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


OBJECTIVE
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
These data provide additional evidence that genetic variation across the paroxanase loci may be common susceptibility factors for SALS.
Cronin
Simon
S
The Irish ALS Research Group, Department of Neurology, Beaumont Hospital, Dublin 9, Ireland. scronin@rcsi.ie
Greenway
Matthew J
MJ
Prehn
Jochen H M
JH
Hardiman
Orla
O
D000328:Adult; D000368:Aged; D000690:Amyotrophic Lateral Sclerosis / Q000235:genetics*; D043303:Aryldialkylphosphatase / Q000235:genetics*; D016022:Case-Control Studies; D016000:Cluster Analysis; D005260:Female; D020022:Genetic Predisposition to Disease / Q000235:genetics; D006801:Humans; D007438:Introns / Q000235:genetics*; D007494:Ireland; D008297:Male; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*
D043303:Aryldialkylphosphatase
Arterioscler Thromb Vasc Biol. 2001 Apr;21(4):542-7
11304470
Bioinformatics. 2005 Jan 15;21(2):263-5
15297300
J Biol Chem. 2001 Nov 30;276(48):44444-9
11579088
Genet Epidemiol. 2003 Sep;25(2):115-21
12916020
Neurology. 2003 Sep 23;61(6):742-9
14504315
Eur J Clin Invest. 2004 Jan;34(1):14-20
14984433
J Hum Genet. 2004;49(9):474-81
15368102
Am J Hum Genet. 1993 Mar;52(3):598-608
7916578
J Neurol Neurosurg Psychiatry. 1993 Nov;56(11):1200-6
8229031
Toxicol Lett. 1995 Apr;76(3):219-26
7539166
Genomics. 1996 May 1;33(3):498-507
8661009
Nat Genet. 1996 Nov;14(3):334-6
8896566
Am J Epidemiol. 1997 Jun 15;145(12):1076-88
9199537
Gene. 1998 Jun 15;213(1-2):149-57
9714608
Atherosclerosis. 1998 Aug;139(2):341-9
9712341
Toxicol Appl Pharmacol. 1999 Jun 15;157(3):227-33
10373407
Hum Mol Genet. 2006 Jan 1;15(1):77-85
16319130
Clin Biochem. 2006 Mar;39(3):191-5
16472799
J Lipid Res. 2006 May;47(5):1014-24
16474172
Neurology. 2006 Sep 12;67(5):771-6
16822964
Neurology. 2006 Sep 12;67(5):766-70
16822965
Am J Epidemiol. 2000 Jan 15;151(2):156-63
10645818
Am J Hum Genet. 2001 Jun;68(6):1428-36
11335891