Bioethics Concerns in Regulating Large DNA Collections: The Israeli Experience David Gurwitz National Laboratory for the Genetics of Israeli Populations Sackler Faculty of Medicine, Tel-Aviv University ABC, Bangkok, Thailand, March 19, 2007

Jews immigrated to Israel from Asian, African and European countries, from communities that were genetically isolated for 1000 – 2000 years Israeli Arabs include groups with minimal admixture: Palestinians, Bedouine, Druze This ethnic diversity is important in clinicla genetics and pharmacogenetics research Israelis Are Ethnically Diverse

Jewish immigration to Israel: (thousands of immigrants) 854 (mostly recent)

The National Laboratory for the Genetics of Israeli Populations The repository includes about 2000 cell lines and matching DNA samples, representing the ethnic diversity of the populations of Israel Blood samples for preparation of cell lines are obtained from adult individuals (>18 y) with informed consent Supervised by the TAU IRB

Cell Lines in the NLGIP Collection ArabsArab Arabs Ashkenazi Jews Sephardic North-African Jews Oriental Jews Ethiopian Jews

Major Public Collections of Human Cell Lines and DNA samples Repository Human Lines DiseaseEthnicity Coriell: ~8,000 geneticfew ATCC: ~1,500 cancerfew ECACC:~25,000 geneticfew Genethon:~43,000 geneticfew NLGIP: ~2,000 healthyall

Coding the samples DNA samples are coded by four-digit codes The only information supplied : ethnicity and gender Example for information accompanying a DNA shipment: Unrelated Ashkenazi donors: Males Females

From the NLGIP DNA Request Form: I, the undersigned, state that: - The requested cell lines/DNA samples will be used in my laboratory only for research. - The cell lines/DNA samples will not be further distributed to other laboratories or any scientists.

DNA Samples distributed by NLGIP: By Ethnic Groups Ashkenazi Jews 44% Arabs 15% Sephardic Jews 7% North-African Jews 16% Oriental 14% Ethiopian 4%

DNA Samples distributed by NLGIP: By Countries USA 43% Israel 27% Japan 14% UK 7% Canada 5% Italy 3% Others 1%

DNA Samples distributed by NLGIP: By Type of Institute Universities 66% National Research Institutes 28% Other Research Centers 6%

Acetaminophen can be toxic! Sulfation (35%) Glucuronidation (60%) CYP2E1(5%) Toxic! UGTGST

Ethnic Diversity Studies are Essential for Drug Development Polymorphic allele distribution differs between ethnic groups – - therefore Drug Safety and Efficacy also differs. A KEY PROBLEM: Most clinical trials are performed in Caucasians Asians and Africans do not always enjoy the same level of safety and efficacy from new medicines

Heart failure in Caucasians vs. African-Americans Exner et al. (2001) NEJM 344, *Enalapril (ACE inhibitor)  No advantage for African-Americans

CYP2D6 & CYP2C19 Luo et al (2004) American Journal of Pharmacogenomics 4:

Middle Eastern Origin of the Jews Hammer et al. (2000) Proc Natl Acad Sci U S A 97,

NLGIP Informed Consent Form The blood sample shall be used for preparing a cell line for research and is not related to my medical care. The repository must maintain the confidentiality of the information resulting from the research, and use it without any identifying details.

Informed Consent Form (cont.) - Altruism is empahsized My refusal to participate in this research will not affect my medical treatment in any way. The individual information from such studies shall not be made available to me. I shall not receive any benefit in return for giving my blood sample and this consent.

Refusal do donate to NLGIP: Women and >50 are more likely to donate By Gender Total 34% Men 43% Women 28% By Age % % % % Over 60 25%

Reasons for refusal do donate (asked to choose from 5 optional replies) 60%  Not willing to donate too much blood 24%  Worried that their identity will be exposed 8%  Do not want their genes to be studied 4%  Find it immoral to perform genetic studies 4%  Other reasons

Personalized Medicine: Can it co-exist with healthcare equity? What should we do about people who do not have the ‘right genotype’ for available medicines? How can society ensure better equity in healthcare, along with better, more personalized, medicine? *** Questions?