Dug Yeo Han

Risk factors for obesity in 7-year-old European children: the Auckland Birthweight Collaborative Study

Objective: To identify risk factors associated with obesity in primary school children, with a particular focus on those which can be modified. To identify critical periods and growth patterns in the development of childhood obesity. Methods: 871 New Zealand European children were enrolled in a longitudinal study at birth and data were collected at birth, 1, 3.5 and 7 years of age. Data collected at 7 years included weight, height, bioelectrical impedance analysis (BIA), television viewing time and a 24 h body movement record (actigraphy). The outcome measure was percentage body fat (PBF), which was calculated at 3.5 and 7 years using BIA. Univariate and multiple regression analyses were carried out using PBF as a continuous variable. Results: Multivariable analysis found maternal overweight/obesity, maternal age, female gender, sedentary activity time and hours of television viewing to be independently associated with PBF at 7 years. Growth variables (birth weight, rapid weight gain in infancy, early (1–3.5 years) and middle childhood (3.5–7 years)) were also independently associated with adiposity at 7 years. There was a strong correlation between PBF at 3.5 years and PBF at 7 years. Conclusions: Many primary school aged children start on the trajectory of obesity in the preschool years, which suggests interventions need to start early. Maternal overweight/obesity, television watching, sedentary activity time and rapid weight gain in infancy, early and middle childhood are risk factors for childhood obesity, and are all potentially modifiable.

Genetic factors in chronic inflammation: Single nucleotide polymorphisms in the STAT-JAK pathway, susceptibility to DNA damage and Crohn's disease in a New Zealand population

The Signal Transducers and Activators of Transcription (STAT)-Janus kinase (JAK) pathway controls signal transduction between cell surface receptors and the nucleus. Two members of that pathway, STAT3 and JAK2, enhanced the risk of Crohns disease (CD) in recent genome-wide association studies. We replicated these findings in a New Zealand Caucasian case-control cohort, by genotyping two single nucleotide polymorphisms (SNPs) in STAT3 (rs744166(G>A) and rs3816769(C>T)) and rs10758669(A>C) in JAK2, in 302 CD patients and 382 controls. For STAT3, there was a significant decrease in the frequency of the G allele of rs744166 and the C allele of rs3816769 in CD patients as compared with controls (OR=0.76, 95% CI=0.61-0.95, p=0.013; OR=0.71, 95% CI=0.56-0.89, p=0.003). For the JAK2 rs10758669 polymorphism, the homozygous C/C or heterozygous A/C genotypes increased the risk of having CD as compared with the homozygous A/A (OR=1.76, 95% CI=1.26-2.45 and OR=2.36, 95% CI=1.44-3.86, respectively, p=0.0003). Variant alleles in either gene significantly modified the likelihood of inflammatory disease in a colonic location, and of developing extra-intestinal manifestations. The JAK2 variant also strongly enhanced the risk of ileocolonic disease, with stricturing or ileal/stricturing behaviour, requiring a bowel resection. We further studied a subset of our control population, stratified for JAK2 rs10758669 and/or STAT3 rs3816769 genotype. Carrying either the JAK2 or STAT3 IBD risk allele was associated with significantly enhanced susceptibility to DNA damage, as estimated by comet assays in peripheral blood leukocytes, with or without a subsequent oxidative challenge. That is, both risk alleles enhance genomic instability. The JAK2 SNP is part of a haplotype previously associated with enhanced susceptibility to myeloproliferative neoplasms, but functional consequences of the STAT3 variant had not been previously demonstrated. It will be of interest to follow up CD patients carrying either JAK2 or STAT3 risk alleles for development of further secondary effects, including cancer.

Environmental factors in the development of chronic inflammation: a case-control study on risk factors for Crohn's disease within New Zealand.

The role of environmental factors in the risk for Crohns disease (CD), an inflammatory bowel disease (IBD), was investigated in a North Island-based New Zealand case-control cohort. A total of 315 CD patients and 536 controls were recruited through various sources to the Auckland CD Risk Factor Study. As well as demographic characteristics, the self-reported questionnaire included (1) smoking and drinking alcohol, (2) breastfeeding in infancy, (3) early life exposures to allergens and microbes, (4) health conditions lasting 6 months or longer and (5) taking antibiotics and any medications. There was strong evidence for familial associations of the disease, and minor effects of birth order and number of siblings. Being a smoker, especially over a long time period, and exposure to smoking during childhood and adolescence periods increased risk, whereas drinking alcohol at least once per week showed a slight protective effect. Long term use of the oral contraceptive pill increased the risk of developing CD, but breastfeeding and immunisation during infancy showed no significant association. Long term and debilitating illness (lasting 6 months or more), taking antibiotics prior to developing CD, or taking four or more antibiotics or any regular medication in a year during adolescence substantially increased the CD risk. Having a pet during childhood was a protective factor, but regularly feeding an animal was not sufficient to protect. Many of these significant factors are likely to impact on the colonic microflora and/or immune system. We conclude that, in addition to strong evidence for genetic associations, factors likely to impact on immune response or reduce early exposure to microbes provide a main risk factor for CD in this New Zealand population.

Falling asleep: the determinants of sleep latency.

Background: Difficulty falling asleep (prolonged sleep latency) is a frequently reported problem in school-aged children. Aims: This study aimed to describe the distribution of sleep latency and factors that influence its duration. Methods: 871 children of European mothers were recruited at birth. 591 (67.9%) children took part in the follow-up at 7 years of age. Sleep and daytime activity were measured objectively by an actigraph worn for 24 h. Results: Complete sleep data were available for 519 children (87.8%) with a mean age of 7.3 years (SD 0.2). Median sleep latency was 26 minutes (interquartile range 13–42). Higher mean daytime activity counts were associated with a decrease in sleep latency (−1.2 minutes per 102 movement count per minute, p = 0.05). Time spent in sedentary activity was associated with an increase in sleep latency (3.1 minutes per hour of sedentary activity, p = 0.01). Conclusions: These findings emphasise the importance of physical activity for children, not only for fitness, cardiovascular health and weight control, but also for promoting good sleep.

Genetic analysis of MDR1 and inflammatory bowel disease reveals protective effect of heterozygous variants for ulcerative colitis

Background: Single nucleotide polymorphisms (SNPs) in the multidrug transporter MDR1 have been associated with inflammatory bowel disease (IBD) in different studies. However, the data are highly controversial. Recently, 6 haplotype tagging SNPs (tSNPs), representing the haplotype variations of the MDR1 gene, were identified. The aims of this study were to genotype these variants and correlate them to disease phenotype in New Zealand IBD patients. Materials and Methods: A total of 784 IBD patients and 200 healthy subjects were genotyped for 5 tSNPs and the triallelic MDR1 variant G2677T/A using the Sequenom MassArray platform. Furthermore, the effects of these variants were examined in correlation with phenotypic clinical features. Results: Heterozygous carriers for the variants C1236T, rs2235046 (an SNP in intron 16), and G2677T/A showed a lower risk of developing ulcerative colitis (C1236T: odds ratio [OR] = 0.63, 95% confidence interval [CI] = 0.42‐0.93, P = 0.03; G2677T/A: OR = 0.59, CI = 0.39‐0.89, P = 0.02; and rs2235046: OR = 0.59, 95% CI = 0.38‐0.91, P = 0.009) as compared with homozygotes. None of the analyzed markers were associated with Crohns disease on a genotypic level. Subgroup analysis revealed an association for 2 variants with IBD when stratified for age of onset (C1236T SNP and rs3789243). The MDR1 variant C3435T was associated with disease behavior in CD (OR = 1.45, 95% CI = 1.01‐2.08, P = 0.04), whereas the SNP rs3789243 was found to be associated with pancolitis in UC patients (OR = 1.35, CI = 1.00‐1.82, P = 0.05). Conclusions: The results of our study support the role of MDR1 as a candidate gene for ulcerative colitis. Furthermore, our results suggest the possibility of a heterozygous advantage for certain MDR1 variants for this disease. Inflamm Bowel Dis 2009

Selenium, Selenoprotein Genes and Crohn's Disease in a Case-Control Population from Auckland, New Zealand

New Zealand has one of the highest incidence rates of Crohn’s Disease (CD), whilst the serum selenium status of New Zealanders is amongst the lowest in the world. A prospective case-control study in Auckland, New Zealand considered serum selenium as a potential CD risk factor. Serum selenium levels were significantly lower in CD patients compared to controls (101.8 ± 1.02 vs. 111.1 ± 1.01 ng/mL) (p = 5.91 × 10−8). Recent detailed studies in the United Kingdom have suggested an optimal serum level around 122 ng/mL, making the average CD patient in New Zealand selenium deficient. Of the 29 single nucleotide polymorphisms (SNPs) tested, 13 were found to significantly interact with serum selenium on CD. After adjustment for multiple testing, a significant interaction with serum selenium on CD was found for three SNPs, namely rs17529609 and rs7901303 in the gene SEPHS1, and rs1553153 in the gene SEPSECS. These three SNPs have not been reported elsewhere as being significantly associated with selenium or CD. It is unclear as to whether lower selenium levels are a cause or an effect of the disease.

Prostate Disease Risk Factors among a New Zealand Cohort

Background: Prostate cancer is a leading public health burden worldwide, and in New Zealand it is the most commonly registered cancer and the third leading cause of cancer deaths among males. Genetic variability and its associations with diet, demographic and lifestyle factors could influence the risk of this disease. Methods: The single nucleotide polymorphisms (SNPs) within a group of antioxidant genes and related markers were tested between patient and control cohorts, adjusted for significant differences between basic lifestyle and demographic characteristics. Results: Increasing age, smoking and low serum selenium levels were significantly associated with an increased risk for prostate disease. Alcohol consumption increased the glutathione peroxidase (GPx) activity. A significant reduction in alcohol consumption was recorded with prostate disease. Three SNPs, namely GPx1 rs1050450, SEL15 rs5845 and CAT rs1001179, were significantly associated with prostate disease risk. A cumulative risk of prostate cancer was noted with 6 risk alleles. A lower GPx activity was recorded with prostate disease compared to the controls. However, the GPx1 rs1050450 allele T in association with prostate cancer recorded a significantly higher GPx activity compared to the controls. Conclusions: These data point to a possibility of identifying individuals at risk of prostate cancer for better management purposes.

Interactions among genes influencing bacterial recognition increase IBD risk in a population-based New Zealand cohort

Bacterial sensing is crucial for appropriate response by the innate and adaptive immune system against invading microorganisms. Single nucleotide polymorphisms (SNPs) in genes involved in bacterial recognition, CARD15 and TLR4, increased the risk of inflammatory bowel disease (IBD) in a New Zealand Caucasian case-control cohort. We now consider the effects of SNPs in CD14, TLR9, and BPI, analyzed individually, in association with one another, and with SNPs in CARD15 or TLR4 in this same population group. SNPs in CD14 (c.-159 C>T), TLR9 (c.-1237T>C) and BPI (c.645A>G) showed no significant allele or genotype frequency differences between IBD cases and controls. Genotype-phenotype mapping reveals an association with BPI and ileocolonic Crohns disease (CD) as well as an association with CD14 and early-onset ulcerative colitis (UC). Genotype interaction analyses using three different statistical approaches provided significant evidence of interaction for the following combinations: CARD15/TLR4 (CD and UC), CARD15/CD14 (CD and UC), CD14/TLR4 (UC only), and CD14/BPI (UC only). A trend for an association between BPI and TLR4 was observed in UC patients, but failed to reach statistical significance. Our findings support the idea of gene-gene interactions for genes involved in closely related pathways (i.e. bacterial detection). There is evidence that carrying two SNPs in genes may lead to statistical significance for genes and SNPs that do not otherwise confirm as risk alleles for disease aetiology when analysed alone.

IL23R and IL12B SNPs and Haplotypes Strongly Associate with Crohn's Disease Risk in a New Zealand Population

DNA samples from 339 Crohns disease (CD) and 407 randomly selected controls from the Auckland (New Zealand) IBD project, were genotyped for five common single nucleotide polymorphisms in IL-23R (rs11805303, rs7517847, rs1343151, rs11209026, and rs10889677) and two in IL-12B (rs1363670 and rs6887695). While the IL-12B variants did not show an overall association and other IL23R variants led to minor changes in the risk of CD, rs1343151 and/or rs7517847 variants in the IL-23R gene strongly reduced the risk of developing CD at both allelic and genotype levels. A significantly decreased risk of first diagnosis of childhood CD was observed in individuals carrying the A allele of rs1343151, or between 17–40 y in individuals carrying the G allele in rs7517847 of IL-23R. A significantly decreased risk of ileocolonic or structuring disease was observed in individuals carrying the A allele in either rs11209026 or rs1343151, or the G allele in rs7517847 of IL-23R, and when such individuals did develop the disease, they were unlikely to require a bowel resection. Certain haplotypes very strongly modified risk. There was evidence for interactions of IL-23R variants with the NOD2 wild-type (d/d) genotype. Down-regulating the function of the IL-23R gene may decrease CD risk in the normal population.

Single nucleotide polymorphisms in arrhythmia genes modify the risk of cardiac events and sudden death in long QT syndrome

BACKGROUND Disease-modifying single nucleotide polymorphisms (SNPs) can help explain incomplete penetrance and variable expressivity in congenital long QT syndrome (LQTS) by altering susceptibility to arrhythmias. OBJECTIVE The purpose of this study was to assess multiple arrhythmia SNPs (in 16 genes) in a distinct cohort of LQTS patients to identify modifier SNPs influencing the risk of sudden death. METHODS This study included 273 patients with LQTS from the New Zealand Cardiac Inherited Disease Registry (154 long QT type 1, 96 long QT type 2, and 23 long QT type 3), including 31 patients who had experienced death or resuscitated sudden cardiac death (RSCD). Patients were genotyped for 29 SNPs and tested for associations with clinical events and QTc length. Caucasian (n = 220) and Pacific Islander/New Zealand Maori (n = 53) ethnic groups were analyzed separately. This subgroup of Polynesian ancestry has not been previously studied for LQTS in either presentation or outcome. RESULTS In Caucasians, four SNPs at two risk loci (NOS1AP: rs12143842 and rs16847548; and KCNQ1: rs10798 and rs8234) were significantly associated with clinical events after correction for multiple testing. Patients homozygous for the risk allele of rs12143842 had an increased risk of death/RSCD [hazard ratio 10.15, 95% confidence interval (2.38, 43.34), q = 0.045). Several other SNPs showed trends toward association with QTc length and clinical events. CONCLUSION This study demonstrates that SNPs in NOS1AP and KCNQ1 are associated with an increased risk of cardiac events in LQTS patients, with the hazard ratio suggesting they have significant potential in clinical risk stratification.