RÉSUMÉ
Alpha-1-antitrypsin (AAT), a serine protease inhibitor (serpin), is increasingly recognized to inhibit SARS-CoV-2 infection and counter many of the pathogenic mechanisms of COVID-19. Herein, we reviewed the epidemiologic evidence, the molecular mechanisms, and the clinical evidence that support this paradigm. As background to our discussion, we first examined the basic mechanism of SARS-CoV-2 infection and contend that despite the availability of vaccines and anti-viral agents, COVID-19 remains problematic due to viral evolution. We next underscored that measures to prevent severe COVID-19 currently exists but teeters on a balance and that current treatment for severe COVID-19 remains grossly suboptimal. We then reviewed the epidemiologic and clinical evidence that AAT deficiency increases risk of COVID-19 infection and of more severe disease, and the experimental evidence that AAT inhibits cell surface transmembrane protease 2 (TMPRSS2) - a host serine protease required for SARS-CoV-2 entry into cells - and that this inhibition may be augmented by heparin. We also elaborated on the panoply of other activities of AAT (and heparin) that could mitigate severity of COVID-19. Finally, we evaluated the available clinical evidence for AAT treatment of COVID-19.
Sujet(s)
COVID-19 , Déficit en alpha-1-antitrypsine , Humains , Héparine , Épidémiologie moléculaire , SARS-CoV-2RÉSUMÉ
Patients with familial pulmonary fibrosis represent a subset of patients with pulmonary fibrosis in whom inherited gene variation predisposes them to disease development. In the appropriate setting, genetic testing allows for personalized assessment of disease, recognition of clinically relevant extrapulmonary manifestations, and assessing susceptibility in unaffected relatives. However currently, the use of genetic testing is inconsistent, partly because of the lack of guidance regarding high-yield scenarios in which the results of genetic testing can inform clinical decision-making. To address this, the Pulmonary Fibrosis Foundation commissioned a genetic testing work group comprising pulmonologists, geneticists, and genetic counselors from the United States to provide guidance on genetic testing in patients with pulmonary fibrosis. This CHEST special feature presents a concise review of these proceedings and reviews pulmonary fibrosis susceptibility, clinically available genetic testing methods, and clinical scenarios in which genetic testing should be considered.
Sujet(s)
Dépistage génétique , Fibrose pulmonaire idiopathique , Humains , Fibrose pulmonaire idiopathique/génétique , États-UnisRÉSUMÉ
BACKGROUND: Fibrotic idiopathic interstitial pneumonias (fIIP) are a group of fatal lung diseases with largely unknown etiology and without definitive treatment other than lung transplant to prolong life. There is strong evidence for the importance of both rare and common genetic risk alleles in familial and sporadic disease. We have previously used genome-wide single nucleotide polymorphism data to identify 10 risk loci for fIIP. Here we extend that work to imputed genome-wide genotypes and conduct new RNA sequencing studies of lung tissue to identify and characterize new fIIP risk loci. RESULTS: We performed genome-wide genotype imputation association analyses in 1616 non-Hispanic white (NHW) cases and 4683 NHW controls followed by validation and replication (878 cases, 2017 controls) genotyping and targeted gene expression in lung tissue. Following meta-analysis of the discovery and replication populations, we identified a novel fIIP locus in the HLA region of chromosome 6 (rs7887 P meta = 3.7 × 10(-09)). Imputation of classic HLA alleles identified two in high linkage disequilibrium that are associated with fIIP (DRB1*15:01 P = 1.3 × 10(-7) and DQB1*06:02 P = 6.1 × 10(-8)). Targeted RNA-sequencing of the HLA locus identified 21 genes differentially expressed between fibrotic and control lung tissue (Q < 0.001), many of which are involved in immune and inflammatory response regulation. In addition, the putative risk alleles, DRB1*15:01 and DQB1*06:02, are associated with expression of the DQB1 gene among fIIP cases (Q < 1 × 10(-16)). CONCLUSIONS: We have identified a genome-wide significant association between the HLA region and fIIP. Two HLA alleles are associated with fIIP and affect expression of HLA genes in lung tissue, indicating that the potential genetic risk due to HLA alleles may involve gene regulation in addition to altered protein structure. These studies reveal the importance of the HLA region for risk of fIIP and a basis for the potential etiologic role of auto-immunity in fIIP.
Sujet(s)
Étude d'association pangénomique/méthodes , Chaines bêta des antigènes HLA-DQ/génétique , Chaines HLA-DRB1/génétique , Fibrose pulmonaire idiopathique/génétique , Fibrose pulmonaire/génétique , Analyse de séquence d'ARN/méthodes , Adulte , Sujet âgé , Chromosomes humains de la paire 6/génétique , Femelle , Analyse de profil d'expression de gènes , Régulation de l'expression des gènes , Locus génétiques , Prédisposition génétique à une maladie , Humains , Déséquilibre de liaison , Mâle , Adulte d'âge moyenRÉSUMÉ
BACKGROUND: To determine the effect of the MUC5B promoter polymorphism (rs35705950) on the CT imaging appearance of pulmonary fibrosis. METHODS: High-resolution CT scans of 1,764 subjects were scored as part of a, genomewide association study with institutional review board approval; 1,491 of these had pulmonary fibrosis on CT scans and were included in the study. Two thoracic radiologists independently scored CT scans systematically. Discrepancies were resolved by a third thoracic radiologist. All patients were genotyped specifically for the rs35705950 single-nucleotide polymorphism (SNP). Two-tailed Fisher exact or χ(2) tests and Student t tests or Mann-Whitney U tests were used to compare proportions and means, respectively. RESULTS: The major and minor alleles at the rs35705950 SNP are guanine (G) and thymine (T), respectively: 514 were homozygous for the major allele (G group), and 977 were heterozygous or homozygous for the minor allele (T group). The G group had a higher proportion than the T group with ground-glass opacity (62.1% vs 54.2%; P = .04). There was no significant difference between the G and T groups regarding presence of honeycombing. The T group showed a significantly higher subpleural axial distribution of fibrosis than did the G group (62.3% vs 42.2%; P < .0001). The T group showed a lower proportion of diagnoses inconsistent with usual interstitial pneumonitis (UIP; 20.3% compared with 30.5% for the G group) and a greater proportion of confident (probable UIP and UIP) UIP diagnoses (43.8% compared with 32.6% for the G group). CONCLUSIONS: The MUC5B promoter polymorphism identifies a pattern of fibrosis that is different from other causes of fibrosis and may respond differently to potential therapies.
Sujet(s)
Fibrose pulmonaire idiopathique/imagerie diagnostique , Poumon/imagerie diagnostique , Mucine 5B/génétique , Sujet âgé , Allèles , Études de cohortes , Femelle , Génotype , Hétérozygote , Humains , Fibrose pulmonaire idiopathique/génétique , Mâle , Adulte d'âge moyen , Phénotype , Polymorphisme génétique , Polymorphisme de nucléotide simple , Régions promotrices (génétique)/génétique , Fibrose pulmonaire/imagerie diagnostique , Fibrose pulmonaire/génétique , TomodensitométrieRÉSUMÉ
BACKGROUND: The current usual interstitial pneumonitis (UIP)/idiopathic pulmonary fibrosis CT scan classification system excludes probable UIP as a diagnostic category. We sought to determine the predictive effect of probable UIP on CT scan on histology and the effect of the promoter polymorphism in MUC5B (rs35705950) on histologic and CT scan UIP diagnosis. METHODS: The cohort included 201 subjects with pulmonary fibrosis who had lung tissue samples obtained within 1 year of chest CT scan. UIP diagnosis on CT scan was categorized as inconsistent with, indeterminate, probable, or definite UIP by two to three pulmonary radiologists. Tissue slides were scored by two expert pulmonary pathologists. All subjects with available DNA (N = 200) were genotyped for rs35705950. RESULTS: The proportion of CT scan diagnoses were as follows: inconsistent with (69 of 201, 34.3%), indeterminate (72 of 201, 35.8%), probable (34 of 201, 16.9%), and definite (26 of 201, 12.9%) UIP. Subjects with probable UIP on CT scan were more likely to have histologic probable/definite UIP than subjects with indeterminate UIP on CT scan (82.4% [28 of 34] vs 54.2% [39 of 72]; P = .01). CT scan and microscopic honeycombing were not associated with each other (P = .76). The minor (T) allele of the MUC5B polymorphism was associated with concordant CT scan and histologic UIP diagnosis (P = .03). CONCLUSIONS: Probable UIP on CT scan is associated with a higher rate of histologic UIP than indeterminate UIP on CT scan suggesting that they are distinct groups and should not be combined into a single CT scan category as currently recommended by guidelines. CT scan and microscopic honeycombing may be dissimilar entities. The T allele at rs35705950 predicts a UIP diagnosis by both chest CT scan and histology.
Sujet(s)
Pneumopathies interstitielles/imagerie diagnostique , Pneumopathies interstitielles/anatomopathologie , Tomodensitométrie , Sujet âgé , Femelle , Génotype , Humains , Pneumopathies interstitielles/génétique , Mâle , Adulte d'âge moyen , Mucine 5B/génétique , Polymorphisme de nucléotide simple , Valeur prédictive des testsSujet(s)
Thorax en entonnoir/complications , Infections à mycobactéries non tuberculeuses/étiologie , Infections de l'appareil respiratoire/étiologie , Scoliose/complications , Maigreur/complications , Thorax en entonnoir/génétique , Thorax en entonnoir/métabolisme , Prédisposition génétique à une maladie , Humains , Infections à mycobactéries non tuberculeuses/génétique , Infections à mycobactéries non tuberculeuses/métabolisme , Infections à mycobactéries non tuberculeuses/microbiologie , Infections de l'appareil respiratoire/génétique , Infections de l'appareil respiratoire/métabolisme , Infections de l'appareil respiratoire/microbiologie , Appréciation des risques , Facteurs de risque , Scoliose/génétique , Scoliose/métabolisme , Maigreur/génétique , Maigreur/métabolismeRÉSUMÉ
IMPORTANCE: Current prediction models of mortality in idiopathic pulmonary fibrosis (IPF), which are based on clinical and physiological parameters, have modest value in predicting which patients will progress. In addition to the potential for improving prognostic models, identifying genetic and molecular features that are associated with IPF mortality may provide insight into the underlying mechanisms of disease and inform clinical trials. OBJECTIVE: To determine whether the MUC5B promoter polymorphism (rs35705950), previously reported to be associated with the development of pulmonary fibrosis, is associated with survival in IPF. DESIGN, SETTING, AND PARTICIPANTS: Retrospective study of survival in 2 independent cohorts of patients with IPF: the INSPIRE cohort, consisting of patients enrolled in the interferon-γ1b trial (n = 438; December 15, 2003-May 2, 2009; 81 centers in 7 European countries, the United States, and Canada), and the Chicago cohort, consisting of IPF participants recruited from the Interstitial Lung Disease Clinic at the University of Chicago (n = 148; 2007-2010). The INSPIRE cohort was used to model the association of the MUC5B genotype with survival, accounting for the effect of matrix metalloproteinase 7 (MMP-7) blood concentration and other demographic and clinical covariates. The Chicago cohort was used for replication of findings. MAIN OUTCOMES AND MEASURES: The primary end point was all-cause mortality. RESULTS: The numbers of patients in the GG, GT, and TT genotype groups were 148 (34%), 259 (59%), and 31 (7%), respectively, in the INSPIRE cohort and 41 (28%), 98 (66%), and 9 (6%), respectively, in the Chicago cohort. The median follow-up period was 1.6 years for INSPIRE and 2.1 years for Chicago. During follow-up, there were 73 deaths (36 GG, 35 GT, and 2 TT) among INSPIRE patients and 64 deaths (26 GG, 36 GT, and 2 TT) among Chicago patients. The unadjusted 2-year cumulative incidence of death was lower among patients carrying 1 or more copies of the IPF risk allele (T) in both the INSPIRE cohort (0.25 [95% CI, 0.17-0.32] for GG, 0.17 [95% CI, 0.11-0.23] for GT, and 0.03 [95% CI, 0.00-0.09] for TT) and the Chicago cohort (0.50 [95% CI, 0.31-0.63] for GG, 0.22 [95% CI, 0.13-0.31] for GT, and 0.11 [95% CI, 0.00-0.28] for TT). In the INSPIRE cohort, the TT and GT genotypes (risk for IPF) were associated with improved survival compared with GG (hazard ratios, 0.23 [95% CI, 0.10-0.52] and 0.48 [95% CI, 0.31-0.72], respectively; P < .001). This finding was replicated in the Chicago cohort (hazard ratios, 0.15 [95% CI, 0.05-0.49] and 0.39 [95% CI, 0.21-0.70], respectively; P < .002). The observed association of MUC5B with survival was independent of age, sex, forced vital capacity, diffusing capacity of carbon monoxide, MMP-7, and treatment status. The addition of the MUC5B genotype to the survival models significantly improved the predictive accuracy of the model in both the INSPIRE cohort (C = 0.71 [95% CI, 0.64-0.75] vs C = 0.68 [95% CI, 0.61-0.73]; P < .001) and the Chicago cohort (C = 0.73 [95% CI, 0.62-0.78] vs C = 0.69 [95% CI, 0.59-0.75]; P = .01). CONCLUSIONS AND RELEVANCE: Among patients with IPF, a common risk polymorphism in MUC5B was significantly associated with improved survival. Further research is necessary to refine the risk estimates and to determine the clinical implications of these findings.
Sujet(s)
Fibrose pulmonaire idiopathique/génétique , Fibrose pulmonaire idiopathique/mortalité , Mucine 5B/génétique , Polymorphisme génétique , Sujet âgé , Études de cohortes , Femelle , Génotype , Humains , Mâle , Adulte d'âge moyen , Régions promotrices (génétique)/génétique , Études rétrospectives , Risque , Analyse de survieRÉSUMÉ
We performed a genome-wide association study of non-Hispanic, white individuals with fibrotic idiopathic interstitial pneumonias (IIPs; n = 1,616) and controls (n = 4,683), with follow-up replication analyses in 876 cases and 1,890 controls. We confirmed association with TERT at 5p15, MUC5B at 11p15 and the 3q26 region near TERC, and we identified seven newly associated loci (Pmeta = 2.4 × 10(-8) to 1.1 × 10(-19)), including FAM13A (4q22), DSP (6p24), OBFC1 (10q24), ATP11A (13q34), DPP9 (19p13) and chromosomal regions 7q22 and 15q14-15. Our results suggest that genes involved in host defense, cell-cell adhesion and DNA repair contribute to risk of fibrotic IIPs.
Sujet(s)
Locus génétiques , Fibrose pulmonaire idiopathique/génétique , Études cas-témoins , Chromosomes humains , Expression des gènes , Fréquence d'allèle , Prédisposition génétique à une maladie , Étude d'association pangénomique , Humains , Poumon/métabolisme , Polymorphisme de nucléotide simple , Analyse de séquence d'ADNRÉSUMÉ
RATIONALE: Peripheral blood biomarkers are needed to identify and determine the extent of idiopathic pulmonary fibrosis (IPF). Current physiologic and radiographic prognostic indicators diagnose IPF too late in the course of disease. We hypothesize that peripheral blood biomarkers will identify disease in its early stages, and facilitate monitoring for disease progression. METHODS: Gene expression profiles of peripheral blood RNA from 130 IPF patients were collected on Agilent microarrays. Significance analysis of microarrays (SAM) with a false discovery rate (FDR) of 1% was utilized to identify genes that were differentially-expressed in samples categorized based on percent predicted D(L)CO and FVC. MAIN MEASUREMENTS AND RESULTS: At 1% FDR, 1428 genes were differentially-expressed in mild IPF (D(L)CO >65%) compared to controls and 2790 transcripts were differentially- expressed in severe IPF (D(L)CO >35%) compared to controls. When categorized by percent predicted D(L)CO, SAM demonstrated 13 differentially-expressed transcripts between mild and severe IPF (< 5% FDR). These include CAMP, CEACAM6, CTSG, DEFA3 and A4, OLFM4, HLTF, PACSIN1, GABBR1, IGHM, and 3 unknown genes. Principal component analysis (PCA) was performed to determine outliers based on severity of disease, and demonstrated 1 mild case to be clinically misclassified as a severe case of IPF. No differentially-expressed transcripts were identified between mild and severe IPF when categorized by percent predicted FVC. CONCLUSIONS: These results demonstrate that the peripheral blood transcriptome has the potential to distinguish normal individuals from patients with IPF, as well as extent of disease when samples were classified by percent predicted D(L)CO, but not FVC.
Sujet(s)
Marqueurs biologiques/sang , Analyse de profil d'expression de gènes , Pneumopathies interstitielles idiopathiques/diagnostic , Fibrose pulmonaire idiopathique/diagnostic , Sujet âgé , Monoxyde de carbone/métabolisme , Études cas-témoins , Évolution de la maladie , Femelle , Humains , Pneumopathies interstitielles idiopathiques/sang , Pneumopathies interstitielles idiopathiques/génétique , Fibrose pulmonaire idiopathique/sang , Fibrose pulmonaire idiopathique/génétique , Mâle , Adulte d'âge moyen , Séquençage par oligonucléotides en batterie , Pronostic , ARN messager/génétique , Réaction de polymérisation en chaine en temps réel , RT-PCR , Capacité vitaleRÉSUMÉ
BACKGROUND: The aim of this study was to describe the high-resolution CT (HRCT) scan features that characterize familial interstitial pneumonia (FIP). METHODS: FIP was defined by the presence of two or more cases of probable or definite idiopathic interstitial pneumonia (IIP) in individuals related within three degrees. The cases were collected consecutively from three centers. We identified 371 individuals with potential FIP from 289 families, including 340 individuals who had HRCT scans. Two chest radiologists independently reviewed the HRCT scans, scoring the extent and distribution of HRCT scan findings, and assessed the overall radiologic diagnosis. RESULTS: HRCT scan abnormalities suggestive of IIP were present in 85% (289 of 340 subjects). The most frequent findings were reticular pattern (n = 238, 82%) and ground-glass opacity (GGO) associated with reticular abnormality (n = 231, 80%). Other changes included GGO in 116 (40%), honeycombing in 92 (32%), and micronodules in 65 (22%). In the 289 cases with evidence of IIP, the findings were diffusely distributed in the craniocaudal plane in 186 (64%), and the lower lung zones were predominantly involved in 89 (31%). In the axial plane, 194 (67%) had a subpleural distribution; 88 (30%) were diffuse. The imaging pattern was classified as definite or probable usual interstitial pneumonia (UIP) in only 62 subjects (22%) and definite or probable nonspecific interstitial pneumonia (NSIP) in 35 subjects (12%). In 160 subjects (55%), the imaging findings did not conform to previously described UIP or NSIP patterns. CONCLUSIONS: Reticulation and a mixed GGO/reticular pattern are the most common HRCT scan findings in FIP. The parenchymal abnormalities are most often diffuse in the craniocaudal dimension and have a predominantly peripheral distribution in the axial dimension. Although a radiologic UIP pattern is not uncommon, most cases do not conform to typical UIP or NSIP patterns.
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Pneumopathies interstitielles idiopathiques/imagerie diagnostique , Pneumopathies interstitielles/imagerie diagnostique , Tomodensitométrie/méthodes , Sujet âgé , Biopsie , Études de cohortes , Diagnostic différentiel , Femelle , Humains , Pneumopathies interstitielles idiopathiques/diagnostic , Pneumopathies interstitielles idiopathiques/anatomopathologie , Poumon/imagerie diagnostique , Poumon/anatomopathologie , Pneumopathies interstitielles/diagnostic , Pneumopathies interstitielles/anatomopathologie , Mâle , Adulte d'âge moyen , Études rétrospectivesRÉSUMÉ
BACKGROUND: The mutations that have been implicated in pulmonary fibrosis account for only a small proportion of the population risk. METHODS: Using a genomewide linkage scan, we detected linkage between idiopathic interstitial pneumonia and a 3.4-Mb region of chromosome 11p15 in 82 families. We then evaluated genetic variation in this region in gel-forming mucin genes expressed in the lung among 83 subjects with familial interstitial pneumonia, 492 subjects with idiopathic pulmonary fibrosis, and 322 controls. MUC5B expression was assessed in lung tissue. RESULTS: Linkage and fine mapping were used to identify a region of interest on the p-terminus of chromosome 11 that included gel-forming mucin genes. The minor-allele of the single-nucleotide polymorphism (SNP) rs35705950, located 3 kb upstream of the MUC5B transcription start site, was present at a frequency of 34% among subjects with familial interstitial pneumonia, 38% among subjects with idiopathic pulmonary fibrosis, and 9% among controls (allelic association with familial interstitial pneumonia, P=1.2×10(-15); allelic association with idiopathic pulmonary fibrosis, P=2.5×10(-37)). The odds ratios for disease among subjects who were heterozygous and those who were homozygous for the minor allele of this SNP were 6.8 (95% confidence interval [CI], 3.9 to 12.0) and 20.8 (95% CI, 3.8 to 113.7), respectively, for familial interstitial pneumonia and 9.0 (95% CI, 6.2 to 13.1) and 21.8 (95% CI, 5.1 to 93.5), respectively, for idiopathic pulmonary fibrosis. MUC5B expression in the lung was 14.1 times as high in subjects who had idiopathic pulmonary fibrosis as in those who did not (P<0.001). The variant allele of rs35705950 was associated with up-regulation in MUC5B expression in the lung in unaffected subjects (expression was 37.4 times as high as in unaffected subjects homozygous for the wild-type allele, P<0.001). MUC5B protein was expressed in lesions of idiopathic pulmonary fibrosis. CONCLUSIONS: A common polymorphism in the promoter of MUC5B is associated with familial interstitial pneumonia and idiopathic pulmonary fibrosis. Our findings suggest that dysregulated MUC5B expression in the lung may be involved in the pathogenesis of pulmonary fibrosis. (Funded by the National Heart, Lung, and Blood Institute and others.).
Sujet(s)
Chromosomes humains de la paire 11 , Fibrose pulmonaire idiopathique/génétique , Pneumopathies interstitielles/génétique , Mucine 5B/génétique , Polymorphisme de nucléotide simple , Sujet âgé , Études cas-témoins , Femelle , Liaison génétique , Prédisposition génétique à une maladie , Étude d'association pangénomique , Humains , Déséquilibre de liaison , Poumon/métabolisme , Mâle , Adulte d'âge moyen , Mucine 5B/métabolisme , Mutation , Régions promotrices (génétique)RÉSUMÉ
Generalized vitiligo is a common autoimmune disorder characterized by the development of white patches of skin and overlying hair due to loss of pigment-forming melanocytes from the involved areas. Family clustering of cases is not uncommon, in a pattern suggestive of multifactorial, polygenic inheritance, and there is strong association between vitiligo and other autoimmune diseases. To map genetic loci that confer susceptibility to generalized vitiligo and perhaps other autoimmune diseases, we performed a genomewide linkage scan in 71 white multiplex families with vitiligo from North America and the United Kingdom. Linkage was assessed by multipoint nonparametric linkage analyses. One linkage signal, AIS1, located at 1p31, met genomewide criteria for highly significant linkage (nonparametric LOD 5.56; P=.000000282), establishing its importance as a major vitiligo susceptibility locus. An additional seven signals, on chromosomes 1, 7, 8, 11, 19, and 22, met genomewide criteria for "suggestive linkage," and will thus be of particular importance for follow-up studies.
Sujet(s)
Chromosomes humains de la paire 1 , Prédisposition génétique à une maladie , Dépistage génétique/méthodes , Vitiligo/génétique , Chromosomes humains de la paire 11 , Chromosomes humains de la paire 19 , Chromosomes humains de la paire 22 , Chromosomes humains de la paire 7 , Chromosomes humains de la paire 8 , Fréquence d'allèle , Liaison génétique , Marqueurs génétiques , Génome humain , Génotype , Humains , Modèles génétiques , Pedigree , PénétranceSujet(s)
Lentigo/génétique , Femelle , Liaison génétique , Humains , Mâle , Neurofibromatose de type 1/génétique , PedigreeRÉSUMÉ
Generalized vitiligo is a common autoimmune disorder in which patchy loss of skin and hair pigmentation results from loss of pigment-forming melanocytes from the involved regions. Vitiligo occurs with a frequency of about 1% in most populations, and is highly associated with other autoimmune disorders, particularly Hashimoto thyroiditis. Most cases of vitiligo are sporadic, although some cases cluster in families, and the disorder is thought to be oligogenic in origin. We have studied a large family cluster in which vitiligo and Hashimoto thyroiditis occur in numerous individuals. A whole-genome scan of 24 family members, including 14 affected with autoimmune disease, showed significant linkage of an oligogenic autoimmune susceptibility locus, termed AIS1, to a 14.4 cM interval in 1p31.3-p32.2. A two-locus analysis of Hashimoto thyroiditis in family members segregating an AIS1 susceptibility allele showed suggestive linkage to markers in chromosome 6p22.3-q14.1, in a region spanning both the major histocompatibility complex and AITD1, a susceptibility locus for autoimmune thyroid disease. Our results indicate that the 1p AIS1 locus is associated with susceptibility to autoimmunity, particularly vitiligo, in this family, and that a chromosome 6 locus, most likely AITD1, may mediate the occurrence of Hashimoto's thyroiditis in AIS1-susceptible family members.