SLE, a severe autoimmune disease is of major public health relevance since it predominantly
affects women at child bearing age and even though immunosuppressives have increased the life
span of SLE patients, lack of absolute cure is still troubling. Risk of premature coronary heart
disease (CHD) is strikingly high in SLE women (35-44 years) than the general population. Low
paraoxonase (PON) activity is associated with increased CHD as well as SLE risk. PON
multigene (PON1, PON2 PON3) are anti-oxidants that cluster on chromosome 7q21-22 at 94.5-
94.6 Mb, in close vicinity to a linkage peak for SLE on 7q21.1 at 77.5Mb. PON1 (PON1/192,
PON1/55) and PON3 (PON3/10340,PON3/2115) single nucleotide polymorphisms (SNPs) are
the known significant modulators of PON/paraoxon activity. The purpose of this study was to
determine the impact of PON2 tagSNPs with PON activity, SLE risk, lupus nephritis, parameters
of LDL oxidation and subclinical carotid vascular disease measures. Nineteen PON2 tagSNPs
were screened from HapMap and SeattleSNP databases in 489 SLE and 569 healthy control
women from two recruitment sites (Pittsburgh and Chicago), using Pyrosequencing, RFLP or
TaqMan allelic discrimination methods. Pairwise linkage disequilibrium (r2¡Ý 0.8) identified 15
tagSNPs that captured all the 19 PON2 variants in our sample. Although none of the PON2
tagSNPs revealed any obvious association with SLE risk, low PON/paraoxon activity was
independently associated with SLE. Two PON2 variants [rs6954345(Ser311Cys) and rs987539]
showed significant association with PON/paraoxon activity in Pittsburgh whites
(cases+controls). Our data revealed few modest associations of PON2 variants with lupus
nephritis (rs17876205, rs17876183, rs10261470, rs987539, rs9641164) in white (Pittsburgh+Chicago) SLE cases, parameters of LDL oxidation [PON2/rs11545941(Ala148Gly),
rs13306702, rs2286233, rs10261470, rs17876205, rs4729189] in white (Pittsburgh) SLE cases
and consistent association of PON2/rs11981433 and rs12704795 SNPs with carotid intima media
thickness and plaque in white(Pittsburgh+Chicago) SLE cases. In conclusion, our data suggest that PON2 genetic variants have modest effect on serum PON activity, risk of lupus nephritis and subclinical carotid vascular disease measures in SLE patients.
| Identifer | oai:union.ndltd.org:PITT/oai:PITTETD:etd-12182008-115618 |
| Date | 29 January 2009 |
| Creators | Dasgupta, Sudeshna |
| Contributors | Dr. Candace M. Kammerer, Dr. Susan Manzi, Dr. F. Yesim Demirci, Dr. M. Ilyas Kamboh, Dr. Robert E. Ferrell |
| Publisher | University of Pittsburgh |
| Source Sets | University of Pittsburgh |
| Language | English |
| Detected Language | English |
| Type | text |
| Format | application/pdf |
| Source | http://etd.library.pitt.edu/ETD/available/etd-12182008-115618/ |
| Rights | restricted, I hereby certify that, if appropriate, I have obtained and attached hereto a written permission statement from the owner(s) of each third party copyrighted matter to be included in my thesis, dissertation, or project report, allowing distribution as specified below. I certify that the version I submitted is the same as that approved by my advisory committee. I hereby grant to University of Pittsburgh or its agents the non-exclusive license to archive and make accessible, under the conditions specified below, my thesis, dissertation, or project report in whole or in part in all forms of media, now or hereafter known. I retain all other ownership rights to the copyright of the thesis, dissertation or project report. I also retain the right to use in future works (such as articles or books) all or part of this thesis, dissertation, or project report. |
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