We report the first large genome-wide association study (GWAS) in a Chinese population to identify susceptibility variants for psoriasis using a two-stage case-control design. In the first stage, we carried out a genome-wide association analysis in 1,139 cases and 1,132 controls of Chinese Han ancestry using Illumina Human 610-Quad BeadChips. In the second stage, we took top SNPs forward for replication in two independent samples of 5,182 cases and 6,516 controls of Chinese Han ancestry, and 539 cases and 824 controls of Chinese Uygur ancestry. In addition to the strong replication for two known susceptibility loci MHC (rs1265181, P = 1.93 x 10(-208), OR = 22.62) and IL12B (rs3213094, P(combined) = 2.58 x 10(-26), OR = 0.78), we identified a new susceptibility locus within the LCE gene cluster on 1q21 (rs4085613, P(combined) = 6.69 x 10(-30), OR = 0.76).

The radial spoke is a ubiquitous component of \u279+2\u27 cilia and flagella, and plays an essential role in the control of dynein arm activity by relaying signals from the central pair of microtubules to the arms. The Chlamydomonas reinhardtii radial spoke contains at least 23 proteins, only 8 of which have been characterized at the molecular level. Here, we use mass spectrometry to identify 10 additional radial spoke proteins. Many of the newly identified proteins in the spoke stalk are predicted to contain domains associated with signal transduction, including Ca2+-, AKAP- and nucleotide-binding domains. This suggests that the spoke stalk is both a scaffold for signaling molecules and itself a transducer of signals. Moreover, in addition to the recently described HSP40 family member, a second spoke stalk protein is predicted to be a molecular chaperone, implying that there is a sophisticated mechanism for the assembly of this large complex. Among the 18 spoke proteins identified to date, at least 12 have apparent homologs in humans, indicating that the radial spoke has been conserved throughout evolution. The human genes encoding these proteins are candidates for causing primary ciliary dyskinesia, a severe inherited disease involving missing or defective axonemal structures, including the radial spokes

Atopic dermatitis is a chronic, relapsing form of inflammatory skin disorder that is affected by genetic and environmental factors. We performed a genome-wide association study of atopic dermatitis in a Chinese Han population using 1,012 affected individuals (cases) and 1,362 controls followed by a replication study in an additional 3,624 cases and 12,197 controls of Chinese Han ethnicity, as well as 1,806 cases and 3,256 controls from Germany. We identified previously undescribed susceptibility loci at 5q22.1 (TMEM232 and SLC25A46, rs7701890, P(combined) = 3.15 × 10(-9), odds ratio (OR) = 1.24) and 20q13.33 (TNFRSF6B and ZGPAT, rs6010620, P(combined) = 3.0 × 10(-8), OR = 1.17) and replicated another previously reported locus at 1q21.3 (FLG, rs3126085, P(combined) = 5.90 × 10(-12), OR = 0.82) in the Chinese sample. The 20q13.33 locus also showed evidence for association in the German sample (rs6010620, P = 2.87 × 10(-5), OR = 1.25). Our study identifies new genetic susceptibility factors and suggests previously unidentified biological pathways in atopic dermatitis.

The radial spoke is a stable structural complex in the 9 ؉ 2 axoneme for the control of flagellar motility. However, the spokes in Chlamydomonas mutant pf24 are heterogeneous and unstable, whereas several spoke proteins are reduced differentially. To elucidate the defective mechanism, we clone RSP16, a prominent spoke protein diminished in pf24 axonemes. Unexpectedly, RSP16 is a novel HSP40 member of the DnaJ superfamily that assists chaperones in various protein-folding-related processes. Importantly, RSP16 is uniquely excluded from the 12S spoke precursor complex that is packaged in the cell body and transported toward the flagellar tip to be converted into mature 20S axonemal spokes. Rather, RSP16, transported separately, joins the precursor complex in flagella. Furthermore, RSP16 molecules in vitro and in flagella form homodimers, a characteristic required for the cochaperone activity of HSP40. We postulate that the spoke HSP40 operates as a cochaperone to assist chaperone machinery at the flagellar tip to actively convert the smaller spoke precursor and itself into the mature stable complex; failure of the interaction between the spoke HSP40 and its target polypeptide results in heterogeneous unstable radial spokes in pf24. INTRODUCTIONThe radial spoke is a conserved macromolecular complex required for regulation of bending in motile 9 ϩ 2 cilia and flagella (Smith and Yang, 2004). The T-shaped structure anchors to the nine outer doublets with a thin stalk, while its bulbous head contacts central pair apparatus periodically during the oscillatory beating (Warner and Satir, 1974;Goodenough and Heuser, 1985). It is hypothesized that this intermittent interaction with central pair apparatus enables the radial spokes to distribute "signals," originating from central pair apparatus, to subsets of outer doublets for localized control of dynein-driven microtubule sliding (Huang et al., 1982). Consistent with this "distributor" model, the central apparatus is asymmetric in structure (Dutcher et al., 1984;Goodenough and Heuser, 1985;Mitchell and Sale, 1999;Mitchell, 2003;Wargo and Smith, 2003; reviewed in Smith and Yang, 2004) and in some organisms central pair rotates once per beat cycle (reviewed by Omoto et al., 1999). The radial spoke is thought to be relatively rigid to endure physical force arising from the interaction with central pair (Warner and Satir, 1974;Goodenough and Heuser, 1985;Lindemann, 2003;Smith and Yang, 2004;Yang et al., 2004) and is extracted as a stable 20S complex of 23 polypeptides that resists disassembly even in buffers containing 0.6 M KI Patel-King et al., 2004). In addition to the mechanical properties, the radial spokes also contain proteins thought to be involved in chemical signaling through calcium or nucleotide binding (Patel-King et al., 2004;Yang et al., 2001Yang et al., , 2004. Based on these data and other studies, it has been postulated that the radial spoke operates as both mechano-and chemo-transducers reviewed by Smith and Yang, 2004).Among the most important issues is ...