Genetic linkage between hereditary hemochromatosis and HLA.

A large Mormon pedigree of a proband with hemochromatosis was studied, using transferrin saturation as the quantitative phenotypic trait. The analysis indicated that the inheritance of hemochromatosis was recessive, with partial expression in some heterozygotes. The lod score of 6.88 (theta = .0) was strongly indicative of linkage between the hemochromatosis locus and the human major histocompatibility (HLA) loci.     

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.     

Genetic linkage studies between congenital adrenal hyperplasia and the HLA blood group system

Seventeen families with one or two children suffering from congenital adrenal hyperplasia (CAH) were not only typed for their HLA-A,B, and D antigens but also tested biochemically forCAH heterozygosity after ACTH stimulation. The lod score analysis showed a close genetic linkage betweenCAH andHLA, indicating that theC-21-hydroxylase deficiency gene(s) causing CAH in the homozygous deficient state are-located in close proximity to theHLA complex on chromosome 6 with an estimated recombination fraction of 0 to 5%. HLA typing in 21 unrelated CAH patients revealed a statistically significant association to the HLA-B5 antigen with a relative risk value of 5.8. There was a significant correlation (P=0.0025) between theHLA segregation data and theCAH heterozygosity test results in relatives of CAH patients although a few ‘false negative’ results in theCAH heterozygosity test were observed. Thus, the combination of HLA typing and this biochemical test at present provides the most precise approach for detecting CAH carriers in families of CAH patients.     

Hereditary cerebellar ataxia and genetic linkage with HLA

Summary Five families with at least three generations of members affected with autosomal dominant spinocerebellar ataxia (SCA) were studied. HLA typing was carried out and the coded HLA haplotypes were used to calculate the likelihood of linkage using the LIPED computer program. The combined lod scores from these five families does not, by itself, support linkage. Negative lod scores were observed in all five families, however, when pooled with the previously published data significant lod scores were obtained [Z=3.343 (=0.20) and +4.286 (=0.30)]. In four families, affected members had clinical features consistent with autosomal dommant cerebellar ataxia (ADCA) type I while in the fifth, ADCA type II was suggested. Clinical heterogeneity within ADCA raises doubts about the significance of summed lod scores. In view of the previous reports probably two genetically heterogeneous types of ADCA exist — HLA linked and nonlinked.     

Genetic linkage and natural selection

The prevalence of recombination in eukaryotes poses one of the most puzzling questions in biology. The most compelling general explanation is that recombination facilitates selection by breaking down the negative associations generated by random drift (i.e. Hill–Robertson interference, HRI). I classify the effects of HRI owing to: deleterious mutation, balancing selection and selective sweeps on: neutral diversity, rates of adaptation and the mutation load. These effects are mediated primarily by the density of deleterious mutations and of selective sweeps. Sequence polymorphism and divergence suggest that these rates may be high enough to cause significant interference even in genomic regions of high recombination. However, neither seems able to generate enough variance in fitness to select strongly for high rates of recombination. It is plausible that spatial and temporal fluctuations in selection generate much more fitness variance, and hence selection for recombination, than can be explained by uniformly deleterious mutations or species-wide selective sweeps.     

HLA as a marker of the hemochromatosis gene in Sweden

Summary The frequency of HLA-A3 and HLA-B14 antigens was found to be significantly (P=<0.0001) higher in a series of 50 unrelated and unselected Swedish patients with idiopathic hemochromatosis (IH) than in controls, being 66% and 32% for A3 and 22% and 2% for B14. The haplotype A3B14 was associated with the highest risk in this material (relative risk 23.4). One family with this haplotype was traced back to the end of the seventeenth century. The pattern of HLA antigens associated with IH in Sweden shows remarkable similarity to those reported from England and Brittany.     

A haplotype and linkage disequilibrium analysis of the hereditary hemochromatosis gene region

Hereditary hemochromatosis is a recessive disease of iron metabolism widely distributed among people of European descent. Most patients have inherited the causative mutation from a single ancestor. In the course of cloning the hemochromatosis gene, genotypes were generated for these samples at 43 microsatellite repeat markers that span the 6.5-Mb hemochromatosis gene region. The data used to reconstruct the ancestral haplotype across the hemochromatosis gene region are presented in this paper. Portions of the ancestral haplotype were present on 85% of patient chromosomes in this sample and ranged in size from approximately 500 kb to greater than 6.5 Mb. Only one marker, D6S2239, was identical by descent on all of the patient chromosomes containing the ancestral mutation. In contrast, only 3 of the 128 control chromosomes, or 2.3%, carried the ancestral mutation and the surrounding ancestral haplotype. To test new methods for gene finding using linkage disequilibrium we analyzed the genotypic data with a multilocus maximum likelihood method (DISMULT) and a single point method (DISLAMB), both written to analyze data generated from multi-allelic markers. The maximum value from DISLAMB analysis occurred at marker D6S2239, which is less than 20 kb from the hemochromatosis gene HFE, consistent with the haplotype analysis. The peak of the multi-point analysis was 700 kb from HFE, possibly due to the nonuniform recombination rates within this large region. The recombination rate appears to be lower than expected centromeric of the HFE gene. Received: 10 June 1997 / Accepted: 4 December 1997     

HLA determinants in an Australian population of hemochromatosis patients and their families.

The frequencies of different HLA-A and -B alleles in 77 Australian patients with hemochromatosis have been compared with frequencies of HLA alleles not associated with hemochromatosis in 63 of their heterozygous relatives and with published population frequencies. As for all other populations reported, an association of HLA-A3 and HLA-B7 with the disease was found. A weak association with HLA-B12 was also detected. No other significant positive or negative associations with HLA alleles were detected. In addition, HLA-A2 and -B12 were in significant linkage disequilibrium in patients but not in controls, which may indicate a new mutation or recent recombination between HLA-A and hemochromatosis either in our patient group or in the founding population. HLA-A1 and -B8 and HLA-A29 and -B12 were in linkage disequilibrium in controls but not in patients, suggesting that this population is not segregating a hemochromatosis allele on either of these haplotypes. Genetic linkage analysis using the program LIPED showed strong linkage in 23/24 families, most of which had additional HLA alleles (other than A3 and B7) associated with hemochromatosis. This provides evidence for a single hemochromatosis locus, possibly with more than one allele.     

Genetic discrimination and screening for hemochromatosis: then and now

Any two people on earth, save for identical twins, share in common roughly 99.9% of their genetic make-up. That 0.1% difference represents not just what, on a molecular level, distinguishes us from one another, but also has reportedly served as a basis for excluding individuals from insurance, employment, adoption, educational opportunities, family relations, as well as perceived life options. The first federal study of genetic discrimination, discrimination based on genotype as opposed to phenotype, included treated hereditary hemochromatosis (HH) as one of only five genotypes possibly providing a basis for discrimination. HH was selected because if a successfully treated condition that is nonetheless genetic but which, if properly managed, leaves affected individuals at no greater morbidity or mortality risk than the general population, then genotype independent of phenotype apparently provided a basis for exclusions. Since the publication of those results, much more is known about the genotypic and phenotypic variation of affected individuals. This paper discusses what is presently known about HH and genetic discrimination.     

Absence of linkage between Alzheimer's disease and the HLA system

The study of a family in which multiple cases of Alzheimer's disease occurred in several generations offers the opportunity to test the genetic transmission of this disease. The HLA grouping of the members of a pedigree containing 10 affected members allowed to demonstrate that the disease is not due to a single dominant gene linked to the major histocompatibility complex. Although a more complex involvement of the major histocompatibility complex cannot be totally ruled out it is obvious that a strong linkage does not exist between Alzheimer's disease and HLA.     

The HLA class I locus: analysis of RFLPs in hereditary hemochromatosis

The gene for hereditary hemochromatosis is linked to the HLA locus on chromosome 6. Four cloned DNA probes originating from the HLA class I region were used to detect seven restriction fragment length polymorphisms (RFLPs). Allele frequencies and segregation of each RFLP was determined. Analysis of RFLPs in 38 unrelated homozygotes with hemochromatosis revealed differences in allele frequencies between the control and the hemochromatotic groups but these differences did not reach statistical significance. Some differences persisted, however, even when only controls with the A3 antigen were compared with A3 hemochromatotics. Since both control and hemochromatotic groups were small, further studies will be necessary to ascertain whether these RFLPs could serve to locate the gene responsible for hereditary hemochromatosis.     

Lack of association and linkage between HLA and familial polyposis coli

Summary We investigated possible association of and linkage between HLA and familial polyposis coli (FPC). In 182 individuals from 66 pedigrees of FPC and 108 individuals from a normal population, HLA-A,-B, and-C antigens were determined. When the frequencies of HLA antigens in 66 unrelated patients and in normal controls were compared, no association of FPC with HLA was observed. For the linkage analysis, HLA haplotypes of 17 affected sib pairs were investigated by the affected sib pair method. The number of pairs which shared two, one, and no haplotypes identical by descent was not significantly different from the number expected with random occurrence (P>0.95). Finally, seven families were analyzed using Morton's sequential test. A maximum lod score of-0.056 at a recombination fraction of 0.4, and a lod of-3.089 at a recombination fraction of 0.05 were obtained. Therefore, there is neither an association of nor linkage between FPC and HLA.     

Genetic hemochromatosis: detection, management, and population screening

Genetic hemochromatosis (GH) is an inherited disease that results in iron overload, and, if untreated, causes irreversible organ damage. Knowledge and understanding of the early features of the condition, often nonspecific, and of the diagnostic route are necessary to detect iron overload and diagnose GH before irremedial damage has been done. Genetic testing now plays an important role in diagnosis. Management of the patient with established GH centers on venesection to return body iron levels to normal, treatment of the complications of GH, and family screening for GH. Population screening for GH, the ideal strategy to prevent any morbidity from iron overload, has not yet been accepted by public health professionals, largely because of the lack of data on the disease penetrance in genetically susceptible individuals.     

Idiopathic hemochromatosis: demonstration of homozygous-heterozygous mating by HLA typing of families

Summary In five families with idiopathic (hereditary) hemochromatosis, clinical and biochemical expression of the disease occurred in offspring of probands, suggesting an autosomal dominant mode of inheritance. However, HLA typing of subjects indicated that a homozygous-heterozygous mating almost certainly had occurred in four of the five families, resulting in homozygous offspring. Thus, in these families inheritance of the hemochromatosis trait was best explained in terms of an autosomal recessive or intermediate mode of inheritance. This study demonstrates the value of HLA typing in identifying homozygous-heterozygous matings in hemochromatosis families.