HIV-1/AIDS

Unraveling the complex genetics of HIV-1/AIDS has been a major goal of my laboratory. In collaboration with Dr. Sadeep Shrestha, one of the best characterized nested-case control sets for HIV infection was developed and analyzed for the CCR5 viral entry pathway. While no gene was strongly implicated in HIV-1 infection, the study design won praise in an accompanying invited commentary, and lays a foundation for future HIV infection studies. The laboratory also sought and seeks to better characterize the role of polymorphic variants at IL10 and its paralogs in HIV, HBV and HCV infections. These studies have laid the foundation for an examination of whole genome association study of HIV-1 infection currently underway in the laboratory.

Mapping by Admixture Linkage Disequilibrium (MALD)

MALD provides a promising approach to understanding racial and ethnic differences in the genetics basis of disease. The laboratory has addressed its promise through development of a MALD map and examination of select genomic regions. We published the first comprehensive set of single nucleotide polymorphism (SNP) markers that are useful for chromosomal segment ancestry determination as part of MALD mapping. We have genotyped these markers for HCV progression, HIV-1/AIDS, focal segmental glomerulosclerosis for a MALD analysis. These studies have recently identified the role of the MYH9 gene in focal segmental glomerulosclerosis and hypertensive end-stage renal disease.

Linkage Disequilibrium and Candidate Genes

Many approaches to human genetics fundamentally rely on fine scale LD. Our earlier work on LD based on a scan of STR data from the CEPH families and our success identifying haplotypes around the CCR2/CCR5 region were cited as examples that lead to establishing a human haplotype map project. This follow-up to the human genome sequencing effort of the past decade has changed the field of genetic epidemiology making it possible to examine the entire genome variants important in human disease and phenotypes. My laboratory has been actively determining the extent of LD around the IL10 gene and its paralogs by genotyping intragenic and flanking SNPs. Together with the work on HIV-infection and the CCR5 infection pathway these studies have laid the groundwork for future studies.

Extending Genomics and Genetics into Molecular Epidemiology

The science of genomics and genetic analysis has application beyond understanding the genetic basis of disease. A renewed recognition of the role of bacterial and viral infections in causing secondary human diseases has been recently coming to the forefront. For example, blood borne pathogens have a large long-term cancer cost with HIV-1 causing lymphomas and sarcomas while Hepatitis B virus (HBV) and Hepatitis C virus (HCV) are causally related to hepatocellular carcinoma. The public health implications of syringe sharing which provides a major route of transmission of these and other pathogens are enormous. We have developed genes as biomarkers for epidemiological studies. We have examined syringe sharing since it is a major cause of infectious diseases. Some of them, like HIV-1, HBV, and HCV are the early etiologic causes of cancer later in life. These studies have addressed the initial stages of the spread of infectious diseases in the intravenous drug user (IDU) community. The laboratory showed that sharing could be determined from known samples and also in syringe exudates from the Baltimore Needle Exchange Program (BNEP) combined with the ALIVE cohort. Integral to this work was the development of specific pentanucleotide short tandem repeats (STRs) as genetic biomarkers and the theory for their use to determine sharing. In addition, a practical laboratory approach was developed that had 94% sensitivity and 100% specificity. Finally, syringes from 1994-1996 from the BNEP were examined to provide a rich picture of IDUs syringe sharing and the reliability of self reports for a taboo behavior. The future of using genes as biomarkers is bright, and offers the opportunity to probe human behavior in areas where only observation and self-reports were available in the past.