ATXN2 and its neighbouring gene SH2B3 are associated with increased ALS risk in the Turkish population

PLoS One. 2012;7(8):e42956. doi: 10.1371/journal.pone.0042956. Epub 2012 Aug 20.

Abstract

Expansions of the polyglutamine (polyQ) domain (≥ 34) in Ataxin-2 (ATXN2) are the primary cause of spinocerebellar ataxia type 2 (SCA2). Recent studies reported that intermediate-length (27-33) expansions increase the risk of Amyotrophic Lateral Sclerosis (ALS) in 1-4% of cases in diverse populations. This study investigates the Turkish population with respect to ALS risk, genotyping 158 sporadic, 78 familial patients and 420 neurologically healthy controls. We re-assessed the effect of ATXN2 expansions and extended the analysis for the first time to cover the ATXN2 locus with 18 Single Nucleotide Polymorphisms (SNPs) and their haplotypes. In accordance with other studies, our results confirmed that 31-32 polyQ repeats in the ATXN2 gene are associated with risk of developing ALS in 1.7% of the Turkish ALS cohort (p=0.0172). Additionally, a significant association of a 136 kb haplotype block across the ATXN2 and SH2B3 genes was found in 19.4% of a subset of our ALS cohort and in 10.1% of the controls (p=0.0057, OR: 2.23). ATXN2 and SH2B3 encode proteins that both interact with growth receptor tyrosine kinases. Our novel observations suggest that genotyping of SNPs at this locus may be useful for the study of ALS risk in a high percentage of individuals and that ATXN2 and SH2B3 variants may interact in modulating the disease pathway.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Amyotrophic Lateral Sclerosis / genetics*
  • Ataxins
  • Case-Control Studies
  • Cohort Studies
  • Genetic Predisposition to Disease*
  • Haplotypes
  • Humans
  • Intracellular Signaling Peptides and Proteins
  • Nerve Tissue Proteins / genetics*
  • Polymorphism, Single Nucleotide
  • Proteins / genetics*
  • Risk Factors
  • Turkey

Substances

  • Ataxins
  • Intracellular Signaling Peptides and Proteins
  • LNK protein, human
  • Nerve Tissue Proteins
  • Proteins

Grant support

Funding provided by Suna and Inan Kirac Foundation (http://en.kiraca.com.tr/Corp-Responsibility/detail_kiracfoundation.aspx?SectionID=C2%2bWE3CIWXkxHtpw8lqgFA%3d%3d&ContentId=faQeVeZudHFv1A4ACnP5uA%3d%3d), Bogazici University Research Funds (http://www.arastirma.boun.edu.tr/arastirma.php?a_l=tr&p=130) and Deutsche Forschungsgemeinschaft(AU96/13-1) (http://www.dfg.de/index.jsp). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.