1. Using HLAMatchMaker: Maternal-Fetal Incompatibility and the Risk of Disease Miguel Angel Gonzalez Mentor: Janet Sinsheimer, UCLA Hsinju Hsieh, UCLA Hsinju Hsieh, UCLA

2. Outline Introduction Introduction HLAMatchMaker HLAMatchMaker Results Results Conclusions Conclusions

3. HLA Incompatibility Human Leukocyte Antigen Human Leukocyte Antigen Presence of structures on cells that are sites for antibody binding Presence of structures on cells that are sites for antibody binding Problems Problems Mother and fetus closely matched Mother and fetus closely matched Fetus does not set up correct immunological barrier Fetus does not set up correct immunological barrier

4. Experimental Data Family Studies Family Studies Mother, father, and at least 1 child with schizophrenia Mother, father, and at least 1 child with schizophrenia HLA-A, B, & DRB1 types were determined HLA-A, B, & DRB1 types were determined Study focuses on mother-fetus relationship Study focuses on mother-fetus relationship

5. Current Studies WHO WHO Current method Current method for HLA comparison Biological Biological comparison using serum screening Match = 1 Match = 1 Mismatch = 0 Mismatch = 0 Chris O’Callaghan – University of Oxford http://neelix.molbiol.ox.ac.uk:8080/userweb/cocallag/

6. Hypothesis Incompatibility between the mother and fetus with respect to HLA can be a risk factor for neurological diseases such as schizophrenia. Incompatibility between the mother and fetus with respect to HLA can be a risk factor for neurological diseases such as schizophrenia. Also, to quantify the level of mismatching and to determine how sensible the WHO method is. Also, to quantify the level of mismatching and to determine how sensible the WHO method is.

7. HLAMatchMaker Written by Rene J. Duquesnoy, Ph.D. Written by Rene J. Duquesnoy, Ph.D. Computer algorithm for identifying acceptable HLA mismatches for patients without the need for extensive serum screening Computer algorithm for identifying acceptable HLA mismatches for patients without the need for extensive serum screening

8. HLAMatchMaker Purpose: to identify the best candidates for organ transplantation Purpose: to identify the best candidates for organ transplantation Compares the Compares the amino acid amino acid sequences of sequences of HLA antigens. HLA antigens.

9. Internship Goal To adapt HLAMatchMaker to the studies of the Sinsheimer lab. To adapt HLAMatchMaker to the studies of the Sinsheimer lab. Use HLAMatchMaker to identify differences in the amino acid sequences of mother and fetus HLA. Use HLAMatchMaker to identify differences in the amino acid sequences of mother and fetus HLA. Compare to the current analysis: Compare to the current analysis: WHO vs HLAMatchMaker To determine mismatch severity To determine mismatch severity

10. HLAMatchMaker Results HVG Compa tibility#mmDonor Donor types asTrp(9-199)Mismatched Trps in Positions 9-199 A*02010,,,,,,,,,,,,,,,,,, A*230199S,,,,,,,,62Ee,66GKv,,74D,76En,80rIa,82aLr,,,,,,,,,,,151aRv,,,,166Dg,,,,,,, B*15010,,,,,,,,,,,,,,,,,, B*490169H,,,,41T,45Ke,,,,,,,76En,80rIa,82aLr,,,,,,,,,,,,,,,,,,,,,, A*02A*23B*15B*49A*02 B*15 ChildMother

11. Visual Comparison A*239S62Ee66GKv74D76En80rIa82aLr A*029F62Ge66rKv74H76Vd80gTl82lRg A*02 A*23 166Ew151aHv149aAh144tKh142T107W 166Dg151aRv149aAr144tQr142I107G

12. HLAMatchMaker WHO Comparison Using an excel macro (efficient), large sets of data can be analyzed. Using an excel macro (efficient), large sets of data can be analyzed. To make comparable to WHO, To make comparable to WHO, Match = 1 Mismatch = 0 Results used to construct a comparison table (Pivot Table). Results used to construct a comparison table (Pivot Table).

13. Pivot Table Count of mmHLA-A match_a (WHO) mmHLA-A01 Grand Total 0158 158 1 8383 15883 241 HLAMatchMaker

14. Conclusion Goal Achieved Goal Achieved Using excel macros it was possible to adapt HLAMatchMaker to the Sinsheimer lab studies. Using excel macros it was possible to adapt HLAMatchMaker to the Sinsheimer lab studies. Results showed no difference between WHO and HLAMatchMaker Results showed no difference between WHO and HLAMatchMaker HLAMatchMaker results can be used to support WHO findings HLAMatchMaker results can be used to support WHO findings

15. Future Studies Determine the severity of mismatching Determine the severity of mismatching Differences in amino acids Differences in amino acids

16. Acknowledgements Dr. Janet Sinsheimer, UCLA Dr. Janet Sinsheimer, UCLA Dr. Christina Palmer, UCLA Dr. Christina Palmer, UCLA Hsinju Hsieh, UCLA Hsinju Hsieh, UCLA Funding Funding NIH NIH NIMH NIMH SoCalBSI SoCalBSI