Mother-To-Child Transmission of HIV (HIV MTCT) is a worldwide public health problem and particularly burdens mothers and children in Sub-Saharan Africa, where in 2006, over 500,000 infants were newly infected with HIV 1. To more clearly understand the mechanisms of transmission, we studied genetic exposures and HIV MTCT in consenting mother-infant pairs receiving antenatal care in Blantyre, Malawi.
We first examined infant genetic susceptibility to maternal infection through a genome wide association (GWA) scan of 655,000 SNPs. Top associations with HIV MTCT were found for 20 SNPs within 7 genes (p<5 x 10-5 , Bonferroni p=1), including rs8069770, located within the gene, HS3ST3A1, which facilitates the biosynthesis of a subtype of Heparan Sulfate that plays a role in viral infection.
We then applied our GWA data to determine how genetic variation in our Malawi population compares to that of African ancestry (AFA) populations from the International HapMap Project. Allele frequency in the Malawian population was highly correlated to that of AFA populations (r2>0.90) but not with other ancestry populations (r2<0.51). Similar findings were observed for adjacent linkage disequilibrium (AFA r2 >0.80, other ancestry r2<0.54). Frequencies of 4 SNPs in the lactase gene (LCT) varied greatly between the Malawi population and Maasai in Kenyawa, Kenya (Bonferroni p<1x10 -33). The Malawi population was genetically homogenous but distinct from other populations.
Finally, we examined the regulation of chemokine co-receptor 5 ( CCR5) expression in human placenta by infant polymorphisms and maternal infection. The CCR5 promoter polymorphisms CCR5-2554T (rs2734648, β= -0.67, 95% CI= -1.23, -0.11) and -2132T (β=-0.75, 95% CI=-0.131, -0.18) were significantly associated with reduced placental expression of CCR5. An incremental increase in CCR5 expression by expression of HS3ST3A1 (β=0.27, 95% CI=0.18, 0.35) and HS3ST3B1 (β=0.11, 95% CI=0.06, 0.18) was observed. CCR5 expression was up-regulated for higher maternal HIV viral load (β=0.76, 95% CI=0.12, 1.39; p=0.020) and malaria infection (β=0.37, 95% CI=-0.43, 1.18, p=0.362), with variable statistical significance. This cumulative body of work provides a fresh look at genetic factors involved in the risk of HIV MTCT as well as how such findings can be generalized to other populations in Africa.
|Advisor:||Meshnick, Steven R.|
|Commitee:||Franceschini, Nora, Lange, Ethan M., Liu, Jian, North, Kari E., Olshan, Andrew F.|
|School:||The University of North Carolina at Chapel Hill|
|School Location:||United States -- North Carolina|
|Source:||DAI-B 70/07, Dissertation Abstracts International|
|Keywords:||AIDS, Genetics, Genome, HIV, Mother-to-child transmission, SNP|
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