Apolipoprotein H promoter polymorphisms in relation to lupus and lupus-related phenotypes.
OBJECTIVE
Sequence variation in gene promoters is often associated with disease risk. We tested the hypothesis that common promoter variation in the APOH gene (encoding for ss(2)-glycoprotein I) is associated with systemic lupus erythematosus (SLE) risk and SLE-related clinical phenotypes in a Caucasian cohort.


METHODS
We used a case-control design and genotyped 345 women with SLE and 454 healthy control women for 8 APOH promoter single-nucleotide polymorphisms (SNP; -1284C>G, -1219G>A, -1190G>C, -759A>G, -700C>A, -643T>C, -38G>A, and -32C>A).Association analyses were performed on single SNP and haplotypes. Haplotype analyses were performed using EH (Estimate Haplotype-frequencies) and Haploview programs. In vitro reporter gene assay was performed in COS-1 cells. Electrophoretic mobility shift assay (EMSA) was performed using HepG2 nuclear cells.


RESULTS
Overall haplotype distribution of the APOH promoter SNP was significantly different between cases and controls (p = 0.009). The -643C allele was found to be protective against carotid plaque formation (adjusted OR 0.37, p = 0.013) among patients with SLE. The -643C allele was associated with a ~2-fold decrease in promoter activity as compared to wild-type -643T allele (mean +/- standard deviation: 3.94 +/- 0.05 vs 6.99 +/- 0.68, p = 0.016). EMSA showed that the -643T>C SNP harbors a binding site for a nuclear factor. The -1219G>A SNP showed a significant association with the risk of lupus nephritis (age-adjusted OR 0.36, p = 0.016).


CONCLUSIONS
Our data indicate that APOH promoter variants may be involved in the etiology of SLE, especially the risk for autoimmune-mediated cardiovascular disease.
Suresh
Sangita
S
Department of Human Genetics, Graduate School of Public Health, A300 Crabtree Hall, 130 DeSoto Street, Pittsburgh, PA 15261, USA.
Demirci
F Yesim K
FY
Jacobs
Erin
E
Kao
Amy H
AH
Rhew
Elisa Y
EY
Sanghera
Dharambir K
DK
Selzer
Faith
F
Sutton-Tyrrell
Kim
K
McPherson
David
D
Bontempo
Franklin A
FA
Kammerer
Candace M
CM
Ramsey-Goldman
Rosalind
R
Manzi
Susan
S
Kamboh
M Ilyas
MI
D000328:Adult; D001665:Binding Sites / Q000235:genetics; D016893:Carotid Stenosis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D016022:Case-Control Studies; D015331:Cohort Studies; D015897:Comorbidity; D004252:DNA Mutational Analysis; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D005787:Gene Frequency / Q000235:genetics; D020022:Genetic Predisposition to Disease / Q000235:genetics*; D005820:Genetic Testing; D006239:Haplotypes; D006801:Humans; D008180:Lupus Erythematosus, Systemic / Q000453:epidemiology / Q000235:genetics* / Q000378:metabolism; D008181:Lupus Nephritis / Q000453:epidemiology / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide / Q000235:genetics*; D011401:Promoter Regions, Genetic / Q000235:genetics*; D053482:beta 2-Glycoprotein I / Q000235:genetics*
D053482:beta 2-Glycoprotein I