ORIGINAL REPORTS:CARDIOVASCULAR DISEASE AND RELATED RISK FACTORS GEOGRAPHIC AND RACIAL/ETHNIC DIFFERENCES IN HFE MUTATION FREQUENCIES IN THE HEMOCHROMATOSIS AND IRON OVERLOAD SCREENING (HEIRS) STUDY Objective: To assess geographic differences in the frequencies of HFE C282Y and H63D genotypes in six racial/ethnic groups recruited in the Hemochromatosis and Iron Overload Screening (HEIRS) Study. Design: HFE C282Y and H63D genotypes of 97,551 participants, ages $25 years, who reported that they belonged to one of six racial/ethnic groups, were analyzed. HFE genotype frequencies were compared among the racial/ethnic groups and among the HEIRS Study field centers within each racial/ethnic group. Results: The distribution of HFE C282Y and H63D genotypes differed among racial/ethnic groups (P,.0001) and among field centers in Hispanics, Asians, Whites, and Blacks (each P,.05). Genotype frequencies were similar among field centers in Native Americans and Pacific Islanders. Frequencies of C282Y and H63D genotypes were greatest in Whites. The lowest frequencies of C282Y genotypes were observed in Asians; Blacks had the lowest H63D genotype frequencies and the highest frequency of the wild-type genotype. Among racial/ethnic groups, Hispanics had the greatest variation in HFE genotypes across geographic regions. Conclusion: HFE C282Y and H63D genotype frequencies vary significantly between racial/ ethnic groups and within some racial/ethnic groups across geographic regions. (Ethn Dis. 2006;16:815–821) Key Words: Geographic Differences, HFE, Race/ethnicity Ronald T. Acton, PhD; James C. Barton, MD; Beverly M. Snively, PhD; Christine E. McLaren, PhD; Paul C. Adams, MD; Emily L. Harris, PhD; Mark R. Speechley, PhD; Gordon D. McLaren, MD; Fitzroy W. Dawkins, MD; Catherine Leiendecker-Foster, MS; Joan L. Holup, MA; Aarthi Balasubramanyam, MStat; for the Hemochromatosis and Iron Overload Screening Study Research Investigators INTRODUCTION Hemochromatosis is characterized by a tendency to absorb excessive amounts of iron that can progress to iron overload and organ damage. 1 C282Y and H63D, the most common mutations of the HFE gene on chromo- some 6p, are associated with suscepti- bility to develop iron overload. 2 Fre- quencies of C282Y and H63D alleles and genotypes vary among racial/ethnic groups in different continents, 3 includ- ing North America. 4–7 Population ge- netic screening for primary iron over- load should take into account both geographic and racial/ethnic differences in HFE genotype and allele frequencies, 4 but studies of larger samples conducted using a standard protocol are needed to quantify the contributions of geography and race/ethnicity to observed allele and genotype frequencies. The Hemochromatosis and Iron Overload Screening (HEIRS) Study obtained HFE genotyping for C282Y and H63D alleles in 101,168 partici- pants recruited at five field centers in North America. 7,8 In a previous report, C282Y and H63D genotype frequencies for each racial/ethnic group were com- bined across all field centers. 7 Herein, we postulate that frequencies of HFE C282Y and H63D alleles and of HFE genotypes vary significantly among participants of a specific racial/ethnic group who reside in different geograph- ic regions. These data are presented, and their pertinence to other estimates of HFE genotype frequencies in North America is discussed. METHODS Study Approval, Design, and Participants The institutional review boards of each field center approved the HEIRS Address correspondence and reprint requests to Ronald T. Acton, PhD; De- partment of Microbiology; University of Alabama at Birmingham; 265 MCLM, 1530 3rd Ave, South; Birmingham, AL 35209-0005; 205-934-2362; 204-934- 4062 (fax); acton@uab.edu From the Department of Microbiology, University of Alabama at Birmingham (RTA), Southern Iron Disorders Center (JCB), Bir- mingham, Alabama; Department of Public Health Sciences, Wake Forest University, Winston-Salem, North Carolina (BMS, AB); Department of Medicine, University of California, Irvine, California (CEM, GDM); Department of Medicine, London Health Sciences Center (PCA), Department of Epidemiology and Biostatistics, University of Western Ontario (MRS), London, Ca- nada; Center for Health Research, Kaiser Permanente Northwest, Portland, Oregon (ELH); Department of Medicine, Veteran Affairs Long Beach Healthcare System, Long Beach, California (GDM); Department of Medicine, Howard University, Washington, DC (FWD); Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, Minnesota (CL); Center for Health Research, Kaiser Perma- nente, Honolulu, Hawaii (JLH). Ethnicity & Disease, Volume 16, Autumn 2006 815