Fine mapping of the multiple sclerosis susceptibility locus on 5p14–p12

Stensland, Hilde Monica Frostad Riise; Saarela, Janna; Bronnikov, Denis; Parkkonen, Maija; Jokiaho, Anne; Palotie, Aarno; Tienari, Pentti J.; Sumelahti, Marja‐Liisa; Elovaara, Irina; Koivisto, Keijo; Pirttilä, Tuula; Reunanen, Mauri; Sobel, Eric M.; Peltonen, Leena

doi:10.1016/j.jneuroim.2005.08.004

Cited by 5 publications

(5 citation statements)

References 70 publications

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“…The following variants were genotyped using allele-specific primer extension assay: LHB I15T, SRD5A2 A49T, SRD5A2 V89L, HSD3B1 N367T, HSD3B1 R71I, HSD17B2 A111T, HSD17B3 G289S, HSD17B3 729_735 delGATAACC, AKR1C3 Q5H, AKR1C3 P180S, CYP19A1 R264C, CYP17A1 À34T>C, AR R726L, KLK3 D102N, and KLK3 L132I. Some modifications were made to the method described by Riise Stensland et al (17). The allele-specific oligonucleotides and multiplex PCR primers are available at http:// www.uta.fi/imt/sgy/schleutker/indexb.html.…”

Section: Methodsmentioning

confidence: 99%

Profiling Genetic Variation along the Androgen Biosynthesis and Metabolism Pathways Implicates Several Single Nucleotide Polymorphisms and Their Combinations as Prostate Cancer Risk Factors

et al. 2006

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Several candidate genes along androgen pathway have been suggested to affect prostate cancer risk but no single gene seems to be overwhelmingly important for a large fraction of the patients. In this study, we first screened for variants in candidate genes and then chose to explore the association between 18 variants and prostate cancer risk by genotyping DNA samples from unselected (n = 847) and familial (n = 121) prostate cancer patients and population controls (n = 923). We identified a novel single nucleotide polymorphism (SNP) in the CYP19A1 gene, T201M, with a mild significant association with prostate cancer [odds ratio (OR), 2.04; 95% confidence interval (95% CI), 1.03-4.03; P = 0.04]. Stratified analysis revealed that this risk was most apparent in patients with organ-confined (T 1 -T 2 ) and low-grade (WHO grade 1) tumors (OR, 5.42; 95% CI, 2.33-12.6; P < 0.0001). In contrast, CYP17A1 À34T>C alteration was associated with moderate to poorly differentiated (WHO grade 2-3) organconfined disease (OR, 1.42; 95% CI, 1.09-1.83; P = 0.007). We also tested a multigenic model of prostate cancer risk by calculating the joint effect of CYP19A1 T201M with five other common SNPs. Individuals carrying both the CYP19A1 and KLK3 À252A>G variant alleles had a significantly increased risk for prostate cancer (OR, 2.87; 95% CI, 1.10-7.49; P = 0.03). In conclusion, our results suggest that several SNPs along the androgen pathway, especially in CYP19A1 and CYP17A1, may influence prostate cancer development and progression. These genes may have different contributions to distinct clinical subsets as well as combinatorial effects in others illustrating that profiling and joint analysis of several genes along each pathway may be needed to understand genetic contributions to prostate cancer etiology. (Cancer Res 2006; 66(2): 743-7)

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Section: Methodsmentioning

confidence: 99%

Profiling Genetic Variation along the Androgen Biosynthesis and Metabolism Pathways Implicates Several Single Nucleotide Polymorphisms and Their Combinations as Prostate Cancer Risk Factors

et al. 2006

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“…[22][23][24] Previous studies in Finnish MS families originating from this high-risk subisolate have demon-strated linkage and association to the HLA locus (HLA-DRB1 [MIM *142857]), [25][26][27] 17q22-24, 25,28,29 and 5p14-p12. 25,[30][31][32] Therefore, we hypothesized that some variants predisposing to MS have either become enriched in SO or can be more easily detected against a homogenous background with a genome-wide, high-density SNP screen. We looked for shared alleles enriched in cases, as well as potential extended homozygous regions and copy number variations (CNVs) enriched in MS cases.…”

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confidence: 99%

Genome-wide Association Study in a High-Risk Isolate for Multiple Sclerosis Reveals Associated Variants in STAT3 Gene

Jakkula

Leppä

Sulonen

et al. 2010

The American Journal of Human Genetics

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Genetic risk for multiple sclerosis (MS) is thought to involve both common and rare risk alleles. Recent GWAS and subsequent meta-analysis have established the critical role of the HLA locus and identified new common variants associated to MS. These variants have small odds ratios (ORs) and explain only a fraction of the genetic risk. To expose potentially rare, high-impact alleles, we conducted a GWAS of 68 distantly related cases and 136 controls from a high-risk internal isolate of Finland with increased prevalence and familial occurrence of MS. The top 27 loci with p < 10(-4) were tested in 711 cases and 1029 controls from Finland, and the top two findings were validated in 3859 cases and 9110 controls from more heterogeneous populations. SNP (rs744166) within the STAT3 gene was associated to MS (p = 2.75 x 10(-10), OR 0.87, confidence interval 0.83-0.91). The protective haplotype for MS in STAT3 is a risk allele for Crohn disease, implying that STAT3 represents a shared risk locus for at least two autoimmune diseases. This study also demonstrates the potential of special isolated populations in search for variants contributing to complex traits.

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“…The most 5' SNP, namely rs2562582, located within 2 kilobases from the initiation of the SLC1A3 transcript, exhibited initial evidence for association with MS ( P = 0.005) in the transmission disequilibrium test (TDT) analysis, suggesting a possible functional role for this variant in the transcriptional regulation of this gene. Moreover, as shown in Table 1 , stratification of the Finnish MS families according to HLA genotype (using the SNP rs2239802, which exhibited strongest evidence for association in the Finnish families in the report by Riise Stensland and coworkers [ 28 ]), strengthened the association between the SLC1A3 SNP and MS ( P = 0.0002, TDT). Thus, based on LA, and supported by association analyses in an MS study sample, the presence of SLC1A3 serves as a potential candidate to connect all four major MS loci identified in Finnish families, elucidating a potential functional relationship between genetically identified genes and loci.…”

Section: Resultsmentioning

confidence: 76%

“…The gene with the greatest LA score was the gene SLC1A3 (glial high affinity glutamate transporter, member 3; see Additional data file 1 [Table S2]). Interestingly, SLC1A3 is located on 5p13.2 (36.6 to 36.7 Mb), within the previously identified MS locus on 5p [ 28 ], which is syntenic to the EAE2 locus in mouse.…”

Section: Resultsmentioning

confidence: 98%