Frequency Of DQA1 Research Articles

Correlation of HLA-DQ and TNF-α gene polymorphisms with ocular myasthenia gravis combined with thyroid-associated ophthalmopathy.

The present study aims to explore the correlation of human leucocyte antigen (HLA)-DQ and tumour necrosis factor (TNF)-α gene polymorphisms with ocular myasthenia gravis (OMG) combined with thyroid-associated ophthalmopathy (TAO). From March 2009 to March 2015, 56 OMG patients complicated with TAO (OMG + TAO group), 134 patients diagnosed with OMG only (OMG group) and 236 healthy individuals (control group) were enrolled in the present study. PCR-sequence specific primer (PCR-SSP) was used for HLA-DQ genotyping and PCR-restriction fragment length polymorphism (PCR-RFLP) for TNF-α genotyping. ELISA kit was applied to detect acetylcholine receptor antibody (AchRAb) level and chemiluminescence immunoassay (CLIA) to measure thyroid-associated antibody (T-Ab) level. Logistic regression analysis was carried out to analyse the risk factors for OMG combined with TAO. DQA1*0103 showed lower frequency in the OMG group than in the control group. DQA1*0301 showed increased and DQB1*0601 showed decreased frequency in the OMG + TAO group. DQB1*0501 showed higher frequency in the OMG and OMG + TAO groups than in the control group. Patients carrying TNF-α -863C > A (CA + AA) might confront with greater risks of OMG combined with TAO. Frequency of DQA1*0103/*0301 and DQB1*0501/*0601, and TNF-α -863C > A, -238G > A and -308G > A were associated with the levels of AchRAb and T-Ab. TNF-α -863C > A (CA + AA) and high level of T-Ab were risk factors for OMG combined with TAO. Our results demonstrate that TNF-α -863 polymorphism is possibly correlated with the risk of OMG combined with TAO.

The association of HLA-DQA1*0401 and DQB1*0604 with thymomatous myasthenia gravis in northern Chinese patients

Genetic analyses indicate that HLA complex genes can be involved in susceptibility to autoimmune myasthenia gravis (MG). Various HLA alleles serve as genetic elements that either predispose to or protect against MG. This study investigates the probable relationship between HLA-DQ allele polymorphisms and MG cases in northern China. The HLA-DQA1 and DQB1 alleles were determined by polymerase chain reaction/sequence-specific primers (PCR-SSP) in 84 MG patients, and the results were compared to 293 healthy controls. Our findings indicate that DQ A1*0401(P = 0.008, OR: 2.5, 95%CI: 1.24–3.07) and B1*0301(P = 0.000, OR: 2.29, 95%CI: 1.48–3.54) were the most frequent allele; the frequencies of DQA1*0103(P = 0.000, OR:0.24, 95%CI 0.13–0.49) and DQB1*0601(P = 0.001, OR:0.40, 95%CI 0.22–0.50) were significantly decreased in MG patients compared with healthy controls. Patients with thymomatous MG were positively associated with DQA1 *0401(P = 0.011, OR:4.57, 95% CI 1.40–14.90) and DQB1 *0604 (P = 0.001, OR:4.01, 95% CI 1.65–9.73) as compared to MG patients without thymoma. Different genetic mechanisms may exist between MG patients with thymoma and those without thymoma. The HLA-DQ associations in MG subgroups suggest that disease heterogeneity may be influenced by different genes or alleles.

EVALUATE THE DISTRIBUTION OF HLA-DQA1 ALLELES ON KING PEOPLE IN GOOD HEALTH AND LIVER CANCER PATIENTS, LING CANCER PATIENTS LIVING IN THE AREA OF BINH TRI THIEN

Objectives: To evaluate the distribution of HLA-DQA1 alleles on Kinh nationality in heathy and in cancer of liver and lung of the area of Binh Tri Thien. Subjects and Methods: PCR-SSP technique is used for analyzing antigen HLA-DQA1 system of 318 healthy people are Kinh people, and 38 patients with HCC and 37 patients ưith lung cancer, aged 7-80, living in Binh Tri Thien area. Results: The frequence found HLA-DQA1 alleles common on Kinh nationality in Binh Tri Thien region is 90.6%, the alleles were found with the highest frequency of DQA1 * 0101 (25.2%), DQA1 * 0104 (20.4%), has two alleles are not found completely that are DQA1 * 0302, DQA1 * 0401 alleles. Only in the Kinh nationality people in Binh Tri Thien region found DQA1 * 0104 allele. For liver cancer, carriers of DQA1 * 0301 allele can protect against the risk of liver cancer (OR = 1.67, 95% of CI from 1,04 to 2,25). In contrast, carriers of DQA1 * 0501 allele may be a signal for liver cancer risk (OR = 4.18, 95% of CI from 3,19 to 5,05). For lung cancer, carriers of allele DQA1 * 0101 and DQA1 * 0102 allele has the ability to protect against the risk of lung cancer (OR = 1.12 and OR = 1.18 for each corresponding allele.) However, carriers of DQA1 * 0501 allele may indicate lung cancer risk (OR = 3.22, 95% of CI from 2,24 to 4,15). Conclusion: The alleles were found with the highest frequency that are DQA1 * 0101, DQA1 * 0104, only in the Kinh people of Binh Tri Thien region found allele HLA-DQA1 * 0104. DQA1 * 0301 allele may be able to protect against the risk of liver cancer, which carriy of DQA1 * 0501 allele may be a signal of the risk of liver cancer, who carry alleles DQA1 * 0101 and DQA1 * 0102 allele can protection to avoid the risk of lung cancer, who had a DQA1 * 0501 allele may signal risk of lung cancer.

Frequency of HLA-DQA1*0501 and DQB1*0201 alleles in patients with coeliac disease, their first-degree relatives and controls in Jordan

The primary genetic marker associated with coeliac disease (CD) is the HLA-DQ2 molecule, encoded by the DQA1*0501 and DQB1*0201 genes. To investigate the frequency of HLA-DQA1*0501 and DQB1*0201 alleles in Jordanian patients with CD and their first-degree relatives. An allele-specific DNA-based PCR-sequence-specific primer was used to investigate DQA1*0501 and DQB1*0201 alleles in 44 CD patients, 47 first-degree relatives and 53 healthy controls. The mean age of the patients at the time of diagnosis was 13.5 years (range 1-39) and at the time of the study was 19.3 years (range 5-42). The DQA1/B1 (0501; 0201) haplotype was present in 80% of patients and 66% of first-degree relatives compared with 32% of controls (p<0.0001 and <0.01, respectively). The remaining 20% of CD patients who were negative for the DQ2 molecule carried the DQB1*0201 allele only. A statistically significant difference was detected in the DQ2 hetero-dimer frequency between CD patients, their first-degree relatives and controls with a higher frequency in the patients group (p<0.001). The significant differences in the frequency of DQA1*0501, DQB1*0201 alleles in CD patients and their first-degree relatives compared with the control group demonstrated the important role of these alleles in the development of CD in the Jordanian population.

From Type 1, through LADA, to Type 2 Diabetes: A Continuous Spectrum?

This study aims to explore whether diabetes mellitus from T1DM, through LADA, to T2DM presents a continuous spectrum in terms of HLA-DQ genetic background. We recruited 223 patients with autoimmune T1DM, 215 with LADA, 206 with T2DM, and 228 nondiabetic controls, and then defined their HLA-DQA1 and -DQB1 genotypes and haplotypes. T1DM patients were divided into two groups depending on age of onset of disease: juvenile-onset (JO; before the age of 20) and adult-onset (AO; after the age of 20). LADA patients were sorted according to the GADA titer: the LADA1 group had titers higher than 175 U/mL, whereas the LADA2 group had lower titers. The susceptible haplotypes of T1DM were DQA1*03-DQB1*0303, DQA1*03-DQB1*0401, and DQA1*05-DQB1*0201. The protective haplotype was DQA1*0102-DQB1*0602. The frequency of DQA1*03-DQB1*0303 in JO, AO, LADA1, LADA2, T2DM, and control groups were 38.2%, 34.2%, 25.3%, 18.9%, 17.5%, and 16.5%, respectively. The frequencies of DQA1*05-DQB1*0201 were 21.2%, 15.0%, 12.7%, 4.6%, 3.6% and 3.3%; the frequencies of DQA1*03-DQB1*0401 were 11.3%, 9.4%, 11.3%, 5.4%, 4.4% and 3.3%; and the frequencies of DQA1*0102-DQB1*0602 were 1.4%, 1.7%, 0.7%, 4.6%, 7.0%, and 5.3%. The linear-by-linear association showed that the frequency of DQA1*03-DQB1*0303, DQA1*05-DQB1*0201, and DQA1*03-DQB1*0401 presented a decremental tendency in JO, AO, LADA1, LADA2, T2DM, and control groups. The preliminary data demonstrated that the susceptible haplotypes of the HLA-DQ gene present a continuous spectrum from typical T1DM, through LADA, to T2DM, which deserves further investigation.

Association of HLA-DQA1 and DQB1 alleles with keloids in Chinese Hans

Some studies have suggested that human HLA status might potentiate development of keloids phenotype, and exists ethnic differences. No report has been published about HLA-DQA1 and DQB1 alleles associated with keloids in Chinese Hans. To investigate whether HLA-DQA1 and DQB1 alleles are associated with genetic susceptibility to keloids in Chinese Hans. Polymerase chain reaction-sequence-specific primer (PCR-SSP) method was used to analyze the distribution of HLA-DQA1 and DQB1 alleles among 192 patients with keloids and 273 healthy controls in Chinese Hans. (1) The frequencies of HLA-DQA1*0104, DQB1*0501 and DQB1*0503 (OR = 2.13, P(c) = 0.0063; OR = 14.42, P(c) < 10(-7) and OR = 6.09, P(c) < 10(-7), respectively) were significantly higher, while the frequencies of DQA1*0501, DQB1*0201 and DQB1*0402 (OR = 0.46, P(c) = 0.0099; OR = 0.24, P(c) < 10(-4) and OR = 0.10, P(c)=0.0054, respectively) were lower in patients than in controls. (2) In this study significant susceptibility haplotypes to keloids were DQA1*0104-DQB1*0501 and DQA1*0104-DQB1*0503. (3) HLA-DQB1*0501 and DQB1*0503 were positively associated with all subgroups of keloid patients. However, the DQA1*0104 (OR = 2.51, P(c) = 0.0009; OR = 2.22, P(c) = 0.0090 and OR = 2.20, P(c) = 0.0117, respectively) was only prevalent in keloid patients with single site, moderate severity and negative family history. (4) HLA-DQB1*0201 (OR = 0.27, P(c) = 0.0018 and OR = 0.27, P(c) = 0.0012, respectively) and DQB1*0402 (OR = 0.07, P(c) = 0.0270 and OR = 0.07, P(c) = 0.0306, respectively) were negatively associated with moderate severity and negative family history in keloids, moreover, HLA-DQB1*0201 (OR = 0.23, P(c) = 0.0003) and DQA1*0501 (OR = 0.43, P(c) = 0.0234) were less prevalent in patients with single site. This study demonstrated the positive association of HLA-DQA1 and DQB1 alleles and haplotypes with keloids.

Islet autoantibodies are associated with HLA‐DQ genotypes in Han Chinese patients with type 1 diabetes and their relatives

The objective of this study was to explore the relationship between islet autoantibodies of glutamic acid decarboxylase (GADA), islet antigen-2A (IA-2A), insulin autoantibody (IAA), and human leukocyte antigen (HLA)-DQ genotypes in type 1 diabetes (T1D) patients and their first-degree relatives (FDRs). Cross-sectional and case-control study. Four hundred and ninety-five T1D patients, 419 FDRs, and 376 control subjects in Han Chinese populations were recruited and tested for GADA and IA-2A, while 71 cases, all FDRs and 300 controls were tested for IAA. The 338 T1D patients (including 187 antibody-positive and 151 antibody-negative patients), 173 FDRs and 278 controls were genotyped for HLA-DQ with polymerase chain reaction sequencing-based method. Compared with the control, the frequency of DQA1*03-DQB1*0303, DQA1*05-DQB1*0201, and DQA1*03-DQB1*0401 haplotypes was higher (P < 0.05-0.01) but DQA1*0102-DQB1*0602 haplotype was lower (P < 0.01) in T1D patients. DQA1*03 allele was less in the FDRs than in their probands (P < 0.05). GADA was more prevalent in T1D patients carrying DQA1*05-DQB1*0201 or DQA1*03-DQB1*0401 haplotype (55.8% vs 41.0%, 65.5% vs 40.3%, P < 0.05-0.01), whereas IA-2A presented more in the patients carrying DQA1*03-DQB1*0303 haplotype (27.0% vs 7.9%, P < 0.05-0.01), both GADA and IA-2A showed frequently in the patients with DQA1*03-DQB1*0303/DQA1*05-DQB1*0201 haplotypes (34.5% vs 9.7%, P < 0.01). GADA positivity was lower in the patients with DQA1*0102-DQB1*0602 haplotype (16.7% vs 45.9%, P < 0.05). The frequency of IAA was not different between patients with and without susceptible DQ haplotypes (P > 0.05). GADA, IA-2A or IAA presented frequently in FDRs with DQA1*03-DQB1*0303 haplotype. The findings in the study indicate that some of specific HLA-DQA1/-DQB1 genotypes and haplotypes not only confer susceptibility to T1D but also are associated with the presence of the islet autoantibodies in the Han Chinese population.

Relationship between autoantibodies and HLA-DQ genotypes in patients with type 1 diabetes mellitus

To explore the relationship between the 3 islet autoantibodies, i.e., glutamic acid decarboxylase antibody (GADA), protein-tyrosine-phosphatase-2 autoantibody (IA-2A), and insulin autoantibody (IAA), and human leukocyte HLA-DQ genotypes in the patients with type 1 diabetes mellitus (T1DM). Peripheral blood samples were collected from 495 T1DM patients and 376 healthy controls. Radioligand assay was used to detect the levels of GADA and IA-2A. Seventy-one of the 495 T1DM patients with insulin treatment less than 14 days underwent radioligand assay to measure the IAA level. 338 TIDM patients, including 187 antibodies-positive and 151 antibodies-negative patients, and 278 healthy controls underwent PCR and sequencing so as to examine the genetic polymorphism of HLA-DQ. (1) The frequencies of DQA1*03-DQB1 *0303, DQA1*05-DQB1*0201, and DQA1*03-DQB1*0401 haplotypes in the T1DM patients were 32.6%, 14.1% and 10.2% respectively, all significantly higher than those in the controls (21.9%, 3.5%, and 2.9% respectively, all P < 0.01), however, the frequency of DQA1*0102-DQB1*0602 haplotype in the T1DM patients was 1.7%, significantly lower than that in the controls (5.3%, P < 0.05). (2) The GADA positive rates of in the T;DM patients with DQA1*05-DQB1*0201 or DQA1*03-DQB1*0401 haplotype were 55.8% and 65.5% respectively, both significantly higher than those of the T1DM patients without DQA1*05-DQB1*0201 or DQA1*03-DQB1*0401 haplotype (41.0% and 40.3%, respectively P < 0.05 or P < 0.01), and the IA-2A positive rate of the T1DM patients with DQA1*03-DQB1*0303 haplotype was 27.0%, significantly higher than that of the T1DM patients without DQA1*03-DQB1*0303 haplotype (7.9%, P < 0.01), there were no significant differences in GADA and IA-2A positivity between the T1DM patients with and without DQA1*03-DQB1*0302 haplotype (48.5% vs 43.9% and 24.2% vs 15.4%, both P > 0.05). The GADA positivity rate of the T1DM patients with DQA1*0102-DQB1 *0602 haplotype was 16.7%, significantly lower than those patients without DQA1*0102-DQB1 *0602 haplotype (45.9%, P < 0.05). There was no significant difference in IAA level between those patients with and without susceptible DQ alleles and haplotypes (P > 0.05). GADA is associated with HLA-DQA1*05-DQB1*0201 and DQA1*03-DQB1*0401 haplotypes, and IA-2A is associated with DQA1*03-DQB1 *0303 haplotype.

Optic neuritis, multiple sclerosis and human leukocyte antigen: results of a 4‐year follow‐up study

In the present study the relation between human leukocyte antigen (HLA), optic neuritis (ON) and multiple sclerosis (MS) has been investigated in 56 Iranian patients (46 females and 10 males). HLA-A and -B typing by microlymphocytotoxicity method and HLA-DRB, DQA and DQB by polymerase chain reaction based on sequence specific primers method was performed for the selected patients with ON. The diagnosis of clinically defined MS (CDMS) was confirmed in 15 of them (26.7%) during their follow-up. HLA-A24 was significantly higher in ON patients, whilst A23, A26, and A30 showed a significant decrease in these patients. HLA-A10 and A26 were absent in CDMS patients and A2 and A11 were significantly decreased in ON and CDMS patients. HLA-B5, B51, B38, B27, and B35 were significantly increased in ON patients compared with control subjects. HLA-B44, B16 and B38 alleles were not present in CDMS patients. Regarding DR locus, the frequency of HLA-DRB1*15 and DRB1*04 has been increased in CDMS patients, whilst the frequency of HLA-DRB1*07 and *11 was much higher in ON patients. In DQA region, the most frequent allele in the MS patients was DQA1*0102, which was significantly higher than ON patients, and control group. The frequency of DQA1*0103 was significantly increased in both patients group. In DQB1, the frequency of DQB1*0602 increased significantly in the MS patients. In conclusion existence of common genetic basis for early manifestations of MS could be suggested.

Human leukocyte antigen class II alleles and natural history of HPV 2/27/57-induced common warts.

Epidemiological studies have demonstrated an association between HLA-DQB1*03 alleles and the risk of cervical cancer induced by human papillomavirus (HPV). As persistence of HPV infection is required for developing cervical cancer, we wanted to elucidate the role of HLA-class II allele polymorphisms in the persistence of common warts induced by HPV 2, HPV 27 or HPV 57. Therefore, we determined the distribution of HLA-DQA1, -DQB1, and -DRB1 alleles in 71 patients presenting with HPV 2/27/57-induced common warts which had persisted for at least 18 months as well as in 92 individuals who had never suffered from common warts or whose warts had healed in less than 18 months. Among patients with long-lasting warts, the carriership frequencies and allele frequencies of DQA1*0301, DQB1*0301, DRB1*07 and DRB1*09 were higher, and the allele frequencies of DQA1*0501, DQB1*0603, DRB1*01 and DRB1*03 were lower. Statistically significant differences (Bonferroni adjusted Fisher's exact test) were found for carriership frequency of DQA1*0301 (46.5 vs 21.7%, P = 0.013) and for carriership frequency (18.3 vs 1.1%, P = 0.0015) and allele frequency (12 vs 0.5%, P = 0.000013) of DQB1*0301. A greater proportion of patients with long-lasting warts than of subjects without persistent warts were homozygous at the DQA1 (14.1 vs 6.5%) and DQB1 (16.9 vs 8.6%) gene loci. These results suggest that the natural history of cutaneous HPV 2/27/57-induced common warts may be modulated by allele polymorphisms at the HLA-DQA1 and HLA-DQB1 gene loci.

Association between HLA class II locus and the susceptibility to Artemisia pollen–induced allergic rhinitis in Chinese population

Objective The aim of the study was to determine whether susceptibility or resistance to Artemisia pollen–induced allergic rhinitis was associated with HLA class II DQA1, DQB1 loci. Study design and setting Forty-one subjects with allergic rhinitis and 41 healthy controls from Beijing were genotyped at HLA class II DQA1, DQB1 alleles by polymerase chain reaction amplification with sequence-specific primers–based technique. Results The allele frequencies of HLA-DQA1*0201, DQB1*0602 were lower in patients with allergic rhinitis compared with the controls (24.39% versus 46.34%, P = 0.038; 4.88% versus 26.83%, P = 0.007), and the frequency of DQA1*0302 was higher among patients than the controls (58.54% versus 14.63%, P = 0.00004, Pc = 0.0004). Conclusion and significance HLA-DQA1 and -DQB1 genes may be involved in the development of Artemisia pollen–induced allergic rhinitis. HLA-DQA1*0201, DQB1*0602 alleles may be a protective factor and DQA1*0302 may be a susceptible factor for Artemisia pollen–induced allergic rhinitis.

Polymorphisms of HLA Class II Predispose Children and Adolescents with Type 1 Diabetes Mellitus to Autoimmune Thyroid Disease

To determine the prevalence of autoimmune thyroid disease (AITD) in children and adolescents with type 1 diabetes mellitus (DM), and assess whether the development of AITD is correlated with specific DQ-A and DQ-B loci of the HLA class II antigens, we analyzed thyroid function using anti-thyroid antibodies and HLA-DQ-A and -DQ-B polymorphisms in 69 patients with type 1 DM, in 75 normal healthy controls, and in 21 patients with AITD but without type 1 DM. Eighteen patients (26%) in the diabetic patients had AITD. In the diabetic patients, DQA1*0301 and DQB1*0302 occurred more frequently than in controls [DQA1*0301: OR=1.939, 95% CI=1.210–3.109 (P=0.008, P c (corrected P) <0.05); DQB1*0302: OR=2.558, 95% CI=1.354–4.832 (P=0.005, P c >0.05)]. Compared with controls, non-diabetic subjects with AITD showed higher frequency of DQA1*0301 (P c <0.05) and DQB1*0601 (P c >0.05), but these alleles were not contributing factors in the development of AITD in diabetic patients. In diabetic patients, DQB1*0201, known as susceptible allele of type 1 DM was not a contributing factor in the development of AITD in diabetic patients. Unlike DQB1*0201, DQB1*0401 was more frequently found in diabetic patients with AITD than in controls [OR=4.053, 95% CI=1.607–10.221 (P=0.0017, P c <0.05)] or than in non-diabetic AITD patients [OR=15.769, 95% CI=1.905–130.530(P=0.002, P c <0.05)]. In non-diabetic subjects, DQB1*0401 did not provide susceptibility for AITD. Our results suggest that HLA DQB1*0401 is a predisposing genetic marker for the development of AITD in patients with type 1 DM in Korea.

Associations of HLA class II alleles with pulmonary tuberculosis in Thais.

Tuberculosis is an important infectious disease in Thailand. Susceptibility to tuberculosis is influenced not only by the environment but also by host genetic factors. In this study, we investigated HLA alleles in 82 patients with tuberculosis from Bangkok and in 160 normal controls. HLA-DRB1, DQA1 and DQB1 genotyping was performed by the PCR-SSO method. The frequency of HLA-DQB1*0502 was increased in tuberculosis patients compared to the normal controls (P = 0.01, OR = 2.06). In contrast, the frequencies of DQA1*0601 and DQB1*0301 were decreased in tuberculosis patients compared to the controls (P = 0.02 and P = 0.01, respectively). Our results suggest that HLA-DQB1*0502 may be involved in the development of pulmonary tuberculosis, whereas HLA-DQA1*0601 and DQB1*0301 may be associated with protection against tuberculosis.

Different distribution of HLA class II alleles according to response to corticosteroid therapy in sudden sensorineural hearing loss.

To investigate the association of HLA class II alleles with the susceptibility to sudden sensorineural hearing loss and with the results of corticosteroid treatment in the Korean population. HLA-DRB1, -DQA1, -DQB1, and -DPB1 genotyping by the sequence-specific oligonucleotide probes method in 41 patients with sudden sensorineural hearing loss and in 206 healthy control subjects. Initial hearing levels at the onset of hearing loss and final hearing levels after treatment were evaluated for the association with HLA class II alleles. Tertiary care referral center, ambulatory and hospitalized care. Forty-one patients (24 men and 17 women; mean age, 49.2 years) were compared with 206 controls. Patients were divided into 2 groups according to their response to corticosteroid therapy (good response vs nonresponse). The frequencies of HLA-DRB1, -DQA1, -DQB1, and -DPB1 alleles were not significantly different between patients and controls (P>.05). When an association between the results of corticosteroid treatment and the frequency of HLA alleles was evaluated, the frequencies of HLA-DRB1*14 (relative risk [RR] = 3.5, P<.02), -DQA1*03 (RR = 4.2, P<.02), and -DQA1*05 (RR = 3.1, P<.03) were significantly increased, but HLA-DQA1*01 (RR = 0.2, P<.004) and -DQB1*06 (RR = 0.2, P<.009) were decreased in the group nonresponsive to corticosteroid therapy, compared with the controls. The distribution of HLA-DQA1*01 (P<.04), -DQB1*06 (P<.02), and -DQA1*03 (P<.003) was significantly different between the responsive and the nonresponsive groups. HLA-DQA1 allelic combination analysis showed that the frequencies of DQA1*03 and *05 had a high RR value in patients with sudden sensorineural hearing loss (RR = 4.1, P<.003) and in patients in the nonresponsive group (RR = 8.9, P<.001), compared with the controls. The presence of HLA class II alleles may be a useful genetic marker in forecasting a prognosis in Korean patients with sudden sensorineural hearing loss.

The human leukocyte antigen HLA DRB3*020/DQA1*0501 haplotype is associated with Graves' disease in African Americans.

Information on genetic susceptibility to Graves' disease in African Americans is limited. We studied DRB1, DQB1, DRB3 subtypes, DQA1*0501, DQA1*0201, and CTLA-4 polymorphisms in 49 African American patients with adult onset Graves' disease and 47 racially-matched controls using PCR-based sequence-specific priming methods. There were no significant differences in DRB1 or DQB1 allelic frequencies or CTLA-4 polymorphisms between patients and controls. However, we found that the frequency of DRB3 was significantly increased in the patients (75.5% vs. 57.4%, P = 0.006, X2 = 3.52), especially for the DRB3*0202 subtype (53.1% vs. 23.4, P = 0.003, X2 = 8.91). In this one respect, the finding was in concordance with our previous observations in Caucasian patients with adult-onset Graves' disease. In addition, whereas the frequency of DQA1*0501 was increased (P = 0.018, X2 = 5.63) in our patients, the haplotype of DRB3/DQA1*0501, or DRB3*0202/DQA1*0501 was found to be more strongly associated (P = 0.008, X2 = 7.0; P = 0.0008, X2 = 11.34, respectively). These data suggest that DRB3*0202, particularly when found with DQA1*0501 in a haplotype is a susceptible gene(s) for Graves' disease in adult African Americans. Considering these data with those in Caucasian patients, our results would suggest that the primary Graves susceptible locus is likely DRB3 and not DRB1.

The influence of age at onset and gender on the HLA-DQA1, DQB1 association in Chinese children with insulin dependent diabetes mellitus

Certain alleles of human leukocyte antigen (HLA)-DR and -DQ genes have been strongly associated with susceptibility and resistance to insulin- dependent diabetes mellitus (IDDM). To further clarify the association of HLA DQ alleles with IDDM and the influence of age at onset and gender on the association with IDDM, we investigated the association of HLA-DQA1, -DQB1 in 54 childhood onset Chinese (21 male) IDDM patients and 65 normal controls by using polymerase chain reaction-sequence specific primer (PCR-SSP). The mean age plus or minus SD at onset of IDDM patients was 8.37 ± 3.54 year old. Our results revealed that the frequencies of DQA1 ∗0301, ∗0302, DQB1 ∗0201, and ∗0302 in IDDM patients were significantly higher than that in the control group ( p < 0.025, < 0.005, < 0.001, and < 0.001, respectively). The frequency of DQA1 ∗0301, ∗0302, DQB1 ∗0201, and ∗0302 were susceptible alleles to IDDM with relative risks of 2.0, 3.5, 5.0 and 4.3, respectively. The protective alleles to IDDM were DQA1 ∗0101, ∗0103, DQB1 ∗0301, ∗0503, and ∗0602. We divided IDDM patients into three groups according to age at onset (1-5, 6-10, and 11-15 years old). The frequency of DQA1 ∗0302 decreased as age increased, and the frequency of DQA1 ∗0501 increased as age increased. Our results also showed that male IDDM patients had higher frequencies of DQA1 ∗0501, DQB1 ∗0201 than female IDDM patients ( p < 0.025 and < 0.025, respectively), while female IDDM patients had higher frequencies of DQB1 ∗0502 than male IDDM patients ( p < 0.05). In our study significant susceptibility haplotypes to IDDM were DQA1 ∗0301-DQB1 ∗0302, DQA1 ∗0501-DQB1 ∗0201, DQA1 ∗0301-DQB1 ∗0201, and DQA1 ∗0302-DQB1 ∗0201.

Molecular IDDM epidemiology: international studies

The WHO DiaMond Molecular Epidemiology Sub-Project is testing the hypothesis that the geographic differences in IDDM incidence reflect population variation in the frequency of IDDM susceptibility genes (i.e., DQA1 and DQB1 alleles with sequences coding for arginine (R) in position 52 of the DQ χ-chain, and an amino acid other than aspartic acid (ND) in position 57 of the DQ β-chain, respectively) using a standardized case-control design. Data from twelve populations which have completed (or have nearly completed) recruitment and HLA molecular analyses are presented. There was an approximate 2-fold increase in the frequencies of DQA1*0301. DQB1*0201 and DQB1*0302 among IDDM cases compared to non-diabetic controls in most populations. Interestingly, DQA1*0301 was more common in low versus moderate-high incidence countries. DQB1*0201 and DQB1*0302 were more prevalent in the moderate-high incidence areas. DQA1*R and DQB1*ND were both consistent markers of IDDM risk, with stronger associations in moderate-high versus low incidence areas. In general, individuals homozygous for both DQA1*R and DQB1*ND had the highest genotype-specific IDDM incidence rates, which approximated risk estimates for first degree relatives in several countries. These data revealed considerable variation in the frequencies of DQB1 and DQA1 alleles across countries, which likely contribute to the global patterns of IDDM incidence.

Molecular IDDM epidemiology: international studies

The WHO DiaMond Molecular Epidemiology Sub-Project is testing the hypothesis that the geographic differences in IDDM incidence reflect population variation in the frequency of IDDM susceptibility genes (i.e., DQA1 and DQB1 alleles with sequences coding for arginine (R) in position 52 of the DQ χ-chain, and an amino acid other than aspartic acid (ND) in position 57 of the DQ β-chain, respectively) using a standardized case-control design. Data from twelve populations which have completed (or have nearly completed) recruitment and HLA molecular analyses are presented. There was an approximate 2-fold increase in the frequencies of DQA1*0301. DQB1*0201 and DQB1*0302 among IDDM cases compared to non-diabetic controls in most populations. Interestingly, DQA1*0301 was more common in low versus moderate-high incidence countries. DQB1*0201 and DQB1*0302 were more prevalent in the moderate-high incidence areas. DQA1*R and DQB1*ND were both consistent markers of IDDM risk, with stronger associations in moderate-high versus low incidence areas. In general, individuals homozygous for both DQA1*R and DQB1*ND had the highest genotype-specific IDDM incidence rates, which approximated risk estimates for first degree relatives in several countries. These data revealed considerable variation in the frequencies of DQB1 and DQA1 alleles across countries, which likely contribute to the global patterns of IDDM incidence.

Class II MHC typing in pemphigoid gestationis.

Pemphigoid gestationis (PG) is a rare, autoimmune skin disease associated with pregnancy or the immediate post-partum period, previously shown to be associated with the HLA class II antigens DR3 and DR4. Advances in molecular analytical techniques now allow the identification of HLA alleles previously difficult to define by serological assays. Unsuspected polymorphism within the HLA-DR3 and DR4 classes can, therefore, be identified. The aim of our study was to apply these newer techniques to the question of genetic predisposition in PG by re-evaluating the association with DR3 and by studying a possible link with DQ. We have investigated by restriction fragment length polymorphism, the DQA, and by sequence specified oligonucleotide probing the DQB and DRB1 (HLA DR) specificities of 41 women with immunofluorescence-confirmed PG. The principal finding of this study is that there is an association between PG and DRB1*0301 (DR3) and DRB1*0401/040X (DR4). Although there is also an increase (P = 0.06) in the concurrent presence of both antigens, this appears to be due to the association with either antigen alone. We also found an increase in the frequency of DQA1*2 (P = 0.016 vs. control) and a decrease in frequency of DQB1*0201 (P = 0.022 vs. controls) and DQB1*0602 (P = 0.026 vs. controls).

HLA-A and -DRB4 genes in controlling the susceptibility to Hashimoto's thyroiditis

HLA-linked genetic factors involved in the pathogenesis of HT were studied in 71 patients with HT by serologic typing for HLA-A, -B, -C, -DR, and -DQ specificities and by DNA typing for HLA-DRB1, -DRB3, -DRB4, -DRB5, -DQA1, -DQB1, and -DPB1 genes using the PCR-SSOP method. Typing results demonstrated significant positive associations of HT with HLA-A2 and -DRB4 ∗0101 (DR53) ( p < 0.01, RR = 2.03, EF = 0.61 and p < 0.0001, RR = 4.48, EF = 0.69, respectively). Although HLA-DR8, -DRB1 ∗0403, -DQA1 ∗03, and -DQB1 ∗0303 were statistically more prevalent in the patient group than in the controls, these associations were presumably due to the strong linkage disequilibria of these alleles with HLA-A2 or -DRB4 ∗0101 in the Japanese population. Ninety-seven percent of the patients (69 out of 71) were positive for HLA-A2 or -DRB4 ∗0101 compared to 79% in controls (RR = 8.7, p < 0.0005). The combination of HLA-A2 and -DRB4 ∗0101 showed higher OR of risk for HT (OR = 12.8) than HLA-A2 (OR = 7.3) or DRB4 ∗0101 (OR = 7.5) alone. These observations suggest that at least two loci, HLA-A and HLA-DRB4 together, may control the susceptibility to HT. On the other hand, the frequency of DQA1 ∗0102 was significantly decreased in the patient group, suggesting that DQA 1 ∗0102 might confer resistance to HT.