Celiac Disease and Human Leukocyte Antigen Genotype: Accuracy of Diagnosis in Self-Diagnosed Individuals, Dosage Effect, and Sibling Risk

Division of Medical and Molecular Genetics, The Guy's, King's and St. Thomas's School of Medicine, King's College, London, United Kingdom.
Journal of Pediatric Gastroenterology and Nutrition (Impact Factor: 2.63). 08/2000; 31(1):22-7. DOI: 10.1097/00005176-200007000-00007
Source: PubMed


Celiac disease is an autoimmune disorder of the small intestine characterized by intolerance to gluten. Traditionally, diagnosis is made by intestinal biopsy. Testing for immunoglobulin (Ig) A endomysial antibodies in the serum also is used for diagnosis. Biopsy and serology revert to normal with adherence to a gluten-free diet. Often, after an index case is diagnosed, siblings with symptoms adhere to a gluten-free diet without biopsy or serologic confirmation. More than 90% of patients with celiac disease have the human leukocyte antigen (HLA) DQA1*0501-DQB1*0201 genotype. Non-HLA genes also have been implicated.
One hundred ninety-five individuals with confirmed or suspected celiac disease were identified in 73 families affected by the disease. IgA endomysial antibody testing was performed for all symptomatic family members who did not have biopsy-confirmed diagnoses. DNA samples were genotyped at D6S276 and the HLA class II loci DQA and DQB.
At the time sampling was begun in families, 88 of 177 (49.7%) individuals were self-diagnosed and adhering to a gluten-free diet. Ninety percent (91/101) of confirmed cases (biopsy or serology) had at least 1 copy of the DQA1*0501-DQB1*0201 genotype, whereas only 67% (46/69) of cases self-diagnosed (adherence to gluten-free diet without confirmation) had at least 1 copy. Of confirmed cases, 61% carried two copies of DQB*0201. It is estimated that the HLA association and other unlinked genes contribute approximately equally to the sibling risk of celiac disease.
A dosage effect of DQB1*0201 may be associated with an increased risk of celiac disease. Self-diagnosis of celiac disease is as common as confirmed diagnosis in families in the United States. Diagnosis of celiac disease on the basis of clinical response to gluten restriction is inaccurate. With long-term adherence to a gluten-free diet, serologic test results are likely to be negative. Based on HLA genotype, approximately one third of self-diagnosed individuals are unlikely to have celiac disease. However, it is not possible to determine which individuals consuming a gluten-free diet have the disease. Therefore, before starting a gluten-free diet, serologic screening and biopsy confirmation are necessary.

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    ABSTRACT: Severe combined immunodeficiency (SCID) is a rare syndrome of profoundly impaired immunity, most often X-linked (XSCID). In past generations male infants with XSCID succumbed to infections during the first year of life, but prompt diagnosis and bone marrow transplantation currently make survival possible for over 80%. This treatment typically requires hospitalization for several months; thus, the burden on the family is considerable. We assessed the psychological impact on sibs of boys with XSCID. Forty adult sibs from families studied by J.M.P. were interviewed by J.H.F., and rating scales developed. The majority expressed distress over prolonged maternal absence during the affected child's hospitalization; 67% believed the mother had unsuccessfully mourned son(s) who died of XSCID. Half of the sibs reported that communication in the family about XSCID had been poor. Families with a spontaneous mutation were significantly more likely to report separation issues (P = 0.05), perhaps due to stronger maternal guilt. Family communication was significantly related to parental mourning (P = 0.001) and to survivor guilt (P = 0.05). Difficulties for daughters included desire to repair the mother's loss of her own child, as well as attempts to undo feelings of being flawed, by heightened wishes to bear a healthy son. In light of these findings we suggest: 1) bone marrow transplantation and the period of isolation places great stress on the family; parents need help balancing needs of well sibs with needs of the affected son; 2) parents need help with mourning the loss of a son so family secrets will not prevail; and 3) sibs, both bone marrow donors and non-donors, face psychological risks and need support.
    American Journal of Medical Genetics 01/2001; 98(1):57-63. DOI:10.1002/1096-8628(20010101)98:1<57::AID-AJMG1007>3.0.CO;2-J · 3.23 Impact Factor
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    ABSTRACT: Background Celiac disease has a strong genetic association with HLA. However, this association only explains approximately half of the sibling risk for celiac disease. Therefore, other genes must be involved in susceptibility to celiac disease. We tested for linkage to genes or loci that could play a role in pathogenesis of celiac disease. Methods DNA samples, from members of 62 families with a minimum of two cases of celiac disease, were genotyped at HLA and at 13 candidate gene regions, including CD4, CTLA4, four T-cell receptor regions, and 7 insulin-dependent diabetes regions. Two-point and multipoint heterogeneity LOD (HLOD) scores were examined. Results The highest two-point and multipoint HLOD scores were obtained in the HLA region, with a two-point HLOD of 3.1 and a multipoint HLOD of 5.0. For the candidate genes, we found no evidence for linkage. Conclusions Our significant evidence of linkage to HLA replicates the known linkage and association of HLA with CD. In our families, likely candidate genes did not explain the susceptibility to celiac disease.
    BMC Medical Genetics 02/2001; 2(1). DOI:10.1186/1471-2350-2-12 · 2.08 Impact Factor
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