Association of SOD2, a mitochondrial antioxidant enzyme, with gray matter volume shrinkage in alcoholics.
Chronic alcoholism leads to gray matter shrinkage and induces the formation of superoxide anions (O(2)(-)) that can cause neuronal cell death. The mitochondrial superoxide dismutase 2 (SOD2) enzyme is critical in the metabolism of superoxide. An Ala16Val polymorphism putatively affects SOD2 enzyme activity in vivo. Brain volumes of 76 treatment-seeking alcohol-dependent individuals were measured with a 1.5T MRI. Intracranial tissue margins were manually outlined on coronal sections. Gray matter, white matter, sulcal, and ventricular CSF volumes were estimated using intensity-based K-means clustering. Ala16Val (rs4880) and a second haplotype tagging SNP, rs10370, were genotyped. The q-value package was used to correct for multiple comparisons. In the alcoholics, cerebrospinal fluid and intra-cranial volumes showed significant differences across the six diplotype categories. The homozygous Ala16-containing diplotype rs10370TT-rs4880GG was associated with lowest gray matter ratio (greater shrinkage; p=0.005). Presence of one or two copies of the low activity Ala16 allele was a risk factor for lower gray matter volume in alcoholics below the median alcohol consumption (p=0.03) but not in alcoholics above this level. White matter ratio was associated with sex (p=0.002) and lifetime total alcohol consumption (p=0.01) but not with diplotypes. In this exploratory analysis, a putative functional missense variant of SOD2 appears to influence gray matter loss in alcoholics. This may be due to impaired clearance of reactive oxygen species formed as a result of alcohol exposure. The risk/protective effect was observed in alcoholics with lower levels of lifetime alcohol consumption. Highest levels of exposure may overwhelm the protective action of the SOD2 enzyme.
Srivastava
Vibhuti
V
Laboratory of Neurogenetics, NIAAA, NIH, Bethesda, MD 20851, USA. srivastavav@mail.nih.gov
Buzas
Beata
B
Momenan
Reza
R
Oroszi
Gabor
G
Pulay
Attila J
AJ
Enoch
Mary-Anne
MA
Hommer
Daniel W
DW
Goldman
David
D
D000328:Adult; D000437:Alcoholism / Q000235:genetics* / Q000473:pathology*; D001921:Brain / Q000473:pathology*; D002555:Cerebrospinal Fluid; D005144:F Factor; D005260:Female; D018628:Gene Dosage; D005838:Genotype; D006801:Humans; D007091:Image Processing, Computer-Assisted; D008099:Liver / Q000201:enzymology; D008279:Magnetic Resonance Imaging; D008297:Male; D020125:Mutation, Missense; D036421:Nerve Fibers, Unmyelinated / Q000473:pathology; D009929:Organ Size; D011110:Polymorphism, Genetic; D012307:Risk Factors; D017422:Sequence Analysis, DNA; D013482:Superoxide Dismutase / Q000235:genetics*; D000099156:Superoxide Dismutase 2
D013482:Superoxide Dismutase; D000099156:Superoxide Dismutase 2