H.-S. Lee

The association between microsatellite polymorphisms in intron II of the human Toll-like receptor 2 gene and tuberculosis among Koreans

The observation that Toll-like receptor (TLR)2-deficient mice are highly susceptible to mycobacteria suggests that mutations altering TLR2 expression may impair host response to Mycobacterium tuberculosis. We evaluated the association between guanine-thymine (GT) repeat polymorphism in intron II of the TLR2 gene and the presence of tuberculosis (TB) in Koreans. The numbers of GT repeats were determined by PCR and gene scans for 176 TB patients and 196 controls. The recombinant TLR2 promoter/exonI/exonII/intronII/luciferase constructs including three representative repeats: (GT)13, (GT)20, and (GT)24 were transfected into K562 cells, and luciferase activities were estimated and compared. The expression of TLR2 on CD14+ peripheral blood mononuclear cells (PBMC) from healthy volunteers were measured with flow cytometry. Genotypes with shorter GT repeats were more common among TB patients (49.4 vs 37.7%, P=0.02). This observation was confirmed among 82 other TB patients as a validation cohort. Shorter GT repeats were associated with weaker promoter activities and lower TLR2 expression on CD14+ PBMCs. In conclusion, the development of TB disease in Koreans was associated with shorter GT repeats in intron II of the TLR2 gene. This association is correlated with lower expression of TLR2 through weaker promoter activity for genes with shorter GT repeats.

Angiotensin-converting enzyme gene polymorphism and vascular manifestations in Korean patients with SLE.

Systemic lupus erythematosus (SLE) is an inflammatory multisystem disease of unknown etiology with immunologic aberrations.Many studies have shown that genetic and environmental factors are implicated in the development of SLE. Angiotensin-converting enzyme (ACE) affects various immune phenomena through the renin–angiotensin and kallikrein–kininogen systems by creating angiotensin II and inactivating bradykinin. We investigated the correlation between insertion= deletion polymorphism of the ACE gene and the clinical manifestations of SLE, especially vascular involvement and lupus nephritis. Two-hundred and eleven Korean patients fulfilling the ACR criteria and 114 healthy subjects were enrolled. The ACE genotype was determined by polymerase chain reaction using genomic DNA from peripheral blood. The nephritis patients were classified by the WHO classification. In addition, the activity and chronicity index were used to assess the severity of renal involvement.We evaluated vascular involvement by the presence or absence of hypertension, Raynauds phenomenon, livedo reticularis, antineutrophil cytoplasmic antibody and the SLICC/ACR Damage Index. The gene frequency of ACE gene polymorphism was as follows: II 39 vs 34%, ID 41 vs 50%, DD 20 vs 16% in SLE patients and controls, respectively. There was no difference in genotype frequency between both groups. There were no significant differences between the distribution of ACE gene genotypes and lupus nephritis and its related parameters, including WHO classification, activity index, chronicity index, renal dysfunction and amount of 24 h urinary protein. The ACE genotypes and alleles did not affect the presence of vascular manifestations evaluated, but the frequency of DD genotype was significantly low in SLE patients with Raynauds phenomenon compared to those without Raynauds phenomenon (P=0.002 for ACE ID vs DD and II, OR 2.7, 95% CI 1.43–5.09; P=0.023 for ACE DD vs ID and II, OR 0.33, 95% CI 0.12–0.89). Also skewing from DD to II genotype was noted in patients with anti-Sm antibody compared to those without anti-Sm antibody (P=0.025 for ACE DD vs ID and II, OR 0.21, 95% CI 0.05–0.93). The onset age of serositis was older in patients with the ID genotype than the others (ID=34.5§ 10.8, II ‡ DD=25.6§ 10.2, P=0.002). Also the onset age of malar rash was older in patients with II genotype than the others (II=26.7§ 8.4, ID ‡ DD=21.3§ 9.0; P=0.021). The patients with I allele showed a significantly higher frequency of serositis (P=0.022). Taken together, the I/D polymorphisms of ACE gene did not affect susceptibility of SLE, lupus nephritis and the vascular manifestations, including Raynauds phenomenon, in Korean SLE patients, although the DD genotype was negatively associated with Raynauds phenomenon among SLE patients. However, it would be valuable to evaluate the role of other genes potentially related to vascular events, such as endothelin, nitric oxide or angiotensin II receptor as well as ACE gene.

What can we learn from genetic studies of systemic lupus erythematosus? Implications of genetic heterogeneity among populations in SLE

Recent progress in genetics has expanded the number of the genes associated with SLE to more than 20 in the past 2 years. One might assign these candidate genetic factors into several pre-existing biological pathways: (i) innate immune response including TLR/interferon signaling pathways (IRF5, STAT4, TNFAIP3, and TREX1); (ii) adaptive immune response (HLA-DR, PTPN22, PDCD1, STAT4, LYN, BLK, and BANK1) including B, T cells, and antigen-presenting cells; and (iii) immune complex clearance mechanism (FCGRs, CRP, and ITGAM). In addition, there are also several genes and loci that could not be assigned into previous known pathways (KIAA1542, PXK, XKR6, ATG5, etc), providing possible novel mechanisms in SLE. It has also been evident that there are similarities and differences in SLE susceptibility loci across ethnic groups. Here we categorize the susceptible genes into four groups. The first group is the consistently associated genes with similar risk allele frequency between multiple ethnic populations such as STAT4, TNFAIP3, BANK1, and IRAK1/MECP2. The second group is the genes that are consistently associated but show marked difference in risk allele frequency (BLK, IRF5). The third group is the genes in which different risk variants exist within a gene or genetic loci (allelic heterogeneity) such as HLA-DR, FCGRs, and IRF5. The fourth group is the genes that show consistently discrepancy between populations such as PTPN22 and possibly ITGAM, PXK, and LYN (genetic heterogeneity). The possible explanations for differences of susceptible genetic factors between populations could be different genetic backgrounds, contribution of gene—gene or gene—environment interaction, and the relation between marker and causal variants. Therefore, efforts to identify ethnic-specific genetic factors or disease causing variants should be necessary for individualized therapy for SLE in future.

Genetic studies of systemic lupus erythematosus in Asia: where are we now?

There have been many genetic studies of systemic lupus erythematosus (SLE) in Asia, but the status of SLE in Asia remains unclear. Genes that have been associated with SLE in Caucasians have shown both consistent and inconsistent results in Asians. This prompted us to review studies of SLE-associated genes and compare the degree of consistency according to ethnicity in Asia. We searched PubMed and the national databases in Korea and Japan for SLE genetic studies. A total of 755 articles were found and after applying various exclusion criteria, 442 studies including 17 linkage studies, 2 genome-wide association studies and 423 candidate-gene analyses were reviewed. Nine linkage loci were confirmed to be associated with SLE susceptibility in non-Asians, but the risk locus (16q12) has been identified in only one Asian study. A total of 156 candidate genes were analyzed, of which 92 were studied in Asians. Although there were allelic (HLA-DRB1 and IRF5) or genetic heterogeneity (FCGR gene family), HLA-DRB1, the FCGR gene family, IRF5, STAT4 and MECP2 showed consistent associations with SLE susceptibility across ethnicities. In conclusion, genetic associations often vary with ethnicity, requiring validation in different ethnic groups, and hence future SLE genetic studies will require strong worldwide collaborations.

The association between FcgRIIIB polymorphisms and systemic lupus erythematosus in Korea

Polymorphisms of FcgR have been proposed as genetic factors that influence susceptibility to SLE. FcgRIIIB polymorphism in systemic lupus erythematosus (SLE) have been studied in various populations, but the results were inconsistent. The aim of this study was to determine the association of FcgRIIIB polymorphism in Korean lupus patients. One-hundred and eighty-three SLE patients (166 female, 17 male) meeting 1982 ACR criteria and 300 Korean disease-free controls were enrolled. Genotyping for the FcgRIIIB NA1/NA2 was performed by PCR of genomic DNA using allele-specific primers. There was no significant skewing in the distribution of the three FcgRIIIB genotypes, and alleles between SLE and the controls. The frequency of FcgRIIIB genotypes in SLE patients and controls was FcgRIIIB NA1/NA1 27.9% versus 26%, NA1/NA2 55.2% versus 51.7%, NA2/NA2 16.9% versus 22.3%, respectively. The gene frequencies of NA1 allele were 0.56 in the SLE and 0.52 in controls, respectively. Among clinical manifestations, thrombocytopenia was more common in FcgRIIIB NA2/NA2 genotype (P = 0.04, OR 2.4, 95% CI 1.0-5.4), and NA2 allele (P = 0.03, OR 1.7, 95% CI 1.1-2.8). Although FcgRIIIB polymorphism was not associated with the development of SLE in Korean, thrombocytopenia was associated with FcgRIIIB NA2/NA2 genotype, and NA2 allele.

The association between interleukin-6 polymorphisms and systemic lupus erythematosus: a meta-analysis.

The aim of this study was to determine whether the functional interleukin-6 (IL-6) promoter -174 G/C and -572 G/C polymorphisms confer susceptibility to systemic lupus erythematosus (SLE) in ethnically different populations. Meta-analysis was conducted on the associations between the IL-6 polymorphisms and SLE using; 1) allele contrast, 2) the recessive model, 3) the dominant model, and 4) the additive model. A total of 11 studies were considered in this study, and ethnicity-specific meta-analysis was performed on European and Asian populations. Meta-analysis of the IL-6 -174 G/C polymorphism showed an association between SLE and the IL-6 -174 G allele in all study subjects (odds ratio (OR) = 1.344, 95% confidence interval (CI) = 1.052–1.718, p = 0.018). Furthermore, stratification by ethnicity indicated an association between the IL-6 -174 G allele and SLE in Europeans (OR = 1.264, 95% CI = 1.037–1.541, p = 0.020). Meta-analysis of the IL-6 -572 G/C polymorphism revealed that an association was found between SLE and the IL-6 -572 G/C polymorphism using the recessive model, but ethnicity-specific meta-analysis revealed no association between SLE and the IL-6 -572 G/C polymorphism in Asians. In conclusion, this meta-analysis demonstrates that the IL-6 -174 G/C polymorphism may confer susceptibility to SLE in Europeans, but that the IL-6 -572 G/C polymorphism is not associated with susceptibility to SLE in Asians.

Palindromic rheumatism: different genetic background implies a distinct disease entity

Palindromic rheumatism is characterised by multiple, episodic and recurrent attacks of arthritis, accompanied by periarticular inflammation without residual joint damage, occurring at irregular intervals and lasting from a few hours to several days.1–3 The definite pathogenesis and disease entity of palindromic rheumatism has not been clarified until now. We investigated the association of rheumatoid arthritis and palindromic rheumatism with regard to genotype by identifying the distribution of human leucocyte antigen (HLA)-DRB1 alleles in patients with palindromic rheumatism and controls in the Korean population. In all, 110 eligible patients with palindromic rheumatism (53 men and 57 women) were recruited. All enrolled patients met our inclusion criteria, which were based on diagnostic features previously described in the literature. …

Red ear(s) syndrome associated with child neuropsychiatric systemic lupus erythematosus

This case illustrates that a child having severe neuropsychiatric systemic lupus erythematosus (NPSLE) with seizure and cerebral vascular disease showed excellent clinical outcome in response to intravenous methylprednisolone and cyclophosphamide pulse, and presented unexplained red ears phenomenon.

Identifying fibromyalgia subgroups using cluster analysis: Relationships with clinical variables

Patients with fibromyalgia (FM) exhibit significant clinical heterogeneity, in terms of physical, social and psychological functions, as well as therapeutic responses. Here, we examined FM patients in terms of pain, physical, social and psychological variables to identify clinical subgroups that may be predictive of treatment patterns.

Observer design for exhaust gas recirculation rate estimation in a variable-geometry turbocharger diesel engine using a model reference identification scheme

Exhaust gas recirculation systems are used in diesel engines to reduce nitrogen oxide emissions. Since excessive recirculation in the cylinders may lead to an increase in generation of particulate matter and to unstable combustion, the exhaust gas recirculation rate should be measured correctly and should be controlled precisely. Unfortunately, the harsh conditions of the exhaust gas recirculation path make it difficult to measure the exhaust gas recirculation mass flow rate directly by using the relevant sensors. Therefore, precise control of the exhaust gas recirculation system depends on accurate estimation of the exhaust gas recirculation rate. To estimate accurately the exhaust gas recirculation rate in a turbocharged diesel engine, we propose an observer based on a model reference identification scheme. A linear parameter-varying model of the intake manifold pressure was derived to serve as the observer’s reference model. An update rule of the observer was designed with the model reference identification scheme. The intake and exhaust temperature models were developed through an empirical approach. Convergence of the proposed observer was proven in terms of the Lyapunov stability criterion. The proposed observer was implemented on a real-time embedded system and validated successfully through experiments on the engine.