Prevalence of HFE C282Y and H63D in Jewish populations and clinical implications of H63D homozygosity

Abstract

The frequencies of C282Y and H63D mutations of the HFE gene vary between different populations. A previous study showed an unexpectedly high H63D frequency in Chuetas (a population of Jewish descent). The present study addressed the question of the distribution of these mutations in Jewish populations from different origins and studied the possible causes of the high H63D frequency in Chuetas. Moreover, to improve the understanding of the controversial relationship between H63D homozygosity and iron overload, a group of patients with altered iron metabolism were studied. The high frequency of H63D mutation in Chuetas is not due to a high prevalence of this mutation in Sephardic Jews. Jewish populations have low C282Y and moderate H63D frequencies, suggesting slight gene flow from their surrounding populations. In accordance with historical and demographic data, genetic drift is the most probable cause for the singular H63D frequency in Chuetas. Clinically, this study of H63D homozygotes supports the conclusion that this genotype must be taken into account, because it confers an increased risk of iron overload and therefore genetic susceptibility to developing hereditary hemochromatosis or to aggravating other diseases.

Analysis of the HFE gene (H63D and C282Y) mutations in patients with iron overload, family members and controls from Antioquia, Northwest Colombia

“…These data suggest that HH is a rare metabolic disorder in this community. Interestingly, the H63D allele frequency present in 17.1% of the chromosomes (95% CI 13.2-21) was similar to data reported from the Southern Europe (13.6-20.4%) (8) and Sephardic Jewish (13.3%) (9) populations. Given that one in 34 paisa subjects is predicted to be homozygous for the H63D mutation and H63D homozygous status could be a pre-disposing factor for other diseases, further population screening is warranted to evaluate the real clinical significance of this allele in the paisa population.…”

Frequencies of C282Y and H63D alleles in the HFE gene among various Jewish ethnic groups in Israel: A change of concept required

“…Even when combined with data reported by Matas et al, 7 the allele frequency of 0.24% in both groups is in the rare range ( Table 1). The Yemenite group investigated here for the first time exhibited an allele frequency of 0%.…”

“…12,22 Although C282Y homozygosity confers the highest risk for iron overload, H63D mutation (in homozygosity or compound heterozygosity) was also associated with increased risk. 7,[23][24][25][26][27] Furthermore, aggravation of iron overload may occur when additional nongenetic or genetic modifier such as ␤-thalassemia trait is coinherited. [27][28][29][30][31][32] The frequency of ␤-thalassemia trait among Oriental Jews originating from Kurdistan is high, with carrier frequency estimated at 20%.…”

“…Only one study assessed these mutations in a non-Ashkenazi Jewish group consisting of 147 Sephardic subjects, but the North African and Oriental cohorts were too small-55 and 53 individuals, respectively-to draw conclusions. 7 No ethnic group-specific stratification was performed in a study from Israel. 9 This lack of data in addition to the absence of reports on endpoint disease in this population have resulted in an unclear view of HH among health care professionals and classification of the disease as relatively rare by the Official Genetic Database web site (Golden Helix-http://www.goldenhelix.org/israeli/).…”

H63D homozygotes with hyperferritinaemia: is this genotype, the primary cause of iron overload?

“…Moreover, a study in mice showed that homozygosity for the orthologous of the H63D mutation also increased iron levels (19). The H63D homozygosity genotype has been associated with an iron overload genotype (12, 24–26). For 80%, this genotype is clinically undetectable; however, 20% do develop biochemical evidence of iron overload which is approximately twice the rate found in HFE wild type subjects.…”