Eight SNPs in ELAC2 were genotyped. Except for snp7, none of the rest of the SNPs was out of Hardy–Weinberg equilibrium among controls (). Because snp7 (rs5030739, Ala541Thr) was a rare allele with no heterozygote and no homozygote variants in this Caucasian population, it was dropped from the haplotype analyses. The internal blinded QC specimens did not show evidence of genotyping error.
The study population included 659 incident prostate cancer cases and 656 matched controls. Age and BMI distributions were similar for cases and controls (), but family history of prostate cancer was statistically significantly different (P = 0.02). The mean age at starting smoking, lifetime average number of cigarettes/day (include non-smokers) and alcohol consumption were similar for cases and controls. The distribution of prostatitis by age group and case–control status did not show statistically significant difference between cases and controls (P = 0.09). Among cases, 79% were in tumor stages T1b–T3a, 49% had Gleason grades 5–6 and 36% had aggressive prostate cancer. Eighteen cases died of prostate cancer before 31 January 2000.
Characteristics of Caucasians in the Health Professionals Follow-Up Study
No SNP (including the non-synonymous SNP Ser217Leu) was associated with prostate cancer risk (). After dropping the rare SNP (snp7, Ala541Thr), seven SNPs spanning ELAC2
formed one block using the algorithm of Gabriel et al.
), where blocks identified with the default settings in Haploview were merged if they had multiallelic D′ >0.8, and the cumulative frequency of common (>5% frequency) haplotypes in the merged block was above 80% (35
). Six common haplotypes (frequency > 5%) were found with an accumulated frequency of 84% in controls (), and the P
-value for the global test was 0.18. Men carrying one copy of the variant hap4 had a 1.39-fold increased risk of prostate cancer (95% CI = 1.05–1.85) compared with non-carriers. When subjects were restricted to sporadic prostate cancer, results changed very little (the P
-value for global test became 0.03; hap4: OR = 1.41, 95% CI = 1.06–1.87; data not shown).
ORs between ELAC2 haplotypes and the risk of prostate cancer
We looked at interactions with the following risk factors: age, BMI and family history of prostate cancer. However, none of these risk factors modify the association between sequence variants of ELAC2 and prostate cancer.
We also explored the main effects for aggressive and non-aggressive prostate cancer separately (). Two SNPs showed a statistically significant association with aggressive prostate cancer (carriers versus non-carriers—snp2: OR = 1.43, 95% CI = 1.06–1.93; snp3: OR = 0.69, 95% CI = 0.50–0.95). For haplotype analysis (global test P-value = 0.11), hap1 and hap4 variant carriers had a 1.47- and 1.51-fold increased risk of aggressive prostate cancer (95% CI = 1.08–1.99 and 1.04–2.18, respectively) compared with non-carriers. Hap2 variant carriers showed 0.72-fold risk of prostate cancer (95% CI = 0.52–0.98) compared with non-carriers. Results were not statistically significant for non-aggressive prostate cancer. After correction for multiple comparisons by the permutation test, hap4 is the only haplotype that remained statistically significantly associated with sporadic prostate cancer (P for permutation test = 0.0069).
ELAC2 SNP and haplotypes and risk of aggressive and non-aggressive prostate cancer
We also assessed whether prostatitis affected the association between ELAC2 genotypes and the risk of prostate cancer. Prostatitis status did not modify the association between hap1 and prostate cancer (one variant carrier of hap1 versus non-carrier: OR = 5.45, 95% CI = 1.60–18.6, P interaction = 0.12) among younger men (age ≤ 60) (data not shown). Results were also not statistically significant among older men (age > 60).