Eight
hemochromatosis probands with HFE C282Y homozygosity had frequent, severe, or unusual
infections and
common variable immunodeficiency (CVID) or
immunoglobulin (Ig) G subclass deficiency (IgGSD). Thus, we performed serum Ig isotyping and other characterization of 43 additional unselected probands, 5
human leukocyte antigen (HLA)-identical siblings, and 240 consecutive CVID or IgGSD index patients. C282Y allele frequencies were estimated in 58 CVID or IgGSD index patients without
hemochromatosis phenotypes and in 341 controls.
HLA-A and -B haplotypes and frequencies were determined in all 51 probands, 186 CVID or IgGSD index patients without
hemochromatosis phenotypes, and 751 controls. Thirteen unselected probands (30%) had CVID or IgGSD. Among all 21
hemochromatosis probands with CVID (n = 4) or IgGSD (n = 17), Ig subclass deficiency patterns were
IgG(1) (n = 5),
IgG(1) and
IgG(3) (n = 6),
IgG(3) (n = 9), and
IgG(1),
IgG(3), and
IgG(4) (n = 1).
IgG(2) or
IgA deficiency was not detected; one proband had
IgM deficiency. Mean values of total
IgG,
IgG(1), and
IgG(3) were significantly lower in probands with CVID or IgGSD. Mean values of age,
transferrin saturation, and
ferritin at diagnosis and phlebotomy units required to induce
iron depletion were similar in probands with or without CVID or IgGSD; phlebotomy had no apparent effect on
IgG levels. C282Y frequencies were similar in CVID or IgGSD index cases without
hemochromatosis phenotypes and in controls. There was concordance of Ig and
hemochromatosis phenotypes in probands and respective HLA-identical siblings. Eight of 240 CVID or IgGSD index patients had
hemochromatosis phenotypes and C282Y homozygosity (3 vs 0.7% and 0.2% controls; P < 0.0001, respectively). The frequency of A*03-B*07 was greater in CVID and IgGSD index cases without
hemochromatosis phenotypes than in controls (0.0968 vs 0.0546, respectively; P = 0.0032).
HLA-A*03-B*07 was the predominant haplotype in probands grouped by presence or absence of CVID or IgGSD. Some probands in each group were A*03-B*07 homozygotes; group A*03-B*07 frequencies were similar. We conclude that serum
IgG abnormalities characteristic of CVID or IgGSD are common in
hemochromatosis probands, and that the prevalence of
hemochromatosis is increased in CVID and IgGSD index cases. These observations could be explained by the increased frequencies of
HLA-A*03-B*07 in C282Y homozygotes and in CVID and IgGSD, and by the common occurrence of putative CVID or IgGSD allele(s) on haplotypes bearing C282Y.