Background: Macrophage scavenger receptor 1 (MSR1) is involved in chronic inflammation, which is a risk factor for prostate cancer. Association studies assessing the relationship between sequence variants of MSR1 and prostate cancer are inconsistent. We hypothesized that sequence variants of MSR1 were associated with prostate cancer risk.

Methods: In a nested case-control design within the Health Professionals Follow-up Study, we identified 700 participants with prostate cancer diagnosed after they had provided a blood specimen in 1993 and before January 2000. Controls were 700 age-matched men without prostate cancer who had had a prostate-specific antigen test after providing a blood specimen. We genotyped three common (>5%) single nucleotide polymorphisms (SNP) that have been reported previously to be associated with risk of prostate cancer.

Results: None of these MSR1 SNPs nor estimated haplotypes were associated with prostate cancer risk (P for the global test for haplotypes = 0.89). These MSR1 SNPs also did not appear to be associated with higher-grade or advanced-stage prostate cancer.

Conclusion: The association between these sequence variants of MSR1 and the risk of prostate cancer was null. Further study of aggressive prostate cancer may be warranted, as we had limited power to assess these. (Cancer Epidemiol Biomarkers Prev 2008;17(4):1001–3)

Macrophage scavenger receptor 1 (MSR1) is located on chromosome 8p22 (1, 2) and was highly expressed in the kidney, colon, prostate, breast, and heart.6

Its isoforms are involved in host defense (inflammation, innate and adaptive immunity; ref. 3). A recent meta-analysis (4) reported five common sequence variants (PRO3, INDEL1, IVS5-59, P275A, and INDEL7) moderately associated with prostate cancer risk. Studies reported after the previous meta-analysis showed inconsistent findings for P275A (5, 6). Abundant evidence supports a possible link between chronic intraprostatic inflammation and risk of prostate cancer (7). MSR1 plays a role in the innate immune response to pathogen infection and therefore may relate to prostate cancer risk.

The materials and methods of this study have been described elsewhere (8). Laboratory assays are available upon request. In a log additive model with 0.05 significance level, we have >80% statistical power to detect a genetic main effect of ≥1.3 [odds ratio (OR)] when population prevalence is assumed to be ≥0.1% and minor allele frequency varies from 0.2 to 0.5.

The three single nucleotide polymorphisms (SNP) in MSR1 associated previously with risk of prostate cancer were genotyped (Table 1). SNP IVS5-59 was out of Hardy-Weinberg equilibrium among controls (P < 0.01) but not among cases (P = 0.11). The internal blinded quality-control specimens showed no evidence of genotyping error. Therefore, we retained IVS5-59 in the statistical analyses.

Table 1.

Characteristics of MSR1 SNPs

SNPNucleotide changeLocationrs #.Controls
Cases
Minor allele frequency (%)Hardy-Weinberg equilibrium PMinor allele frequency (%)Hardy-Weinberg equilibrium P
PRO3 A→G Promoter rs433235 8.8 0.08 8.4 0.25 
IVS5-59 C→A Intron 5 N/A 4.9 <0.01 5.1 0.11 
P275A C→G Exon 6 rs3747531 5.1 0.95 6.2 <0.01 
SNPNucleotide changeLocationrs #.Controls
Cases
Minor allele frequency (%)Hardy-Weinberg equilibrium PMinor allele frequency (%)Hardy-Weinberg equilibrium P
PRO3 A→G Promoter rs433235 8.8 0.08 8.4 0.25 
IVS5-59 C→A Intron 5 N/A 4.9 <0.01 5.1 0.11 
P275A C→G Exon 6 rs3747531 5.1 0.95 6.2 <0.01 

The characteristics of the study population are available elsewhere (8). The three SNPs exhibited high pairwise linkage disequilibrium (∣D'∣ > 0.8). We observed three common haplotypes with a cumulative frequency of 95.2% (Table 2). The P value for the global test comparing the case and control distribution of the three common haplotypes was 0.89. Statistical analyses showed that none of the three common SNPs or their haplotypes was associated with prostate cancer risk (Table 2). Prostate cancer family history, body mass index, and age were not effect modifiers for the association between MSR1 and prostate cancer. Case-only analysis [aggressive (defined as stage T3b or T4 or N1 or M1 or death due to prostate cancer, n = 56) versus nonaggressive] showed no significant association between these sequence variants of MSR1 and tumor aggressiveness.

Table 2.

OR between MSR1 SNPs and haplotypes and the risk of prostate cancer

SNP0 copies
1 copy
2 copies
P*
Case/controlORCase/controlOR (95% CI)Case/controlOR (95% CI)
PRO3  569/563 1.00 99/101 1.00 (0.7-1.3) 7/9 0.8 (0.3-2.1) 0.88 
IVS5-59  584/587 1.00 58/53 1.1 (0.7-1.6) 4/5 0.8 (0.2-3.2) 0.87 
P275A  603/622 1.00 68/67 1.1 (0.7-1.5) 8/2 4.1 (0.9-19.5) 0.13 
         
Haplotype Prevalence among controls, % (95% CI) Global test P = 0.89
 
     P
  0 copies
 
 1 copy
 
 2 copies
 
  

 

 
Case/control
 
OR
 
Case/control
 
OR (95% CI)
 
Case/control
 
OR (95% CI)
 

 
Hap1: ACG 85.3 (83.5-87.2) 20/16 1.00 172/174 0.7 (0.4-1.5) 508/510 0.7 (0.36-1.5) 0.68 
Hap2: ACC 5.1 (3.9-6.2) 625/631 1.00 72/68 1.1 (0.8-1.5) 3/1 3.1 (0.31-31.7) 0.54 
Hap3: GCG 4.8 (3.7-5.9) 641/635 1.00 55/64 0.8 (0.6-1.3) 4/1 3.3 (0.4-25.3) 0.32 
Cumulative frequency (%) 92.5        
SNP0 copies
1 copy
2 copies
P*
Case/controlORCase/controlOR (95% CI)Case/controlOR (95% CI)
PRO3  569/563 1.00 99/101 1.00 (0.7-1.3) 7/9 0.8 (0.3-2.1) 0.88 
IVS5-59  584/587 1.00 58/53 1.1 (0.7-1.6) 4/5 0.8 (0.2-3.2) 0.87 
P275A  603/622 1.00 68/67 1.1 (0.7-1.5) 8/2 4.1 (0.9-19.5) 0.13 
         
Haplotype Prevalence among controls, % (95% CI) Global test P = 0.89
 
     P
  0 copies
 
 1 copy
 
 2 copies
 
  

 

 
Case/control
 
OR
 
Case/control
 
OR (95% CI)
 
Case/control
 
OR (95% CI)
 

 
Hap1: ACG 85.3 (83.5-87.2) 20/16 1.00 172/174 0.7 (0.4-1.5) 508/510 0.7 (0.36-1.5) 0.68 
Hap2: ACC 5.1 (3.9-6.2) 625/631 1.00 72/68 1.1 (0.8-1.5) 3/1 3.1 (0.31-31.7) 0.54 
Hap3: GCG 4.8 (3.7-5.9) 641/635 1.00 55/64 0.8 (0.6-1.3) 4/1 3.3 (0.4-25.3) 0.32 
Cumulative frequency (%) 92.5        

NOTE: From left to right, the haplotypes above were composed of PRO3, IVS5-59, and P275A.

*

P tested the null hypothesis: OR1 copy = OR2 copies = 1.

This study showed little evidence of association between these particular common sequence variants of MSR1 and prostate cancer risk. The chromosome 8p22-23 region was first linked to prostate cancer susceptibility in 2001 (9). In 2003, Xu et al. (10) reported that these three common SNPs (PRO3, IVS-59, and P275A) were significantly associated with prostate cancer risk [PRO3: OR, 1.81; 95% confidence interval (95% CI), 1.15-2.85; IVS-59: OR, 1.73; 95% CI, 1.10-2.72; P275A: OR, 1.75; 95% CI, 1.05-2.94] among 301 cases and 250 controls of Caucasian descent. However, the remaining studies including the current one failed to replicate these findings for PRO3 (11-14), IVS5-59 (6, 11, 13, 14), and P275A (5, 6, 11-13, 15). The different findings between Xu et al. (10) and our research may result from study design (hospital-based case-control study versus nested case-control study), time period (unspecified versus 1993-2000), differences in local linkage disequilibrium patterns, and sample size (301 versus 700 cases). In addition, prostate-specific antigen screening, done in most of our cases, led to the identification of less aggressive prostate cancer. However, the consistent null findings in previous studies reflect the possibility of chance findings in Xu et al. (10), whose study had a relatively small sample size.

Each of the three SNPs explored in this study may affect the MSR1 function. The PRO3 in the 5′ untranslated region, where the promoter and transcription factor binding sites are located, may have a regulatory effect. The IVS5-59, an intronic SNP, may relate to cancer risk by influencing the MSR1 mRNA alternative splicing. The nucleotide changes (C → G) of P275A, a nonsynonymous SNP, lead to an amino acid change (Pro → Ala). However, the null findings in this study suggest that these common SNPs contribute little to prostate cancer risk. Except for study by Rennert et al. (14), previous studies suggested that rare MSR1 mutations related to high risk of prostate cancer (5, 13, 16). On the contrary, common sequence variants were associated with relatively low or even no risk of prostate cancer (5, 6, 10-12, 15). Similarly, a rare mutation, E265X, in the prostate cancer susceptibility gene RNASEL was associated with a higher risk of hereditary prostate cancer (17), whereas the common variants R462Q were only weakly associated with hereditary prostate cancer risk (17-20).

Although the nominal P values we present did not control the family-wise error rate for these post hoc comparisons, type I error rate was controlled by the single multiple degree-of-freedom test of association between MSR1 haplotypes and prostate cancer. Population stratification cannot be excluded in a case-control study (21), but this study had a large sample (n = 1,400); controls were selected from the population that gave rise to the cases and were composed of 94% Caucasians. Results were similar after the exclusion of non-Caucasians.

Chronic intraprostatic inflammation has been reported to increase the risk of prostate cancer (7). Our previous study (8) showed that variants in the innate immune gene TLR4 played a role in prostate cancer susceptibility. However, in our study and most previous studies, no association between sequence variants of MSR1 and prostate cancer risk has been observed.

Grant support: NIH grants UO1 CA98233 and CA55075.

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.

We thank Monica Coleman for assistance, Pati Soule and Ana-Tereza Andrade for DNA sample extraction, and the Partners High-Throughput Genotyping Center (Dr. David Kwiatkowski, Alison Brown, and Maura Regan) for genotyping.

1
Kodama T, Freeman M, Rohrer L, et al. Type I macrophage scavenger receptor contains α-helical and collagen-like coiled coils.
Nature
1990
;
343
:
531
–5.
2
Emi M, Asaoka H, Matsumoto A, et al. Structure, organization, and chromosomal mapping of the human macrophage scavenger receptor gene.
J Biol Chem
1993
;
268
:
2120
–5.
3
Pearson AM. Scavenger receptors in innate immunity.
Curr Opin Immunol
1996
;
8
:
20
–8.
4
Sun J, Hsu FC, Turner AR, et al. Meta-analysis of association of rare mutations and common sequence variants in the MSR1 gene and prostate cancer risk.
Prostate
2006
;
66
:
728
–37.
5
Maier C, Vesovic Z, Bachmann N, et al. Germline mutations of the MSR1 gene in prostate cancer families from Germany.
Hum Mutat
2006
;
27
:
98
–102.
6
Noonan-Wheeler FC, Wu W, Roehl KA, et al. Association of hereditary prostate cancer gene polymorphic variants with sporadic aggressive prostate carcinoma.
Prostate
2006
;
66
:
49
–56.
7
Platz EA, De Marzo AM. Epidemiology of inflammation and prostate cancer.
J Urol
2004
;
171
:
S36
–40.
8
Chen YC, Giovannucci E, Lazarus R, et al. Sequence variants of Toll-like receptor 4 (TLR4) and susceptibility to prostate cancer.
Cancer Res
2005
;
65
:
11771
–8.
9
Xu J, Zheng SL, Hawkins GA, et al. Linkage and association studies of prostate cancer susceptibility: evidence for linkage at 8p22-23.
Am J Hum Genet
2001
;
69
:
341
–50.
10
Xu J, Zheng SL, Komiya A, et al. Common sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.
Am J Hum Genet
2003
;
72
:
208
–12.
11
Lindmark F, Jonsson BA, Bergh A, et al. Analysis of the macrophage scavenger receptor 1 gene in Swedish hereditary and sporadic prostate cancer.
Prostate
2004
;
59
:
132
–40.
12
Seppala EH, Ikonen T, Autio V, et al. Germ-line alterations in MSR1 gene and prostate cancer risk.
Clin Cancer Res
2003
;
9
:
5252
–6.
13
Miller DC, Zheng SL, Dunn RL, et al. Germ-line mutations of the macrophage scavenger receptor 1 gene: association with prostate cancer risk in African-American men.
Cancer Res
2003
;
63
:
3486
–9.
14
Rennert H, Zeigler-Johnson CM, Addya K, et al. Association of susceptibility alleles in ELAC2/HPC2, RNASEL/HPC1, and MSR1 with prostate cancer severity in European American and African American men.
Cancer Epidemiol Biomarkers Prev
2005
;
14
:
949
–57.
15
Wang L, McDonnell SK, Cunningham JM, et al. No association of germline alteration of MSR1 with prostate cancer risk.
Nat Genet
2003
;
35
:
128
–9.
16
Xu J, Zheng SL, Komiya A, et al. Germline mutations and sequence variants of the macrophage scavenger receptor 1 gene are associated with prostate cancer risk.
Nat Genet
2002
;
32
:
321
–5.
17
Rokman A, Ikonen T, Seppala EH, et al. Germline alterations of the RNASEL gene, a candidate HPC1 gene at 1q25, in patients and families with prostate cancer.
Am J Hum Genet
2002
;
70
:
1299
–304.
18
Casey G, Neville PJ, Plummer SJ, et al. RNASEL Arg462Gln variant is implicated in up to 13% of prostate cancer cases.
Nat Genet
2002
;
32
:
581
–3.
19
Chen H, Griffin AR, Wu YQ, et al. RNASEL mutations in hereditary prostate cancer.
J Med Genet
2003
;
40
:
e21
.
20
Maier C, Haeusler J, Herkommer K, et al. Mutation screening and association study of RNASEL as a prostate cancer susceptibility gene.
Br J Cancer
2005
;
92
:
1159
–64.
21
Freedman ML, Reich D, Penney KL, et al. Assessing the impact of population stratification on genetic association studies.
Nat Genet
2004
;
36
:
388
–93.