 7.4±2.5 mmol/L. 80.8% of patients were on lipid-lowering therapy with a mean treated LDL-cholesterol of 3.3±1.7 mmol/L. Among patients receiving lipid-lowering therapies, 25.6% achieved an LDL-cholesterol target of <2.5 mmol/L without CAD or <1.8 mmol/L with CAD. CONCLUSION: Patients in the national FH registry are detected later in life, have a high burden of CAD and risk factors, and do not achieve guideline-recommended LDL-cholesterol targets. Genetic and cascade testing are under-utilised. These deficiencies in care need to be addressed as a public health priority.

Novel missense MTTP gene mutations causing abetalipoproteinemia.

OBJECTIVE: The microsomal triglyceride transfer protein (MTTP) plays a critical role in the formation of hepatic very low density lipoprotein. Abetalipoproteinemia (ABL) is a rare, naturally occurring extreme form of MTTP inhibition, which is characterized by the virtual absence of apolipoprotein (apo) B-containing lipoproteins in blood. The goal of this study was to examine the effect that four novel MTTP missense mutations had on protein interactions, expression and lipid-transfer activity, and to determine which mutations were responsible for the ABL phenotype observed in two patients. APPROACH AND RESULTS: In two patients with ABL, we identified in MTTP a novel frameshift mutation (K35Ffs*37), and four novel missense mutations, namely, G264R, Y528H, R540C, and N649S. When transiently expressed in COS-7 cells, all missense MTTP mutations interacted with apoB17, apoB48, and protein disulfide isomerase. Mutations Y528H and R540C, however, displayed negligible levels of MTTP activity and N649S displayed a partial reduction relative to the wild-type MTTP. In contrast, G264R retained full lipid-transfer activity. CONCLUSIONS: These studies indicate that missense mutations Y528H, R540C, and N649S appear to cause ABL by reducing MTTP activity rather than by reducing binding of MTTP with protein disulfide isomerase or apoB. The region of MTTP containing amino acids 528 and 540 constitutes a critical domain for its lipid-transfer activity.

Paternal dietary folate, B6 and B12 intake, and the risk of childhood brain tumors.

It is biologically plausible that a paternal preconception diet low in nutrients related to DNA integrity could affect sperm DNA and subsequently risk of cancer in the offspring. The aim of this analysis was to investigate whether paternal preconception dietary folate, B6, or B12 intake was associated with the risk of childhood brain tumors (CBT) in an Australian case-control study. Cases <15 years of age were recruited from 10 Australian pediatric oncology centers between 2005 and 2010, and controls from random-digit dialing, frequency-matched to cases on age, sex, and state of residence. Paternal dietary information was obtained by food-frequency questionnaires. Nutrient values were energy adjusted and divided into tertiles for analysis by unconditional logistic regression. In fathers with relevant data (237 cases and 629 controls), no association with dietary folate and B6 and risk of CBT was seen; high B12 intake was associated with an increased risk of CBT (odds ratio highest vs. lowest tertile: 1.74, 95% confidence interval: 1.14, 2.66) without an increasing trend. These results do not support the hypothesis that paternal dietary folate intake influences the risk of CBT. The increased OR observed between dietary B12 intake and risk of CBT is without any certain explanation.

Whole exome sequencing of familial hypercholesterolaemia patients negative for LDLR/APOB/PCSK9 mutations.

BACKGROUND: Familial hypercholesterolaemia (FH) is an autosomal dominant disease of lipid metabolism, which leads to early coronary heart disease. Mutations in LDLR, APOB and PCSK9 can be detected in 80% of definite FH (DFH) patients. This study aimed to identify novel FH-causing genetic variants in patients with no detectable mutation. METHODS AND RESULTS: Exomes of 125 unrelated DFH patients were sequenced, as part of the UK10K project. First, analysis of known FH genes identified 23 LDLR and two APOB mutations, and patients with explained causes of FH were excluded from further analysis. Second, common and rare variants in genes associated with low-density lipoprotein cholesterol (LDL-C) levels in genome-wide association study (GWAS) meta-analysis were examined. There was no clear rare variant association in LDL-C GWAS hits; however, there were 29 patients with a high LDL-C SNP score suggestive of polygenic hypercholesterolaemia. Finally, a gene-based burden test for an excess of rare (frequency <0.005) or novel variants in cases versus 1926 controls was performed, with variants with an unlikely functional effect (intronic, synonymous) filtered out. CONCLUSIONS: No major novel locus for FH was detected, with no gene having a functional variant in more than three patients; however, an excess of novel variants was found in 18 genes, of which the strongest candidates included CH25H and INSIG2 (p<4.3×10(-4) and p<3.7×10(-3), respectively). This suggests that the genetic cause of FH in these unexplained cases is likely to be very heterogeneous, which complicates the diagnostic and novel gene discovery process.

Abdominal aortic aneurysm is associated with a variant in low-density lipoprotein receptor-related protein 1.

Abdominal aortic aneurysm (AAA) is a common cause of morbidity and mortality and has a significant heritability. We carried out a genome-wide association discovery study of 1866 patients with AAA and 5435 controls and replication of promising signals (lead SNP with a p value < 1 × 10(-5)) in 2871 additional cases and 32,687 controls and performed further follow-up in 1491 AAA and 11,060 controls. In the discovery study, nine loci demonstrated association with AAA (p < 1 × 10(-5)). In the replication sample, the lead SNP at one of these loci, rs1466535, located within intron 1 of low-density-lipoprotein receptor-related protein 1 (LRP1) demonstrated significant association (p = 0.0042). We confirmed the association of rs1466535 and AAA in our follow-up study (p = 0.035). In a combined analysis (6228 AAA and 49182 controls), rs1466535 had a consistent effect size and direction in all sample sets (combined p = 4.52 × 10(-10), odds ratio 1.15 [1.10-1.21]). No associations were seen for either rs1466535 or the 12q13.3 locus in independent association studies of coronary artery disease, blood pressure, diabetes, or hyperlipidaemia, suggesting that this locus is specific to AAA. Gene-expression studies demonstrated a trend toward increased LRP1 expression for the rs1466535 CC genotype in arterial tissues; there was a significant (p = 0.029) 1.19-fold (1.04-1.36) increase in LRP1 expression in CC homozygotes compared to TT homozygotes in aortic adventitia. Functional studies demonstrated that rs1466535 might alter a SREBP-1 binding site and influence enhancer activity at the locus. In conclusion, this study has identified a biologically plausible genetic variant associated specifically with AAA, and we suggest that this variant has a possible functional role in LRP1 expression.

Effect of B vitamins and lowering homocysteine on cognitive impairment in patients with previous stroke or transient ischemic attack: a prespecified secondary analysis of a randomized, placebo-controlled trial and meta-analysis.

BACKGROUND AND PURPOSE: High plasma total homocysteine (tHcy) has been associated with cognitive impairment but lowering tHcy with B-vitamins has produced equivocal results. We aimed to determine whether B-vitamin supplementation would reduce tHcy and the incidence of new cognitive impairment among individuals with stroke or transient ischemic attack≥6 months previously. METHODS: A total of 8164 patients with stroke or transient ischemic attack were randomly allocated to double-blind treatment with one tablet daily of B-vitamins (folic acid, 2 mg; vitamin B6, 25 mg; vitamin B12, 500 µg) or placebo and followed up for 3.4 years (median) in the VITAmins TO Prevent Stroke (VITATOPS) trial. For this prespecified secondary analysis of VITATOPS, the primary outcome was a new diagnosis of cognitive impairment, defined as a Mini-Mental State Examination (MMSE) score<24 on ≥2 follow-up visits. Secondary outcomes were cognitive decline, and the mean tHcy and MMSE at final follow-up. RESULTS: A total of 3089 participants (38%) voluntarily undertook the MMSE>6 months after the qualifying stroke; 2608 participants were cognitively unimpaired (MMSE≥24), of whom 2214 participants (1110 B-vitamins versus 1104 placebo) had follow-up MMSEs during 2.8 years (median). At final follow-up, allocation to B-vitamins, compared with placebo, was associated with a reduction in mean tHcy (10.2 µmol/L versus 14.2 µmol/L; P<0.001) but no change from baseline in the mean MMSE score (-0.22 points versus -0.25 points; difference, 0.03; 95% confidence interval, -0.13 to 0.19; P=0.726) and no difference in the incidence of cognitive impairment (5.51% versus 5.47%; risk ratio, 1.01; 95% confidence interval, 0.69-1.48; P=0.976), cognitive decline (9.1% versus 10.3%; risk ratio, 0.89; 0.67-1.18; P=0.414), or cognitive impairment or decline (11.0% versus 11.3%; risk ratio, 0.98; 0.75-1.27; P=0.855). CONCLUSIONS: Daily supplementation with folic acid, vitamin B6, and vitamin B12 to a self-selected clinical trial cohort of cognitively unimpaired patients with previous stroke or transient ischemic attack lowered mean tHcy but had no effect on the incidence of cognitive impairment or cognitive decline, as measured by the MMSE, during a median of 2.8 years. CLINICAL TRIAL REGISTRATION: URL: http://www.controlled-trials.com. Unique identifier: ISRCTN74743444; URL: http://www.clinicaltrials.gov. Unique identifier: NCT00097669.

Plasma total homocysteine is associated with abdominal aortic aneurysm and aortic diameter in older men.

OBJECTIVE: This study was conducted to determine whether plasma total homocysteine (tHcy) and the methylenetetrahydrofolate reductase (MTHFR) C677T polymorphism are associated with abdominal aortic aneurysm (AAA) and aortic diameter. METHODS: This was a cross-sectional study set in Western Australia of 4248 community-dwelling men aged 70 to 88 years. Infrarenal aortic diameter was measured using ultrasound scan, tHcy was measured by immunoassay, and MTHFR 677T polymorphism was detected by polymerase chain reaction. RESULTS: Adjusted multinomial logistic regression analysis showed the odds of having an AAA (aortic diameter ≥ 30 mm) for men with high tHcy (≥ 15 µmol/L) compared with those with normal tHcy (<15 µmol/L) was 1.45 (95% confidence interval [CI], 1.10-1.91). Every 5-µmol/L increment in tHcy was associated with 0.15-mm (95% CI, 0.01-0.28 mm) increase in mean aortic diameter. The tHcy concentration was higher in MTHFR TT homozygote individuals than in wild-type CC individuals. There was, however, no apparent association between MTHFR C677T polymorphism with AAA (TT vs CC genotype: odds ratio, 0.97; 95% CI, 0.72-1.31) or aortic diameter (TT vs CC genotype: mean increment of 0.01 mm; 95% CI, -0.63 to 0.65 mm). CONCLUSIONS: Elevated tHcy is associated with the presence of AAA in older men. There is also a positive dose-response relationship between tHcy and abdominal aortic diameter. Longitudinal studies and clinical trials of lowering tHcy are required to assess whether these relationships are causal.

Molecular pathology of familial hypercholesterolemia, related dyslipidemias and therapies beyond the statins.

The development of the statin class of cholesterol-lowering drugs is one of the most significant success stories of modern pharmacotherapy. World-wide there are an estimated 150 million people on statins, with the emerging economies of India and China predicted to contribute significantly to that number. Notwithstanding their success, a significant number of people cannot tolerate statins because of serious side effects; of equal concern, a substantial proportion of high risk patients fail to reach cholesterol-lowering targets. For these subjects there is an urgent need for new cholesterol-lowering agents to be used alone or in combination with statins. The success of statins has been largely underpinned by knowledge of cholesterol homeostasis at a molecular level, knowledge that was first gleaned in the 1980s from Brown and Goldstein's pioneering studies of familial hypercholesterolemia (FH, OMIM 143890). Follow-up work that has identified a number of intracellular and circulating factors, all capable of disrupting LDL clearance, has revealed that the low-density lipoprotein receptor- (LDLR) mediated clearance pathway is substantially more complex than previously thought. These factors were discovered in studies of individuals with very rare inherited conditions that lead to either hypo- or hypercholesterolemia. These investigations, besides providing clearer insight into the molecular mechanisms regulating plasma LDL concentrations, have also revealed a number of novel therapeutic targets independent from statins. Consequently, a number of novel therapeutic approaches that are based on small interfering bio-molecules, including antisense oligonucleotides, are now in clinical development. These are aimed at impairing the assembly, synthesis and secretion of apolipoprotein B-containing lipoproteins and/or accelerating their hepatic catabolism. The aim of this article is to focus on these recent advances in the understanding of the molecular basis of cholesterol metabolism that should herald novel cholesterol-lowering agents beyond the statins.

Effect modification by population dietary folate on the association between MTHFR genotype, homocysteine, and stroke risk: a meta-analysis of genetic studies and randomised trials.

BACKGROUND: The MTHFR 677C→T polymorphism has been associated with raised homocysteine concentration and increased risk of stroke. A previous overview showed that the effects were greatest in regions with low dietary folate consumption, but differentiation between the effect of folate and small-study bias was difficult. A meta-analysis of randomised trials of homocysteine-lowering interventions showed no reduction in coronary heart disease events or stroke, but the trials were generally set in populations with high folate consumption. We aimed to reduce the effect of small-study bias and investigate whether folate status modifies the association between MTHFR 677C→T and stroke in a genetic analysis and meta-analysis of randomised controlled trials. METHODS: We established a collaboration of genetic studies consisting of 237 datasets including 59,995 individuals with data for homocysteine and 20,885 stroke events. We compared the genetic findings with a meta-analysis of 13 randomised trials of homocysteine-lowering treatments and stroke risk (45,549 individuals, 2314 stroke events, 269 transient ischaemic attacks). FINDINGS: The effect of the MTHFR 677C→T variant on homocysteine concentration was larger in low folate regions (Asia; difference between individuals with TT versus CC genotype, 3·12 µmol/L, 95% CI 2·23 to 4·01) than in areas with folate fortification (America, Australia, and New Zealand, high; 0·13 µmol/L, -0·85 to 1·11). The odds ratio (OR) for stroke was also higher in Asia (1·68, 95% CI 1·44 to 1·97) than in America, Australia, and New Zealand, high (1·03, 0·84 to 1·25). Most randomised trials took place in regions with high or increasing population folate concentrations. The summary relative risk (RR) of stroke in trials of homocysteine-lowering interventions (0·94, 95% CI 0·85 to 1·04) was similar to that predicted for the same extent of homocysteine reduction in large genetic studies in populations with similar folate status (predicted RR 1·00, 95% CI 0·90 to 1·11). Although the predicted effect of homocysteine reduction from large genetic studies in low folate regions (Asia) was larger (RR 0·78, 95% CI 0·68 to 0·90), no trial has evaluated the effect of lowering of homocysteine on stroke risk exclusively in a low folate region. INTERPRETATION: In regions with increasing levels or established policies of population folate supplementation, evidence from genetic studies and randomised trials is concordant in suggesting an absence of benefit from lowering of homocysteine for prevention of stroke. Further large-scale genetic studies of the association between MTHFR 677C→T and stroke in low folate settings are needed to distinguish effect modification by folate from small-study bias. If future randomised trials of homocysteine-lowering interventions for stroke prevention are undertaken, they should take place in regions with low folate consumption. FUNDING: Full funding sources listed at end of paper (see Acknowledgments).

Plasma homocysteine and MTHFRC677T polymorphism as risk factors for incident dementia.

BACKGROUND: Elevated total plasma homocysteine (tHcy) has been associated with increased risk of dementia. The C677T polymorphism of the 5,10-methylenetetrahydrofolate reductase gene (MTHFR) increases tHcy and provides a means of studying the association between tHcy and dementia while not being as susceptible to the common biases and confounding of observational studies. The authors designed this longitudinal study to determine if high tHcy and the MTHFR C677T polymorphism increase the risk of incident dementia among older men. METHODS: The authors studied 4227 men aged 70-89 years from the Health in Men Study cohort and established the diagnosis of dementia (International Classification of Diseases-10th edition) using morbidity and mortality records. Information on tHcy, MTHFR gene status, lifestyle and clinical variables were obtained using postal and face-to-face assessments. RESULTS: 230 men (5.4%) developed dementia during the mean follow-up period of 5.8 ± 1.6 years (range 0.1-8.2 years). The hazard of dementia increased with a doubling of tHcy concentration (adjusted HR 1.48, 95% CI 1.10 to 2.00) and was higher in men with tHcy >15 µmol/l (adjusted HR 1.36 95% CI 1.03 to 1.81, p=0.032). Men with the TT genotype had a HR of dementia of 1.25 (95% CI 0.81 to 1.92). CONCLUSIONS: The results of this prospective study are consistent with a causal link between high tHcy and incident dementia, but the study lacked power to determine an effect of the MTHFR genotype.

Maternal dietary intake of folate and vitamins B6 and B12 during pregnancy and the risk of childhood acute lymphoblastic leukemia.

Our aim was to address the hypothesis that maternal dietary intake of folate during pregnancy is inversely associated with risk of acute lymphoblastic leukemia (ALL) in the offspring. Dietary intake of folate, vitamins B6 and B12 in the last 6 mo of pregnancy from 333 cases and 695 frequency-matched controls were assessed using a food frequency questionnaire. Data were analyzed using unconditional logistic regression, adjusting for study matching variables, total energy, and potentially confounding variables. Higher levels of dietary folate and B12 appeared to be associated with a decreased risk of ALL. Higher levels of vitamin B6 were associated with an increased risk. The strongest associations of ALL with these variables were seen when mothers consumed alcohol in pregnancy. Our findings are consistent with a modest protective effect of higher dietary intake of folate and vitamin B12 against ALL in the offspring, more particularly among women who drank alcohol during pregnancy. These findings are consistent with previous reports of the protective effects of a maternal diet high in fruit, vegetables, and nondairy protein sources. The vitamin B6 findings are not consistent with evidence that it is a protective factor against other cancers, and may be a chance finding.

Statistical adjustment of genotyping error in a case-control study of childhood leukaemia.

BACKGROUND: Genotyping has become more cost-effective and less invasive with the use of buccal cell sampling. However, low or fragmented DNA yields from buccal cells collected using FTA cards often requires additional whole genome amplification to produce sufficient DNA for genotyping. In our case-control study of childhood leukaemia, discordance was found between genotypes derived from blood and whole genome amplified FTA buccal DNA samples. We aimed to develop a user-friendly method to correct for this genotype misclassification, as existing methods were not suitable for use in our study. METHODS: Discordance between the results of blood and buccal-derived DNA was assessed in childhood leukaemia cases who had both blood and FTA buccal samples. A method based on applying misclassification probabilities to measured data and combining results using multiple imputations, was devised to correct for error in the genotypes of control subjects, for whom only buccal samples were available, to minimize bias in the odds ratios in the case-control analysis. RESULTS: Application of the correction method to synthetic datasets showed it was effective in producing correct odds ratios from data with known misclassification. Moreover, when applied to each of six bi-allelic loci, correction altered the odds ratios in the logically anticipated manner given the degree and direction of the misclassification revealed by the investigations in cases. The precision of the effect estimates decreased with decreasing size of the misclassification data set. CONCLUSIONS: Bias arising from differential genotype misclassification can be reduced by correcting results using this method whenever data on concordance of genotyping results with those from a different and probably better DNA source are available.

A new model of care for familial hypercholesterolaemia: what is the role of cardiology?

Familial hypercholesterolaemia (FH) is a co-dominantly inherited disorder that causes marked elevation in plasma cholesterol and premature coronary heart disease. There are at least 45,000 people with FH in Australia and New Zealand, but most remain undiagnosed and undertreated. To bridge this gap in coronary prevention the FH Australasia Network has developed a model of care for FH. We present the executive summary, with a commentary contrasting the recommendations with other international guidelines and highlighting the role of the cardiologist.

Familial hypercholesterolemia: epidemiology, Neolithic origins and modern geographic distribution.

The elucidation of the molecular basis of familial hypercholesterolemia (FH) by Brown and Goldstein about three decades ago provided the most convincing evidence for a causative relationship between a high plasma level of low-density lipoprotein (LDL) cholesterol and the conditions of atherosclerosis and premature atherosclerotic cardiovascular disease. Today, with a prevalence of about one in 500 individuals, FH remains the most common monogenic disorder of lipoprotein metabolism, and is mainly due to mutations in the LDL receptor (LDLR) gene that lead to the plasma accumulation of cholesterol ester-laden LDL particles. Another form of autosomal dominant hypercholesterolemia, familial defective apolipoprotein B-100, a genocopy of FH caused by defects in the APOB gene that lead to decreased clearance of LDL, is now established as a significant cause of coronary heart disease. Yet another form, due to mutations in the proprotein convertase subtilisin/kexin type 9 (PCSK9) gene, has been recently identified that similarly causes decreased clearance of LDL by novel mechanisms also involving the hepatic LDLR endocytotic pathway. Recent advances in molecular genotyping technology have yielded a staggering amount of detail about human genetic diversity at the single nucleotide level in both private and public databases including the International HapMap Consortium. This, as well as the availability of ancient human DNA from burial sites and the development of new statistical methods, now provide an unprecedented capacity to study human demography and the ability to examine the genealogical ties between ancient and modern people. The aim of this article is to review the epidemiology of FH, and to attempt to draw inferences from our knowledge at a DNA level of inherited hypercholesterolemia of contemporary people that may contribute to the understanding of human population history and adaptation that resulted in the massive demographic expansion following the adoption of agriculture in the Neolithic period.

Awareness of cognitive deficits in older adults with cognitive-impairment-no-dementia (CIND): comparison with informant report.

Impaired awareness of cognitive deficits is a common symptom of dementia, but its prognostic importance in people with cognitive impairment-no dementia (CIND) is uncertain. In this study, we examined whether community volunteers with CIND and reduced awareness had worse cognitive performance and cognitive decline over 18 months than CIND participants with intact awareness or healthy controls. We recruited 92 participants with CIND and 91 healthy controls with their respective informants. We used discrepancy scores (informant minus participant) on the Anosognosia Questionnaire for Dementia and Dysexecutive Questionnaire to ascertain participants' awareness of their cognitive performance. The main cognitive outcome variable was the Alzheimer Disease Assessment Scale: Cognitive Section. Bivariate correlations showed no relationship between the awareness measures and cognitive performance or decline. Overall, CIND participants' ratings of cognitive deficits correlated significantly with their Alzheimer Disease Assessment Scale: Cognitive Section score after 18-months (for Anosognosia Questionnaire for Dementia, r=0.45, P <0.001) and showed a stronger relationship with cognitive performance than informant ratings. These results indicate that reduced awareness of deficit may be uncommon in community volunteer samples with CIND. In addition, self-report of cognitive complaints may be at least as useful as informant report when screening community-dwelling older adults at risk of cognitive decline and dementia.

Maternal folate and other vitamin supplementation during pregnancy and risk of acute lymphoblastic leukemia in the offspring.

The Australian Study of Causes of Acute Lymphoblastic Leukemia in Children (Aus-ALL) was designed to test the hypothesis, raised by a previous Western Australian study, that maternal folic acid supplementation during pregnancy might reduce the risk of childhood acute lymphoblastic leukemia (ALL). Aus-ALL was a national, population-based, multicenter case-control study that prospectively recruited 416 cases and 1,361 controls between 2003 and 2007. Detailed information was collected about maternal use of folic acid and other vitamin supplements before and during the index pregnancy. Data were analyzed using logistic regression, adjusting for matching factors and potential confounders. A meta-analysis with the results of previous studies of folic acid supplementation was also conducted. We found weak evidence of a protective effect of maternal folate supplementation before pregnancy against risk of childhood ALL, but no evidence for a protective effect of its use during pregnancy. A meta-analysis including this and 2 other studies, but not the study that raised the hypothesis, also found little evidence that folate supplementation during pregnancy protects against ALL: the summary odds ratios (ORs) for folate supplementation were 1.06 [95% confidence interval (CI): 0.77-1.48] with reference to no folate supplementation and 1.02 (95% CI: 0.86-1.20) with reference to no vitamin supplementation. For vitamin supplementation in general, the summary OR from a meta-analysis of 5 studies-including Aus-ALL-was 0.83 (95% CI: 0.73-0.94). Vitamin supplementation in pregnancy may protect against childhood ALL, but this effect is unlikely to be large or, if real, specifically due to folate.

A new model of care for familial hypercholesterolaemia from Western Australia: closing a major gap in preventive cardiology.

Familial hypercholesterolaemia (FH) is the most common monogenic cause of premature coronary artery disease. FH remains underdiagnosed and inadequately treated, with no national strategies for dealing with the problem. We report an executive summary of a comprehensive model of care for FH developed in Western Australia.

Angiotensin II type 1 receptor 1166C polymorphism is associated with abdominal aortic aneurysm in three independent cohorts.

OBJECTIVE: Although polymorphic variations in genes of the RAS system have previously been associated with susceptibility to AAA, such studies have been significantly limited by small sample sizes. This study was undertaken, using the largest case series yet reported, to determine whether common genetic variants of the RAS are associated with either susceptibility or severity of AAA. METHODS AND RESULTS: The frequencies of 4 common genetic variants of genes related to the renin-angiotensin system were investigated in 3 geographically distinct, but ethnically similar, case-control cohorts, resulting in comparison of 1226 AAA cases with 1723 controls. In all 3 the AGTR1 1166C allele was significantly more common in AAA patients than controls (overall adjusted OR 1.60, 95% CI 1.32 to 1.93, P=1.1x10(-6)). Overall, the ACE ID genotype was associated with AAA (OR 1.33, 95% CI 1.06 to 1.67, P<0.02). The AGT 268T allele appeared to have an epistatic effect on large aneurysm size. CONCLUSIONS: This study has identified a strong and repeated association between the AGTR1 1166C allele and susceptibility to AAA, and a weaker effect associated with the ACE deletion allele, in 3 geographically distinct, but ethnically similar, case-control cohorts. This study highlights the key role of the RAS in AAA and emphasizes the need for replication and validation of results in suitable independent cohorts.

Apolipoprotein epsilon alleles in sporadic inclusion body myositis: a reappraisal.

Previous studies have differed as to whether APOE epsilon4 is a susceptibility factor for developing sporadic inclusion body myositis (sIBM), with a positive association being found only in an Australian cohort of cases. We have now re-examined this in a larger cohort of 57 sIBM cases and have also carried out a meta-analysis of all the published studies looking for evidence of a risk association or effect of APOE alleles on disease expression. Our findings argue against a specific role for any APOE alleles in conferring susceptibility to sIBM but have demonstrated a non-significant trend towards an earlier age-of-onset in patients with the epsilon2 allele.

Variation in Niemann-Pick C1-like 1 gene as a determinant of apolipoprotein B-100 kinetics and response to statin therapy in centrally obese men.

OBJECTIVE: Niemann-Pick C1-like 1 protein (NPC1L1) plays a key role in lipoprotein metabolism. We examined the association of common genetic polymorphisms in NPC1L1 on apolipoprotein (apo) B-100 metabolism and the response to statin treatment in 37 men with central obesity. RESEARCH METHODS AND PROCEDURE: Very-low density lipoprotein (VLDL) and low-density lipoprotein (LDL)-apoB kinetics were determined using stable isotope method. NPC1L1 genotypes (1735G > C, 25432A > C and 27677T > C) were determined by allele-specific methods. These three polymorphisms are defined as haplotype, namely 1735C-25432A-27677T, and was designated as 'haplotype 2'. RESULTS: Relative to non-2/2 haplotype (n = 23), subjects with the 2/2 haplotype (n = 14) had significantly increased plasma concentrations of total, LDL-cholesterol, and total apoB (P < 0.05). The fractional catabolic rate (FCR) of LDL-apoB was significantly lower in 2/2 subjects compared with non-2/2 subjects (P < 0.05), with an associated increase in LDL-apoB pool size in the former group. Sixteen subjects were then treated with 40 mg atorvastatin (6 weeks): 2/2 subjects (n = 8) had a significantly greater reduction in plasma concentrations of cholesterol and total apoB and in LDL-apoB pool size, as well as a greater increase in LDL-apoB FCR compared with non-2/2 subjects. There were no significant treatment-related between-haplotype differences in VLDL-apoB kinetics or in plasma concentrations of lathosterol and campesterol. CONCLUSION: Our data demonstrate that NPC1L1 2/2 haplotype was associated with variation in LDL-apoB metabolism and its response to statin therapy in centrally obese men, by a mechanism that did not involve changes in VLDL-apoB kinetics, nor cholesterol synthesis or absorption.