Il Kim

Kallikrein genes are associated with lupus and glomerular basement membrane-specific antibody-induced nephritis in mice and humans.

Immune-mediated nephritis contributes to disease in systemic lupus erythematosus, Goodpasture syndrome (caused by antibodies specific for glomerular basement membrane [anti-GBM antibodies]), and spontaneous lupus nephritis. Inbred mouse strains differ in susceptibility to anti-GBM antibody-induced and spontaneous lupus nephritis. This study sought to clarify the genetic and molecular factors that maybe responsible for enhanced immune-mediated renal disease in these models. When the kidneys of 3 mouse strains sensitive to anti-GBM antibody-induced nephritis were compared with those of 2 control strains using microarray analysis, one-fifth of the underexpressed genes belonged to the kallikrein gene family,which encodes serine esterases. Mouse strains that upregulated renal and urinary kallikreins exhibited less evidence of disease. Antagonizing the kallikrein pathway augmented disease, while agonists dampened the severity of anti-GBM antibody-induced nephritis. In addition, nephritis-sensitive mouse strains had kallikrein haplotypes that were distinct from those of control strains, including several regulatory polymorphisms,some of which were associated with functional consequences. Indeed, increased susceptibility to anti-GBM antibody-induced nephritis and spontaneous lupus nephritis was achieved by breeding mice with a genetic interval harboring the kallikrein genes onto a disease-resistant background. Finally, both human SLE and spontaneous lupus nephritis were found to be associated with kallikrein genes, particularly KLK1 and the KLK3 promoter, when DNA SNPs from independent cohorts of SLE patients and controls were compared. Collectively, these studies suggest that kallikreins are protective disease-associated genes in anti-GBM antibody-induced nephritis and lupus.

Genetic associations of LYN with systemic lupus erythematosus.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case–control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 × 10−4, odds ratio (OR)=0.81 (95% confidence interval: 0.73–0.90)). This single nucleotide polymorphism (SNP) is located in the 5′ untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 × 10−3, OR=0.75 (95% CI: 0.62−0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets.

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.

Putative Role of Functional Interferon Regulatory Factor 5 (IRF5) Polymorphism in Rheumatoid Arthritis in a Korean Population

Objective Recent studies suggest that polymorphisms of interferon regulatory factor 5 (IRF5) are significantly associated with systemic lupus erythematosus in several populations. The effect of IRF5 polymorphism on susceptibility to rheumatoid arthritis (RA) has been investigated, and the results were inconsistent. We analyzed the genetic effects of IRF5 polymorphisms on RA in a Korean population. Methods Eight single-nucleotide polymorphisms (SNP) and 2 insertion-deletion polymorphisms in IRF5 were genotyped in 2183 subjects (1204 RA cases and 979 controls) using the TaqMan® method. The genetic effects of SNP on the risk of RA were evaluated using chi-square tests and multivariate logistic regression, controlling for age, sex, and shared epitope (SE), and we then performed conditional analysis by SE status and anti-cyclic citrullinated peptide (anti-CCP) antibody (Ab) status. Data from a Mantel-Haenszel metaanalysis of odds ratios (OR) were subsequently combined in a separate analysis with the results of the association of rs2004640 with RA from a previous study. Results Two of the IRF5 polymorphisms, CGGGGindel (OR 1.38, 95% CI 1.09–1.76, pcorr = 0.04) and rs2004640 (OR 1.36, 95% CI 1.09–1.68, pcorr = 0.03), and one haplotype, including the rs2004640 and the CGGGGindel, ht3 (A-Del-T-C-del-A-T) (OR 1.39, 95% CI 1.09–1.79, pcorr = 0.04) were significantly associated with an increased risk of RA. After stratification according to anti-CCPAb and SE status, rs2004640 SNP was associated with the anti-CCPAb-positive (OR 1.47, 95% CI 1.15–1.88, pcorr = 0.01) or SE-positive group (OR 1.54, 95% CI 1.14–2.09, pcorr = 0.03). A combined analysis including all 3 independent cohorts from the previous study revealed an association of the rs2004640 with RA (pooled OR 1.21, 95% CI 1.07–1.38, pooled p = 0.0031 in dominant model). Conclusion Our results suggest that the IRF5 polymorphism is associated with genetic susceptibility to RA at least in a Korean population, and that it may contribute to disease susceptibility in SE-positive or anti-CCP Ab-positive patients with RA.

No association between interleukin 23 receptor gene polymorphisms and systemic lupus erythematosus

The objective of this study was to elucidate whether polymorphisms of the interleukin 23 receptor gene (IL23R) are associated with susceptibility to systemic lupus erythematosus (SLE) in a Korean population. We recruited 602 SLE patients and 991 healthy controls. Seven single nucleotide polymorphisms (rs1004819, rs7517847, rs10489629, rs2201841, rs1343151, rs11209032, and rs1495965) were selected for genotyping among previously reported variants used in a genome-wide association study of inflammatory bowel disease. Polymorphic sites were genotyped using the TaqMan assay. The genotype distributions of IL23R polymorphisms and haplotypes were compared between the SLE patients and healthy controls using multiple logistic regression models. None of the IL23R genetic variants differed significantly between SLE patients and healthy controls, which suggests that IL23R polymorphisms play no role in the susceptibility to SLE in the Korean population.

Different Genetic Effects of Interferon Regulatory Factor 5 (IRF5) Polymorphisms on Systemic Lupus Erythematosus in a Korean Population

Objective In an effort to replicate additional associations of interferon regulatory factor 5 (IRF5) polymorphisms with systemic lupus erythematosus (SLE) in an Asian population, we examined those genetic effects in a Korean SLE cohort. Methods Each IRF5 polymorphism was genotyped in 1565 subjects using the TaqMan method and examined to determine whether it could explain the association with SLE. Results Three single-nucleotide polymorphisms (IRF5-15-1, rs2070197, and rs10488631), which showed strong and/or independent association in Caucasian populations, were not polymorphic in our Korean population. Association analysis revealed different genetic effects in Koreans compared with Caucasian populations. In addition, conditional analysis suggested independent genetic effects of 3 variant groups in the Korean population. Conclusion We demonstrate different genetic effects of IRF5 polymorphisms on the risk of SLE according to ethnicity.

Association of genetic polymorphisms in CD40 with susceptibility to SLE in the Korean population

OBJECTIVE The aim of this study was to examine the association of CD40 polymorphisms with the risk of SLE in the Korean population. METHODS A total of 601 Korean SLE patients and 984 healthy controls were enrolled. We selected seven CD40 gene SNPs based on previous results of CD40 gene sequencing in the Korean population. Statistical analysis was carried out by logistic regression, controlling for age and sex as covariates. Odds ratios (ORs) and P-values in co-dominant, dominant and recessive models were also calculated. RESULTS SNP rs3765456 showed significant association with risk of SLE (OR = 1.34, P = 0.007, Pcorr = 0.03) in the dominant model. SNPs rs1883832 and rs4810485, and haplotype 2 (GTTCTAA) were also associated with the risk of SLE in the dominant model, but statistical significance disappeared after correction for multiple testing. Haplotype 2 had a protective effect on LN (OR = 0.47, P = 0.01, Pcorr = 0.05) in the recessive model while rs73115010, rs6074028 and haplotype 3 (ACGTCGG) resulted in increased risk of arthritis in the recessive model (OR = 2.87, 2.76 and 2.46, P = 0.002, 0.004 and 0.01, Pcorr = 0.009, 0.02 and 0.05, respectively). CONCLUSION CD40 gene polymorphisms are possible risk factors for SLE development, especially rs3765456 in the dominant model. CD40 polymorphisms are also associated with SLE clinical manifestation, mainly nephritis and arthritis. Further replication with larger numbers, and populations of different ethnicities, are needed to confirm our findings.

Erratum: Genetic associations of LYN with systemic lupus erythematosus (Genes and Immunity (2009) 10 (397-403) DOI: 10.1038/gene.2009.19)

R Lu, GS Vidal, JA Kelly, AM Delgado-Vega, XK Howard, SR Macwana, N Dominguez, W Klein, C Burrell, IT Harley, KM Kaufman, GR Bruner, KL Moser, PM Gaffney, GS Gilkeson, EK Wakeland, Q-Z Li, CD Langefeld, MC Marion, J Divers, GS Alarcón, EE Brown, RP Kimberly, JC Edberg, R Ramsey-Goldman, JD Reveille, G McGwin Jr, LM Vilá, MA Petri, S-C Bae, S-K Cho, S-Y Bang, I Kim, CB Choi, J Martin, TJ Vyse, JT Merrill, JB Harley, ME Alarcón-Riquelme, SK Nath, JA James and JM Guthridge, for the BIOLUPUS and GENLES Multicenter Collaborations