In nine patients already found to be heterozygous for Cys282Tyr, they found that 8 out of the 9 “non-ancestral chromosomes” (?) contained this variant, compared to 51 out of 308 control chromosomes (p < 10^-4). In 21 remaining patients without Cys282Tyr, out of 42 chromosomes 9 carried the His62 variant, no higher than control frequency. (The combined numbers are case+: 17, case-: 34, control+: 51, control-: 257, which has p = .007 and OR = 2.5) The authors hypothesize that this variant is only causal for the disease in the presence of the Cys282.
115 unrelated patients with hereditary haemochromatosis and 101 controls were genotyped. The H63D variant was present in 5 of the 230 patient chromosomes and 28 of the 202 control chromosomes, contradicting a link with the disease. In contrast, there was a very high rate of C282Y mutations in patients (105 out of 115 were homozygous for this compared to 1 out of 101 controls).
H41 here refers to the position in the mature protein, which corresponds to H63 in the immature protein.
Abstract: “OBJECTIVES: Hereditary haemochromatosis is a disease that affects iron metabolism and leads to iron overload. Homozygosity for the H63D mutation is associated with increased transferrin saturation (TS) and ferritin levels. Our objective was to find out if the homozygosity of H63D mutation was the primary cause of iron overload. PATIENTS AND METHODS: We studied 45 H63D homozygotes (31 males and 14 females) with biochemical iron overload and/or clinical features of haemochromatosis. The simultaneous detection of 18 known HFE, TFR2 and FPN1 mutations and sequencing of the HAMP gene were performed to rule out the possible existence of genetic modifier factors related with iron overload. RESULTS: Values of biochemical iron overload, measured as percentage TS and serum ferritin concentration (SF), in our H63D homozygotes were significantly higher in patients than in controls: TS 55 +/- 15% vs. 35 +/- 15% and SF 764 (645-883) microg/L vs. 115 (108-123) microg/L for patients and controls, respectively. These H63D homozygotes presented extreme hyperferritinaemia and no additional mutations in HFE, TFR2, FPN1 and HAMP genes were detected. CONCLUSIONS: The lack of additional mutations in our H63D homozygotes suggests that this genotype could be the primary cause of iron overload in these patients. Despite our results, we cannot entirely discount the possibility that one or more genetic modifier factor exists, simply because we were unable to find it, although there was a precedent in the HFE gene. Genetic modifier factors have been described for C282Y mutations in the HFE gene, but at the present time they have never been reported in H63D homozygotes.”