[Show abstract][Hide abstract]ABSTRACT: Background:
Recent genome-wide association studies (GWAS) and a meta-analysis of GWAS for atopic dermatitis (AD) have identified some AD genetic loci in European and Japanese populations.
To investigate whether some novel susceptibility loci are associated with AD in the Chinese Han population.
We first selected eight novel susceptibility loci to replicate in 2,205 AD patients and 2,116 healthy controls using the Sequenom platform. Data were analyzed with PLINK 1.07 software.
We found that rs12634229 (3q13.2), rs7927894 (11p13.5) and rs878860 (11p15.4) showed a slight association with AD (P = 0.012, P = 0.033, P = 0.020, respectively); rs6780220 (3p21.33) was preferentially related to AD with keratosis pilaris, but did not reach the threshold of significance after correction. The frequency of rs7927894 allele T was significantly different between AD patients with a positive and negative family history of atopy.
The loci rs7927894 (11p13.5) are related to AD with a positive family history of atopy in Chinese Han population, providing novel insight into the genetic pathogenesis of AD.
Preview · Article · Mar 2016 · Asian Pacific journal of allergy and immunology / launched by the Allergy and Immunology Society of Thailand
[Show abstract][Hide abstract]ABSTRACT: IgA nephropathy (IgAN) is one of the most common primary glomerulonephritis. Previously identified genome-wide association study (GWAS) loci explain only a fraction of disease risk. To identify novel susceptibility loci in Han Chinese, we conduct a four-stage GWAS comprising 8,313 cases and 19,680 controls. Here, we show novel associations at ST6GAL1 on 3q27.3 (rs7634389, odds ratio (OR)=1.13, P=7.27 × 10(-10)), ACCS on 11p11.2 (rs2074038, OR=1.14, P=3.93 × 10(-9)) and ODF1-KLF10 on 8q22.3 (rs2033562, OR=1.13, P=1.41 × 10(-9)), validate a recently reported association at ITGAX-ITGAM on 16p11.2 (rs7190997, OR=1.22, P=2.26 × 10(-19)), and identify three independent signals within the DEFA locus (rs2738058, P=1.15 × 10(-19); rs12716641, P=9.53 × 10(-9); rs9314614, P=4.25 × 10(-9), multivariate association). The risk variants on 3q27.3 and 11p11.2 show strong association with mRNA expression levels in blood cells while allele frequencies of the risk variants within ST6GAL1, ACCS and DEFA correlate with geographical variation in IgAN prevalence. Our findings expand our understanding on IgAN genetic susceptibility and provide novel biological insights into molecular mechanisms underlying IgAN.
Full-text · Article · Jun 2015 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: Genetic interaction has been considered as a hallmark of the genetic architecture of systemic lupus erythematosus (SLE). Based on two independent genome-wide association studies (GWAS) on Chinese populations, we performed a genome-wide search for genetic interactions contributing to SLE susceptibility.
The study involved a total of 1 659 cases and 3 398 controls in the discovery stage and 2 612 cases and 3 441 controls in three cohorts for replication. Logistic regression and multifactor dimensionality reduction were used to search for genetic interaction.
Interaction of CD80 (rs2222631) and ALOX5AP (rs12876893) was found to be significantly associated with SLE (OR_int=1.16, P_int_all=7.7E-04 at false discovery rate<0.05). Single nuclear polymorphism rs2222631 was found associated with SLE with genome-wide significance (P_all=4.5E-08, OR=0.86) and is independent of rs6804441 in CD80, whose association was reported previously. Significant correlation was observed between expression of these two genes in healthy controls and SLE cases, together with differential expression of these genes between cases and controls, observed from individuals from the Hong Kong cohort. Genetic interactions between BLK (rs13277113) and DDX6 (rs4639966), and between TNFSF4 (rs844648) and PXK (rs6445975) were also observed in both GWAS data sets.
Our study represents the first genome-wide evaluation of epistasis interactions on SLE and the findings suggest interactions and independent variants may help partially explain missing heritability for complex diseases.
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Full-text · Article · Apr 2015 · Annals of the rheumatic diseases
[Show abstract][Hide abstract]ABSTRACT: Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease. Currently, numerous genetic loci of SLE have been confirmed. Here we try to further explore additional genes contributing to SLE susceptibility in this study.
Forty nine single nucleotide polymorphisms (SNPs) with moderate-risk for SLE in previous study were genotyped in a large-scale replication study with a total of 3,522 cases and 8,252 controls using the Sequenom Massarray system. Association analyses were performed using logistic regression with gender or sample cohorts as a covariate through PLINK 1.07 software.
This replication effort confirmed five reported SLE susceptibility loci reaching genome-wide levels of significance (P meta <5.00 × 10(-08)): TNFSF4 (rs1418190, odds ratio (OR) = 0.81, P meta = 1.08 × 10(-08); rs4916219, OR = 0.80, P meta = 7.77 × 10(-09)), IRF8 (rs2934498, OR = 1.25, P meta = 4.97 × 10(-09)), miR-146a (rs2431697, OR = 0.69, P meta = 1.15 × 10(-22)), CD44 (rs2732547, OR = 0.82, P meta = 1.55 × 10(-11)), and TMEM39A (rs12494314, OR = 0.84, P meta = 1.01 × 10(-09)). Further logistic regression analysis indicated that the genetic effects within TNFSF4 detected in this study are independent from our previously reported signals.
This study increases the number of established susceptibility loci for SLE in Han Chinese population and highlights the contribution of multiple variants of modest effect. Although further studies will be required to identify the causal alleles within these loci, the findings make a significant step forward in our understanding of the genetic contribution to SLE in Chinese population.
Full-text · Article · Mar 2015 · Arthritis research & therapy
[Show abstract][Hide abstract]ABSTRACT: Systemic lupus erythematosus (SLE) is a heterogeneous disease with a diverse spectrum of clinical symptoms from skin rash to end-organ damage. 22q11.21 has been identified as a susceptibility region for several autoimmune diseases, including SLE. However, the detailed information for SLE association and the underlying functional mechanism(s) are still lacking.
Through meta-analysis of two genome-wide association studies (GWAS) on Chinese Han populations with a total of 1659 cases and 3398 controls matched geographically, we closely examined this region, especially on the reported single nucleotide polymorphisms (SNPs) associated with different autoimmune diseases and their relationships. We further replicated the most significant association SNP with SLE using 2612 cases and 2323 controls of Asian ancestry.
All reported SNPs in this region with different autoimmune diseases were examined in the two GWAS data and meta- analysis result, and supportive evidence of association with SLE was found (meta-analysis P_meta ≤ 7.27E-05), which might require further investigation. SNP rs2298428 was identified as the most significant SNP associated with SLE in this region (P_meta = 2.70E-09). It showed independent effect through both stepwise and conditional logistic regression, and there is no evidence of other independent association signals for SLE in this region. The association of rs2298428 was further replicated in three cohorts from Hong Kong, Anhui and Thailand with a total of 2612 cases and 2323 controls (joint analysis of GWAS and replication result P_all = 1.31E-11, OR = 1.23). SNP rs2298428 was shown to be an eQTL for UBE2L3 gene in different cell types, with the risk allele (T) being correlated with higher expression of UBE2L3. This is consistent with earlier reports on higher expression of UBE2L3 in SLE cases.
Association to distinct autoimmune diseases highlights the significance of this region in autoreactive responses and potentially shared functional mechanisms by these diseases.
Full-text · Article · Mar 2015 · Arthritis research & therapy
[Show abstract][Hide abstract]ABSTRACT: Systemic lupus erythematosus (SLE) is a prototypic autoimmune disease that affects mainly females. What role the X chromosome
plays in the disease has always been an intriguing question. In this study, we examined the genetic variants on the X chromosome
through meta-analysis of two genome-wide association studies (GWAS) on SLE on Chinese Han populations. Prominent association
signals from the meta-analysis were replicated in 4 additional Asian cohorts, with a total of 5373 cases and 9166 matched
controls. We identified a novel variant in PRPS2 on Xp22.3 as associated with SLE with genome-wide significance (rs7062536, OR = 0.84, P = 1.00E−08). Association of the L1CAM-MECP2 region with SLE was reported previously. In this study, we identified independent contributors in this region in NAA10 (rs2071128, OR = 0.81, P = 2.19E−13) and TMEM187 (rs17422, OR = 0.75, P = 1.47E−15), in addition to replicating the association from IRAK1-MECP2 region (rs1059702, OR = 0.71, P = 2.40E−18) in Asian cohorts. The X-linked susceptibility variants showed higher effect size in males than that in females,
similar to results from a genome-wide survey of associated SNPs on the autosomes. These results suggest that susceptibility
genes identified on the X chromosome, while contributing to disease predisposition, might not contribute significantly to
the female predominance of this prototype autoimmune disease.
Full-text · Article · Aug 2014 · Human Molecular Genetics
[Show abstract][Hide abstract]ABSTRACT: We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in individuals of Chinese ancestry (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% confidence interval (CI) = 0.82-0.88; P = 7.72 × 10(-20)) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10 × 10(-13)). rs7447927 is a synonymous SNP in TMEM173, and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (OR = 1.33, 95% CI = 1.22-1.46; P = 1.99 × 10(-10)). Our joint analysis identifies new ESCC susceptibility loci overall as well as a new locus unique to the population in the Taihang Mountain region at high risk of ESCC.
[Show abstract][Hide abstract]ABSTRACT: Severe acne is a chronic inflammatory skin disorder characterized by widespread inflammatory lesions including nodules, cysts and potential scarring. Here we perform the first genome-wide association study of severe acne in a Chinese Han population comprising 1,056 cases and 1,056 controls using the Illumina HumanOmniZhongHua-8 BeadChip. In an independent cohort of 1,860 cases and 3,660 controls of Chinese Han, we replicate 101 SNPs of which 3 showed consistent association. We identify two new susceptibility loci at 11p11.2 (DDB2, rs747650, Pcombined=4.41 × 10(-9) and rs1060573, Pcombined=1.28 × 10(-8)) and 1q24.2 (SELL, rs7531806, Pcombined=1.20 × 10(-8)) that are involved in androgen metabolism, inflammation processes and scar formation in severe acne. These results point to new genetic susceptibility factors and suggest several new biological pathways related to severe acne.
No preview · Article · Jan 2014 · Nature Communications
[Show abstract][Hide abstract]ABSTRACT: The purpose of this study was to investigate whether risk of gastric cancer (GC) was associated with single nucleotide polymorphisms (SNPs) in a gene cluster on the chromosome 17q12-q21 (ERBB2 amplicon) in the Chinese Han population. We detected twenty-six SNPs in this gene cluster containing START domain containing 3 (STARD3), protein phosphatase 1 regulatory subunit 1B (PPP1R1B/DARPP32), titin-cap (TCAP), per1-like domain containing 1(PERLD1/CAB2), human epidermal growth factor receptor-2 (ERBB2/HER2), zinc-finger protein subfamily 1A 3 (ZNFN1A3/IKZF3) and DNA topoisomerase 2-alpha (TOP2A) genes in 311 patients with GC and in 425 controls by Sequenom. We found no associations between genetic variations and GC risk. However, hapolotype analysis implied that the haplotype CCCT of STARD3 (rs9972882, rs881844, rs11869286 and rs1877031) conferred a protective effect on the susceptibility to GC (P=0.043, odds ratio [OR]=0.805, 95% confidence intervals [95%CI]=0.643-0.992). The STARD3 rs1877031 TC genotype endued histogenesis of gastric mucinous adenocarcinoma and signet-ring cell carcinoma (P=0.021, OR=2.882, 95%CI=1.173-7.084). We examined the expression of STARD3 in 243 tumor tissues out of the 311 GC patients and 20 adjacent normal gastric tissues using immumohistochemical (IHC) analysis and tissue microarrays (TMA). Expression of STARD3 was observed in the gastric parietal cells and in gastric tumor tissues and significantly correlated with gender (P=0.004), alcohol drinking (P<0.001), tumor location (P=0.007), histological type (P=0.005) and differentiation (P=0.023) in GC. We concluded that the combined effect of haplotype CCCT of STARD3 might affect GC susceptibility. STARD3 expression might be related to the tumorigenesis of GC in the Chinese population.
[Show abstract][Hide abstract]ABSTRACT: Our previous genome-wide association studies on SLE have identified several susceptibility genes involved in NF-κB signaling pathway, including TNFSF4, TNFAIP3, TNIP1, BLK, SLC15A4 and UBE2L3. The aim of this study is to investigate the association model (additive, dominant, recessive) of these genes and search for possible gene-gene interactions between them. In this study, we explored the association model of these six genes and search for possible gene-gene interactions based on identified single-nucleotide polymorphisms (SNPs) among them by using logistic regression analysis in the combined sample of 4,199 cases and 8,255 controls. The most significant association evidence was observed under recessive model for all of these SNPs. Besides, significant interactions between these SNPs were observed in this study: the TNFSF4 and TNIP1 SNPs (P adjusted = 1.68E-10), the TNFSF4 and SLC15A4 SNPs (P adjusted = 3.55E-08), the TNFSF4 and UBE2L3 SNPs (P adjusted = 8.74E-13), the TNIP1 and BLK SNPs (P adjusted = 9.45E-10), the TNIP1 and UBE2L3 SNPs (P adjusted = 8.25E-11), the TNFAIP3 and UBE2L3 SNPs (P adjusted = 3.06E-14) and the BLK and SLC15A4 SNPs (P adjusted = 4.51E-12). These results may contribute to our understanding of SLE genetic interactions and account for the additional risk of certain patients to develop SLE.
No preview · Article · Oct 2013 · Rheumatology International
[Show abstract][Hide abstract]ABSTRACT: Genome-wide association studies (GWASs) have revealed a large number of genetic risk loci for many autoimmune diseases. One clear finding emerging from the published genetic studies of autoimmunity is that different autoimmune diseases, such as psoriasis and systemic lupus erythematosus (SLE), share susceptibility loci. Our study explores additional susceptibility loci shared by psoriasis and SLE in the Chinese Han population.
In total, 20 single nucleotide polymorphisms (SNPs) in 17 previously reported psoriasis susceptibility loci and 34 SNPs from 24 previously reported SLE susceptibility loci were investigated in our initial psoriasis and SLE GWAS dataset. Among these SNPs, we selected two SNPs (rs8016947 and rs4649203) with association values of p<5×10(-2) for both diseases in the GWAS data for further investigation in psoriasis (7260 cases and 9842 controls) and SLE (2207 cases and 9842 controls) using a Sequenom MassARRAY system.
We found that these two SNPs (rs8016947 and rs4649203) in two loci (NFKBIA and IL28RA) were associated with psoriasis and SLE with genome-wide significance (Pcombined<5×10(-8) in psoriasis and Pcombined<5×10(-8) in SLE): rs8016947 at NFKBIA (Pcombined-psoriasis=3.90×10(-10), Pcombined-SLE=1.08×10(-13)) and rs4649203 at IL28RA (Pcombined-psoriasis=3.91×10(-12), Pcombined-SLE=9.90×10(-9)).
These results showed that two common susceptibility loci (NFKBIA and IL28RA) are shared by psoriasis and SLE in the Chinese Han population.
No preview · Article · Sep 2013 · Journal of Medical Genetics