Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
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ABSTRACT: Background
The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.Results
The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the combination of lung and skin involvement at diagnosis may distinguish sporadic from familial sarcoidosis (p = 0.016 and p = 0.041). We observed also that Sarcoid Clinical Activity Classification (SCAC) profiles were significantly different between familial and sporadic cases (p = 0.0497). Variant rs2076530 was more frequent in patients than in controls (OR = 2.02; 95% CI: [1.32-3.09]) but showed no difference between sporadic and familial cases and no difference according to the clinical phenotype or the outcome.Conclusion
Despite a significant difference in BTNL2 polymorphism between sarcoid patients and controls, there was no such difference between familial and sporadic sarcoidosis cases and no correlation between BTNL2 polymorphism and disease severity or outcome. Thus, BTNL2 difference cannot be considered as a key marker for disease classification or patient management.
SUBMITTER: Pacheco Y
PROVIDER: S-EPMC5135764 | biostudies-literature | 2016 Dec
REPOSITORIES: biostudies-literature
Publications
Familial vs. sporadic sarcoidosis: BTNL2 polymorphisms, clinical presentations, and outcomes in a French cohort.
Pacheco Yves Y Calender Alain A Israël-Biet Dominique D Roy Pascal P Lebecque Serge S Cottin Vincent V Bouvry Diane D Nunes Hilario H Sève Pascal P Pérard Laurent L Devouassoux Gilles G Freymond Nathalie N Khouatra Chahira C Wallaert Benoît B Lamy Raphaelle R Elsensohn Mad-Hélénie MH Bardel Claire C Valeyre Dominique D
Orphanet journal of rare diseases 20161203 1
<h4>Background</h4>The occurrence of familial forms of sarcoidosis (OMIM 181100) suggests a genetic predisposition. The involvement of butyrophilin-like 2 (BTNL2) gene (rs2076530 variant) has to be investigated.<h4>Results</h4>The study performed independent analyses of BTNL2 polymorphism, clinical phenotypes, and outcomes in familial vs. sporadic presentations in 256 sporadic and 207 familial cases from 140 families. The logistic multivariate model showed that a young age at diagnosis and the c ...[more]
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Project description:BackgroundButyrophilin-like 2 (BTNL2) rs2076530 gene polymorphism has been implicated in susceptibility to sarcoidosis. However, results from previous studies are not consistent. To assess the association of BTNL2 polymorphism and sarcoidosis susceptibility, a meta-analysis was performed.MethodsPubMed, Embase were searched for eligible case-control studies. Data were extracted and pooled odds ratios (OR) with 95% confidence intervals (CI) were calculated.ResultsTen studies involving a total of 3303 cases and 2514 controls were included in this meta-analysis. Combined data indicated that BTNL2 rs2076530 polymorphism was associated with sarcoidosis susceptibility in allelic model (A vs. G, OR = 1.59, 95%CI: 1.47-1.72), dominant model (AA + AG vs. GG, OR = 2.10, 95%CI: 1.67-2.65), and recessive model (AA vs. AG + GG, OR = 1.93, 95%CI: 1.49-2.50).ConclusionsThis meta-analysis indicates that BTNL2 rs2076530 polymorphism contributes to the risk of sarcoidosis.
| S-EPMC4388687 | biostudies-literature
Project description:Sarcoidosis is a multisystemic granulomatous disease of unknown etiology that primarily affects adults between the ages of 20 and 40 years old. It is characterized by the activation of Th1 lymphocytes resulting in the production of inflammatory cytokines and the formation of noncaseating epithelioid cell granulomas in affected tissues. The lungs and lymphatic system are the ones most frequently affected. The disease usually presents spontaneous remission in the first two years and, in a few patients, the disease progresses to pulmonary fibrosis or other fatal complications depending on the affected organ. The pathogenesis of sarcoidosis is still not clearly defined, and is considered an interaction between the environment and risk alleles in many genes. The present case control study consisted of 146 Greek patients with sarcoidosis and 90 healthy volunteers from the same ethnic group. The coding and neighboring intronic regions of the BTNL2 gene were sequenced and risk alleles were compared amongst the two groups. Thirty-seven different variants were detected from which 12 were synonymous substitutions and 25 non-synonymous. With the help of in silico tools (SIFT, PolyPhen, PROVEAN, PMut and EX_SKIP), 13 variants were classified as possible pathological risk variants including 4 novel ones. The most common risk variants contributing to phenotypic modulation of sarcoidosis were p.S360G and p.S334L, with the latter contributing to a more severe disease stage with extra-pulmonary manifestations such as skin granulomas and relapses being more common.
| S-EPMC4287805 | biostudies-literature
Project description:The BTNL2 gene is a member of the B7 receptor family that probably functions as a T-cell costimulatory molecule. It resides in the class II major histocompatibility complex (MHC) region of chromosome 6p and has recently been associated with sarcoidosis susceptibility in a white German population. We sought to replicate the BTNL2 association in an African American family-based study population (n=219 nuclear families) and two case-control populations--one African American (n=295 pairs) and one white (n=366 pairs). Ten SNPs were detected within a 490-bp region spanning exon/intron 5 of BTNL2. Haplotype variation within this region was significantly associated with sarcoidosis in all three study populations but more so in whites (P=.0006) than in the African American case-control (P=.02) or family-based (P=.03) samples. The previously reported BTNL2 SNP with the strongest sarcoidosis association, rs2076530, was also the SNP with the strongest association in our white population (P<.0001). The A allele of rs2076530 results in a premature exon-splice site and increases risk for sarcoidosis (odds ratio=2.03; 95% confidence interval 1.32-3.12). Although rs2076530 was not associated with sarcoidosis in either African American sample, a three-locus haplotype that included rs2076530 was associated with sarcoidosis across all three study samples. Multivariable logistic regression analyses showed that BTNL2 effects are independent of human leukocyte antigen class II genes in whites but may interact antagonistically in African Americans. Our results underscore the complexity of genetic risk for sarcoidosis emanating from the MHC region.
| S-EPMC1226214 | biostudies-literature
Project description:OBJECTIVE:To investigate the association between SNP in the BTNL2 gene region and the susceptibility to osteoarthritis of the knee. METHODS:The blood samples of 103 knee osteoarthritis and 134 healthy subjects were collected. Four SNP in the BTNL2 gene region were selected, whole DNA was extracted using the QIAamp blood DNA purification mini reagent, the BTNL2 gene fragment was amplified and sequenced, and the genotype and corresponding frequency were counted. The results were statistically analyzed. RESULTS:The four SNP (rs41521946, rs28362677, rs28362678, rs28362675) in the BTNL2 gene region were analyzed using a chi-square test (mutation heterozygote, homozygous, and normal homozygote), and the genotypes of the four mutation points were found to be statistically significant (P=0.003, 0.013, 0.005, and 0.045, respectively). Among the four SNP, the first three SNP were in Hardy-Weinberg equilibrium, and a multivariate logistic regression analysis was used to correlate them with knee osteoarthritis (P=0.003, 0.013, 0.005, respectively). rs28362675 was not in Hardy-Weinberg equilibrium but was associated with knee osteoarthritis (P=0.045), which might be smaller samples or an ethnicity differential allelic variation. The P values of the statistical analysis of age and height in the baseline data of both groups were less than 0.05. Considering the possible impact on the results, they were used as covariates in the analysis. The SNP of rs41521946 and rs28362677 showed a significant change in their associations with mutations, and the genotype P values of rs41521946 (AC+AA)/CC and rs2836267 (AG+AA)/GG were 0.002, 0.006, respectively. CONCLUSION:Four SNP (rs41521946, rs28362677, rs28362678, rs28362675) in the BTNL2 gene region were significantly associated with knee osteoarthritis, and the target population might be significantly affected by rs28362675.
| S-EPMC6949757 | biostudies-literature
Project description:BackgroundsOur aim was to evaluate the role of 20 genetic polymorphisms in the development and prognosis of sporadic and familial PC. A case-control study of 185 patients who underwent radical prostatectomy from 1997 to 2011. These patients were divided into two groups based on their family history. Gleason grade, PSA value and pathological TNM 2002 stage were used as prognostic factors. Blood samples from 70 men without PC were used as controls. The SNPs were genotyped using a TaqMan® SNP Genotyping Assay Kit.ResultsConsidering susceptibility, the polymorphic allele in the SNP rs2660753 on chromosome 3 was significantly more prevalent in controls (p = 0.01). For familial clustering, the polymorphic homozygote genotype of the SNP rs7931342 was five times more frequent in patients with familial PC compared to sporadic PC (p = 0.01). Regarding the SNP 1447295, the polymorphic homozygote genotype was more prevalent in patients with organ-confined PC (p = 0.05), and most importantly, the polymorphic allele occurred more frequently in patients without biochemical recurrence (p = 0.01). Kaplan-Meier analysis showed a median biochemical recurrence free survival of 124.2 compared to 85.6 months for patients with the wild-type allele (p = 0.007).ConclusionOur findings provide the evidence for the association of 20 recently highlighted SNPs and their susceptibility, familial clustering, staging, Gleason score and biochemical recurrence of PC. We believe that the association between these SNPs and PC may contribute to the development of alternative tools that can facilitate the early detection and prognosis of this disease.
| S-EPMC5132395 | biostudies-literature
Project description:BACKGROUND:It is unknown whether clinical parameters differ between migraineurs with and without first-degree family members with migraine. OBJECTIVES:The present cross-sectional study describes differences between familial and sporadic migraine with a focus on migraine characteristics, migraine severity, comorbidities, and treatment. METHOD:From the Danish Headache Center we recruited 358 patients with familial migraine and 1727 patients with sporadic migraine. Each participant was assessed using a validated semi-structured interview. RESULTS:No differences in age (Mean = 44 and 44 [SD = 12.28 and 12.58] for familial and sporadic migraineurs, respectively; P = .900) or sex (295/358 (82.4%) and 1413/1727 (81.8%) women in familial and sporadic migraineurs, respectively; P = .853) were found. Familial migraineurs had more aphasic aura than sporadic migraineurs (41% vs 27%, P = .001). Sporadic migraineurs had more lifetime attacks ie, >100 attacks (45% vs 70%, P < .001) and prolonged attacks ie, lasting >72 hours (5% vs 12%, P < .001) than familial migraineurs. Further, sporadic migraineurs had a higher incidence of concussions (37% vs 41%, P = .001) compared to familial migraineurs. In agreement with a previous study, there was no difference between familial and sporadic migraine regarding triptan response (84% vs 81%, P = .440). CONCLUSION:Headache characteristics, triptan response, and comorbidities where similar in individulas with and without inherited migraine, suggesting that migraine are to be considered a hmogenoues disease. The difference in the clinical presentation of migraine with aura symptoms among patients with familial migraine should be considered in future studies. Further, more severe migraine among patients with sporadic migraine with aura could suggest that sporadic migraineurs have been exposed to stronger or multiple environmental factors and indicate that an early intervention in migraine treatment could lessen the severity of migraine.
| S-EPMC6899493 | biostudies-literature
Project description:IntroductionThe possibility to generalize our understandings on treatments and assessments to both familial frontotemporal dementia (f-FTD) and sporadic FTD (s-FTD) is a fundamental perspective for the near future, considering the constant advancement in potential disease-modifying therapies that target particular genetic forms of FTD. We aimed to investigate differences in clinical features, cerebrospinal fluid (CSF), and blood-based biomarkers between f-FTD and s-FTD.MethodsIn this longitudinal cohort study, we evaluated a consecutive sample of symptomatic FTD patients, classified as f-FTD and s-FTD according to Goldman scores (GS). All patients underwent clinical, behavioral, and neuropsychiatric symptom assessment, CSF biomarkers and serum neurofilament light (NfL) analysis, and brain atrophy evaluation with magnetic resonance imaging.ResultsOf 570 patients with FTD, 123 were classified as f-FTD, and 447 as s-FTD. In the f-FTD group, 95 had a pathogenic FTD mutation while 28 were classified as GS = 1 or 2; of the s-FTD group, 133 were classified as GS = 3 and 314 with GS = 4. f-FTD and s-FTD cases showed comparable demographic features, except for younger age at disease onset, age at diagnosis, and higher years of education in the f-FTD group (all P < .05). f-FTD showed worse behavioral disturbances as measured with Frontal Behavioral Inventory (FBI) negative behaviors (14.0 ± 7.6 vs. 11.6 ± 7.4, P = .002), and positive behaviors (20.0 ± 11.0 vs. 17.4 ± 11.8, P = .031). Serum NfL concentrations were higher in patients with f-FTD (70.9 ± 37.9 pg/mL) compared to s-FTD patients (37.3 ± 24.2 pg/mL, P < .001), and f-FTD showed greater brain atrophy in the frontal and temporal regions and basal ganglia. Patients with f-FTD had significantly shorter survival than those with s-FTD (P = .004).Discussionf-FTD and s-FTD are very similar clinical entities, but with different biological mechanisms, and different rates of progression. The parallel characterization of both f-FTD and s-FTD will improve our understanding of the disease, and aid in designing future clinical trials for both genetic and sporadic forms of FTD.HighlightsDo clinical features and biomarkers differ between patients with familial frontotemporal dementia (f-FTD) and sporadic FTD (s-FTD)?In this cohort study of 570 patients with FTD, f-FTD and s-FTD share similar demographic features, but with younger age at disease onset and diagnosis in the f-FTD group.f-FTD showed higher serum neurofilament light concentrations, greater brain damage, and shorter survival, compared to s-FTD.f-FTD and s-FTD are very similar clinical entities, but with different cognitive reserve mechanisms and different rates of progression.
| S-EPMC9310192 | biostudies-literature
Project description:UnlabelledBackgroundIdiopathic pulmonary fibrosis (IPF) is an adult-onset Idiopathic Interstitial Pneumonia (IIP) usually diagnosed between age 50 to 70 years. Individuals with Familial Pulmonary Fibrosis (FPF) have at least one affected first or second-degree relative and account for 0.5-20% of cases.MethodsWe ascertained and collected DNA samples from a large population-based cohort of IPF patients from Newfoundland, Canada. For each proband, a family history was documented and medical records were reviewed. Each proband was classified as familial (28 patients) or sporadic (50 patients) and all 78 probands were screened for variants in four highly penetrant, adult-onset PF genes (SFTPC, SFTPA2, TERT,TERC).ResultsSeventy-eight IPF probands were enrolled of whom 28 (35.9%) had a positive family history. These 28 familial patients led to the recruitment of an additional 49 affected relatives (total of 77 FPF patients). By age 60 years, 42% of the familial cohort had been diagnosed with PF compared with only 16% of the sporadic patient collection (χ2 = 8.77, p = 0.003). Mean age of diagnosis in the familial group was significantly younger than the sporadic group (61.4 years vs. 66.6 yrs, p = 0.012) with a wider age range of diagnosis (19-92 years compared with 47-82 years). Thirty-three of 77 (42.8%) FPF patients had a tissue diagnosis and all but five had usual interstitial pneumonia histology. Compared with other published case series, the familial IIP histologies were more homogeneous. Three of 28 familial probands (10.7%) and none of the 50 sporadic probands had pathogenic variants in the four genes tested. All three familial probands had mutations in TERT. Other phenotypes associated with telomerase deficiency were present in these families including cirrhosis, bone marrow hypoplasia and premature graying. Telomere length assays were performed on mutation carriers from two families and confirmed telomere-related deficiency.ConclusionThe proportion of familial cases in our cohort is higher than any previously reported estimate and we suggest that this is due to the fact that Newfoundland cohort is ethnically homogeneous and drawn from a founder population. In our patient collection, diagnosis with IPF prior to age 45 years predicted familial disease. In two of the three TERT mutation families, the pedigree appearance is consistent with genetic anticipation. In the other 25 FPF families negative for mutations in known PF genes, we did not identify other telomerase associated medical problems (bone marrow dysfunction, cirrhosis) and we hypothesize that there are novel PF genes segregating in our population.
| S-EPMC3463483 | biostudies-literature
Project description:Digestive tract sarcoidosis (DTS) is rare and case-series are lacking. In this retrospective case-control study, we aimed to compare the characteristics, outcome, and treatment of patients with DTS, nondigestive tract sarcoidosis (NDTS), and Crohn disease.We included cases of confirmed sarcoidosis, symptomatic digestive tract involvement, and noncaseating granuloma in any digestive tract. Each case was compared with 2 controls with sarcoidoisis without digestive tract involvement and 4 with Crohn disease.We compared 25 cases of DTS to 50 controls with NDTS and 100 controls with Crohn disease. The major digestive clinical features were abdominal pain (56%), weight loss (52%), nausea/vomiting (48%), diarrhea (32%), and digestive bleeding (28%). On endoscopy of DTS, macroscopic lesions were observed in the esophagus (9%), stomach (78%), duodenum (9%), colon, (25%) and rectum (19%). As compared with NDTS, DTS was associated with weight loss (odds ratio [OR] 5.8; 95% confidence interval [CI] 1.44-23.3) and the absence of thoracic adenopathy (OR 5.0; 95% CI 1.03-25). As compared with Crohn disease, DTS was associated with Afro-Caribbean origin (OR 27; 95% CI 3.6-204) and the absence of ileum or colon macroscopic lesions (OR 62.5; 95% CI 10.3-500). On the last follow-up, patients with DTS showed no need for surgery (versus 31% for patients with Crohn disease; P?=?0.0013), and clinical digestive remission was frequent (76% vs. 35% for patients with Crohn disease; P?=?0.0002).The differential diagnosis with Crohn disease could be an issue with DTS. Nevertheless, the 2 diseases often have different clinical presentation and outcome.
| S-EPMC5265782 | biostudies-other
Project description:BackgroundIt is not known if genetic background, characteristics at diagnosis, physical and psychological well-being, and adherence to a gluten-free diet are comparable between patients with familial or sporadic celiac disease. These issues were investigated in a follow-up study.MethodsAltogether 1064 patients were analyzed for celiac disease-associated serology, predisposing HLA-DQ, and non-HLA genotypes. Medical data were collected from patient records and supplementary interviews. Current symptoms and quality of life were further evaluated with the Gastrointestinal Symptom Rating Scale (GSRS), the Psychological General Well-Being questionnaire (PGWB), and Short Form 36 (SF-36) questionnaires.ResultsFamilial and sporadic groups differed (P < 0.001) in the reason for diagnosis and clinical presentation at diagnosis, familial patients being more often screen-detected (26% vs. 2%, P < 0.001) and having less often gastrointestinal (49% vs. 69%) and severe symptoms (47% vs. 65%). The groups were comparable in terms of histological damage, frequency of malabsorption, comorbidities, childhood diagnoses, and short-term treatment response. At the time of the study, familial cases reported fewer symptoms (21% vs. 30%, P = 0.004) and lower prevalence of all (78% vs. 86%, P = 0.007), neurological (10% vs. 15%, P = 0.013), and dermatological (9% vs. 17%, P = 0.001) comorbidities. Dietary adherence and GSRS scores were comparable, but familial cases had better quality of life according to PGWB and SF-36. High-risk genotype HLA-DQ2.5/DQ2.5 was more frequent among familial cases, and four non-HLA SNPs were associated with familial celiac disease.ConclusionsDespite the greater proportion of high-risk genotypes, familial cases had milder symptoms at presentation than did sporadic cases. Worse experience of symptoms and poorer quality of life in sporadic disease indicate a need for intensified support.
| S-EPMC8163668 | biostudies-literature