• Journal of Korean Neurosurgical Society
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• v.46 no.6
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• pp.558-563
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• 2009

Objective : Moyamoya disease (MMD) is an uncommon cerebrovascular disorder, characterized by progressive occlusion at the terminal portion of the internal carotid artery. Incidence of the disease is high in East Asia and familial MMD accounts for about 15% of the disease. Although the pathogenesis is unknown, association of HLA class I or II alleles with MMD has been reported with conflicting results. We investigated whether there is a difference in HLA class II association between familial and non-familial forms of the disease. Methods : A total of 70 Korean children with MMD, including 16 familial cases (10 probands), and 207 healthy controls were studied. Among familial cases, only 10 probands were used for the HLA frequency analysis. High resolution HLA-DRB1 and DQB1 genotyping was performed using polymerase chain reaction (PCR)-sequence specific oligonucleotide hybridization and PCR-single strand conformation polymorphism methods. Results : The phenotype frequencies of HLA-DRB1*1302 (70.0%) and DQB1*0609 (40.0%) were significantly increased in familial MMD compared to both controls [vs. 15.5%, corrected p ($p_c$) = 0.008, odds ratio (OR) = 12.76; vs. 4.3%, $p_c\;=\;0.02$, OR = 14.67] and non-familial MMD patients (vs. 14.8%, $p_c\;=\;0.02$, OR = 13.42; vs. 1.9%, $p_c\;=\;0.02$, OR = 35.33). The frequencies of DRB1 and DQB1 alleles in non-familial MMD patients were not significantly different from those in controls. Conclusion : Our findings suggest that the genetic polymorphism of HLA class II genes or other closely linked disease relevant gene(s) could be a genetic predisposing factor for familial MMD.

• Asian Pacific Journal of Cancer Prevention
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• v.14 no.7
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• pp.4427-4433
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• 2013

Cervical cancer is the second most common cancer in women. HLA class I and II alleles polymorphisms have been shown to be associated with cervical cancer risk, but results have varied among different populations. In this study, the HLA-A, -B, and -DRB1 alleles among 100 southern Chinese women with cervical squamous cell carcinoma (SCC) were compared to 254 controls. Our results showed that $B^*51$:01:02 allele frequency was significantly higher in patients with SCC than in healthy controls ($P=3.17{\times}10^{-5}$, $P_c$=0.005, OR=26.7). Statistical analysis also revealed a significantly decreased frequency of $B^*51$:01:02 ($P=7.01{\times}10^{-4}$, $P_c$=0.03, OR=0.12) in patients with SCC when compared with healthy controls. These results indicate that HLA-$B^*51$:01:02 may confer susceptibility to SCC and HLA-$B^*51$:01:02 may contribute to resistance to the development of SCC in Chinese women. None of the HLA-A-B or HLA-A-B-DRB1 haplotypes were significantly different in cases and controls after multiple testing corrections, indicating the individual allele associations to be independent of the identified haplotypes. These results support the hypothesis that some HLA-B alleles could be involved with susceptibility for developing SCC.

• Clinical and Experimental Pediatrics
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• v.48 no.6
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• pp.624-633
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• 2005

Purpose : This study analyzed the expression of HLA-DR and DQ genotypes and anti-thyroid autoantibodies[anti-thyroid peroxidase(TPO) and anti-thyroglobulin(TG) antibodies] in Korean patients with type 1 diabetes(T1DM) to investigate the susceptible HLA alleles to T1DM in Korea and the prevalence of thyroid autoantibodies and their significance for the development of thyroid disorders. Methods : A total of 59 Korean patients with type 1 diabetes[26 males, median age 13.7 years(range 5.7-29.9 years), diabetes duration 7.6 years(-1.7-22.5 years)] were enrolled in this study, and 200 healthy Koreans without a family history of diabetes were selected as a normal control for the comparison of HLA genotypes. Seventeen patients with anti-TPO or anti-TG were followed [median duration 3.96 years(1 day-10.7 years)] with measurement of anti-TPO, anti-TG, $T_3$, $T_4$ or free $T_4$, TSH levels and physical examinations. HLA-DR and DQ genotyping were done by PCR-SSO, PCR-SSCP, PCR-RFLP and PCR-SSP methods. Results : HLA analysis showed higher frequencies of HLA-DRB1*0301, *090102 and DQB1*0201, *030302 alleles, DRB1*0301/*090102, *090102/*090102 and DQB1 *0201/*030302, *030302/*030302, *0201/ *0302 genotypes in T1DM patients compared to controls(Pc<0.05). Fifteen(25.4 percent) had anti-TPO antibody, 12(20.3 percent) had anti-TG, 17(28.8 percent) had either autoantibody and 10(16.9 percent) had both autoantibodies. No clinical or subclinical hypothyroidism developed during follow-up after the first detection of anti-thyroid autoantibody. There was no significant correlation between thyroid autoimmunity and gender, onset age of T1DM, and diabetes duration, respectively(P>0.05). Conclusion : We thought this unique HLA-DR, DQ allele distribution might be an important factor for the low incidence of T1DM in Korea. And a high prevalence of thyroid autoantibodies in these populations suggests examinations of thyroid antibodies should be performed regularly. Optimal age for the initial screening and the frequency of re-screening for associated thyroid autoimmune diseases in T1DM remains to be determined through prospective follow-up.

• IMMUNE NETWORK
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• v.2 no.4
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• pp.248-255
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• 2002

Background: TAP1 and TAP2 are two ABC transporter genes located within the class II region of the human MHC. Their protein products form a heterodimer whose function is to transport peptides from the cytoplasm into the endoplasmic reticulum. This study was performed to examine the polymorphism of TAP genes and the distribution of HLA-TAP haplotypes in the Korean population through family analysis. Methods: The subjects used in this study were 50 healthy Korean families consisting of 233 individuals. TAP1 (codons 333 and 637) and TAP2 (codons 379, 565, 577, 651, 665, and 687) typings were carried out by the PCR-restriction fragment length polymorphism (RFLP) method. HLA-DRB1 and DQB1 genotyping results from a previous study were used for HLA-TAP haplotype analysis. Results: The number (gene frequency) of TAP1 and TAP2 alleles detected were 3 for TAP1 (A 81.5%, B 17.0%, and C 1.5%) and 8 for TAP2 (A1 32.0%, A2 12.5%, B 34.0%, Bky2 6.5%, C 7.0%, D 3.0%, E 4.5%, and G 0.5%). Eleven TAP1-TAP2 haplotypes were observed with $frequency{\geq}1%$, among which 4 haplotypes (A-B, B-A1, A-Bky2, and C-E) showed weak but significant positive linkage disequilibrium (P<0.05). When DRB1-DQB1 haplotypes were extended to TAP1 and TAP2 loci, much diversification of haplotypes was observed: 19 different DRB1-DQB1 haplotypes formed 58 different haplotypes extended to TAP1 and TAP2 loci. These results add more evidence to the view that recombination hotspot is present within and around TAP gene region. Conclusion: The allele frequencies of TAP1 and TAP2 genes and the distribution of TAP1-TAP2 and HLA-TAP haplotypes were studied in Koreans based on a family study.

• BMB Reports
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• v.31 no.2
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• pp.111-116
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• 1998

HLA-DR4 is the dominant allele of MHC class II genes in Koreans. In particular, the $DRB1^*0405$ subtype has been reported to be almost exclusively expressed in Far East Asians, and has also been observed to be strongly associated with rheumatoid arthritis in Koreans and the Japanese. Identification of this specific allele has been mainly performed by PCR-based methods, which is often time consuming, costly, and involves tedious procedures such as the isolation of genomic DNA, PCR, and gel electrophoresis. To develop a more convenient tool for screening vast amounts of samples as well as to generate reagents which might also be used in other applications, in this study, antibodies were produced against this specific HLA subtype. By PCR, an allelespecific region covering the ${\beta}1$ domain of $DRB1^*0405$ was amplified and recombinantly expressed in E.coli. Immunization of Lewis rats with the purified protein yielded an allele specific antiserum. Western blot analysis showed the selective detection of the HLA-DR ${\beta}-chain$. Using this antiserum, established cell lines and peripheral blood lymphocytes were analyzed on their HLA haplotype by fluorescence activated flow cytometry. These novel antibodies will provide a powerful tool in the detection and investigation of DR4 alleles.

• Childhood Kidney Diseases
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• v.4 no.1
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• pp.33-39
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• 2000

Purpose: Our study was designed to investigate the association of MHC Class II (DR, DQ) allele with IgA nephropathy and its significance as a prognostic factor for progression to ESRD Material and Methods: 69 children with IgA nephropathy with normal renal function(serum creatinine $\leq$ 1.5mg/dL) was classified as group A and 70 patients who received renal transplantation due to IgA nephropathy were selected as group B. The HLA-DQB1 and HLA-DRB1 alleles were studied by polymerase chain reaction using sequence specific primers. We have compared the difference in alleles between these two groups and with normal control and also examined any possible effect of the MHC class II genes on the histopathological severity and prognosis of IgAN. Results: Mean age was $8.8{\pm}2.9$ years in group A and $35.0{\pm}15.5$ years in group B. Male to female ratio was 2.8:1 in group A and 2.5:1 in group B. There was a significantly higher frequency of HLA-$DQB1^*03\;and\;DQB1^*05$ in Group B. The frequency of HLA-$DQB1^*0302\;and\;^*05031$ allele had increasing tendency in Group B(P<0.05). HLA-$DRB1^*03\;and\;^*05$ were more common in Group B(P<0.05). HLA-$DRB1^*04$ allele was the most common DR alleles in both group, but there was no statistical significance. There were no significant correlation with MHC class 13 genes on the hjstopathological severity in Group A. Conclusion: In conclusion, $HLA-DQB1^*0302\;and\;HLA-DQB1^*05031 $ allele seemed to be more common in transplanted patients compared to group with normal renal function suggesting that this allele is associated with poor prognosis in IgAN. However larger studies and follow up are required to confirm this due to uncharacterized heterogeneity in etiopathogenesis of IgA nephropathy and possibly one or more than one gene may exert influence in determining susceptibility to the diseases.

• Clinical and Experimental Pediatrics
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• v.46 no.5
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• pp.467-473
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• 2003

Purpose : The Epstein-Barr virus(EBV), gamma herpesvirus, is an important pathogen that is widespread around the world. The EBV causes various diseases depending on the geographic location, and on the immunity or the premorbid condition of the person exposed to EBV. To evaluate EBV typing may be the most important step to figure out the pathogenesis of EBV associated diseases, and we need to re-evaluate the pathologic role of human leukocyte antigen(HLA) in developing Epstein- Barr virus associated acute infectious mononucleosis by using newly developed methods. Methods : This study included 24 children(age range : 6 to 13 years), serologically confirmed with acute infectious mononucleosis. The control group for the HLA type consisted of 200 age-matched healthy children. To classify HLA I, modified ARMs-PCR was used, while modified PCR-SSOP was utilized in typing of HLA II. Also, we performed EBV typing in study patients by using a one-step PCR. Results : The results of HLA types : In HLA class I, HLA-A24 was positive in 69 of 200 healthy children and positive in 14 of 24 patients in the study group(relative risk : 3.5724, chi-square; 5.26, P<0.05). In HLA class II, HLA-DRB1*07 was detected in 18 of 200 healthy children, and eight of 24 patients in the study group(relative risk; 506173, chi-square; 9.73, P<0.01). The results of EBV types : In the research group, 20(83.8%) of 24 patients were shedding type A virus, while 4(16.7%) were type B. Conclusion : We conclude that development of infectious mononucleosis may be associated with HLA types, and these results suggest that acute infectious mononucleosis could have hereditary traits. And we confirm that type A EBV is highly prevalent in patients with acute infectious mononucleosis in Korea. Also, our results suggest that further large scale studies, including adult groups, regarding the association between pathogenesis of EBV with HLA-DP or HLA-DQ will be warranted.

• 대한위암학회:학술대회논문집
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• 2005.10a
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• pp.27-27
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• 2005

• Parasites, Hosts and Diseases
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• v.40 no.4
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• pp.165-172
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• 2002

Collaborative studies have identified some genetic factors contributing to the development of severe forms of malaria and schistosomiasis. In Thailand, the $TNF-{\alpha}{\;}5'-flanking$ region shows biallelic polymorphic sites at nucleotides -238, -308, -857, -863, and -1031, and seven alleles have been identified in patients from Myanmar. We found that the TNF promoter (TNFP)-D allele was significantly associated with cerebral malaria in populations from Karen (P < 0.0001. OR ＝ 124.86) and ethnic Burma (P < 0.0001, OR = 34.50) . In China, we have identified two major genes related to the severity of liver fibrosis, one an HLA class II gene, and the other the IL-13 gene. The frequency of the HLA- DRB5*0101 allele and that of the IL-13 promoter A/A (IL- l3P- A/A) genotype were elevated in fibrotic patients, although the two genes are located on different chromosomes, chromosomes 6p and 5q, respectively Subjects with both genotypes had odds ratios (OR = 24.5) much higher than the sum of the ratios for each individual genotype (OR ＝ 5.1,95% Confidence Interval 1.3-24.7 for HLA-DRB5*0101, OR ＝ 3.1 95% CI 1.5 - 6.5 for IL-l3P-A/A). That the effects of the two susceptibility markers are synergistic rather than additive, strongly suggests that the pathogenic Th2 response directly influences the prognosis of post-schistosomal liver fibrosis.

• Dementia and Neurocognitive Disorders
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• v.17 no.4
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• pp.131-136
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• 2018

Alzheimer's disease (AD) related genes have been elucidated by advanced genetic techniques. Familial autosomal dominant AD genes founded by linkage analyses are APP, PSEN1, PSEN2, ABCA7, and SORL1. Genome-wide association studies have found risk genes such as ABCA7, BIN1, CASS4, CD33, CD2AP, CELF1, CLU, CR1, DSG2, EPHA1, FERMT2, HLA-DRB5-HLA-DRB1, INPP5D, MEF2C, MS4A6A/MS4A4E, NME8, PICALM, PTK2B, SLC24A4, SORL1, and ZCWPW1. ABCA7, SORL1, TREM2, and APOE are proved to have high odds ratio (>2) in risk of AD using next generation sequencing studies. Thanks to the promising genetic techniques such as CRISPR-CAS9 and single-cell RNA sequencing opened a new era in genetics. CRISPR-CAS9 can directly link genetic knowledge to future treatment. Single-cell RNA sequencing are providing useful information on cell biology and pathogenesis of diverse diseases.