Kim Th

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.

Ethnic specificity of lupus-associated loci identified in a genome-wide association study in Korean women

Objectives To identify novel genetic candidates for systemic lupus erythematosus (SLE) in the Korean population, and to validate the risk loci for SLE identified in previous genome-wide association studies (GWAS). Methods We performed a GWAS in 400 Korean female SLE patients and 445 controls. Selected single-nucleotide polymorphisms (SNP) were then replicated in an independent cohort of 385 SLE patients and 583 controls (replication cohort 1), and in a further 811 SLE patients and 1502 controls (replication cohort 2). Results In the GWAS phase, rs9275428 located near HLA-DQB1 showed the strongest association with SLE (OR 0.50, false discovery rate (FDR) p=3.07×10−6). Although no loci reached genome-wide significance outside major histocompatibility complex (MHC), C8orf13-BLK, STAT4, CSMD1, DIAPH3, GLDC and TNFSF4 showed FDR p < 0.05. Our results suggest that STAT4, BLK, IRF5, PTTG1-miR-146a, UBE2L3 and TNFAIP3 are shared susceptibility loci among Caucasians and Asians, while ETS1, IKZF1, SLC15A4 are likely to be Asian-specific loci. In a combined analysis of 1596 SLE patients and 2540 controls for selected 22 candidate SNP, STAT4 and BLK as positive controls showed a strong association with SLE (FDR p=9.85×10−13 and 2.28×10−8, respectively). Of these, 16 candidates (PEX5L, TRAJ50, MYO18B, SOS1, ARHGAP26, SMURF1, CADPS, HAND1, FAM78B, DIAPH3, TBL1XR1, CSMD1, ZBTB20, C3orf21, HIPK1 and AP001042.1) showed only nominal significance (7.05×10−4≤FDR p≤4.38×10−2). Conclusions There are similarities and differences in genetic susceptibility for SLE between Caucasian and Asian ethnic groups. Although 16 putative novel loci for SLE have been suggested in the Korean population, further research on a larger sample is required to discriminate truth from error.

Multiple gene polymorphisms can improve prediction of nonvertebral fracture in postmenopausal women.

Clinical risk factors (CRFs), with or without bone mineral density (BMD), are used to determine the risk of osteoporotic fracture (OF), which has a heritable component. In this study we investigated whether genetic profiling can additionally improve the ability to predict OF. Using 1229 unrelated Korean postmenopausal women, 39 single‐nucleotide polymorphisms (SNPs) in 30 human genomic loci were tested for association with osteoporosis‐related traits, such as BMD, osteoporosis, vertebral fracture (VF), nonvertebral fracture (NVF), and any fracture. To estimate the effects of genetic profiling, the genetic risk score (GRS) was calculated using five prediction models: (Model I) GRSs only; (Model II) BMD only; (Model III) CRFs only; (Model IV) CRFs and BMD; and (Model V) CRFs, BMD, and GRS. A total of 21 SNPs within 19 genes associated with one or more osteoporosis‐related traits and were included for GRS calculation. GRS associated with BMD before and after adjustment for CRFs (p ranging from <0.001 to 0.018). GRS associated with NVF before and after adjustment for CRFs and BMD (p ranging from 0.017 to 0.045), and with any fracture after adjustment for CRFs and femur neck BMD (p = 0.049). In terms of predicting NVF, the area under the receiver operating characteristic curve (AUC) for Model I was 0.55, which was lower than the AUCs of Models II (0.60), III (0.64), and IV (0.65). Adding GRS to Model IV (in Model V) increased the AUC to 0.67, and improved the accuracy of NVF classification by 11.5% (p = 0.014). In terms of predicting any fracture, the AUC of Model V (0.68) was similar to that of Model IV (0.68), and Model V did not significantly improve the accuracy of any fracture classification (p = 0.39). Thus, genetic profiling may enhance the accuracy of NVF predictions and help to delineate the intervention threshold.

Response to Intravenous Cyclophosphamide Treatment for Lupus Nephritis Associated with Polymorphisms in the FCGR2B-FCRLA Locus

Objective. Cyclophosphamide (CYC) is an immunosuppressant drug widely used to treat various diseases including lupus nephritis, but its efficacy highly varies from individual to individual. This pharmacogenomics association study searched for genetic variations associated with CYC efficacy. Methods. Genome-wide association scan was performed for 109 Korean patients with systemic lupus erythematosus with lupus nephritis (classes III–V) who received intravenous CYC induction therapy. Genetic differences between responders and nonresponders were examined using Cochran–Armitage trend tests, and genotype imputation was used for defining the association locus. Results. Genetic polymorphisms in the Fcγ receptor gene (FCGR) cluster at human chromosome 1q23, previously associated with lupus nephritis susceptibility, were associated with the response to CYC treatment for lupus nephritis. Significant response association was found for 3 perfectly correlated (r2 = 1) single-nucleotide polymorphisms (SNP): rs6697139, rs10917686, and rs10917688, located between the FCGR2B and FCRLA genes (p = 3.4 × 10−8). Carriage of the minor alleles in these SNP was found only in nonresponders (31%) and none in responders (0%). Conclusion. This first genome-wide association approach for CYC response yielded a robust profile of genetic associations including large-effect SNP in the FCGR2B-FCRLA locus, which may provide better insights to CYC metabolism and efficacy.

Replicated association of a regulatory polymorphism in the interferon γ gene with lupus susceptibility

Single-nucleotide polymorphisms (SNPs) of the human interferon γ gene ( IFNG ) were found to be associated with susceptibility to systemic lupus erythematosus (SLE) in our recent case–control study on 1759 unrelated Korean participants (742 SLE patients and 1017 controls).1 In particular, the SLE-susceptible (minor) allele in an SNP (rs2430561) located on an NF-κB binding site in the first intron was associated with elevated IFNG expression,2,–,4 consistent with previous functional implications of high expression levels of IFNG in lupus pathogenesis in human disease and murine models,5,–,7 although this SNP showed no association in several previous small studies.8,–,10 In our original study,1 the effect size of this SNP was considerable with an OR of …