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Our research program studies the link between genetic variation among individuals and disease susceptibility. Type 1 diabetes (T1DM), formerly called juvenile diabetes, is the autoimmune form of diabetes, in which the immune system destroys insulin-producing cells in the pancreas. The strongest genetic component to T1DM susceptibility is known to reside on the short arm of chromosome 6 in a region that includes the genes encoding the HLA (Human Leukocyte Antigen) proteins. HLA proteins are cell surface molecules whose function is to bind to and present peptides to the T-cell receptor. This binding of the HLA/peptide complex to the T-cell receptor determines the specificity of the immune response. The genes encoding the HLA proteins are highly polymorphic, with over 400 alleles (variants) at some loci. The distribution of these alleles varies among ethnic groups, so cross-ethnic comparisons of genetic data are extremely valuable. Some of the HLA alleles with major roles in T1DM susceptibility are known; however, these alleles do not explain the full extent of susceptibility attributable to the HLA chromosomal region. One goal of our research is to further delineate the role of individual HLA alleles, and combinations of alleles, in T1DM susceptibility. We are also studying natural variants of genes, in locations other than the HLA region, which are relevant to the immune response. We utilize two large, family-based sample sets for these studies: a set of 283 Caucasian T1DM families, and a set of 85 Mexican-American T1DM families. Through collaborations, we have also studied Puerto Rican, Basque, and Korean samples. We are currently collecting family-based samples from the patient population of Children’s Hospital Oakland (CHO), a very ethnically diverse group. Through these studies, we aim to generate data that will increase the predictive power of genetics for T1DM susceptibility.
In addition to our work on T1DM, we are looking at genetic predictors of stroke in children with sickle cell anemia (SCA). This project is a collaborative effort with Dr. Lori Styles in the CHO hematology department and is spearheaded by Dr. Carolyn Hoppe. Although SCA is generally considered a single gene disorder, variation in disease severity and complications among patients suggest that other factors may modulate the course of the disease. Stroke is a common complication in children with SCA. Genes involved in immune regulation may be involved with stroke; therefore, we are studying the association of HLA genes with the tendency to stroke in SCA patients. We are also examining a number of other markers with known associations with cardiovascular disease, such as angiotensisn-1-converting enzyme (ACE). We are looking both at the patient population from CHO and at samples from a nationwide, cooperative, prospective SCA trial. The ability to predict stroke in children with SCA has profound implications for clinical management of the disease.
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