This is the first study to examine genetic variation in HSD17b2 and HSD17b4 genes in relation to endometrial cancer risk. We evaluated the association between 47 tag SNPs that efficiently covered the genes HSD17b2 and HSD174 and endometrial cancer risk, in two case-control studies nested within the NHS and WHS. After combining results from the two studies, we observed no significant associations between polymorphisms in HSD17b2 and HSD17b4 and endometrial cancer risk among Caucasians.
Previous studies have examined a small number of SNPs (n<3) in HSD17b2
in relation to mammographic density (12
), prostate cancer (10
), human spermatogenic defect (11
) and circulating sex hormones (9
). None of these studies observed any significant associations. Similarly, a handful of studies have examined a select number of SNPs (n<13) in HSD17b4
in relation to testicular germ cell tumors (13
), ovarian cancer (14
), and androgen deprivation prostate cancer therapy (15
). The study by Beesly et al.
) observed a borderline association of non-synonymous SNP rs17145454 with the clear cell subtype of ovarian cancer but not with overall ovarian cancer suggesting the association maybe due to chance. The study by Ross et al.
) observed a significant association of intronic SNP rs24543 with androgen deprivation prostate cancer therapy. We genotyped these two SNPs as well as newly discovered non-synonymous SNPs in our genes of interest and SNPs in known regulatory regions. We also included SNPs genotyped in the Breast and Prostate Cancer Consortium where no association was observed with breast and prostate cancer (personal communication). We did not observe an association with any of the above selected SNPs nor with the remaining tag SNPs we genotyped.
Mice knock-out studies on HSD17b2
highlight the importance of these genes for survival to birth and adulthood. Mice lacking the gene HSD17b2
exhibit placenta structural abnormalities and die at the embryo stage (22
). Mice overexpressing HSD17b2
show growth retardation, ovarian dysfunction and mammary gland hyperplasia (23
). Mice lacking the gene HSD17b4
do not die at the embryo stage but exhibit growth retardation and structural abnormalities in several organs such as the eye (atrophic retina), brain, and testis (infertility) (24
in addition to sex steroid metabolism plays a central role in fatty acid metabolism. Humans deficient in HSD17b4, also named multifunctional protein or D-bi-functional protein (DBP), are diagnosed with a developmental syndrome known as Zellweger syndrome otherwise called DBP deficiency. Patients die within their first to third year of life, and have brain abnormalities and seizures (24
). The deficiency is caused by point mutations, deletions or truncations that severely affect the structure and activity of HSD17b4 (25
). We observed that all known SNPs in these genes as listed in the HapMap database were located in introns, except 3 non-synonymous SNPs in HSD17b4
. Taken together all of the above observations underscore the important role these two genes play in biological function and support that these proteins are more likely to be functionally conserved (26
We also did not observe any association between a subset of our tag SNPs and plasma hormone levels suggesting that variation in these genes does not influence levels of circulating hormones. It is possible that circulating hormone levels may not accurately reflect local hormone levels which may be influenced by variation in HSD17b2 and HSD17b4.
This is the first report to investigate genetic variation in HSD17b2 and HSD17b4 in relation to endometrial cancer risk. The main strengths of this study include the comprehensive evaluation of SNPs in HSD17b2 and HSD17b4 in two prospective case-control studies. We selected 47 tagging SNPs that provided complete coverage across the genes and regulatory regions. In addition, we investigated SNPs with possible functional significance and we replicated findings from previous studies on other health outcomes. The use of two prospective case-control studies in which to validate our findings and the homogeneous population are among other strengths of the study. However, our study was limited to Caucasians therefore the results may not be generalized to other ethnicities. We also did not examine rare variants and may not have had sufficient power to detect weak associations. The lack of significant associations does not rule out the possibility that polymorphisms in these genes may have a larger impact when they interact with other genes or lifestyle factors. Our findings suggest that common genetic variation in HSD17b2 and HSD17b4 does not substantially influence the risk of endometrial cancer in Caucasian women.
- Comprehensive examination of SNPs in estrogen metabolism genes HSD17b2 and HSD17b4
- Examined in two prospective case-control studies nested within the NHS and WHS
- Novel findings reported in relation to endometrial cancer risk
- Endometrial cancer is a model of estrogen carcinogenesis
- SNP variation in these genes may not influence the risk of endometrial cancer