We extended our previous GWAS for psoriasis with a a multistage replication study including 8,312 cases and 12,919 controls from China as well as 3,293 cases, 4,188 controls from Germany and the USA, and 254 nuclear families from the USA. We identified 6 new susceptibility loci associated to psoriasis in Chinese, containing candidate genes ERAP1, PTTG1, CSMD1, GJB2, SERPINB8, ZNF816A (PCombined<5×10−8) and replicated one locus 5q33.1 (TNIP1/ANXA6) previously reported (PCombined=3.8×10−21) in European studies. Two of these loci showed evidence for association evidence in the German study, at ZNF816A and GJB2 with P=3.6×10−3 and P=7.9×10−3, respectively. ERAP1 and ZNF816A were preferentially associated with Type I (early onset) psoriasis in Chinese Han population (test for heterogeneity P=6.5×10−3 and P=1.5×10−3, respectively). Comparisons with previous GWAS of psoriasis highlight the heterogeneity of disease susceptibility between Chinese and European populations. Our study identifies new genetic susceptibility factors and suggests new biological pathways in psoriasis.
We conducted a genome-wide association study of generalized vitiligo in the Chinese Han population by genotyping 1,117 cases and 1,429 controls. The 34 most promising SNPs were carried forward for replication in samples from individuals of the Chinese Han (5,910 cases and 9,916 controls) and Chinese Uygur (713 cases and 824 controls) populations. We identified two independent association signals within the major histocompatibility complex (MHC) region (rs11966200, Pcombined=1.48x10(-48), OR=1.90; rs9468925, Pcombined=2.21x10(-33), OR=0.74). Further analyses suggested that the strong association at rs11966200 might reflect the reported association of the HLA-A*3001, HLA-B*1302, HLA-C*0602 and HLA-DRB1*0701 alleles and that the association at rs9468925 might represent a previously unknown HLA susceptibility allele. We also identified one previously undescribed risk locus at 6q27 (rs2236313, Pcombined=9.72x10(-17), OR=1.20), which contains three genes: RNASET2, FGFR1OP and CCR6. Our study provides new insights into the genetic basis of vitiligo.
Graves' disease is a common autoimmune disorder characterized by thyroid stimulating hormone receptor autoantibodies (TRAb) and hyperthyroidism. To investigate the genetic architecture of Graves' disease, we conducted a genome-wide association study in 1,536 individuals with Graves' disease (cases) and 1,516 controls. We further evaluated a group of associated SNPs in a second set of 3,994 cases and 3,510 controls. We confirmed four previously reported loci (in the major histocompatibility complex, TSHR, CTLA4 and FCRL3) and identified two new susceptibility loci (the RNASET2-FGFR1OP-CCR6 region at 6q27 (P(combined) = 6.85 × 10(-10) for rs9355610) and an intergenic region at 4p14 (P(combined) = 1.08 × 10(-13) for rs6832151)). These newly associated SNPs were correlated with the expression levels of RNASET2 at 6q27, of CHRNA9 and of a previously uncharacterized gene at 4p14, respectively. Moreover, we identified strong associations of TSHR and major histocompatibility complex class II variants with persistently TRAb-positive Graves' disease.
UDP-glucuronosyltransferases (UGTs) play an important role in the metabolism and excretion of various endogenous and xenobiotic compounds, including carcinogens and chemotherapeutic agents. The goal of the present study was to examine UGT2A1 expression in human tissues, determine its glucuronidation activity against tobacco carcinogens, and assess the potential functional role of UGT2A1 missense single nucleotide polymorphisms on UGT2A1 enzyme activity. As determined by reverse-transcription polymerase chain reaction, UGT2A1 was expressed in aerodigestive tract tissues including trachea, larynx and tonsil, and was also expressed in lung and colon; no expression was observed in breast, whole brain, pancreas, prostate, kidney, liver or esophagus. Real-time PCR suggested that UGT2A1 exhibited highest expression in the lung, followed by trachea > tonsil > larynx > colon > olfactory tissue. Cell homogenates prepared from wild-type UGT2A175Lys308Gly-over-expressing HEK293 cells showed significant glucuronidation activity, as observed by reverse-phase UPLC, against a variety of polycyclic aromatic hydrocarbons (PAHs) including, 1-hydroxy-benzo(a)pyrene, benzo(a)pyrene-7,8-diol, and 5-methylchrysene-1,2-diol. No activity was observed in UGT2A1-over-expressing cell homogenate against substrates that form N-glucuronides, such as NNAL, nicotine, or N-OH-PhIP. A significant (p<0.05) ~25% decrease in glucuronidation activity (Vmax/KM) was observed against all PAH substrates for the UGT2A175Arg308Gly variant as compared to homogenates from wild-type UGT2A175Lys308Gly; no activity was observed for cell homogenates over-expressing the UGT2A175Lys308Arg variant for all substrates tested. These data suggest that UGT2A1 is an important detoxification enzyme in the metabolism of PAHs within target tissues for tobacco carcinogens, and functional polymorphisms in UGT2A1 may play a role in tobacco-related cancer risk.
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