ABSTRACT. The DNA of 287 healthy white elderly volunteers in the New Mexico Aging Process Study, between 63 and 91 years of age, was examined for mutations of the HLA-H gene at nt 845 and nt 187. None were found to be homozygous for the 845A mutation and there were no gender differences in the percentage of the various mutations. The frequency of the 845A mutation was 0.061 resulting in a carrier frequency of 12.2%. The frequency of the 187G mutation was 0.136 resulting in a carrier frequency of 19.9% for a single mutation; 2.4% were compound heterozygous, 845A/187G and 2.4% were homozygous for the 187G mutation. After excluding 5 men and 4 women with microcytic or macrocytic anemia, mean percent transferrin saturation (PSAT) and iron stores, as estimated from serum ferritin concentrations, were calculated for each mutation. Estimated iron stores were normally distributed (range ~50 to 1,550 mg) with men (n=111) having significantly higher mean estimated iron stores than women (n=167), 826+/-318 and 753+/-287 mg,respectively. More men, 15 of 28, (54%) with estimated iron stores in the upper quartile, greater than or equal to 1,050 mg, had a HLA-H mutation compared to 25 of 83 (30%) who had a mutation and whose estimated iron stores were <1,050 mg, p<0.05. Seven were heterozygous for the 845A mutation with mean estimated iron stores of 1,300+/-127 mg,7 were heterozygous for the 187G mutation with mean estimated iron stores of 1,233+/-165 mg and 1 was compound heterozygous with estimated iron stores of 1,439 mg. Similar differences were not noted in women. Even though the potential role of the 187G mutation in the phenotypic expression of HH is less certain than the 845A mutation, the increase in PSAT seen in men with the 187G mutation and the equal distribution of 845A and 187G mutations seen with iron stores greater than or equal to 1,050 mg lends support for the involvement of the 187G mutation, or a linked mutation, in iron metabolism.We concluded that men having either a single chromosomal 845A and/or 187G mutation results in higher PSAT's and estimated iron stores than if no HLA-H mutation were present.

Keywords: HLA-H, ageing, iron stores, PSAT, serum transferrin saturation, serum ferritin, hemochromatosis.

Reprint requests to: Philip J. Garry, Ph.D., Clinical Nutrition Program, Rm. 215 Surge Building, University of New Mexico School of Medicine, Albuquerque, NM 87131, phone: (505) 272-0402, fax: (505) 272-9135, e-mail: pgarry@salud.unm.edu.

ABSTRACT. We have examined normal individuals and all the patients currently being treated for hemochromatosis at the Norfolk and Norwich hospital for mutations in the HLA-H gene. We found a gene frequency in 200 normal subjects for the 845A (C282Y) allele of 0.085, corresponding to a carrier frequency of 17% which is among the highest reported anywhere in the world. The frequency for the less penetrant 187G (H63D) allele was 0.16 among 58 of the normal subjects, which corresponds to a carrier frequency of 32%. All 18 hemochromatosis patients were homozygous for the 845A allele which is not significantly different from other reports in our subset of 12 unrelated patients. These findings present a snapshot of a relatively stable population containing a predicted 3,500 individuals homozygous for the 845A allele but not diagnosed with hemochromatosis. This population will be an excellent model for studies on the penetrance of the 845A homozygous genotype and population screening.

Keywords: Hemochromatosis, haemochromatosis, iron, penetrance, Norfolk, genetics, screening.

Reprint requests to: Gavin Willis, Ph.D., Department of Molecular Genetics, Norfolk and Norwich Hopital, Brunswick Road, Norwich, NR1 3SR, UNITED KINGDOM, phone: 01603 287068, fax: 01603 286928, e-mail: gain@molgennn.demon.co.uk.