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SEARCHING FOR GENETIC DETERMINANTS FOR SODIUM LITHIUM COUNTERTRANSPORT, AN INTERMEDIATE TRAIT FOR ESSENTIAL HYPERTENSION

Zheng, Xiaojing (2007) SEARCHING FOR GENETIC DETERMINANTS FOR SODIUM LITHIUM COUNTERTRANSPORT, AN INTERMEDIATE TRAIT FOR ESSENTIAL HYPERTENSION. Doctoral Dissertation, University of Pittsburgh. (Unpublished)

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Abstract

Essential hypertension (EH) is a major risk factor for cardiovascular disorders, the leading cause of death in the United States. Given its great public health impact, it is crucial to understand the genetic basis of EH. EH is highly heterogeneous and to use an intermediate phenotype of EH, sodium lithium countertransport (SLC), will provide substantial advantage for disease genes discovery. We proposed two approaches to explore the genes for SLC.The first study examined the relationship between SLC and a positional candidate gene, SLC34A2, which is linked to SLC in baboon. We sequenced gene SLC34A2 in baboon and human. Strong homology was established in exonic organization and sequence between human and baboon SLC34A2 genes and extensive variation in both species was identified. Association studies between SLC and SLC34A2 were carried out in 1856 RFHS phase II individuals and 634 baboons. Significant association of SLC with human SNP rs3775909 (p=0.03) in SLC34A2 and haplotype block 2 (p<0.005) were observed. Strong evidence for association of SLC with SLC34A2 was found for baboon SNP Asn136Asn (p=0.0001). Consistent findings in two different species implied that SLC34A2 may be one of the genes involved in SLC. However, linkage analyses conditional on genotypes of baboon Asn136Asn suggest that Asn136Asn is not the primarily functional site for SLC. We conclude that SLC34A2 is associated with SLC, though it may not be the major effect gene.In second study, we integrated gene expression micrarray with linkage analysis to search for genes for SLC. Two independent microarrays (U133A and U133_plus_2.0) were used to identify the differentially expressed genes in high verse low SLC groups. Five genes, IER3, ARHGAP15, CD47, CDKAL1 and PRKRA, were among top 1% of differentially expressed genes in both arrays and also mapped to linkage region for SLC in RFHS Phase II population. A follow-up association study for IER3 shows that SNP rs8512 is significantly associated with SBP (p=0.002) and DBP (p=0.0008), and SNP rs2284174 has marginal association with SLC (p=0.055) and SBP (p=0.085). In conclusion, we identified some interesting susceptible genes for SLC by combining gene expression profiling and linkage study.


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Details

Item Type: University of Pittsburgh ETD
Status: Unpublished
Creators/Authors:
CreatorsEmailPitt UsernameORCID
Zheng, Xiaojingxiaojing.zheng@hgen.pitt.eduXIZ5
ETD Committee:
TitleMemberEmail AddressPitt UsernameORCID
Committee ChairFerrell, Robert E.rferrell@mail.hgen.pitt.eduRFERRELL
Committee MemberKammerer, Candaceckammerer@hgen.pitt.eduCMK3
Committee MemberFinegold, Daviddavid.finegold@mail.hgen.pitt.eduDNF
Committee MemberFeingold, Eleanoreleanor.feingold@hgen.pitt.eduFEINGOLD
Committee MemberBarmada, M. Michaelmichael.barmada@hgen.pitt.eduBARMADA
Date: 26 September 2007
Date Type: Completion
Defense Date: 8 May 2007
Approval Date: 26 September 2007
Submission Date: 15 June 2007
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: Genotyping; linkage and association; microarray
Other ID: http://etd.library.pitt.edu/ETD/available/etd-06152007-101742/, etd-06152007-101742
Date Deposited: 10 Nov 2011 19:47
Last Modified: 19 Dec 2016 14:36
URI: http://d-scholarship.pitt.edu/id/eprint/8110

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