Genotyping of a 615 kb region within 8q24 with 49 haplotype-tagged SNPs in 2109 samples (797 cases and 1312 controls) of two ethnic/racial groups found SNPs that are significantly associated with the risk for PCa. The highest significance in Caucasian men was found for rs6983267 for which the A allele is associated with a decreased risk for PCa. This SNP shows an independent effect from other significant SNPs in the studied region in this ethnic group. SNP rs6983267 is also significantly associated with a decreased risk for PCa in Hispanic men. However, rs7837328 and rs921146 reached higher significance and both SNPs showed independent effects, which was not found for rs6983267 in this ethnic group.
These results are consistent with previous reports showing significant association of rs6983267 in different ethnicities, including European American, Asian Indian and Japanese (31
). In addition to confirming previous findings, these data now show this marker to play a role in the susceptibility of PCa in Hispanic men; to our knowledge, this is the first report of the involvement of this SNP in this ethnic group.
SNP rs6983267 has been shown to be associated with high Gleason and advanced PCa (1
), albeit with inconsistent outcomes. Our results suggest that there might be a more pronounced effect of rs6983267 in Caucasian and Hispanic cases when measuring Gleason grade or prognosis. We found a trend toward increased risk of high Gleason grade and poor prognosis in Caucasians, whereas the opposite (decreased risk) was found in Hispanics. These data should be cautiously interpreted due to the small sample sizes; and thus, the association of rs6983267 with clinical features of PCa remains an open question.
One of two SNPs, rs7837328, that showed independent effect in Hispanics, has been shown to confer susceptibility of PCa in Europeans (32
). However, rs921146 to date has not been reported to be significantly association with PCa risk. Of interest is that this marker has a change in transcription binding for FOXJ2, a transcriptional activator. Further studies may identify the effect of this allele-specific change and its contribution to prostate carcinogenesis.
The frequency of the A allele of rs1447295, previously found to be a risk allele for PCa, among the Caucasian cases and controls in this study (11.6 and 9.3%, respectively) were similar to those reported by Amundadottir et al.
). The allele frequency distribution of the microsatellite marker DG8S737 was similar to that found in previous reports (19
). While the frequencies were consistent with previous reports, neither the −8 allele at microsatellite marker DG8S737 nor SNP rs1447295 was significantly associated with PCa risk in any of our ethnic groups.
Analysis of the significant SNPs in each ethnic group that are not in LD with each other further indicate a significant synergist effect for increasing numbers of potential high-risk genotypes in both ethnicities. In Caucasians, a >3-fold increase in the risk of PCa (OR
= 3.18, P
) was found for carriers of all risk alleles of the five significant SNPs (rs6983267, rs6985419, rs7357486, rs10109622 and rs1447293). Carriers of all three risk alleles for rs7837328, rs921146 and rs6981321 had a 4.98 increased of PCa in Hispanics (P
). Analysis of the significant single SNPs in each ethnic group revealed major haplotypes containing the non-risk alleles, which were significantly protective against PCa. Both findings indicate that multiple interacting SNPs within 8q24 most probably confer increased risk of PCa.
The significant findings within 8q24 together with the fact that this region is gene poor has led many to speculate about hypotheses related to this region's involvement in PCa risk (2
). The results from SNPmatrix of the LD across chromosome 8 in this report emphasize the importance of a possible involvement of other regions far beyond the candidate 8q24 region. Indeed, we found that several SNPs in this region are in high LD with SNPs on the short arm of chromosome 8, a region often deleted in PCa (16
). Of interest is that four SNPs found significant in Caucasians and three significant SNPs in Hispanics, showed high LD (LOD>3) with SNPs located within the CSMD1
gene on chromosome 8p23 when using ethnic-specific genotype data from HapMap. The CSMD1
gene, which contains multiple CUB and Sushi domains, encodes a large, type I transmembrane protein located on the surfaces of neuronal and epithelial cells; this protein's function is unknown but is thought to participate in cell migration (38
). No association studies between CSMD1
variants and risk of PCa have been reported so far. The gene has been shown to extend into the minimal regions of deletions within 8p23 and has been suggested as a candidate for a suppressor of multiple types of cancer (39
). Decreased expression of CSMD1
is associated with advanced PCa (39
). Both the sequence of the gene and the organization of the protein are highly conserved in the mouse. In light of these observations, further studies are warranted to clarify this interaction of CSMD1
with the 8q24 region.
Of note is that SNPs in other genes across chromosome 8 were found that showed high LD (LOD>3) with those studied in this report. In particular, SNPs within the β-defensin-1 gene (DEFB1
) located at 8p23 in Caucasians, within the pleckstrin and Sec7 domain containing 3 gene (PSD3
) located at 8p22 in both Caucasians and Hispanics and the CSMD3
gene at 8q23 in Hispanics were in strong LD with 8q24 SNPs. Cancer-specific loss of DEFB1
, which plays an important role in the innate and adaptive immune response, has been found in prostatic carcinomas and is suggested to play a specific role in tumor suppression of advanced PCa via a pathway involving cMYC
). A meta-analysis in breast cancer metastasis indicated that the PSD3
is significantly downregulated (43
). The CSMD3
gene has previously been shown to have upregulated expression associated with chromosomal gains (44
). Consistent with the findings of Camp et al.
), LD was also found between the 8q24 region under study and the more telomeric located gene TMEM75
A limitation of our study is that selection of the 49 tagged SNPs, covering a 615 kb region within the 8q24 candidate region, was based on HapMap data of the European population. Due to the ethnic-specific LD patterns, we might have missed some non-tagged SNPs in Hispanics and therefore the SNPs selected in the study may not fully represent all tagged variants in this ethnic group. In addition, our selection of SNPs differs from other reports and thus a complete comparison with several previously reported SNPs was not possible. However, it is clear that even with these weaknesses, our findings, coupled with data from previous reports, indicate that variants within 8q24 play a significant role in the susceptibility to PCa risk.
In summary, our results support the hypothesis that variants in the 8q24 region play an important role in susceptibility of PCa risk in several ethnic groups. This study is the first to confirm the importance of this region in Hispanic men. Our findings further suggest that multiple interacting SNPs within 8q24 but also in different regions on chromosome 8 far beyond this 8q24 candidate region most probably confer increased risk of PCa.