Abstract
Genome-wide association studies (GWAS) of renal cell carcinoma (RCC) in populations of European ancestry have identified four susceptibility loci. No GWAS has been conducted among African Americans (AA), who experience a higher incidence of RCC. We conducted a GWAS in which we analyzed 1,136,723 common single-nucleotide polymorphisms (SNP) among 255 cases and 375 controls of African ancestry, and further investigated 16 SNPs in a replication set (140 cases and 543 controls). The 12p11.23 variant rs10771279, located 77 kb from the European-ancestry RCC marker rs718314, was associated with RCC risk in the GWAS (P = 1.2 × 10−7) but did not replicate (P = 0.99). Consistent with European-ancestry findings, the A allele of rs7105934 on 11q13.3 was associated with decreased risk [OR, 0.76, 95% confidence interval (CI), 0.64–0.91; P = 0.0022]. The frequency of this allele was higher than that observed in the European-ancestry GWAS (0.56 and 0.07, respectively, among controls). The rs7105934 association was stronger for clear cell RCC (ccRCC: OR, 0.56; P = 7.4 × 10−7) and absent for cases of other or unknown histology (OR, 1.02; P = 0.86). Analyses of rs7105934 by subtype among European-ancestry participants from these studies yielded similar findings (ORs 0.69 and 0.92, respectively). This study provides, to our knowledge, the first evidence that rs7105934 is an RCC susceptibility locus among AAs. Our finding that the association with this SNP may be specific to clear-cell RCC is novel and requires additional investigation. Additional investigation of rs10771279 and other suggestive GWAS findings is also needed. Cancer Epidemiol Biomarkers Prev; 23(1); 209–14. ©2013 AACR.
Introduction
Renal cell carcinoma (RCC) is the deadliest type of urologic malignancy, with a 5-year survival rate of approximately 65% (1). In the United States, the overall incidence rate of RCC is higher among African Americans than those of European descent (2), although African Americans have a lower incidence of clear-cell RCC (ccRCC), the most common histologic subtype of this malignancy (3). There is a clear genetic component to RCC, with an approximate 2-fold increased relative risk among individuals of European or African American descent reporting a first-degree relative with kidney cancer (4). In particular, dysregulation of the hypoxia-inducible factor (HIF)/von Hippel-Lindau (VHL) hypoxia-response pathway is a hallmark of ccRCC; very high rates of familial ccRCC are observed among patients with inherited mutations within the VHL tumor suppressor gene, and the majority of sporadic ccRCC cases exhibit VHL inactivation and constitutively high expression of HIF transcription factors (5).
Recent genome-wide association studies (GWAS) conducted among study populations of European ancestry have identified four susceptibility loci for RCC (6–8). The variant rs7579899 maps to EPAS1 on 2p21, which encodes HIF-2α, a critical factor in HIF/VHL-mediated development of ccRCC (5). The variants rs7105934, on 11q13.3, and rs12105918, mapping to ZEB2 on 2q22.3, are also suspected to influence RCC risk in a HIF-dependent manner (6, 8, 9). The biologic basis for the association with rs718314 (mapping to ITPR2 on 12p11.23) is unclear, although ITPR2 was associated with waist-to-hip ratio in an earlier GWAS (10); the latter is interesting because an elevated BMI is an established risk factor for RCC in all populations studied (2).
To our knowledge, no GWAS of RCC among African Americans has been conducted to date, nor have the associations with established European-ancestry RCC loci been investigated in this racial group. Thus, we conducted a GWAS among African American participants in which we scanned one study and followed up promising loci in a second case–control study.
Materials and Methods
Study populations
Two case–control studies with comparatively large numbers of African American participants conducted by the National Cancer Institute (NCI) and the University of Texas MD Anderson Cancer Center (MDACC, Houston, TX) were included in this investigation. The designs of these studies have been described (7, 11). Both studies were approved by institutional review boards at all participating institutions, and written informed consent was obtained from all participants before interview and biospecimen collection.
Briefly, the NCI population-based case–control study of RCC was conducted between 2002 and 2007 in the metropolitan areas of Chicago (Cook County) and Detroit (Wayne, Macomb, and Oakland Counties). The case series included residents between the ages of 20 and 79 years with histologically confirmed RCC. Control subjects aged 20 to 64 years were selected randomly from Department of Motor Vehicle (DMV) records in each state, and controls aged 65 to 79 years were selected from Medicare beneficiary records in the study area. Controls were frequency matched to the age-, race-, and gender-specific distributions of cases of RCC in each of the two study centers. Participating cases (843 European descent, 358 African American; 77% of contactable eligible individuals) and controls (707, 519; 54%) underwent interviews to collect information on lifestyle, medical, and occupational risk factors. Copies of medical records were obtained from all cases to confirm diagnosis and collect information on histologic and clinical factors. In addition, the original diagnostic slides were obtained for 706 cases (487 European descent and 219 African American) for central review by a single experienced pathologist. Germline DNA was extracted from blood (90%) or buccal cell (10%) specimens from 1,087 cases (774 European descent, 313 African American) and 1,091 controls (643, 448) using a phenol-chloroform protocol. We included 267 cases and 384 controls of African American race with genomic DNA in this investigation.
The MDACC study included newly diagnosed, histopathologically confirmed RCC patients recruited at the University of Texas MD Anderson Cancer Center from 2002 onward. Controls with no prior history of cancer (except non-melanoma skin cancer) were recruited through random digit dialing (RDD). The controls were frequency matched to the cases by age (±5 years), gender, ethnicity, and county of residence. The overall response rate for RDD screening was 51% and, among those who agreed to participate, the response rate was 88%. The response rate for the eligible cases was 87%. RCC histology was ascertained through medical chart review. Genomic DNA was extracted from whole blood for all the samples by use of QIAamp DNA Mini kits (Qiagen). We included 140 cases and 543 controls of African American race with available genomic DNA in this investigation.
Genotyping
A total of 672 NCI study samples were genotyped using the Illumina 1M Duo BeadChip at the NCI Cancer Genomics Research Laboratory. Samples were excluded on the basis of completion rates lower than 94% (n = 7 samples), abnormal heterozygosity values of <25% or >35% (n = 1), gender discordance (n = 2), and missing phenotype data (n = 6). Genotypes for 20 pairs of duplicates were merged into unique individual level, and the overall concordance rate for this merging was more than 99.9%. Using a set of 12,898 unlinked SNPs (12), 6 individuals with less than 20% African ancestry were excluded on the basis of STRUCTURE analysis (13) and principal components analysis (PCA; ref. 14). SNPs were excluded on the basis of completion rates lower than 90% (N = 62,464). After these exclusions, we had genotype data for 1,136,723 SNPs from 255 cases and 375 controls. Sixteen SNPs, listed in Table 1, were genotyped in the MDACC study using TaqMan assays. These include 11 variants with NCI study associations approaching genome-wide significance (5 × 10−8), four variants with NCI study associations at P<0.005 and located within 250 kb of one of the four European-ancestry RCC risk markers, and the 11q13 European-ancestry RCC risk marker rs71059344. The three other European-ancestry risk markers (rs718314, rs7579899, rs12105918) were not genotyped as they did not demonstrate any evidence of association with RCC in the NCI samples.
. | . | . | NCI Study (255 cases, 375 controls) . | MDACC Study (140 cases, 543 controls) . | Meta-analysis . | |||||
---|---|---|---|---|---|---|---|---|---|---|
Locus . | SNP . | Alleles, M/m . | MAF, case/control . | OR (95% CI) . | P . | MAF, case/control . | OR (95% CI) . | P . | OR (95% CI) . | P . |
SNPs established as RCC risk loci among individuals of European descent | ||||||||||
2p21 | rs7579899a | A/G | 0.37/0.38 | 0.98 (0.76–1.25)b | 0.86 | |||||
2q22.3 | rs12105918a | T/C | 0.08/0.08 | 0.87 (0.57–1.35)b | 0.54 | |||||
11q13.3 | rs7105934a | G/A | 0.53/0.57c | 0.83 (0.66–1.05)b | 0.11 | 0.44/0.54 | 0.68 (0.52–0.89) | 0.0045 | 0.76 (0.64–0.91) | 0.0022 |
12p11.23 | rs718314a | T/C | 0.19/0.19 | 0.95 (0.71–1.29)b | 0.76 | |||||
SNPs with P < 0.005 in the NCI study and within 250 kb of European-descent RCC locus | ||||||||||
2p21 | rs10197384 | T/G | 0.24/0.18 | 1.72 (1.26–2.35) | 0.0005 | 0.27/0.28 | 0.91 (0.68–1.22) | 0.52 | 1.23 (0.99–1.52) | 0.06 |
2p21 | rs3754568 | G/A | 0.32/0.25 | 1.46 (1.13–1.87) | 0.0033 | 0.29/0.29 | 0.93 (0.69–1.24) | 0.60 | 1.20 (0.99–1.45) | 0.06 |
11q13.3 | rs4255548 | G/A | 0.27/0.35 | 0.67 (0.52–0.86) | 0.0017 | 0.32/0.34 | 0.96 (0.72–1.27) | 0.76 | 0.79 (0.65–0.95) | 0.01 |
12p11.23 | rs10771279 | T/C | 0.19/0.34 | 0.48 (0.36–0.63) | 1.2 × 10−7 | 0.20/0.20 | 1.00 (0.72–1.38) | 0.99 | 0.65 (0.53–0.81) | 7.6 × 10−5 |
Top-ranked SNPs from the NCI study | ||||||||||
1p22.3 | rs233072 | A/G | 0.41/0.30 | 1.81 (1.39–2.35) | 7.3 × 10−6 | 0.33/0.31 | 1.09 (0.83–1.45) | 0.53 | 1.43 (1.18–1.73) | 2.5 × 10−4 |
1p31.3 | rs1390473 | C/T | 0.27/0.16 | 2.05 (1.53–2.76) | 1.2 × 10−6 | 0.18/0.18 | 1.05 (0.75–1.48) | 0.77 | 1.54 (1.23–1.92) | 1.6 × 10−4 |
2q35 | rs3834 | C/T | 0.21/0.33 | 0.50 (0.38–0.66) | 7.3 × 10−7 | 0.31/0.28 | 1.10 (0.82–1.47) | 0.51 | 0.73 (0.60–0.89) | 0.0022 |
4q23 | rs1528545 | A/G | 0.31/0.43 | 0.58 (0.45–0.74) | 1.2 × 10−5 | 0.45/0.37 | 1.35 (1.03–1.76) | 0.03 | 0.86 (0.72–1.03) | 0.10 |
4q24 | rs2866430 | A/G | 0.41/0.31 | 1.61 (1.27–2.04) | 7.2 × 10−5 | 0.33/0.33 | 0.93 (0.70–1.24) | 0.62 | 1.29 (1.07–1.54) | 0.0069 |
4q31.3 | rs10010950 | T/C | 0.21/0.29 | 0.51 (0.38–0.70) | 1.6 × 10−5 | 0.28/0.26 | 1.08 (0.81–1.45) | 0.59 | 0.76 (0.62–0.94) | 0.01 |
4q31.3 | rs10020317 | T/C | 0.26/0.36 | 0.53 (0.40–0.69) | 2.8 × 10−6 | 0.33/0.32 | 1.05 (0.79–1.39) | 0.73 | 0.74 (0.61–0.90) | 0.0021 |
4q34.1 | rs7686453 | C/A | 0.29/0.39 | 0.59 (0.46–0.77) | 5.5 × 10−5 | 0.44/0.39 | 1.26 (0.97–1.65) | 0.09 | 0.85 (0.71–1.02) | 0.09 |
11q24.3 | rs4937504 | G/A | 0.49/0.36 | 1.88 (1.46–2.43) | 8.1 × 10−7 | 0.40/0.45 | 0.84 (0.64–1.10) | 0.20 | 1.28 (1.07–1.54) | 0.0084 |
16q13 | rs1645893 | T/C | 0.39/0.52 | 0.56 (0.44–0.71) | 1.5 × 10−6 | 0.44/0.49 | 0.83 (0.63–1.09) | 0.18 | 0.67 (0.56–0.80) | 9.5 × 10−6 |
20q13.33 | rs6062941 | T/C | 0.09/0.17 | 0.45 (0.31–0.66) | 2.3 × 10−5 | 0.14/0.15 | 0.97 (0.65–1.45) | 0.87 | 0.64 (0.49–0.85) | 0.0017 |
. | . | . | NCI Study (255 cases, 375 controls) . | MDACC Study (140 cases, 543 controls) . | Meta-analysis . | |||||
---|---|---|---|---|---|---|---|---|---|---|
Locus . | SNP . | Alleles, M/m . | MAF, case/control . | OR (95% CI) . | P . | MAF, case/control . | OR (95% CI) . | P . | OR (95% CI) . | P . |
SNPs established as RCC risk loci among individuals of European descent | ||||||||||
2p21 | rs7579899a | A/G | 0.37/0.38 | 0.98 (0.76–1.25)b | 0.86 | |||||
2q22.3 | rs12105918a | T/C | 0.08/0.08 | 0.87 (0.57–1.35)b | 0.54 | |||||
11q13.3 | rs7105934a | G/A | 0.53/0.57c | 0.83 (0.66–1.05)b | 0.11 | 0.44/0.54 | 0.68 (0.52–0.89) | 0.0045 | 0.76 (0.64–0.91) | 0.0022 |
12p11.23 | rs718314a | T/C | 0.19/0.19 | 0.95 (0.71–1.29)b | 0.76 | |||||
SNPs with P < 0.005 in the NCI study and within 250 kb of European-descent RCC locus | ||||||||||
2p21 | rs10197384 | T/G | 0.24/0.18 | 1.72 (1.26–2.35) | 0.0005 | 0.27/0.28 | 0.91 (0.68–1.22) | 0.52 | 1.23 (0.99–1.52) | 0.06 |
2p21 | rs3754568 | G/A | 0.32/0.25 | 1.46 (1.13–1.87) | 0.0033 | 0.29/0.29 | 0.93 (0.69–1.24) | 0.60 | 1.20 (0.99–1.45) | 0.06 |
11q13.3 | rs4255548 | G/A | 0.27/0.35 | 0.67 (0.52–0.86) | 0.0017 | 0.32/0.34 | 0.96 (0.72–1.27) | 0.76 | 0.79 (0.65–0.95) | 0.01 |
12p11.23 | rs10771279 | T/C | 0.19/0.34 | 0.48 (0.36–0.63) | 1.2 × 10−7 | 0.20/0.20 | 1.00 (0.72–1.38) | 0.99 | 0.65 (0.53–0.81) | 7.6 × 10−5 |
Top-ranked SNPs from the NCI study | ||||||||||
1p22.3 | rs233072 | A/G | 0.41/0.30 | 1.81 (1.39–2.35) | 7.3 × 10−6 | 0.33/0.31 | 1.09 (0.83–1.45) | 0.53 | 1.43 (1.18–1.73) | 2.5 × 10−4 |
1p31.3 | rs1390473 | C/T | 0.27/0.16 | 2.05 (1.53–2.76) | 1.2 × 10−6 | 0.18/0.18 | 1.05 (0.75–1.48) | 0.77 | 1.54 (1.23–1.92) | 1.6 × 10−4 |
2q35 | rs3834 | C/T | 0.21/0.33 | 0.50 (0.38–0.66) | 7.3 × 10−7 | 0.31/0.28 | 1.10 (0.82–1.47) | 0.51 | 0.73 (0.60–0.89) | 0.0022 |
4q23 | rs1528545 | A/G | 0.31/0.43 | 0.58 (0.45–0.74) | 1.2 × 10−5 | 0.45/0.37 | 1.35 (1.03–1.76) | 0.03 | 0.86 (0.72–1.03) | 0.10 |
4q24 | rs2866430 | A/G | 0.41/0.31 | 1.61 (1.27–2.04) | 7.2 × 10−5 | 0.33/0.33 | 0.93 (0.70–1.24) | 0.62 | 1.29 (1.07–1.54) | 0.0069 |
4q31.3 | rs10010950 | T/C | 0.21/0.29 | 0.51 (0.38–0.70) | 1.6 × 10−5 | 0.28/0.26 | 1.08 (0.81–1.45) | 0.59 | 0.76 (0.62–0.94) | 0.01 |
4q31.3 | rs10020317 | T/C | 0.26/0.36 | 0.53 (0.40–0.69) | 2.8 × 10−6 | 0.33/0.32 | 1.05 (0.79–1.39) | 0.73 | 0.74 (0.61–0.90) | 0.0021 |
4q34.1 | rs7686453 | C/A | 0.29/0.39 | 0.59 (0.46–0.77) | 5.5 × 10−5 | 0.44/0.39 | 1.26 (0.97–1.65) | 0.09 | 0.85 (0.71–1.02) | 0.09 |
11q24.3 | rs4937504 | G/A | 0.49/0.36 | 1.88 (1.46–2.43) | 8.1 × 10−7 | 0.40/0.45 | 0.84 (0.64–1.10) | 0.20 | 1.28 (1.07–1.54) | 0.0084 |
16q13 | rs1645893 | T/C | 0.39/0.52 | 0.56 (0.44–0.71) | 1.5 × 10−6 | 0.44/0.49 | 0.83 (0.63–1.09) | 0.18 | 0.67 (0.56–0.80) | 9.5 × 10−6 |
20q13.33 | rs6062941 | T/C | 0.09/0.17 | 0.45 (0.31–0.66) | 2.3 × 10−5 | 0.14/0.15 | 0.97 (0.65–1.45) | 0.87 | 0.64 (0.49–0.85) | 0.0017 |
Abbreviations: M, major allele; m, minor allele; MAF, minor allele frequency.
aNot genotyped in MDACC study given absence of evidence of association with RCC in NCI study.
bThe OR, 95% CI, and P value previously reported for these SNPs from GWAS within European-ancestry populations are as follows: rs7579899: 1.15, 1.10–1.21, 2.3 × 10−9; rs12105918: 1.29, 1.18–1.41, 1.8 × 10−8; rs7105934: 0.69, 0.62–0.76, 7.8 × 10−14; rs718314: 1.19, 1.13–1.26, 8.9 × 10−10.
cWe present results for rs7105934 using the G allele (the minor allele among African Americans) as the reference for comparibility with European-descent findings.
Statistical analysis
For the NCI study, ORs and 95% confidence intervals (CI) for each SNP were calculated assuming a log-additive model of genetic effects using unconditional logistic regression with adjustment for age group, sex, study center, and one significant eigenvector (P < 0.05 in the base model with covariates only) associated with RCC. Quantile–quantile plots (Supplementary Fig. S1) of the results showed little evidence for inflation of the test statistics compared with the expected distribution as would be expected from population stratification bias (λ = 1.009; λ1000 = 1.03; ref. 15). For the MDACC study, SNP associations assuming a log-additive genetic model were calculated using unconditional logistic regression with adjustment for age group and sex.
For those SNPs genotyped in both studies, we calculated combined OR estimates by meta-analysis using a fixed effect model. In addition, we conducted analyses stratified by age group, sex, smoking status, body mass index (BMI), and hypertension (the latter two variables in the NCI study only). We included cross-product terms in regression models to test for differences in SNP associations across strata.
We also investigated SNP associations by RCC histology (ccRCC, all other RCC combined), with tests of OR homogeneity between the two histologic subgroups computed using a case-only approach (16). We similarly investigated histology-specific associations among subjects of European ancestry previously genotyped in both studies (NCI, 812 cases and 712 controls; MDACC, 1,318 cases and 1,500 controls).
Results
A Manhattan plot summarizing the GWAS results from the NCI study is shown in Supplementary Fig. S2. No markers achieved genome-wide significance. The strongest GWAS finding was for a variant located nearby the 12p11.23 European-ancestry RCC risk marker rs718314 (rs10771279: per-allele OR, 0.48; 95% CI, 0.36–0.63; P = 1.2 × 10−7). However, this association was not observed in the MDACC (OR, 1.00; 95% CI, 0.72–1.38; P = 0.99). None of the other selected GWAS findings replicated (Table 1).
The SNP association results for the four European-ancestry RCC risk markers are also summarized in Table 1. The 11q13.3 variant rs7105934 demonstrated the most consistent evidence of association across both studies (NCI study, P = 0.11; MDACC study; P = 0.0045). After meta-analysis, the A allele of rs7105934 was associated with a 24% reduced risk of RCC (OR, 0.76; 95% CI, 0.64–0.91; P = 0.0022). The frequency of the protective allele across controls from both studies was 0.56. The rs7105934 association did not differ across strata defined by age, sex, smoking status, BMI, or hypertension (data not shown). However, as shown in Table 2, in histology-specific analyses, the SNP association was stronger for ccRCC (OR, 0.56; 95% CI, 0.44–0.70; P = 7.4 × 10−7), with no association apparent for non-ccRCC tumors (OR, 1.02; 95% CI, 0.80–1.30; P = 0.86). A test of OR homogeneity between ccRCC and non-ccRCC cases was statistically significant (P = 0.00018). We observed a similar pattern by subtype in histology-specific analyses among European-ancestry participants (Table 2), with a stronger rs7105934 association observed for ccRCC than for non-ccRCC tumors (ORs 0.69 and 0.92, respectively; Phomogeneity = 0.04).
. | . | NCI study . | MDACC study . | Meta-analysis . | |||||
---|---|---|---|---|---|---|---|---|---|
Race . | RCC subtype . | NCase/NCont . | OR (95% CI) . | P . | NCasea/NCont . | OR (95% CI) . | P . | OR (95% CI) . | P . |
African American | |||||||||
Clear cell | 127/375 | 0.69 (0.52–0.93) | 0.01 | 74/543 | 0.39 (0.26–0.56) | 7.2 × 10−7 | 0.56 (0.44–0.70) | 7.4 × 10−7 | |
Other | 127/375 | 1.00 (0.75–1.34) | 0.99 | 51/543 | 1.07 (0.71–1.61) | 0.76 | 1.02 (0.80–1.30) | 0.86 | |
Phom = 0.03 | Phom = 0.00061 | Phom = 0.00018 | |||||||
European ancestry | |||||||||
Clear cell | 544/712 | 0.79 (0.57–1.09) | 0.15 | 949/1,500 | 0.64 (0.51–0.81) | 2.3 × 10−4 | 0.69 (0.57–0.83) | 1.0 × 10−4 | |
Other | 268/712 | 1.00 (0.68–1.48) | 0.98 | 369/1,500 | 0.86 (0.63–1.17) | 0.35 | 0.92 (0.72–1.17) | 0.47 | |
Phom = 0.18 | Phom = 0.10 | Phom = 0.04 |
. | . | NCI study . | MDACC study . | Meta-analysis . | |||||
---|---|---|---|---|---|---|---|---|---|
Race . | RCC subtype . | NCase/NCont . | OR (95% CI) . | P . | NCasea/NCont . | OR (95% CI) . | P . | OR (95% CI) . | P . |
African American | |||||||||
Clear cell | 127/375 | 0.69 (0.52–0.93) | 0.01 | 74/543 | 0.39 (0.26–0.56) | 7.2 × 10−7 | 0.56 (0.44–0.70) | 7.4 × 10−7 | |
Other | 127/375 | 1.00 (0.75–1.34) | 0.99 | 51/543 | 1.07 (0.71–1.61) | 0.76 | 1.02 (0.80–1.30) | 0.86 | |
Phom = 0.03 | Phom = 0.00061 | Phom = 0.00018 | |||||||
European ancestry | |||||||||
Clear cell | 544/712 | 0.79 (0.57–1.09) | 0.15 | 949/1,500 | 0.64 (0.51–0.81) | 2.3 × 10−4 | 0.69 (0.57–0.83) | 1.0 × 10−4 | |
Other | 268/712 | 1.00 (0.68–1.48) | 0.98 | 369/1,500 | 0.86 (0.63–1.17) | 0.35 | 0.92 (0.72–1.17) | 0.47 | |
Phom = 0.18 | Phom = 0.10 | Phom = 0.04 |
Abbreviations: NCase, number of cases; NCont, number of controls; Phom, P value from the test of OR homogeneity across subtypes.
aFifteen African American cases of unknown histology were excluded from this analysis.
The other established European-ancestry risk variants rs7579899, rs718314, and rs12105918 were not associated with risk within the NCI study (P = 0.86, 0.76, and 0.54, respectively), and were not carried over for replication. Investigations of these SNPs across the aforementioned strata and by histologic type were similarly null (data not shown).
Discussion
Our GWAS of RCC among African Americans did not identify novel genome-wide significant susceptibility loci. However, we observed an association with reduced RCC risk for the A allele of the 11q13.3 variant rs7105934, consistent with European-ancestry GWAS findings (6). Interestingly, the protective allele of rs7105934 is more common among African Americans compared with individuals of European ancestry (6), with frequencies among controls of 0.56 and 0.07, respectively. We did not observe clear evidence of an association with RCC for other variants.
In both studies, the association with rs7105934 was stronger for ccRCC than for other RCC subtypes combined among both African American and European-ancestry participants. Our investigation represents first evidence for RCC susceptibility loci by histologic type. It is plausible for the rs7105934 association to be specific to ccRCC, as this variant has recently been shown in pVHL-deficient renal cancer cell lines to modulate HIF-2α binding and function at a transcriptional enhancer of the oncogene CCND1 (9). HIF-2α plays a critical role in ccRCC pathogenesis with VHL inactivation leading to unchecked HIF-mediated expression of oncogenic factors such as VEGF, platelet-derived growth factor B, TGF-α, and the CCND1 gene product cyclin D1 (5, 17–19). Given this observed specificity in the rs7105934 association for ccRCC, it is possible that the difference in frequency of the protective allele between racial groups may contribute to the lower incidence of ccRCC among African Americans compared with Americans of European ancestry. However, it is important for our finding of ccRCC specificity to be replicated in additional studies.
We did not observe clear evidence of an association with the other established European-ancestry RCC risk markers and associations with other SNPs in the NCI study were not replicated. The 12p11.23 SNP rs10771279, an intronic variant within ITPR2 located 77 kb from the European-ancestry RCC risk marker rs718314 (7), was strongly associated with RCC in the NCI study (P = 1.2 × 10−7), but showed no evidence of association in the MDACC samples (P = 0.99). Our null findings for the other established European-ancestry GWAS risk markers and failure to replicate other African American GWAS findings may reflect one or a combination of several factors, including weaker underlying patterns of linkage disequilibrium in African-ancestry populations, false-positive findings from the African American GWAS, and low statistical power within the GWAS and replication sets to detect SNP associations of effect magnitude typically observed for GWAS-identified susceptibility loci. We also note that the analysis of MDACC findings did not adjust for population structure due to the small number of SNPs assayed. However, a reanalysis of the NCI study data without model adjustment for the PCA eigenvector yielded virtually identical findings for the 16 SNPs selected for replication (data not shown), suggesting that the lack of adjustment for population structure in the MDACC study is unlikely to have affected the results for these SNPs. Additional high-density genotyping and fine mapping in a larger number of samples will be needed to resolve whether these and other loci influence RCC risk among African Americans.
In conclusion, our study findings demonstrate that the 11q13.3 variant rs7105934 is a promising susceptibility locus for RCC among African Americans, and our current data suggest that this association may be specific to ccRCC.
Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
Authors' Contributions
Conception and design: M.P. Purdue, Y. Ye, J.S. Colt, N. Rothman, W.-H. Chow, X. Wu, S.J. Chanock
Development of methodology: J.S. Colt, X. Wu
Acquisition of data (provided animals, acquired and managed patients, provided facilities, etc.): M.P. Purdue, K.L. Schwartz, F. Davis, N. Rothman, W.-H. Chow, X. Wu, S.J. Chanock
Analysis and interpretation of data (e.g., statistical analysis, biostatistics, computational analysis): M.P. Purdue, Y. Ye, Z. Wang, X. Wu, S.J. Chanock
Writing, review, and/or revision of the manuscript: M.P. Purdue, Y. Ye, Z. Wang, J.S. Colt, K.L. Schwartz, N. Rothman, W.-H. Chow, X. Wu, S.J. Chanock
Administrative, technical, or material support (i.e., reporting or organizing data, constructing databases): M.P. Purdue, Y. Ye, K.L. Schwartz, X. Wu
Study supervision: K.L. Schwartz, X. Wu, M.P. Purdue
Grant Support
This research was supported by the Intramural Research Program of the NCI (NCI study) and NCI grant CA098897 and MD Anderson Research Trust (X. Wu; MDACC study).
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.