MS関連遺伝子

多発性硬化症は炎症性、自己免疫性など疑われ、特に、中枢神経系のリンパ球やマクロファージの浸潤、時に抗体や補体の異常等を伴う。脊髄横断性の障害が早期にみられることもある。
系統的な調節性T細胞機能障害をともなう細胞性、液性の免疫反応がみられる。

双生児・兄弟研究にて遺伝的影響は示唆されていた。MHC内の多型性との関連研究およびSNPｓ研究がなされている。一方、各種疾患に関して、Genomewide association analysesというらしいが、仮説無し“hypothesis-free”scanという手法がなされつつある。


IL2RAとIL7RAの対立遺伝子、HLA locusとの関係が多発性硬化症の遺伝的リスク要因として同定された。



Risk Alleles for Multiple Sclerosis Identified by a Genomewide Study
The International Multiple Sclerosis Genetics Consortium
www.nejm.org July 29, 2007 (10.1056/NEJMoa073493)

９３１の family trios(子供と両親)におけるDNA microarray technologyにてＤＮＡ配列偏位を同定

複製にて６０９の family trios、２３２２症例、７８９対照調査

alleleと多発性硬化症リスクの包括的意義と相関のeffect sizeを推定

334,923ＳＮＰＳのtransmission disequilibrium test

９３２ family triosにて、４９の多発性硬化症関係するSNPs (P<1x10^–4)

このSNPsうち、３８が二段階解析に選別された

９３１名のfalily trios有する事例と、２４３１名の対照を比較し、３２のオーバーラップすることのないSNPｓを同定した。(P<0.001).

P値が最も少ない４０のSNPSを選択し、総計１１０のSNPｓを二段階解析とした

これらのSNPSのうち、IL2Rα遺伝子（IL2RA）は多発性硬化症と強い相関(P=2.96x10^–8)あり、HLA-DRA locusとも強い相関(P=8.94x10^–81)あり

Glossary

Genetic association testing: The genotyping of a genetic variant in a population for which information on phenotypes, such as disease occurrence or a range of various trait values, is available. Allele frequencies of that variant, for example, in case subjects and control subjects, are compared. If a significant difference is observed, there is said to be an association between the variant (genotype) and the disease or trait (phenotype).

Genomewide association study: A comprehensive search of the human genome for genetic risk factors with the use of association testing, typically involving hundreds of thousands to millions of genotypes (e.g., testing of SNPs) per sample.

Genomic inflation factor: A comparison of unassociated genetic markers with those of control subjects for potential differences in allele frequency related to imperfect matching between case subjects and control subjects (also referred to as population substructure or stratification). The expectation is that there should be no difference (or, technically, inflation of the test statistic) over the majority of markers tested. If inflation is observed, the observed test statistic can be adjusted accordingly. These values do not control for multiple testing.

Genotyping call rate: Percentage of nonmissing genotype calls in a set of DNA samples (the number of nonmissing genotypes divided by the number of all genotypes, multiplied by 100).

HapMap: A public resource created by the International HapMap Project (www.hapmap.org), a catalogue of genetic variants (SNPs) that are common in human populations.

Mendelian error: A situation in which a child's genotype is incompatible with the observed genotypes of the biologic parents, usually caused by an experimental genotyping error or by erroneous identification of the subjects as related.

Minor allele frequency: The allele frequency of the less frequently occurring allele of a SNP.

Nonsynonymous SNP: A SNP that leads to a change in the amino acid sequence of the gene's resulting protein and that may therefore affect the three-dimensional structure and its function.

PLINK: A free, open-source statistical tool for genomewide association analyses (pngu.mgh.harvard.edu/~purcell/plink/).

Transmission disequilibrium test: A family-based test of genetic association that measures the overtransmission of an allele from heterozygous parents to affected offspring.