Combined segregation and linkage analysis of genetic hemochromatosis using affection status, serum iron, and HLA.

Characterizing the distribution of parameters of iron metabolism by hemochromatosis genotype remains an important goal vis-à-vis potential screening strategies to identify individuals at genetic risk, since a specific marker to detect the abnormal gene has not been identified as yet. In the present investigation, we analyze serum iron values in ascertained families using a method which incorporates both segregation of the clinical affection status and the HLA linkage information to identify the underlying genotypes. The analysis is performed using an extension of the model presented by Bonney et al., comprising regressive models for segregation analysis and the multipoint linkage strategy implemented in LINKAGE. The gene was found to be completely recessive with respect to both clinical manifestations and serum iron abnormalities, with significant differences in expression by sex. Clinical manifestations were present for all male homozygotes in this data set, suggesting that the recessive hemochromatosis genotype is fully penetrant at all ages in males. This was not the case for younger females. Significant genotype-specific age and sex effects were found for serum iron values. It is interesting that deletion of the HLA marker information did not affect our ability to resolve the genetic model when we analyzed a bivariate phenotype. This serves as a reminder that a search for relevant biological markers can be equally important in discerning the genetic etiology of a disease trait, as a search for linked genetic markers.