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Association of three 8q24 polymorphisms with prostate cancer susceptibility: evidence from a meta-analysis with 50,854 subjects.

Li Q, Liu X, Hua RX, Wang F, An H, Zhang W, Zhu JH - Sci Rep (2015)

Bottom Line: Overall, each of studied 8q24 polymorphisms was significantly associated with PCa risk individually.Interestingly, the effect of rs1447295 on PCa risk was observed among Caucasians and Asians, but not Africa-Americans.The effect of rs16901979 was more prominent among Africa-Americans than Asians.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, First Affiliated Hospital, Xinjiang Medical University, 137 Liyushan Road, Urumqi, Xinjiang, 830054, China.

ABSTRACT
The 8q24 polymorphisms have been implicated in various cancers. Three 8q24 polymorphisms (rs1447295 C>A, rs16901979 C>A, and rs6983267 T>G) have been extensively investigated for their association with prostate cancer (PCa) susceptibility, yet conclusions are contradictory. We conducted a comprehensive meta-analysis to reevaluate the associations between those polymorphisms and PCa susceptibility, according to the latest meta-analysis guidelines (PRISMA). Eligible publications were searched from MEDLINE, EMBASE and CBM. False positive report possibility analysis was performed. We totally collected 20184 cases and 20439 controls from 20 studies for the rs1447295 C>A, 1850 cases and 2090 controls from 7 studies for the rs16901979 C>A, and 12233 cases and 7582 controls from 17 studies for the rs6983267 T>G. Overall, each of studied 8q24 polymorphisms was significantly associated with PCa risk individually. Significant associations were also observed in stratified analysis by ethnicity, source of control, and quality score. Interestingly, the effect of rs1447295 on PCa risk was observed among Caucasians and Asians, but not Africa-Americans. The effect of rs16901979 was more prominent among Africa-Americans than Asians. Likewise, rs6983267 conferred a higher Pca risk among Caucasians than Asians. Collectively, these 8q24 variant(s) may modulate PCa risk in an ethnic-specific manner.

No MeSH data available.


Related in: MedlinePlus

Linkage disequilibrium in the 8q24 region for the previously reported polymorphisms.Linkage disequilibrium coefficients (r2) between SNPs in the 8q24 region between 128.12 and 128.54 Mb.
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f3: Linkage disequilibrium in the 8q24 region for the previously reported polymorphisms.Linkage disequilibrium coefficients (r2) between SNPs in the 8q24 region between 128.12 and 128.54 Mb.

Mentions: Moreover, although mechanisms by which 8q24 modulates the risk of PCa is poorly understood, mounting evidence from genetic association studies and fine-mapping informatics supports that 8q24 genetic variant may impart susceptibility to PCa in an ethnic-specific manner. 8q24 region is commonly subdivided into three regions on the basis of the local genetic characteristics of 8q24 and the fine-mapping study11. Region 1 (126.54–128.62 Mb) was initially identified by the original linkage and admixture studies in Icelandic families populations; and initial association studies indicated that this region might contribute to a higher incidence of PCa in Africa-American men than men of European ancestry78. Region 2 (128.14–128.28 Mb) harbors a 14-SNP haplotype that efficiently tags a relatively uncommon (2–4%) susceptibility variant in individuals of European descent, which happens to be very common (42%) in Africa-Amricans210. And region 3 (128.47–128.54 Mb) is defined as a recombination hot-spot among European Americans. There is little linkage disequilibrium among SNPs across the three regions. Although regions 1 and 3 are physically close to each other, they are separated by a recombination hotspot among individuals of European ancestry2. Hence, SNPs across all three neighboring regions seem to independently influence 8q24 signal transduction, and the combined effects of SNPs across regions closely follow a multiplicative model210. Human chromosome 8q24 contains three regions spanning 6000 kb, according to the dbSNP database (http://www.ncbi.nlm.nih.gov/SNP), in which more than 207 variants were reported. Twenty previously reported 8q24SNPs statistically significantly associated with PCa risk show various linkage disequilibrium (LD) with a range from low to high degree (Fig. 3). These SNPs can be divided into three blocks. For example, block1 included rs698267, rs10505476, rs10505474, and rs7837328, showing LD with r2 values ranging from 0.28 to 0.95. Block2 consisted of rs1447295, rs4242382, rs7017300, rs11986220, rs10090154, and 7837688, with LD (r2) varying from 0.23 to 1.0. Additionally, rs16901979 was found in high LD of 1.0 with some polymorphisms including rs6983561, rs16901966, and rs1551512. None of the variants resides within known genes, of which there are few across the regions of 8q24. It was predicted that those risk-associated variants could affect the regulation or transcription of a causal pseudogene or gene outside the region, including proto-oncogene MYC (located approximately 260 kb telomeric to region 1), FAM84B, TCF7L2, and POU5F12144, but the biological mechanisms underlying these findings remain unclear. Another speculation that may help to explain the association is that some functional polymorphisms linked to those SNPs may account for the association. However, based on current understanding, none of these variants and their respectively linked-SNPs seems to be potentially functional. Therefore, the exact mechanisms underlying the observed association of the SNPs with PCa risk need more investigations.


Association of three 8q24 polymorphisms with prostate cancer susceptibility: evidence from a meta-analysis with 50,854 subjects.

Li Q, Liu X, Hua RX, Wang F, An H, Zhang W, Zhu JH - Sci Rep (2015)

Linkage disequilibrium in the 8q24 region for the previously reported polymorphisms.Linkage disequilibrium coefficients (r2) between SNPs in the 8q24 region between 128.12 and 128.54 Mb.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4498192&req=5

f3: Linkage disequilibrium in the 8q24 region for the previously reported polymorphisms.Linkage disequilibrium coefficients (r2) between SNPs in the 8q24 region between 128.12 and 128.54 Mb.
Mentions: Moreover, although mechanisms by which 8q24 modulates the risk of PCa is poorly understood, mounting evidence from genetic association studies and fine-mapping informatics supports that 8q24 genetic variant may impart susceptibility to PCa in an ethnic-specific manner. 8q24 region is commonly subdivided into three regions on the basis of the local genetic characteristics of 8q24 and the fine-mapping study11. Region 1 (126.54–128.62 Mb) was initially identified by the original linkage and admixture studies in Icelandic families populations; and initial association studies indicated that this region might contribute to a higher incidence of PCa in Africa-American men than men of European ancestry78. Region 2 (128.14–128.28 Mb) harbors a 14-SNP haplotype that efficiently tags a relatively uncommon (2–4%) susceptibility variant in individuals of European descent, which happens to be very common (42%) in Africa-Amricans210. And region 3 (128.47–128.54 Mb) is defined as a recombination hot-spot among European Americans. There is little linkage disequilibrium among SNPs across the three regions. Although regions 1 and 3 are physically close to each other, they are separated by a recombination hotspot among individuals of European ancestry2. Hence, SNPs across all three neighboring regions seem to independently influence 8q24 signal transduction, and the combined effects of SNPs across regions closely follow a multiplicative model210. Human chromosome 8q24 contains three regions spanning 6000 kb, according to the dbSNP database (http://www.ncbi.nlm.nih.gov/SNP), in which more than 207 variants were reported. Twenty previously reported 8q24SNPs statistically significantly associated with PCa risk show various linkage disequilibrium (LD) with a range from low to high degree (Fig. 3). These SNPs can be divided into three blocks. For example, block1 included rs698267, rs10505476, rs10505474, and rs7837328, showing LD with r2 values ranging from 0.28 to 0.95. Block2 consisted of rs1447295, rs4242382, rs7017300, rs11986220, rs10090154, and 7837688, with LD (r2) varying from 0.23 to 1.0. Additionally, rs16901979 was found in high LD of 1.0 with some polymorphisms including rs6983561, rs16901966, and rs1551512. None of the variants resides within known genes, of which there are few across the regions of 8q24. It was predicted that those risk-associated variants could affect the regulation or transcription of a causal pseudogene or gene outside the region, including proto-oncogene MYC (located approximately 260 kb telomeric to region 1), FAM84B, TCF7L2, and POU5F12144, but the biological mechanisms underlying these findings remain unclear. Another speculation that may help to explain the association is that some functional polymorphisms linked to those SNPs may account for the association. However, based on current understanding, none of these variants and their respectively linked-SNPs seems to be potentially functional. Therefore, the exact mechanisms underlying the observed association of the SNPs with PCa risk need more investigations.

Bottom Line: Overall, each of studied 8q24 polymorphisms was significantly associated with PCa risk individually.Interestingly, the effect of rs1447295 on PCa risk was observed among Caucasians and Asians, but not Africa-Americans.The effect of rs16901979 was more prominent among Africa-Americans than Asians.

View Article: PubMed Central - PubMed

Affiliation: Department of Pathology, First Affiliated Hospital, Xinjiang Medical University, 137 Liyushan Road, Urumqi, Xinjiang, 830054, China.

ABSTRACT
The 8q24 polymorphisms have been implicated in various cancers. Three 8q24 polymorphisms (rs1447295 C>A, rs16901979 C>A, and rs6983267 T>G) have been extensively investigated for their association with prostate cancer (PCa) susceptibility, yet conclusions are contradictory. We conducted a comprehensive meta-analysis to reevaluate the associations between those polymorphisms and PCa susceptibility, according to the latest meta-analysis guidelines (PRISMA). Eligible publications were searched from MEDLINE, EMBASE and CBM. False positive report possibility analysis was performed. We totally collected 20184 cases and 20439 controls from 20 studies for the rs1447295 C>A, 1850 cases and 2090 controls from 7 studies for the rs16901979 C>A, and 12233 cases and 7582 controls from 17 studies for the rs6983267 T>G. Overall, each of studied 8q24 polymorphisms was significantly associated with PCa risk individually. Significant associations were also observed in stratified analysis by ethnicity, source of control, and quality score. Interestingly, the effect of rs1447295 on PCa risk was observed among Caucasians and Asians, but not Africa-Americans. The effect of rs16901979 was more prominent among Africa-Americans than Asians. Likewise, rs6983267 conferred a higher Pca risk among Caucasians than Asians. Collectively, these 8q24 variant(s) may modulate PCa risk in an ethnic-specific manner.

No MeSH data available.


Related in: MedlinePlus