All ETDs from UAB

Advisory Committee Chair

Sadeep Shrestha

Advisory Committee Members

Brahim Aissani

Jeffrey C Edberg

Shawn E Levy

Hemant K Tiwari

Document Type

Dissertation

Date of Award

2012

Degree Name by School

Doctor of Public Health (DrPH) School of Public Health

Abstract

Gene copy number of the CC Chemokine ligand 3-Like-1 (CCL3L1) located on chromosome 17 position q12 varies between ethnicities. Previously, gene copy number of CCL3L1 greater than the ethnic median copy has been associated with an increased risk of Rheumatoid Arthritis. Three later studies found no association between CCL3L1 and RA. All studies were conducted in non-African Americans and an objective of this study was to determine this association in an African American cohort. CCL3L1 shares significant homology with three other genes within the same cluster; CC Chemokine ligand 3 (CCL3), CC Chemokine ligand 3-Like-2 (CCL3L2) and CC Chemokine ligand 3-Like-3 (CCL3L3). Primers and probes that have been used in determining CCL3L1 gene copy number have been specific to two or more of the genes within the cluster potentially resulting in spurious association findings. The first step of this study was to characterize the nucleotide structure of CCL3L1 and CCL3L3 which share 100% homology in the exonic region and 98.7% in the whole gene region and develop a pyrosequencing assay that will accurately quantitate CCL3L1 gene copy number. CCL3L1 and CCL3L3 genes were sequenced and a pyrosequencing assay that quantifies CCL3L1 and CCL3L3 gene copy number using the CCL3 gene that has two copies per diploid genome as the reference was developed. Finally, CCL3L1 gene copy number was quantified for 747 African American RA cases and 375 frequency matched African American controls and association between CCL3L1 gene copy number and RA determined. Based on the characterization of CCL3L1 and CCL3L3, 12 novel single nucleotide polymorphisms (SNPs) and five known SNPs were determined. The median CCL3L1 gene copy number in the African American cohort was three and CCL3L1 gene copy number <3 or > 3 was not associated with the risk of RA. Results of this study are in agreement with three previous studies although conducted in Non-African American populations. Characterization of CCL3L1 and CCL3L3 however provides a platform for accurately quantifying CCL3L1 gene copy number in future association studies.

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