Showing papers by "Jim Stankovich published in 2009"

Genome-wide association study identifies new multiple sclerosis susceptibility loci on chromosomes 12 and 20

Abstract: To identify multiple sclerosis (MS) susceptibility loci, we conducted a genome-wide association study (GWAS) in 1,618 cases and used shared data for 3,413 controls. We performed replication in an independent set of 2,256 cases and 2,310 controls, for a total of 3,874 cases and 5,723 controls. We identified risk-associated SNPs on chromosome 12q13-14 (rs703842, P = 5.4 x 10(-11); rs10876994, P = 2.7 x 10(-10); rs12368653, P = 1.0 x 10(-7)) and upstream of CD40 on chromosome 20q13 (rs6074022, P = 1.3 x 10(-7); rs1569723, P = 2.9 x 10(-7)). Both loci are also associated with other autoimmune diseases. We also replicated several known MS associations (HLA-DR15, P = 7.0 x 10(-184); CD58, P = 9.6 x 10(-8); EVI5-RPL5, P = 2.5 x 10(-6); IL2RA, P = 7.4 x 10(-6); CLEC16A, P = 1.1 x 10(-4); IL7R, P = 1.3 x 10(-3); TYK2, P = 3.5 x 10(-3)) and observed a statistical interaction between SNPs in EVI5-RPL5 and HLA-DR15 (P = 0.001).

Past environmental sun exposure and risk of multiple sclerosis: a role for the Cdx-2 Vitamin D receptor variant in this interaction

Abstract: Multiple studies have provided evidence for an association between reduced sun exposure and increased risk of multiple sclerosis (MS), an association likely to be mediated, at least in part, by the vitamin D hormonal pathway. Herein, we examine whether the vitamin D receptor (VDR), an integral component of this pathway, influences MS risk in a population-based sample where winter sun exposure in early childhood has been found to be an important determinant of MS risk. Three polymorphisms within the VDR gene were genotyped in 136 MS cases and 235 controls, and associations with MS and past sun exposure were examined by logistic regression. No significant univariate associations between the polymorphisms, rs11574010 (Cdx-2A > G), rs10735810 (Fok1T > C), or rs731236 (Taq1C > T) and MS risk were observed. However, a significant interaction was observed between winter sun exposure during childhood, genotype at rs11574010, and MS risk (P = 0.012), with the 'G' allele conferring an increased risk of MS in the low sun exposure group (

HLA-DRB1 associations with disease susceptibility and clinical course in Australians with multiple sclerosis

Abstract: Human leucocyte antigen (HLA)-DRB1*1501 and other class II alleles influence susceptibility to multiple sclerosis (MS), but their contribution if any to the clinical course of MS remains uncertain. Here, we have investigated DRB1 alleles in a large sample of 1230 Australian MS cases, with some enrichment for subjects with primary progressive (PPMS) disease (n = 246) and 1210 healthy controls. Using logistic regression, we found that DRB1*1501 was strongly associated with risk (P = 7 x 10-45), as expected, and after adjusting for DRB1*1501, a predisposing effect was also observed for DRB1*03 (P = 5 x 10-7). Individuals homozygous for either DRB1*15 or DRB1*03 were considerably more at risk of MS than heterozygotes and non-carriers. Both the DRB1*04 and the DRB1*01/DRB1*15 genotype combination, respectively, protected against PPMS in comparison to subjects with relapsing disease. Together, these data provide further evidence of heterogeneity at the DRB1 locus and confirm the importance of HLA variants in the phenotypic expression of MS.

Apolipoprotein genotype does not influence MS severity, cognition, or brain atrophy.

Abstract: Background: The influence of APOE allelic heterogeneity on multiple sclerosis (MS) disease severity has been reported in multiple datasets with conflicting results. Several studies have reported an unfavorable association of APOE e4 with more severe clinical disease course while, in contrast, APOE e2 has been associated with a more benign disease course. In this study, we examine the influence of heterogeneity of the APOE gene on disease severity in a large, Australian, population-based MS cohort. Methods: Associations between APOE allele status, 2 promoter region single nucleotide polymorphisms (−219 G/T and +113 C/G), and 4 measures of disease severity were tested in 1,006 patients with relapsing-remitting MS and secondary progressive MS: 1) Multiple Sclerosis Severity Score; 2) Progression Index (Expanded Disability Status Scale/disease duration); 3) age at first symptom; and 4) interval between the first and second attack. The Symbol Digit Modalities Test was used as a single cognitive marker in 889 patients. Brain atrophy was measured in 792 patients using the intercaudate ratio. APOE e4 and e3 carriers were stratified by −219 G/T or +113 C/G to investigate haplotypic heterogeneity in the APOE gene region. Results: In this MS study, neither APOE allele status nor promoter region heterogeneity at positions −219 G/T or +113 C/G influenced the clinical disease severity, cognition, or cerebral atrophy. Conclusions: Allelic and haplotypic heterogeneity of the APOE gene region does not influence multiple sclerosis disease course in this well-defined Australian multiple sclerosis cohort.

Identification of a prostate cancer susceptibility gene on chromosome 5p13q12 associated with risk of both familial and sporadic disease

Abstract: Genetic heterogeneity is a difficulty frequently encountered in the search for genes conferring susceptibility to prostate cancer. To circumvent this issue, we selected a large prostate cancer pedigree for genome-wide linkage analysis from a population that is genetically homogeneous. Selected cases and first-degree relatives were genotyped with Affymetrix 10K SNP arrays, identifying a 14 Mb haplotype on chromosome 5 (5p13–q12) inherited identical-by-descent (IBD) by multiple cases. Microsatellite genotyping of additional deceased case samples confirmed that a total of eight cases inherited the common haplotype (P=0.0017). Re-sequencing of eight prioritised candidate genes in the region in six selected individuals identified 15 SNPs segregating with the IBD haplotype, located within the ITGA2 gene. Three of these polymorphisms were selected for genotyping in an independent Tasmanian data set comprising 127 cases with familial prostate cancer, 412 sporadic cases and 319 unaffected controls. Two were associated with prostate cancer risk: rs3212649 (OR=1.67 (1.07–2.6), P=0.0009) and rs1126643 (OR=1.52 (1.01–2.28), P=0.0088). Significant association was observed in both familial and sporadic prostate cancer. Although the functional SNP remains to be identified, considerable circumstantial evidence, provided by in vivo and in vitro studies, supports a role for ITGA2 in tumour development.

Molecular markers and methods related thereto

Abstract: A method of evaluating prostate cancer by determining nucleotides in the ITGA2 gene. A risk haplotype or set of risk alleles has been identified comprising SNPs set out in Table 6, Table 9 and Figure (5). In some embodiments, the method comprises identifying the SNPs, or alleles and distinguishing between risk and non-risk alleles. Primers and probes are described for evaluating prostate cancer in a subject and kits and arrays comprising these. Methods also include monitoring expression levels of the ITGA2 gene in a subject. Methods of treatment or prevention are described comprising modulating the level or activity of alpha2betal integrin polypeptide or a ligand or down stream effector thereof. Some methods also include testing the subject for a risk allele. Modulators of the level or activity of alpha2betal integrin polypeptide or a ligand or down stream effector thereof are proposed for use in treatment or prevention of prostate cancer. Methods of determining markers for prostate cancer are described.