PRKCA and multiple sclerosis: Association in independent populations

Autor: Janna Saarela, Denis Bronnikov, George C. Ebers, Thomas J. Hudson, Pentti J. Tienari, Keijo Koivisto, Matthew R. Lincoln, Anne Jokiaho, Alexandre Montpetit, Aarno Palotie, Suvi P. Kallio, A. Dessa Sadovnick, Rosanna Asselta, Leena Peltonen, Eva Choi, Daniel Chen
Předmět:
Male
Cancer Research
Genetic Linkage
0302 clinical medicine
Homo (Human)
Finland
Genetics (clinical)
Mammals
Genetics
0303 health sciences
3. Good health
Female
Research Article
SNP array
Adult
Genetic Markers
Primates
Canada
Multiple Sclerosis
Protein Kinase C-alpha
dbSNP
lcsh:QH426-470
Population
Immunology
Genetics/Genetics of Disease
Single-nucleotide polymorphism
Biology
Polymorphism
Single Nucleotide
Open Reading Frames
03 medical and health sciences
Gene mapping
Genetic predisposition
Humans
Animals
SNP
PRKCA Gene
Molecular Biology
Alleles
Ecology
Evolution
Behavior and Systematics
030304 developmental biology
Genetics/Gene Discovery
Models
Genetic
Haplotype
Genetic Variation
Sequence Analysis
DNA
Genetics/Complex Traits
lcsh:Genetics
Haplotypes
030217 neurology & neurosurgery
Neuroscience
Zdroj: University of Helsinki
PLoS Genetics, Vol 2, Iss 3, p e42 (2006)
PLoS Genetics
Popis: Multiple sclerosis (MS) is a chronic disease of the central nervous system responsible for a large portion of neurological disabilities in young adults. Similar to what occurs in numerous complex diseases, both unknown environmental factors and genetic predisposition are required to generate MS. We ascertained a set of 63 Finnish MS families, originating from a high-risk region of the country, to identify a susceptibility gene within the previously established 3.4-Mb region on 17q24. Initial single nucleotide polymorphism (SNP)-based association implicated PRKCA (protein kinase C alpha) gene, and this association was replicated in an independent set of 148 Finnish MS families (p = 0.0004; remaining significant after correction for multiple testing). Further, a dense set of 211 SNPs evenly covering the PRKCA gene and the flanking regions was selected from the dbSNP database and analyzed in two large, independent MS cohorts: in 211 Finnish and 554 Canadian MS families. A multipoint SNP analysis indicated linkage to PRKCA and its telomeric flanking region in both populations, and SNP haplotype and genotype combination analyses revealed an allelic variant of PRKCA, which covers the region between introns 3 and 8, to be over-represented in Finnish MS cases (odds ratio = 1.34, 95% confidence interval 1.07–1.68). A second allelic variant, covering the same region of the PRKCA gene, showed somewhat stronger evidence for association in the Canadian families (odds ratio = 1.64, 95% confidence interval 1.39–1.94). Initial functional relevance for disease predisposition was suggested by the expression analysis: The transcript levels of PRKCA showed correlation with the copy number of the Finnish and Canadian “risk” haplotypes in CD4-negative mononuclear cells of five Finnish multiplex families and in lymphoblast cell lines of 11 Centre d'Etude du Polymorphisme Humain (CEPH) individuals of European origin.
Synopsis Complex diseases such as multiple sclerosis (MS) likely result from problems in networks of interactions between several genes and largely unidentified environmental and lifestyle factors. Identification of MS-specific genes has been challenging. HLA-DRB1*15 is the only consistent locus observed in most populations; however, the recent genome scan on more than 700 European families implicated 17q as a second-best MS locus [12]. Since MS families from the high-risk region of Finland initially revealed linkage to 17q, the authors used the regionally ascertained set of 63 families to identify a MS predisposing gene within a major non–HLA locus on 17q. The initial association was observed with single nucleotide polymorphisms (SNPs) located in intron 3 of the PRKCA (protein kinase C alpha) gene in Finnish MS families and replicated in an independent set of 148 MS families from Finland and 554 from Canada, two populations with a different genetic background. Combining the data of two SNP variants revealed two allele combinations of PRKCA, which were over-represented in Finnish or Canadian MS cases (odds ratio = 1.34, 95% confidence interval, 1.07–1.68, and odds ratio = 1.64, 95% confidence interval 1.39–1.94, respectively). Linkage and association of the PRKCA gene, encoding a regulator of immune responses, in two populations imply its involvement in the etiology of MS.
Databáze: OpenAIRE
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