[Whole exome sequencing and analysis of a Chinese family with familial pulmonary sarcoidosis].

Objective: To analyze the clinical features and the results of the whole exome sequencing (WES) of a Chinese family containing both pulmonary sarcoidosis patients and healthy members, and to find potent genes and variants that may be involved in the pathogenesis of sarcoidosis. Methods: Three patients with pulmonary sarcoidosis and 1 healthy member was included from a Chinese Han family in the north of China diagnosed in November 2016, which characterized as 2 consecutive generations including 2 males and 1 female, aged from 23 to 69 years old. The proband is Ⅱ-6. Pulmonary sarcoidosis was diagnosed by clinical features, imaging and pathological findings, and clinical data such as family history were collected. Whole blood samples were taken and WES (Illumina NovaSeq S2) was performed. The pathogenicity analysis and gene annotation analysis were performed by ExAC, SIFT, Polyphenv2, Metascape databases. Results: It was found that 27 genes were highly pathogenic in the database filtering result. After gene annotation analysis, we found that ZC3H12A gene can negatively regulate the differentiation of Th17 cells, which may be involved in the onset of pulmonary sarcoidosis. Sanger sequencing confirmed the c.1361 A>G variant in 3 sarcoidosis patients but normal in healthy member. Conclusions: In patients with familial pulmonary sarcoidosis, the genetic background could regulate immune response which is one of the pathogenic mechanisms of sarcoidosis. The whole exome test and gene ontology analysis showed that Ⅱ-2, Ⅱ-6 and Ⅲ-1 pulmonary sarcoidosis patients in this family were all shared the same variant on ZC3H12A gene, which played a pivotal role in differentiation of Th17 cells and is a potent pathogenesis gene in this Chinese pulmonary sarcoidosis family.

Clinical Features of Extrapulmonary Sarcoidosis Without Lung Involvement.

BACKGROUND: Compared with pulmonary sarcoidosis, sarcoidosis without lung involvement may involve other immunopathologic mechanisms and be associated with other demographic and clinical features. METHODS: This was a retrospective analysis of clinical data collected in real time on 1,686 patients with biopsy-proven sarcoidosis from two large university sarcoidosis outpatient clinics in the United States. We compared differences in demographics characteristics and clinical presentation between pulmonary and nonpulmonary sarcoidosis (NPS). Patients were considered to have NPS only if they had normal chest imaging and no features consistent with pulmonary involvement on the basis of currently accepted criteria. RESULTS: A total of 8.3% of this sarcoidosis cohort met criteria for NPS. NPS was significantly more common in white than black patients, and more common in women than men. The skin was the most common organ involved, and was observed in nearly one-half of patients with NPS. Isolated skin sarcoidosis was the overwhelmingly most common pattern of organ involvement seen in the NPS group (25%), and no other pattern of involvement was found in more than 5% of patients with NPS. CONCLUSIONS: Significant demographic and sex differences were observed between patients with pulmonary and nonpulmonary sarcoidosis. These differences reflect previous data concerning differences between patients with skin and lung sarcoidosis because the skin was the major organ involved with NPS. Although the lungs are likely the primary site of exposure in pulmonary sarcoidosis, the high prevalence of skin involvement in NPS suggests the skin is the most conducive site of antigen capture outside of the respiratory tract.

Clinical and Biological Insights from the University of California San Francisco Prospective and Longitudinal Cohort.

INTRODUCTION: Sarcoidosis is a systemic inflammatory disease characterized by non-necrotizing granulomas in involved organs, most commonly the lung. Description of patient characteristics in the Western United States is limited. Furthermore, blood-based measures that relate to clinical sarcoidosis phenotypes are lacking. We present an analysis of a prospective, longitudinal sarcoidosis cohort at a Northern Californian academic medical center. METHODS: We enrolled 126 sarcoidosis subjects and 64 healthy controls and recorded baseline demographic and clinical characteristics. We used regression models to identify factors independently associated with pulmonary physiology. We tested whether blood transcript levels at study entry could relate to longitudinal changes in pulmonary physiology. RESULTS: White, non-Hispanics composed ~70% of subjects. Hispanics and Blacks had a diagnostic biopsy at an age ~7 years younger than whites. Obstructive, but not restrictive, physiology characterized Scadding Stage IV patients. Subjects reporting use of immunosuppression had worse FEV1%p, FVC%p, and DLCO%p compared to subjects never treated, regardless of Scadding stage. We defined sarcoidosis disease activity by a drop in pulmonary function over 36 months and found that subjects meeting this definition had significant repression of blood gene transcripts related to T cell receptor signaling pathways, referred to as the "TCR factor." CONCLUSION: Obstructive pulmonary physiology defined Stage IV patients which were mostly white, non-Hispanics. Genes comprising the composite gene expression score, TCR factor, may represent a blood-derived measure of T-cell activity and an indirect measure of active sarcoidosis inflammation. Validation of this measure could translate into individualized treatment for sarcoidosis patients.

Characteristics of sarcoidosis in Maori and Pacific Islanders.

BACKGROUND AND OBJECTIVE: Ethnicity is strongly associated with variable clinical presentation in sarcoidosis but the association between ethnicity and clinical characteristics has not previously been described in patients of Polynesian ancestry, Maori and Pacific Islander (PI). The objective of this study was to describe the clinical characteristics of sarcoidosis in Maori and PI patients and determine if those were different to European patients. METHODS: A retrospective review of the medical records of 406 patients (69 Maori/PI) attending a specialist interstitial lung disease (ILD) clinic. RESULTS: The population (207 females, mean age at presentation: 36) reflected the current New Zealand census data (2013) with only people of Indian ethnicity over-represented. Parenchymal lung involvement was uncommon in Maori and PI patients (21% Scadding stage 2, 2% stage 3), and no patient had extensive pulmonary fibrosis (stage 4). Computed tomography (CT) patterns of sarcoid parenchymal lung involvement were less commonly reported for Maori/PI. There were no differences in respect of baseline lung function or requirement for treatment. Ocular and skin involvement occurred more frequently in Maori and PI (P = 0.0045, P = 0.03), and erythema nodosum was more common in Caucasians (P = 0.0008). CONCLUSION: People of Polynesian ancestry appear to have less pulmonary and more extra-pulmonary manifestations of sarcoidosis. This adds to our knowledge that sarcoidosis heterogeneity is influenced by ethnicity.

Clinical features of Sarcoidosis in Oman: A report from the Middle East region.

BACKGROUND: Though clinical features of sarcoidosis follow a similar pattern, some heterogeneity is seen in different ethnic and racial groups. OBJECTIVES: To describe for the first time the clinical characteristics of sarcoidosis patients in the Sultanate of Oman. METHODS: The data on all cases of sarcoidosis followed up in the two tertiary hospitals in Oman were retrieved retrospectively. RESULTS: Of the 92 patients, for representing the ethnic data only Omani patients (n=83) were included. The mean age was 52.90±12.35 years. Majority were females (72.3%, n=60). Cough (n=44, 53.0%), dyspnea (n=39, 47%), arthralgia (n=26, 31.3%) and fatigue (30.1%) were the major symptoms. Arthralgia was reported by 41.7% of the females and 4.3% of the males (p= 0.001). Uveitis was present in 16 (19.3%), erythema nodosum in 8 (9.6%) and hypercalcemia in 13 (15.7%). The radiological stage at presentation was stage 0, 18.7%; I, 28%; II, 17.3%; III, 24% and IV, 12%. Majority (61.4%) of the patients had tissue diagnosis; intra-thoracic site 70.6%. Pulmonary function showed abnormal diffusion in 75%. Sixty eight received treatment, 81.9% took prednisolone. Based on radiograph good outcome (Resolving) was noted in 20.9%, intermediate (Stable) in 73.1% and poor (Progressive) in 6%. Lung function wise, resolving, stable and progressive disease was seen in 31.4%, 40.0% and 28.6% respectively. CONCLUSION: The clinical picture of the patients with sarcoidosis from Oman was similar to that reported from the rest of the world. Region wise, our patients were older and arthralgia and hypercalcemia were more common. The management of sarcoidosis needs a more organized approach in the country with clear guidelines on monitoring and treatment.

Cardiovascular magnetic resonance-guided diagnosis of cardiac affection in a Caucasian sarcoidosis population.

BACKGROUND: Clinically evidenced cardiac involvement in systemic sarcoidosis occurs in approximately 5% of patients, whereas post-mortem examinations identify cardiac sarcoidosis in over 60% of cases. OBJECTIVE: Given the inconsistency of diagnostic approaches, we took aim at prospectively investigating the prevalence of cardiac sarcoidosis by cardiovascular magnetic resonance (CMR) in a primary Caucasian population and at correlating the results with standard clinical parameters. METHODS: 188 patients with histologically proven sarcoidosis were included, provenient from the local pneumological department and a national sarcoidosis self-help association. All of them underwent CMR-imaging. Complementary 12-lead ECG, Holter monitoring, laboratory and pulmonary function testing were performed. RESULTS: CMR-based diagnosis of cardiac sarcoidosis was made in 29 patients (15.4%), of whom 17 patients (9% of total cohort) exhibited increased relative gadolinium enhancement - reflecting acute inflammatory processes -, while 11 patients (5.9% of total cohort) showed late gadolinium enhancement as a marker for nonviable tissue damage. Both abnormalities were present in 1 patient (0.5%). Correlation analysis evinced significant association between CMR-diagnosed cardiac sarcoidosis and reduction in LVEF, increase in diastolic interventricular septal thickness, diastolic dysfunction as well as limited electrocardiographic abnormalities. Neither laboratory values nor pulmonary function parameters correlated with presence or activity of cardiac sarcoidosis. CONCLUSIONS: Among our predominantly Caucasian sarcoidosis study population, CMR-detected cardiac affection occurred in 15.4% and was missed by internationally valid standard clinical testing in all but one case. It reinforces CMR's diagnostic value as modality of choice to evaluate cardiac sarcoidosis. The estimation of its prognostic potential and its value in assessing the incidence of cardiac sarcoidosis however requires further longitudinal investigation.

Annexin A11 is associated with pulmonary fibrosis in African American patients with sarcoidosis.

Not available.

Lung sarcoidosis in children: update on disease expression and management.

BACKGROUND: Sarcoidosis is a rare lung disease in children. The aim of the present study was to provide update information on disease presentation and progression, patient management and prognosis factors in a cohort of children with lung sarcoidosis. METHODS: With the network of the French Reference Centre for Rare Lung Diseases (RespiRare), we collected information on a large cohort of paediatric thoracic sarcoidosis to provide information on disease presentation, management and outcome. RESULTS: Forty-one patients were included with a median age at diagnosis of 11.8  years (1.1-15.8), mostly from Afro-Caribbean and Sub-Saharan origin. At diagnosis, 85% presented with a multi-organic disease, and no major differences were found regarding disease severity between the patients diagnosed before or after 10 years old. Corticosteroids were the most used treatment, with more intravenous pulses in the youngest patients. The 18-month outcome showed that patients diagnosed before 10 years old were more likely to recover (50% vs 29%), and presented fewer relapses (29% vs 58%). At 4-5 years of follow-up, relapses were mostly observed for patients diagnosed after 10 years old. DISCUSSION: In the included children, mostly of Afro-Caribbean and Sub-Saharan origin, sarcoidosis seems severe, with multi-organic involvement and foreground general symptoms. Common prognosis factors are not suitable in paediatric patients, and a young age at diagnosis does not seem to be associated with a poorer prognosis. The study is ongoing to provide further information on the very-long-term follow-up of paediatric sarcoidosis.

Racial difference in sarcoidosis mortality in the United States.

BACKGROUND: The clinical presentation and outcome of sarcoidosis varies by race. However, the race difference in mortality outcome remains largely unknown. METHODS: We studied mortality related to sarcoidosis from 1999 through 2010 by examining data on multiple causes of death from the National Center for Health Statistics. We compared the comorbid conditions between sarcoidosis-related deaths with deaths caused by car accidents (previously healthy control subjects) and rheumatoid arthritis (chronic disease control subjects) in both African Americans and Caucasians. RESULTS: From 1999 through 2010, sarcoidosis was reported as an immediate cause of death in 10,348 people in the United States with a combined overall mean age-adjusted mortality rate of 2.8 per 1 million person-years. Of these, 6,285 were African American and 3,984 Caucasian. The age-adjusted mortality rate for African Americans was 12 times higher than for Caucasians. African Americans died at an earlier age than Caucasians. African Americans living in the District of Columbia and North Carolina and Caucasians living in Vermont had higher mortality rates. Although the total sarcoidosis age-adjusted mortality rate had not changed over the 12 year period studied, this rate increased for Caucasians (R = 0.747, P = .005) but not for African Americans. Compared with the control groups, pulmonary hypertension was significantly more common in individuals with sarcoidosis. CONCLUSIONS: This nationwide population-based study exposes a significant difference in ethnicity and sex among people dying of sarcoidosis in the United States. Pulmonary hypertension investigation should be considered in all patients with sarcoidosis, especially African Americans.

Epidemiology of sarcoidosis in Afro-Caribbean people: a 7-year retrospective study in Guadeloupe.

BACKGROUND: There are no reliable epidemiological data on sarcoidosis in the French West Indies, although this disease is known to be more frequent and more severe in Black African-Americans and West Indians. OBJECTIVES: This retrospective study aimed to assess the incidence and prevalence of sarcoidosis in Guadeloupe over a 7-year period and to determine its epidemiological, clinical, and evolutionary characteristics. METHODS: Patients were identified through the computerized databases of the three pathology laboratories and two hospitals on the islands of Guadeloupe. Histologically proven cases of sarcoidosis were selected. All patients were recalled at a single study time-point. RESULTS: A total of 75 patients were identified. These included 44 women and 31 men (sex ratio: 1.4), with a mean ± standard deviation (SD) age of 47 ± 14 years and Fitzpatrick skin types IV-VI. The average incidence was 2.28 per 100,000 inhabitants per year (95% confidence interval [CI] 1.69-3.02). The prevalence of sarcoidosis in 2009 was 21.09 per 100,000 inhabitants (95% CI 16.00-26.18). Most patients (61/71, 85.9%) exhibited multiple organ involvement; the mean ± SD number of organs involved was 2.6 ± 1.1. The initiation of systemic therapy was required in 75.7% of cases. Several lines of treatment were necessary in 41.5% of affected patients. At the study time-point, seven patients were found to have died. Four of these deaths were directly attributable to sarcoidosis (mortality rate: 5.3%). CONCLUSIONS: This epidemiological study on sarcoidosis in Guadeloupe reveals a low incidence of the disease and a high degree of severity as evidenced by the average number of affected organs, the high frequency of extrathoracic organ involvement, the frequent use of corticosteroids, and a mortality rate of 5.3%.

Association of HLA-DRB1 with Sarcoidosis Susceptibility and Progression in African Americans.

HLA-DRB1 is a sarcoidosis risk gene, and the *03:01 allele is strongly associated with disease resolution in European sarcoidosis cases. Whereas the HLA-DRB1 variation is associated with sarcoidosis susceptibility in African Americans, DRB1 risk alleles are not as well defined, and associations with disease resolution have not been studied. Associations between genotyped and imputed HLA-DRB1 alleles and disease susceptibility/resolution were evaluated in a sample of 1,277 African-American patients with sarcoidosis and 1,467 control subjects. In silico binding assays were performed to assess the functional significance of the associated alleles. Increased disease susceptibility was associated with the HLA-DRB1 alleles *12:01 (odds ratio [OR], 2.11; 95% confidence interval [CI], 1.65-2.69; P = 3.2 × 10(-9)) and *11:01 (OR, 1.69; 95% CI, 1.42-2.01; P = 3.0 × 10(-9)). The strongest protective association was found with *03:01 (OR, 0.56; 95% CI, 0.44-0.73; P = 1.0 × 10(-5)). The African-derived allele *03:02 was associated with decreased risk of persistent radiographic disease (OR, 0.52; 95% CI, 0.37-0.72; P = 1.3 × 10(-4)), a finding consistent across the three component studies comprising the analytic sample. The DRB1*03:01 association with disease persistence was dependent upon local ancestry, with carriers of at least one European allele at DRB1 at a decreased risk of persistent disease (OR, 0.36; 95% CI, 0.14-0.94; P = 0.037). Results of in silico binding analyses showed that DRB1*03:01 consistently demonstrated the highest binding affinities for six bacterial peptides previously found in sarcoidosis granulomas, whereas *12:01 displayed the lowest binding affinities. This study has identified DRB1*03:01 and *03:02 as novel alleles associated with disease susceptibility and course in African Americans. Further investigation of DRB1*03 alleles may uncover immunologic factors that favor sarcoidosis protection and resolution among African Americans.

Cardiac involvement in Caucasian patients with pulmonary sarcoidosis.

BACKGROUND: Cardiac sarcoidosis (CS) is a potentially life-threatening condition. At present, there is no consensus with regard to the optimal non-invasive clinical evaluation and diagnostic procedures of cardiac involvement in patients with sarcoidosis. The aim of this study in a large homogenous Scandinavian sarcoidosis cohort was therefore to identify risk factors of cardiac involvement in patients with sarcoidosis, and the value of initial routine investigation with ECG and cardiac related symptoms in screening for CS. METHODS: In this retrospective study a cohort of 1017 Caucasian patients with sarcoidosis were included. They were all screened with ECG at disease onset and investigated for CS according to clinical routine. RESULTS: An abnormal ECG was recorded in 166 (16.3%) of the 1017 patients and CS was later diagnosed in 22 (13.2%) of them, compared to in one (0.1%) of the 851 sarcoidosis patients with a normal ECG (p < 0.0001). The risk for CS was higher in patients with a pathologic ECG combined with cardiac related symptoms (11/40) (27.5%) compared to those with pathologic ECG changes without symptoms (11/126) (8.7%) (p < 0.01). Furthermore, patients with Löfgren's syndrome had a reduced risk for CS compared to those without (p < 0.05) the syndrome. CONCLUSIONS: This study on an unusually large and homogenous sarcoidosis population demonstrate the importance of an abnormal ECG and cardiac related symptoms at disease onset as powerful predictors of a later diagnosis of cardiac sarcoidosis. In contrast, CS is very rare in subjects without symptoms and with a normal ECG. This knowledge is of importance, and may be used in a clinical algorithm, in identifying patients that should be followed and investigated extensively for the presence of CS.

Increased prevalence of cigarette smoking in Japanese patients with sarcoidosis.

BACKGROUND AND OBJECTIVE: Several studies have shown that individuals with sarcoidosis in Western populations are less likely to have smoked before diagnosis. Epidemiological characteristics of sarcoidosis are known to differ between Japanese and Westerners. Therefore, the relationship between cigarette smoking and sarcoidosis in a Japanese population was investigated. METHODS: Three hundred eighty-eight patients newly diagnosed with sarcoidosis between 2000 and 2008 were retrospectively identified. The results of two large surveys of smoking prevalence in Japan provided reference data. Specific clinical manifestations of sarcoidosis were compared between current smokers and never-smokers, after excluding former smokers. RESULTS: The prevalence of current smokers at the time of the diagnosis of sarcoidosis was 59.6% in men and 27.9% in women. With the exception of men in their 30s, the prevalence was higher in all age groups compared with the general Japanese population. The prevalence of lung parenchymal involvement tended to be higher in current smokers than in never-smokers (odds ratio = 1.33 (0.99-1.77), P = 0.054). CONCLUSIONS: This retrospective cohort study suggests that smoking prevalence is higher in Japanese sarcoidosis patients than that reported in Western sarcoidosis patients and that there could be different relationships between smoking and the development of sarcoidosis in these populations.

Preliminary characterizations of a serum biomarker for sarcoidosis by comparative proteomic approach with tandem-mass spectrometry in ethnic Han Chinese patients.

BACKGROUND: The diagnosis of sarcoidosis is still a significant challenge in China because of the need to exclude other diseases including granulomatous infections and malignancies that may be clinically and radiographically similar. The specific aim of the study is to search for serum protein biomarkers of sarcoidosis and to validate their clinical usefulness in differential diagnosis. METHODS: Serum samples were collected from patients with sarcoidosis (n = 37), and compared to those from patients with tuberculosis (n = 20), other pulmonary diseases (n = 20), and healthy volunteers (n = 20) for determination of sarcoidosis-specific or -associated protein expression profiles. The first part of this study focused on proteomic analysis of serum from patients with sarcoidosis to identify a pattern of peptides capable of differentiating the studied populations using the ClinProt profiling technology based on mass spectrometry. Enzyme Linked Immunosorbent Assay (ELISA) was then used to verify corresponding elevation of the serum protein concentration of the potential biomarkers in the same patients sets. Receiver operating characteristic curve (ROC) analyses was performed to determine the optimal cutoff value for diagnosis. Immunohistochemistry was carried out to further confirm the protein expression patterns of the biomarkers in lung tissue. RESULTS: An unique protein peak of M/Z 3,210 Daltons (Da) was found to be differentially expressed between the sarcoidosis and control groups and was identified as the N-terminal peptide of 29 amino acids (94-122) of serum amyloid A (SAA). ELISA confirmed that the serum SAA level was significantly higher in the sarcoidosis group than that of the other 3 control groups (p < 0.05). The cutoff for serum SAA concentration determined by ROC analysis was 101.98 ng/ml, with the sensitivity and specificity of 96.3% and 52.5%, respectively. Immunohistochemical staining showed that the SAA depositions in lung tissue of the sarcoidosis patients were also significantly more intense than in non-sarcoid lung tissue (p < 0.05). CONCLUSION: This is the first study to investigate serum protein markers in Chinese subjects with sarcoidosis. This study shows that the serum SAA expression profiles were different between the sarcoidosis and non-sarcoidosis groups. SAA may be a potential serum biomarker for ruling-out the diagnosis of sarcoidosis in Chinese subjects.

Unexpectedly high prevalence of sarcoidosis in a representative U.S. Metropolitan population.

The prevalence of sarcoidosis in the United States is unknown, with estimates ranging widely from 1 to 40 per 100,000. We sought to determine the prevalence of sarcoidosis in our health system compared to other rare lung diseases and to further establish if the prevalence was changing over time. We interrogated the electronic medical records of all patients treated in our health system from 1995 to 2010 (1.48 million patients) using the common ICD9 codes for sarcoidosis (135), lung cancer (162), and several other lung diseases characterized, like sarcoidosis, as "rare lung diseases". The patient demographic information (race, gender, age) was further analyzed to identify signature data patterns. The prevalence of sarcoidosis in our health system increased steadily from 164/100,000 in 1995 to 330/100,000 in 2010, and this trend could not be ascribed simply to changes in patient demographics or patient referral patterns. We further estimate that the prevalence of sarcoidosis exceeds 48 per 100,000 in Franklin County, Ohio, the demographic profile of which is nearly identical to that of the U.S. Sarcoidosis prevalence increased over time relative to lung cancer, a benchmark disease with stable disease prevalence, and exceeded that of other rare lung diseases. We postulate that the observed 2-fold increase in sarcoidosis disease prevalence in our health system is primarily related to improved detection and diagnostic approaches, and we conclude that the actual prevalence of sarcoidosis in central Ohio greatly exceeds current U.S. estimates.

The clinical course of sarcoidosis: presentation, diagnosis, and treatment in a large white and black cohort in the United States.

BACKGROUND: Although numerous reports have described the clinical features of sarcoidosis in various ethnic and racial groups, many have been limited by small size, homogenous populations, and relatively short follow-up periods. We report the clinical characteristics of a large, race-sex-age diverse cohort of sarcoidosis clinic patients followed in a large university medical center for an extended period of time. METHODS: This study included clinical data for sarcoidosis patients followed over a 12-year period at a sarcoidosis clinic at the Medical University of South Carolina. RESULTS: 1774 sarcoidosis patients were identified. Black females were more common (44%) than other race/gender combinations (p = 0.01). The diagnosis of sarcoidosis occurred > 3 months after the onset of symptoms in 48% of the cohort and > 1 year after the onset of symptoms in 25%. Anti-sarcoidosis treatment was required in 61% of the patients. Pulmonary function improved over time and the median corticosteroid requirement lessened. Compared to whites, blacks had more advanced radiographic stages of sarcoidosis (p < 0.0001), more organ involvement (p < 0.0001), and more frequently required anti-sarcoidosis medication (p < 0.0001). Compared to women, men had more advanced radiographic stages of sarcoidosis (p < 0.0001). CONCLUSIONS: The analysis indicates that sarcoidosis tends to improve over time in terms of pulmonary function and medication requirements. The disease was found to be more severe in blacks than whites. Treatment was not necessarily required. These results provide a comprehensive model of the course and treatment of sarcoidosis in the clinical setting.

Sarcoidosis HLA class II genotyping distinguishes differences of clinical phenotype across ethnic groups.

The HLA class II (DRB1 and DQB1) associations with sarcoidosis have been studied by several groups but often without consistent results. In this paper, we consider the hypothesis that observed inconsistencies relate to distinct, genetically encoded disease phenotypes which differ in prevalence between centres. We therefore typed HLA-DRB1 and DQB1 in 340 UK, 139 Dutch and 163 Japanese sarcoidosis patients and, respectively, 354, 218 and 168 healthy controls from these populations. We applied consistent phenotyping and genotyping and investigated associations between HLA class II alleles and distinct disease phenotypes within and between ethnic groups. DRB1*01 and DQB1*0501 are protective against all manifestations of sarcoidosis. Lung-predominant sarcoidosis is associated with DRB1*12 and *14. Löfgren's syndrome is a common sarcoidosis phenotype in the Dutch and is strongly associated with the DRB1*0301 allele. This phenotype is not seen among the Japanese in whom DRB1*0301 is absent. The same allele is protective for UK uveitis. Sarcoid uveitis is common in Japan. The DRB1*04-DQB1*0301 haplotype is a risk factor for this disease manifestation in Japanese and UK subjects but protective for sarcoidosis overall. We show that distinct sarcoidosis phenotypes have similar genetic associations across ethnic groups. The disease case mix differs between centres and may be explained by different ethnic allelic frequencies.