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ASSOCIATION OF PARAOXONASE-2 GENETIC VARIATION WITH SERUM PARAOXONASE ACTIVITY AND SYSTEMIC LUPUS ERYTHEMATOSUS

Dasgupta, Sudeshna (2009) ASSOCIATION OF PARAOXONASE-2 GENETIC VARIATION WITH SERUM PARAOXONASE ACTIVITY AND SYSTEMIC LUPUS ERYTHEMATOSUS. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

SLE, a severe autoimmune disease is of major public health relevance since it predominantlyaffects women at child bearing age and even though immunosuppressives have increased the lifespan of SLE patients, lack of absolute cure is still troubling. Risk of premature coronary heartdisease (CHD) is strikingly high in SLE women (35-44 years) than the general population. Lowparaoxonase (PON) activity is associated with increased CHD as well as SLE risk. PONmultigene (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) arethe known significant modulators of PON/paraoxon activity. The purpose of this study was todetermine the impact of PON2 tagSNPs with PON activity, SLE risk, lupus nephritis, parametersof LDL oxidation and subclinical carotid vascular disease measures. Nineteen PON2 tagSNPswere screened from HapMap and SeattleSNP databases in 489 SLE and 569 healthy controlwomen from two recruitment sites (Pittsburgh and Chicago), using Pyrosequencing, RFLP orTaqMan 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 PON2tagSNPs revealed any obvious association with SLE risk, low PON/paraoxon activity wasindependently 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 lupusnephritis (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 casesand consistent association of PON2/rs11981433 and rs12704795 SNPs with carotid intima mediathickness 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.


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Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Dasgupta, Sudeshnayuban79@gmail.com
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robert Erferrell@pitt.eduRFERRELL
Committee MemberKammerer, Candace Mcmk3@pitt.eduCMK3
Committee MemberDemirci, F. Yesimfyd1@pitt.eduFYD1
Committee MemberKamboh, M. Ilyaskamboh@pitt.eduKAMBOH
Committee MemberManzi, Susansxm6@pitt.eduSXM6
Date: 29 January 2009
Date Type: Completion
Defense Date: 3 November 2008
Approval Date: 29 January 2009
Submission Date: 18 December 2008
Access Restriction: 5 year -- Restrict access to University of Pittsburgh for a period of 5 years.
Institution: University of Pittsburgh
Schools and Programs: Graduate School of Public Health > Human Genetics
Degree: PhD - Doctor of Philosophy
Thesis Type: Doctoral Dissertation
Refereed: Yes
Uncontrolled Keywords: candidate gene; cardiovascular; paraoxonase; PON activity; SLE
Other ID: http://etd.library.pitt.edu/ETD/available/etd-12182008-115618/, etd-12182008-115618
Date Deposited: 10 Nov 2011 20:11
Last Modified: 15 Nov 2016 13:54
URI: http://d-scholarship.pitt.edu/id/eprint/10424

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