This study addressed two important issues following the discovery of a novel PCa risk locus at Xp11 from GWASs (1
). Using a family-based association test, we showed that the risk alleles of the two reported SNPs were over-transmitted to affected offspring in PCa families and therefore suggested that they are associated with PCa risk. Because family-based association test does not depend on a comparison between cases and controls, it avoids potential problem of comparability in genetic background between the two groups in case-control studies (4
). Therefore, the results of this family-based association study accomplished the first goal of the study (issue of potential population stratification) and provided an independent confirmation of the PCa risk locus at Xp11.
The fine mapping analysis of this study addressed the second issue regarding the location of potential functional variants in the region. By systematically evaluating association for SNPs in the ~800 kb region among two case-control studies, we found SNPs in an ~140kb region had the strongest association with PCa risk. On this basis, priority should be given to this region, especially the NUDT11 gene, for future studies that intend to identify functional variants at Xp11. Unfortunately, due to strong LD among the SNPs in the region, the region that is highly associated with PCa risk remains broad.
codes for a member of the MutT or nudix family of nucleoside hydrolyzing enzymes (18
), metabolizing the small signaling molecules, diphosphoinositol polyphosphates, IP7 and IP8, as well as diadenosine polyphosphates. Transfection of NUDT11
into human embryonic kidney cells results in a reduction of IP7and IP8 by 35% and 45% respectively (19
). Turnover of diphosphoinositol polyphosphates have been implicated in a variety of physiologic functions including apoptosis, endocytosis, telomere length maintenance, and chemotaxis (20
Our fine mapping study also revealed another region at Xp11, ~94 kb from the two initially reported SNPs, is highly associated with PCa. Although the significance of association at this new locus decreases considerably after adjusting for the original SNP, additional studies are needed to further test the independence between the two regions. If confirmed, this is another example of an independent locus in the flanking region of a locus initially identified from GWAS, as previously observed for PCa risk loci at 8q24 (6
), 17q12 (10
), and 11q13 (2
). Two known genes are in this new region (GSPT2
(G1 to S phase transition 2), also known as eRF3b
(eukaryotic peptide chain release factor subunit 3b), may play a role in translation termination and in cell cycle regulation (21
(melanoma antigen family D, 1) is a member of the melanoma antigen gene (MAGE) family and has been shown to be involved in cell cycle progression and apoptosis (23
Consistent with the findings from the published studies (1
), we did not observe significantly different allele frequencies between patients with aggressive or non-aggressive disease for these SNPs at Xp11 in either the JHH or CGEMS study (data not shown). Lack of association with aggressiveness of PCa is also found for other PCa risk variants recently identified from GWAS, including at 8q24, 17q12, 17q24, 3p12, 7q21, 11q13, and 10q11 (3
). Other study designs, including those comparing aggressive with non-aggressive PCa may be more appropriate to discover risk variants for aggressive PCa.