Across multiancestry groups, we analyzed Human Leukocyte Antigen (HLA) associations in over 176,000 individuals with Parkinson's disease (PD) and Alzheimer's disease (AD) versus controls. We demonstrate that the two diseases share the same protective association at the HLA locus. HLA-specific fine-mapping showed that hierarchical protective effects of HLA-DRB1*04 subtypes best accounted for the association, strongest with HLA-DRB1*04:04 and HLA-DRB1*04:07, and intermediary with HLA-DRB1*04:01 and HLA-DRB1*04:03. The same signal was associated with decreased neurofibrillary tangles in postmortem brains and was associated with reduced tau levels in cerebrospinal fluid and to a lower extent with increased Aβ42. Protective HLA-DRB1*04 subtypes strongly bound the aggregation-prone tau PHF6 sequence, however only when acetylated at a lysine (K311), a common posttranslational modification central to tau aggregation. An HLA-DRB1*04-mediated adaptive immune response decreases PD and AD risks, potentially by acting against tau, offering the possibility of therapeutic avenues.

• MeSH
• Alzheimerova nemoc * genetika   MeSH
• histokompatibilita - antigeny MeSH
• HLA antigeny MeSH
• HLA-DRB1 řetězec * genetika   MeSH
• lidé MeSH
• Parkinsonova nemoc * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND: Little is known on the genetic susceptibility to type 1 diabetes mellitus (T1DM) in the nations of the former Soviet part of south-west Asia. OBJECTIVE: The aim of the study was to characterize the genetic association of T1DM in the Azeri, the majority population of Azerbaijan. SUBJECTS AND METHODS: One hundred and sixty patients with childhood-onset T1DM, and 271 healthy unrelated controls were compared in a case-control study. All declared themselves as Azeri. The human leukocyte antigen (HLA)-DQB1, -DQA1 alelles, of DRB1*04 subtypes, and of insulin gene and cytotoxic T-lymphocyte-associated protein 4 (CTLA4) single nucleotide polymorphisms were determined using polymerase chain reaction (PCR) techniques, the association was tested from cross-tabulations, and quantified using odds ratios (OR). In the non-HLA factors, analyses were also stratified according to the HLA-conferred risk. RESULTS: Risk for T1DM was associated with presence of the HLA-DQB1*02-DQA1*05, OR = 6.6 [95% confidence interval (CI) 4.3-10], the HLA-DQB1*0302-DQA1*03, OR = 3.9 (95% CI 2.6-6.0), and an unexpectedly high risk was observed for DQB1*0304, OR = 10.9, but the very wide CI (CI 95% 2.4-49) prompts careful interpretation. A negative association with diabetes was observed for the DQB1*0602, 0503, 0301, and 0601 alleles, as well as the DRB1*0403 subtype. A strong protection was also associated with the less frequent variant of the insulin gene (OR of the phenotypic positivity was 0.28, CI 95% 0.17-0.46), while the CTLA4 +49 A/G transition was not associated with T1DM. CONCLUSIONS: We bring the first report on both HLA, and non-HLA association of T1DM from the majority Azeri population of Azerbaijan.

• MeSH
• antigen CTLA-4 MeSH
• CD antigeny MeSH
• diabetes mellitus 1. typu genetika   MeSH
• diferenciační antigeny genetika   MeSH
• dítě MeSH
• HLA-DQ antigeny genetika   MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DRB1 řetězec MeSH
• inzulin genetika   MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dítě MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH

The determination of GADA may be useful for clinical classification of diabetes mellitus (DM) in clinically unclear cases. This GADA positivity may persist in any diabetics Type 1 Diabetes Mellitus (T1D) with an onset in adulthood and Late Autoimmune Diabetes of Adults (LADA) many years after appearance of DM. The study was aimed at comparing the levels of GADA between both diabetic subsets with their clinical parameters, age of onset DM, period of insulin need, body mass index, HbA1C, fasting and postprandial C-peptide, risky HLA-DRB1* alleles, occurrence of micro- and macrovascular diabetic complications. Further analysis of GADA titers in different time consequences to the development of DM and relations to IA-2 were made. In the study, we included 130 diabetics with an onset of diabetes (T1D or LADA) 35+ y. who were hospitalized and afterwards long-term observed in the diabetological outpatient department. Out of this number there were 62 men and 68 women of the average age 65.5 +/- 14.0 y. (range 35-93 y.). 54 were assessed as the T1D patients and 76 as the LADA ones. Patients of the T1D subgroup were GADA positive 22 times and of the LADA subgroup 21 times. LADA 2 patients that were GADA negative were more obese than GADA positive LADA diabetics (p < 0.01). Also postprandial C-peptide was higher in LADA patients GADA negative (p < 0.05). Other clinical characteristics were without statistically significant differences. We found in our diabetic patients a relation between alleles HLA-DRB1*03 and particularly combination with HLA-DRB1*04 with positive GADA levels. In the GADA negative group obesity, coronary heart disease, hypertension, syndrome of diabetic foot and dyslipidaemia appeared more frequently (OR = 2.8; 3.1; 6.2 and 2.4). We found no significant differences in observed parameters--comparison GADA positivity and negativity according to the duration of DM. GADA positive were even 10 y. duration 16 times and after 20 y. even 6 times. Recent DM had positive GADA in 11 cases and 13 cases of recent DM had GADA negative. IA-2 antibodies were positive (> 1.0 U/ml) 18 times altogether and always with positive GADA, but only 7 times in recent DM. The presence of elevated GADA identifies patients unequivocally suitable for early insulin therapy. Our observations and experiences confirm that GADA can be found increased after more than 10-20 years duration of DM, although in decreasing trend.

• MeSH
• alely MeSH
• autoprotilátky krev   MeSH
• C-peptid krev   MeSH
• diabetes mellitus 1. typu krev   genetika   imunologie   MeSH
• dospělí MeSH
• glutamát dekarboxyláza imunologie   MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DRB1 řetězec MeSH
• index tělesné hmotnosti MeSH
• lidé středního věku MeSH
• lidé MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• tyrosinfosfatasy receptorového typu, třída 8 imunologie   MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH

Type 1 Diabetes Mellitus (T1D) with an onset in adulthood and Late Autoimmune Diabetes of Adults (LADA) are connected with autoimmune insulitis (associated with islet cell autoantibodies) and the specific high-risk HLA class II genotype. The study was aimed at analyzing time and clinical characteristics of the diabetics with an onset of the disease after 35 y. (T1D and LADA). Main target of the study was to assess possible role of the old age onset and compare it with diabetics with the onset in the middle age (incl. analyzing HLA-DRB1 genotype). In the study, we included 103 diabetics with an onset of autoimmune diabetes at 35+ y. who were hospitalized and afterwards long-term observed in the diabetological outpatient department. 46 men and 57 women of the average age 65.7 +/- 13.8 y. (range 35-93 y.) were out of this number. 41 were assessed as the T1D patients and 61 as the LADA ones. As a control group we used 99 healthy individuals. Patients of the T1D subgroup developed diabetes in the age of 50.8 +/- 15.1 y. and of the LADA subgroup in the age of 52.6 +/- 12.8 y. Its duration in the time of this study was 10.7 +/- 11.6 y.; respectively 5.3 +/- 7.1 y. Fasting and postprandial C-peptide levels were statistically higher (p < 0.01) in the LADA subgroup vs. T1D. Obesity 1st and 2nd grade were present together only in 12.6%. BMI was not statistically significantly different between both groups. We found in our diabetic patients the predisposition alleles HLA-DRB1*03, HLA-DRB1*04 and particularly their combination. The occurrence of these HLA alleles is significantly higher in T1D patients in comparison to control groups (p = 0.01, OR = 4.0). In our study, the occurrence of the susceptible HLA-DRB1*03 and HLA-DRB1*04 alleles in T1D patients is higher than in LADA. The presence of these alleles identifies patients of high risk and requirement of insulin therapy. Since risk alleles are similarly present in middle and old age, environmental factors probably play similar role in these onsets of autoimmune diabetes.

• MeSH
• alely MeSH
• C-peptid krev   MeSH
• diabetes mellitus 1. typu diagnóza   farmakoterapie   epidemiologie   genetika   MeSH
• dospělí MeSH
• frekvence genu MeSH
• genetická predispozice k nemoci MeSH
• genotyp MeSH
• glykovaný hemoglobin analýza   MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DRB1 řetězec MeSH
• hypoglykemika aplikace a dávkování   terapeutické užití   MeSH
• inzulin aplikace a dávkování   terapeutické užití   MeSH
• lidé středního věku MeSH
• lidé MeSH
• polymerázová řetězová reakce MeSH
• prediktivní hodnota testů MeSH
• riziko MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• stárnutí genetika   MeSH
• studie případů a kontrol MeSH
• věk při počátku nemoci MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• senioři nad 80 let MeSH
• senioři MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

• MeSH
• diabetes mellitus 1. typu genetika   MeSH
• diabetes mellitus genetika   MeSH
• finanční podpora výzkumu jako téma MeSH
• genotyp MeSH
• lidé MeSH
• Check Tag
• lidé MeSH

• MeSH
• autoimunitní nemoci diagnóza   MeSH
• diabetes mellitus 1. typu diagnóza   genetika   imunologie   MeSH
• HLA-DR antigeny diagnostické užití   MeSH
• lidé MeSH
• studie případů a kontrol MeSH
• Check Tag
• lidé MeSH

Pemphigus vulgaris (PV) je autoimunitná choroba, ktorá sa spája s genetickou predispozíciou, na ktorej sa najväčšou mierou podieľajú gény HLA-komplexu. Cieľom našej práce bolo zistiť, či táto choroba v slovenskej populácii, podobne ako je tomu v iných kaukazoidných populáciách, je tiež asociovaná s alelami HLA-komplexu. V súbore 32 pacientov s PV sme stanovili frekvencie HLA-DRB1 a -DQB1 aliel a porovnávali so zdravou populáciou. Zistili sme štatisticky signifikantnú pozitívnu asociáciu s alelami DRB1*14 (20,31 % vs. 2,69 %, OR = 9,2, Pc< 0,001) a DRB1*04 (39,06 % vs. 11,16 %, OR = 5,1, Pc< 0,001). Alely DQB1*03 a DQB1*05 sa vyskytovali častejšie tiež, ale signifikantnú úroveň nedosiahli. Frekvencia alely DQB1*06 bola u pacientov s PV, v porovnaní s kontrolnou skupinou, signifikantne nižšia (3,12 % vs. 20,61 %; OR = 0,12, Pc = 0,002). Nižšie, ale štatisticky nesignifikantné, alelové frekvencie sme zaznamenali tiež pri DRB1*11 a DRB1*15. Uvedené výsledky sú v súlade s údajmi uvádzanými v literatúre a prispievajú tak k celkovej genetickej charakteristike choroby.

Pemphigus vulgaris (PV) is an autoimmune disease with genetic predisposition associated mostly with HLA complex alleles. We examined whether this holds true for Slovak population similarly to other Caucasian populations. In 32 patients the frequency of HLA-DRB1 and DQB1 alleles was examined and compared to healthy population. The statistically significant positive association with alleles DRB1*14 (20,31 % vs. 2,69 %, OR = 9,2, Pc< 0,001) and DRB1*04 (39,06 % vs. 11,16 %, OR = 5,1, Pc< 0,001) was found. DQB1*03 and DQB1*05 alleles were more frequent but not on a significant level. DQB1*06 were significantly lower in PV patients in comparison with control group (3,12 % vs. 20,61 %; OR = 0,12, Pc = 0,002). Lower, statistically non-significant frequency was noted for DRB1*11 and DRB1*15 alleles. These results correspond well with the literature and help to overall genetic characteristics of the disease.

• MeSH
• genetická predispozice k nemoci MeSH
• HLA-DQ antigeny diagnostické užití   MeSH
• HLA-DR antigeny diagnostické užití   MeSH
• in situ značení DNA s primerem využití   MeSH
• lidé MeSH
• pemfigus genetika   imunologie   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• srovnávací studie MeSH

Polymorphic genes with immune functions, namely those of the human leukocyte antigen (HLA) system, have been implicated in sarcoidosis pathogenesis. As HLA polymorphisms in sarcoidosis have not been yet investigated in the Korean population, we used next-generation sequencing (NGS), allowing detailed characterization of HLA alleles to investigate the role of HLA variation in Korean sarcoidosis patients. We enrolled 103 patients diagnosed by the ATS/ERS/WASOG guidelines at Asan Medical Centre, Seoul, Korea. Among those, genotyping of 7 HLA loci (HLA-A, -B, -C, -DQA1, -DQB1, -DRB1, -DPB1) was performed using Omixon HolotypeTM kit and HLATwin softwareTM. HLA allele frequencies were compared with frequency data on healthy Koreans from the allelic frequency databases, and 4-digit characteristics of HLA genotyping were used. Associations were assessed by two-tailed Fischer's exact test with correction for multiple comparisons. Variants previously associated with sarcoidosis risk (HLA-C*03:04, HLA-DRB1*12:01, HLA-DRB1*14:54) and a known protective variant HLA-DPB1*04:01, were associated with sarcoidosis in Koreans. Further, we suggest new HLA variants associated with sarcoidosis risk (e.g., HLA-DQA1*05:08) and novel protective variants HLA-DQB1*03:02 and HLA-DQA1*01:02 in Koreans. This first study of HLA variation in Korean patients with sarcoidosis by precise genotyping methodology reports data that could serve future meta-analyses on HLA variation's role in sarcoidosis.

• MeSH
• alely MeSH
• frekvence genu MeSH
• haplotypy MeSH
• histokompatibilita - antigeny třídy I genetika   MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé MeSH
• sarkoidóza * genetika   MeSH
• vysoce účinné nukleotidové sekvenování * MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH

Synucleinopathies-related disorders such as Lewy body dementia (LBD) and isolated/idiopathic REM sleep behavior disorder (iRBD) have been associated with neuroinflammation. In this study, we examined whether the human leukocyte antigen (HLA) locus plays a role in iRBD and LBD. In iRBD, HLA-DRB1*11:01 was the only allele passing FDR correction (OR = 1.57, 95% CI = 1.27-1.93, p = 2.70e-05). We also discovered associations between iRBD and HLA-DRB1 70D (OR = 1.26, 95%CI = 1.12-1.41, p = 8.76e-05), 70Q (OR = 0.81, 95%CI = 0.72-0.91, p = 3.65e-04) and 71R (OR = 1.21, 95%CI = 1.08-1.35, p = 1.35e-03). Position 71 (pomnibus = 0.00102) and 70 (pomnibus = 0.00125) were associated with iRBD. Our results suggest that the HLA locus may have different roles across synucleinopathies.

• MeSH
• demence s Lewyho tělísky * genetika   MeSH
• HLA antigeny MeSH
• HLA-DRB1 řetězec genetika   MeSH
• lidé MeSH
• porucha chování v REM spánku * genetika   komplikace   MeSH
• synukleinopatie * genetika   MeSH
• Check Tag
• lidé MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH

AIM: To explore whether predisposition to autoimmune gastritis (AIG) is found in human leukocyte antigen (HLA), cytokine or killer cell immunoglobulin-like receptor (KIR) gene variations. METHODS: Twelve Finnish patients with autoimmune-type severe atrophy of the gastric corpus were included. The patients' serum was analyzed for pepsinogen I and Helicobacter pylori (H. pylori) antibodies. DNA was separated and the patients were genotyped for HLA-A, B, Cw, DRB1 and DQB1 antigens, and studied for single nucleotide polymorphisms for the following cytokines: interleukin (IL)-1 gene cluster, IL-2, IL-4, IL-6, IL-10, IL-12, interferon gamma, transforming growth factor beta, and tumor necrosis factor alpha. Variation in KIR genes was also explored. The results were compared with prevalence of the polymorphisms in Finnish or European populations. RESULTS: All patients had pepsinogen I levels below normal (mean: 11 microg/L, range: < 5 to 25 microg/L). Three patients had elevated H. pylori IgG antibodies, while H. pylori serology was negative in the rest of the patients. AIG patients carried significantly more often HLA-DRB1*04 (58%) and DQB1*03 (83%) than the general Finnish population did (28% and 51%, respectively; P = 0.045 and 0.034 by the Fisher's exact test). No patient was positive for HLA-B8-DRB1*03, a well-established autoimmune marker. Neither cytokine polymorphisms nor KIR gene variation showed association with AIG. CONCLUSION: As explored with modern DNA-based methods, HLA-DRB1*04 and DQB1*03 alleles, but not HLA-B8-DRB1*03, may predispose to AIG.

• MeSH
• autoimunitní nemoci etnologie   genetika   MeSH
• cytokiny genetika   MeSH
• dospělí MeSH
• draslíkové kanály dovnitř usměrňující genetika   MeSH
• gastritida etnologie   genetika   MeSH
• genetická predispozice k nemoci genetika   MeSH
• genotyp MeSH
• HLA-DQ antigeny genetika   MeSH
• HLA-DQ beta řetězec MeSH
• HLA-DR antigeny genetika   MeSH
• HLA-DRB1 řetězec MeSH
• jednonukleotidový polymorfismus genetika   MeSH
• lidé středního věku MeSH
• lidé MeSH
• membránové glykoproteiny genetika   MeSH
• studie případů a kontrol MeSH
• Check Tag
• dospělí MeSH
• lidé středního věku MeSH
• lidé MeSH
• mužské pohlaví MeSH
• ženské pohlaví MeSH
• Publikační typ
• časopisecké články MeSH
• práce podpořená grantem MeSH
• Geografické názvy
• Česká republika MeSH
• Finsko MeSH
• Itálie MeSH