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Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis.

ABSTRACT: The paraoxonases, PON1-3, play a major protective role both against environmental toxins and as part of the antioxidant defence system. Recently, non-synonymous coding single nucleotide polymorphisms (SNPs), known to lower serum PON activity, have been associated with sporadic ALS (SALS) in a Polish population. A separate trio based study described a detrimental allele at the PON3 intronic variant INS2+3651 (rs10487132). Association between PON gene cluster variants and SALS requires external validation in an independent dataset.To examine the association of the promoter SNPs PON1(-162G>A) and PON1(-108T>C); the non-synonymous functional SNPs PON1(Q192R and L55M) and PON2(C311S and A148G); and the intronic marker PON3(INS2+3651A>G), with SALS in a genetically homogenous population.221 Irish patients with SALS and 202 unrelated control subjects were genotyped using KASPar chemistries. Statistical analyses and haplotype estimations were conducted using Haploview and Unphased software. Multiple permutation testing, as implemented in Unphased, was applied to haplotype p values to correct for multiple hypotheses.Two of the seven SNPs were associated with SALS in the Irish population: PON1(55M) (OR 1.52, p = 0.006) and PON3(INS2+3651 G) (OR 1.36, p = 0.03). Two locus haplotype analysis showed association only when both of these risk alleles were present (OR 1.7, p = 0.005), suggesting a potential effect modification. Low functioning promoter variants were observed to influence this effect when compared with wild-type.These data provide additional evidence that genetic variation across the paroxanase loci may be common susceptibility factors for SALS.

SUBMITTER: Cronin S

PROVIDER: S-EPMC2117866 | biostudies-literature | 2007 Sep

REPOSITORIES: biostudies-literature

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Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis.

Cronin Simon S Greenway Matthew J MJ Prehn Jochen H M JH Hardiman Orla O

Journal of neurology, neurosurgery, and psychiatry 20070901 9

<h4>Background</h4>The paraoxonases, PON1-3, play a major protective role both against environmental toxins and as part of the antioxidant defence system. Recently, non-synonymous coding single nucleotide polymorphisms (SNPs), known to lower serum PON activity, have been associated with sporadic ALS (SALS) in a Polish population. A separate trio based study described a detrimental allele at the PON3 intronic variant INS2+3651 (rs10487132). Association between PON gene cluster variants and SALS r ...[more]

PMID: 17702780

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Project description:IMPORTANCE:Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease in which microglia play a significant and active role. Recently, a rare missense variant (p.R47H) in the microglial activating gene TREM2 was found to increase the risk of several neurodegenerative diseases, including Alzheimer disease. Whether the p.R47H variant is a risk factor for ALS is not known. OBJECTIVES:To determine whether p.R47H (rs75932628) in TREM2 is a risk factor for ALS and assess whether TREM2 expression is dysregulated in disease. DESIGN, SETTING, AND PARTICIPANTS:Samples of DNA from 923 individuals with sporadic ALS and 1854 healthy control individuals self-reported as non-Hispanic white were collected from ALS clinics in the United States and genotyped for the p.R47H variant in TREM2. Clinical data were obtained on ALS participants for genotype/phenotype correlations. Expression of TREM2 was measured by quantitative polymerase chain reaction and compared in spinal cord samples from 18 autopsied patients with ALS and 12 neurologically healthy controls, as well as from wild-type and transgenic SOD1G93A mice. MAIN OUTCOMES AND MEASURES:Minor allele frequency of rs75932628 and relative expression of TREM2. RESULTS:The TREM2 variant p.R47H was more common in patients with ALS than in the controls and is therefore a significant risk factor for ALS (odds ratio, 2.40; 95% CI, 1.29-4.15; P?=?4.1×10-3). Furthermore, TREM2 expression was increased in spinal cord samples from ALS patients and SOD1G93A mice (P?=?2.8×10-4 and P?=?2.8×10-9, respectively), confirming dysregulated TREM2 in disease. Expression of TREM2 in the human spinal cord was negatively correlated with survival (P?=?.04) but not with other phenotypic aspects of disease. CONCLUSIONS AND RELEVANCE:This study demonstrates that the TREM2 p.R47H variant is a potent risk factor for sporadic ALS. To our knowledge, these findings identify the first genetic influence on neuroinflammation in ALS and highlight the TREM2 signaling pathway as a therapeutic target in ALS and other neurodegenerative diseases.

Dataset Information

Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis.

Publications

Paraoxonase promoter and intronic variants modify risk of sporadic amyotrophic lateral sclerosis.

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