Papers by David Zhen Zhen
Nature Genetics, 2009
Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterised ... more Paget's disease of bone (PDB) is a common disorder with a strong genetic component characterised by focal increases in bone turnover which in some cases is caused by SQSTM1 mutations. To identify additional susceptibility genes we performed a genome wide association study in 750 PDB cases without SQSTM1 mutations and 1002 controls and identified three candidate loci for the disease which were replicated in an independent set of 500 cases and 535 controls. The strongest signal was with rs484959 on 1p13 close to the CSF1 gene (P = 5.38 × 10 −24 ) and significant associations were also observed with rs1561570 on 10p13 within the OPTN gene (P = 6.09 × 10 −13 ) and with rs3018362 on 18q21 close to the TNFRSF11A gene (P = 5.27 × Users may view, print, copy, download and text and data-mine the content in such documents, for the purposes of academic research, subject always to the full Conditions of use:
BACKGROUND: Folate metabolism is critical to embryonic development, in¯uencing neural tube defect... more BACKGROUND: Folate metabolism is critical to embryonic development, in¯uencing neural tube defects (NTD) and recurrent early pregnancy loss. Polymorphisms in 5,10-methylenetetrahydrofolate reductase (MTHFR) have been associated with dizygotic (DZ) twinning through pregnancy loss. METHODS: The C677T and A1298C polymorphisms in MTHFR were genotyped in 258 Australasian families (1016 individuals) and 118 Dutch families (462 individuals) of mothers of DZ twins and a population sample of 462 adolescent twin families (1861 individuals). Haplotypes were constructed from the alleles, and transmission of the MTHFR haplotypes to mothers of DZ twins and from parents to twins in the adolescent twin families analysed. RESULTS: The C677T and A1298C were common in all three populations (frequencies > 0.29). There was strong linkage disequilibrium (D¢ = 1) between the variants, showing that speci®c combinations of alleles (haplotypes) were transmitted together. Three haplotypes accounted for nearly all the variation. There was no evidence of any association between MTHFR genotype and twinning in mothers of twins, or of the loss of speci®c MTHFR genotypes during twin pregnancies. CONCLUSIONS: It is concluded that variation in twinning frequency is not associated with MTHFR genotype.
Diabetologia, 2009
Aims/hypothesis There has been much focus on the potential role of mitochondria in the aetiology ... more Aims/hypothesis There has been much focus on the potential role of mitochondria in the aetiology of type 2 diabetes and the metabolic syndrome, and many case–control mitochondrial association studies have been undertaken for these conditions. We tested for a potential association between common mitochondrial variants and a number of quantitative traits related to type 2 diabetes in a large sample of >2,000 healthy Australian adolescent twins and their siblings, many of whom were measured on more than one occasion. Methods To the best of our knowledge, this is the first mitochondrial association study of quantitative traits undertaken using family data. The maternal inheritance pattern of mitochondria means established association methodologies are unsuitable for analysis of mitochondrial data in families. We present a methodology, implemented in the freely available program Sib-Pair for performing such an analysis. Results Despite our study having the power to detect variants with modest effects on these phenotypes, only one significant association was found after correction for multiple testing in any of four age groups. This was for mt14365 with triacylglycerol levels (unadjusted p = 0.0006). This association was not replicated in other age groups. Conclusions/interpretation We find little evidence in our sample to suggest that common European mitochondrial variants contribute to variation in quantitative phenotypes related to diabetes. Only one variant showed a significant association in our sample, and this association will need to be replicated in a larger cohort. Such replication studies or future meta-analyses may reveal more subtle effects that could not be detected here because of limitations of sample size.
Langmuir, 2009
Cationic polystyrene latex was flocculated with mixtures of hydroxypropyl guar (HPG) and boric ac... more Cationic polystyrene latex was flocculated with mixtures of hydroxypropyl guar (HPG) and boric acid, which form an anionic polyelectrolyte HPG-borate. Flocculation could be reversed by either lowering pH or by adding fructosesboth procedures remove labile borate ions weakly bound to the HPG chains. Mixtures of phenyl boronic acid (PBA) and HPG also flocculate latex although the range of HPG-PBA concentrations, giving flocculation was much narrower than HPG-borate. The differences were explained by the tendency of borate ion to cross-link HPG chains, whereas PBA is monofunctional and cannot cross-link HPG. * Corresponding author. [email protected].
Nature Genetics, 2011
Genome-wide association studies and candidate gene studies in ulcerative colitis have identified ... more Genome-wide association studies and candidate gene studies in ulcerative colitis have identified 18 susceptibility loci. We conducted a meta-analysis of six ulcerative colitis genome-wide association study datasets, comprising 6,687 cases and 19,718 controls, and followed up the top association signals in 9,628 cases and 12,917 controls. We identified 29 additional risk loci (P…
Journal of Clinical Endocrinology & Metabolism, 2006
Context: Genes from the ovarian bone morphogenetic signaling pathway (GDF9 and BMP15) are critica... more Context: Genes from the ovarian bone morphogenetic signaling pathway (GDF9 and BMP15) are critical for normal human fertility. We previously identified a deletion mutation in GDFS in sisters with spontaneous dizygotic (DZ) twins, but the prevalence of rare GDFS variants in twinning families is unknown.
American Journal of Human Genetics, 2007
We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q account... more We have previously shown that a quantitative-trait locus linked to the OCA2 region of 15q accounts for 74% of variation in human eye color. We conducted additional genotyping to clarify the role of the OCA2 locus in the inheritance of eye color and other pigmentary traits associated with skin-cancer risk in white populations. Fifty-eight synonymous and nonsynonymous exonic single-nucleotide polymorphisms (SNPs) and tagging SNPs were typed in a collection of 3,839 adolescent twins, their siblings, and their parents. The highest association for blue/nonblue eye color was found with three OCA2 SNPs: rs7495174 T/C, rs6497268 G/T, and rs11855019 T/C (P values of , , and 561 596
Molecular Human Reproduction, 2005
The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a comple... more The progesterone receptor (PR) is a candidate gene for the development of endometriosis, a complex disease with strong hormonal features, common in women of reproductive age. We typed the 306 base pair Alu insertion (AluIns) polymorphism in intron G of PR in 101 individuals, estimated linkage disequilibrium (LD) between five single-nucleotide polymorphisms (SNPs) across the PR locus in 980 Australian triads (endometriosis case and two parents) and used transmission disequilibrium testing (TDT) for association with endometriosis. The five SNPs showed strong pairwise LD, and the AluIns was highly correlated with proximal SNPs rs1042839 (⌬ 2 = 0.877, D = 1.00, P < 0.0001) and rs500760 (⌬ 2 = 0.438, D = 0.942, P < 0.0001). TDT showed weak evidence of allelic association between endometriosis and rs500760 (P = 0.027) but not in the expected direction. We identified a common susceptibility haplotype GGGCA across the five SNPs (P = 0.0167) in the whole sample, but likelihood ratio testing of haplotype transmission and non-transmission of the AluIns and flanking SNPs showed no significant pattern. Further, analysis of our results pooled with those from two previous studies suggested that neither the T2 allele of the AluIns nor the T1/T2 genotype was associated with endometriosis.
Gastroenterology, 2006
This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG)... more This study examined whether the prevention of diabetes-related albuminuria by aminoguanidine (AG) or ramipril (RAM) may be mediated by a common postglomerular basement membrane renal intracellular mechanism involving protein kinase C (PKC). The renal handling of albumin was examined over 24 weeks in control and streptozotocin (STZ)-induced diabetic rats. A radioimmunoassay (RIA) that measures intact albumin, and intravenously injected tritium-labeled rat serum albumin, was used to assess the proportion of intact albumin and albumin fragments in urine. Diabetes was induced in male Sprague-Dawley rats by the intravenous administration of STZ at a dose of 5 0 mg/kg. Age-matched control rats received buff e r alone. Diabetes was characterized by an increase in blood glucose (>15 mmol/l), an increase in GHb (means at 24 weeks 29.3 ± 1.1%; control 6.1 ± 0.1%, P < 0.005), an increase in glomerular filtration rate (GFR) (4.13 ± 0 . 1 5 ml/min; control 3.54 ± 0.19 ml/min, P < 0.005), an increase in intact albumin excretion rate (expressed as geometric mean 11.64 / 2 . 1 1 mg/24 h; control 0.74 / 1 . 5 7 mg/24 h, P < 0.005) as measured by RIA, and an increase in glomerular PKC activity (26.83 ± 2 . 3 8 p m o l · m g -1 · min -1 ; control 14.6 ± 2.99 p m o l · m g -1 · m i n -1 , P < 0.005). Treatment of diabetic rats with either AG or RAM prevented the rise in intact albuminuria and glomerular PKC activity. Renal lysosomal cathepsin activity decreased in diabetic rats and this was not prevented by AG or RAM. Neither drug affected glycemic control or GFR, but RAM reduced systolic blood pressure (BP), whereas AG did not. These data indicate that urinary excretion of intact albumin and albuminderived fragments in diabetes may be modulated independently of glycemic control (AG and RAM) and sys-tolic BP (RAM). While both drugs are known for their d i fferent mechanisms of action, the fact that both prevent diabetes-related increases in glomerular PKC activity and albuminuria supports the hypothesis that PKC plays a central role in the development of diabetic n e p h r o p a t h y. D i a b e t e s 4 9 :8 7-93, 2000
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Papers by David Zhen Zhen