Rates of common communicable illnesses in non-anaemic 12-24 month old South Island, New Zealand children

Aims : To describe the incidence of parentally reported illness in otherwise healthy South Island toddlers; characterise the predictors of illness; and determine whether there was a relationship between teething and illness in this population.Methods : A 20-week randomised controlled trial was conducted on 1-year-old children (n=225) from Otago and Southland between February 2004 and December 2005. Information on symptoms of morbidity, occurrence of teething, and childcare attendance were recorded daily throughout the intervention period. Morbidity symptoms were categorised into respiratory illness (RI), gastrointestinal illness (GII), ear infection, and total illness, and the number and duration of events were determined.Results : The mean (SD) number of total illnesses was 3.4 (2.3) per 20 weeks, with an average duration of 4.5 days. Episodes of RI were most common (50% of total illness events), and tended to be the longest in duration (mean of 3.7 days). Having siblings aged less than 5 years (23% increase, 95%CI 6%&ndash;42%, p=0.007) and attending childcare (72% increase, 95%CI 38%&ndash;113%, p&lt;0.001)), were positively associated with the number of total illness events but not duration. In addition, teething was positively associated with total events (OR 1.94, 95%CI 1.45&ndash;2.60, p&lt;0.001), RI events (OR 2.03, 95%CI 1.41&ndash;2.93, p&lt;0.001) and GII events (OR 1.90, 95%CI 1.36&ndash;2.67, p&lt;0.001). Conclusion : This study has shown that illness (particularly RI) is common in the second year of life. It has also confirmed that attending childcare and having siblings aged under 5 years increases the number of illness events. An association between teething and the occurrence of illness was also seen but the exact nature of this relationship requires verification. <br /

Dietary Patterns, Their Nutrients, and Associations with Socio-Demographic and Lifestyle Factors in Older New Zealand Adults

Dietary patterns analyse combinations of foods eaten. This cross-sectional study identified dietary patterns and their nutrients. Associations between dietary patterns and socio-demographic and lifestyle factors were examined in older New Zealand adults. Dietary data (109-item food frequency questionnaire) from the Researching Eating, Activity and Cognitive Health (REACH) study ( = 367, 36% male, mean age = 70 years) were collapsed into 57 food groups. Using principal component analysis, three dietary patterns explained 18% of the variation in diet. Dietary pattern associations with sex, age, employment, living situation, education, deprivation score, physical activity, alcohol, and smoking, along with energy-adjusted nutrient intakes, were investigated using regression analysis. Higher 'Mediterranean' dietary pattern scores were associated with being female, higher physical activity, and higher education ( <0.001, R = 0.07). Higher 'Western' pattern scores were associated with being male, higher alcohol intake, living with others, and secondary education ( <0.001, R = 0.16). Higher 'prudent' pattern scores were associated with higher physical activity and lower alcohol intake ( <0.001, R = 0.15). There were positive associations between beta-carotene equivalents, vitamin E, and folate and 'Mediterranean' dietary pattern scores ( <0.0001, R ≥ 0.26); energy intake and 'Western' scores ( <0.0001, R = 0.43); and fibre and carbohydrate and 'prudent' scores ( <0.0001, R ≥ 0.25). Socio-demographic and lifestyle factors were associated with dietary patterns. Understanding relationships between these characteristics and dietary patterns can assist in health promotion

Predictors of vitamin D status and its association with parathyroid hormone in young New Zealand children.

BACKGROUND: Despite increased awareness of the adverse health effects of low vitamin D status, few studies have evaluated 25-hydroxyvitamin D [25(OH)D] status in young children. OBJECTIVES: We aimed to assess vitamin D status on the basis of 25(OH)D and its relation with parathyroid hormone (PTH) and to identify possible predictors of 25(OH)D status in young children living in a country with minimal vitamin D fortification. DESIGN: Serum 25(OH)D and PTH concentrations were measured in a cross-sectional sample of children aged 12-22 mo [n = 193 for 25(OH)D, n = 144 for PTH] living in Dunedin, New Zealand (latitude: 45 degrees S). Anthropometric, dietary, and sociodemographic data were collected. RESULTS: The majority of children sampled in the summer (94%; 47 of 50) had 25(OH)D >50 nmol/L; however, nearly 80% of children sampled in the winter (43 of 55) had serum concentrations 60-65 nmol/L, a plateau in PTH was evident. CONCLUSIONS: Seasonal variation in 25(OH)D concentration implies that postsummer vitamin D stores were insufficient to maintain status >50 nmol/L year-round. Examination of the predictors of 25(OH)D in our model shows few modifiable risk factors, and thus effective dietary strategies may be required if future research determines that children with 25(OH)D concentrations <50 nmol/L are at significant health risk. This trial was registered at www.actr.org.au as ACTRN12605000487617

Mutations in TOP3A Cause a Bloom Syndrome-like Disorder

Bloom syndrome, caused by biallelic mutations in BLM, is characterized by prenatal-onset growth deficiency, short stature, an erythematous photosensitive malar rash, and increased cancer predisposition. Diagnostically, a hallmark feature is the presence of increased sister chromatid exchanges (SCEs) on cytogenetic testing. Here, we describe biallelic mutations in TOP3A in ten individuals with prenatal-onset growth restriction and microcephaly. TOP3A encodes topoisomerase III alpha (TopIIIα), which binds to BLM as part of the BTRR complex, and promotes dissolution of double Holliday junctions arising during homologous recombination. We also identify a homozygous truncating variant in RMI1, which encodes another component of the BTRR complex, in two individuals with microcephalic dwarfism. The TOP3A mutations substantially reduce cellular levels of TopIIIα, and consequently subjects’ cells demonstrate elevated rates of SCE. Unresolved DNA recombination and/or replication intermediates persist into mitosis, leading to chromosome segregation defects and genome instability that most likely explain the growth restriction seen in these subjects and in Bloom syndrome. Clinical features of mitochondrial dysfunction are evident in several individuals with biallelic TOP3A mutations, consistent with the recently reported additional function of TopIIIα in mitochondrial DNA decatenation. In summary, our findings establish TOP3A mutations as an additional cause of prenatal-onset short stature with increased cytogenetic SCEs and implicate the decatenation activity of the BTRR complex in their pathogenesis

Cerebral small vessel disease genomics and its implications across the lifespan

White matter hyperintensities (WMH) are the most common brain-imaging feature of cerebral small vessel disease (SVD), hypertension being the main known risk factor. Here, we identify 27 genome-wide loci for WMH-volume in a cohort of 50,970 older individuals, accounting for modification/confounding by hypertension. Aggregated WMH risk variants were associated with altered white matter integrity (p = 2.5×10-7) in brain images from 1,738 young healthy adults, providing insight into the lifetime impact of SVD genetic risk. Mendelian randomization suggested causal association of increasing WMH-volume with stroke, Alzheimer-type dementia, and of increasing blood pressure (BP) with larger WMH-volume, notably also in persons without clinical hypertension. Transcriptome-wide colocalization analyses showed association of WMH-volume with expression of 39 genes, of which four encode known drug targets. Finally, we provide insight into BP-independent biological pathways underlying SVD and suggest potential for genetic stratification of high-risk individuals and for genetically-informed prioritization of drug targets for prevention trials.Peer reviewe

Multiple novel prostate cancer susceptibility signals identified by fine-mapping of known risk loci among Europeans

Genome-wide association studies (GWAS) have identified numerous common prostate cancer (PrCa) susceptibility loci. We have fine-mapped 64 GWAS regions known at the conclusion of the iCOGS study using large-scale genotyping and imputation in 25 723 PrCa cases and 26 274 controls of European ancestry. We detected evidence for multiple independent signals at 16 regions, 12 of which contained additional newly identified significant associations. A single signal comprising a spectrum of correlated variation was observed at 39 regions; 35 of which are now described by a novel more significantly associated lead SNP, while the originally reported variant remained as the lead SNP only in 4 regions. We also confirmed two association signals in Europeans that had been previously reported only in East-Asian GWAS. Based on statistical evidence and linkage disequilibrium (LD) structure, we have curated and narrowed down the list of the most likely candidate causal variants for each region. Functional annotation using data from ENCODE filtered for PrCa cell lines and eQTL analysis demonstrated significant enrichment for overlap with bio-features within this set. By incorporating the novel risk variants identified here alongside the refined data for existing association signals, we estimate that these loci now explain ∼38.9% of the familial relative risk of PrCa, an 8.9% improvement over the previously reported GWAS tag SNPs. This suggests that a significant fraction of the heritability of PrCa may have been hidden during the discovery phase of GWAS, in particular due to the presence of multiple independent signals within the same regio

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 &lt; 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 &lt; 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

Genome-wide association study identifies six new loci influencing pulse pressure and mean arterial pressure.

Numerous genetic loci have been associated with systolic blood pressure (SBP) and diastolic blood pressure (DBP) in Europeans. We now report genome-wide association studies of pulse pressure (PP) and mean arterial pressure (MAP). In discovery (N = 74,064) and follow-up studies (N = 48,607), we identified at genome-wide significance (P = 2.7 × 10(-8) to P = 2.3 × 10(-13)) four new PP loci (at 4q12 near CHIC2, 7q22.3 near PIK3CG, 8q24.12 in NOV and 11q24.3 near ADAMTS8), two new MAP loci (3p21.31 in MAP4 and 10q25.3 near ADRB1) and one locus associated with both of these traits (2q24.3 near FIGN) that has also recently been associated with SBP in east Asians. For three of the new PP loci, the estimated effect for SBP was opposite of that for DBP, in contrast to the majority of common SBP- and DBP-associated variants, which show concordant effects on both traits. These findings suggest new genetic pathways underlying blood pressure variation, some of which may differentially influence SBP and DBP