Prostate cancer risk–associated variants have been reported in populations of European descent, African-Americans and Japanese using genome-wide association studies (GWAS). To systematically investigate prostate cancer risk–associated variants in Chinese men, we performed the first GWAS in Han Chinese. In addition to confirming several associations reported in other ancestry groups, this study identified two new risk-associated loci for prostate cancer on chromosomes 9q31.2 (rs817826, P = 5.45 × 10−14) and 19q13.4 (rs103294, P = 5.34 × 10−16) in 4,484 prostate cancer cases and 8,934 controls. The rs103294 marker at 19q13.4 is in strong linkage equilibrium with a 6.7-kb germline deletion that removes the first six of seven exons in LILRA3, a gene regulating inflammatory response, and was significantly associated with the mRNA expression of LILRA3 in T cells (P < 1 × 10−4). These findings may advance the understanding of genetic susceptibility to prostate cancer.

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To date, 10 members of the UDP-N-acetyl-␣-D-galactosamine:polypeptide N-acetylgalactosaminyltransferase (pp-GalNAc-T) family have been cloned and analyzed in human. In this study, we cloned and analyzed a novel human pp-GalNAc-T from an NT2 cell cDNA library, and we named it pp-GalNAc-T13. In amino acid sequences, pp-GalNAc-T13 was highly homologous, showing 84.3% identity, to pp-GalNAc-T1. Real time PCR analysis revealed pp-GalNAc-T13 to be highly and restrictively expressed in the brain and present at very low or undetectable levels in other tissues, in contrast to the ubiquitous expression of pp-GalNAc-T1. pp-GalNAc-T13 was abundantly expressed in all neuroblastoma cells examined and primary cultured neurons but not in glioblastoma cells and primary cultured astrocytes. pp-GalNAc-T13 exhibited much stronger activity to transfer GalNAc to mucin peptides, such as Muc5Ac and MUC7, than did pp-GalNAc-T1. In addition, pp-GalNAc-T13 differed in substrate specificity to pp-GalNAc-T1. pp-GalNAc-T13 was able to form a triplet Tn epitope, three consecutive GalNAc-Ser/Thr structures, on peptides encoded in syndecan-3, a proteoglycan expressed in neurons. pp-GalNAc-T13-deficient mice have been established in a previous work. Immunohistochemical study showed a remarkable decrease in Tn antigen expression in the cerebellum of the pp-GalNAc-T13 knockout mouse. pp-GalNAc-T13 would be a major enzyme responsible for the synthesis of O-glycan and specifically the Tn antigen epitope in neurons.O-Linked glycosylation of mucin is initiated by the transfer of N-acetylgalactosamine with an ␣-linkage to a serine or threonine residue in protein. The GalNAc residue attached to the peptide is usually extended to form more complex O-glycan structures by the action of multiple glycosyltransferases. The addition of GalNAc is controlled by multiple members of the pp-GalNAc-T 1 (EC 2.4.1.41) family. To date, 10 distinct members have been identified in human (pp-GalNAc-T1, -T2, -T3, -T4, -T6 to -T9, -T11, and -T12) (1-10) and 7 in rodent (ppGaN- Tase-T1, -T2, -T3, -T4, -T5, -T7, -T10 2 ) (11-17). All share a highly homologous primary sequence, 40 -60% homology at the amino acid level, to each other particularly in the predicted catalytic domain. Each member exhibits different substrate specificity toward peptide sequences. Thus, the positions of O-glycan in proteins are determined by the substrate specificity of each pp-GalNAc-T. The genes encoding these enzymes are distributed at different genomic localizations on chromosomes and have distinct genomic structures (4).pp-GalNAc-T1, which was the first pp-GalNAc-T to be cloned from bovine tissue (1), is the best characterized of the members. It shows activity toward Muc1, Muc2, Muc5Ac, and Muc7 peptides (4, 18). Peptide sequences derived from these mucins were used to determine the site of the O-glycosylation of the Muc2 and Muc5Ac mucin tandem repeat region by pp-GalNAc-T1 (19 -22).Many pp-GalNAc-Ts, including pp-GalNAc-T1, were found to * This work was performed as a part of the R&D Project o...