|Summary||Possibility of progesterone receptor gene haplotype with 1.98x endometrial cancer risk.|
Haplotype of the progesterone receptor gene PGR which has been linked with increased ovarian cancer and endometrial cancer risk for caucasian women. This haplotype has been determined using available 23andMeV3 genotypes.
DNA microarray genotyping results are normally unphased, and haplotypes cannot normally be determined from it. These tag-SNP's have been specifically chosen [PMID 12890923] so that having at least one risk allele for each SNP listed on a line indicates you have the haplotype for that grouping. Since many of the SNP's are not tested, this result is mostly a hint. You can try to estimate probability for missing SNP's by multiplying with frequence of each missing SNP's risk allele in population, although due to the number of matching genotypes you probably have this haplotype.
In a multi-ethnic study strongest association and odds ratio for endometrial cancer among whites (383 cases and 840 controls) was found with this haplotype (OR 1.98 (1.28-3.06) P 0.002) [PMID 20547493]. Prevalence of the full haplotype was approximately 4.5% for white controls. In a 2005 study [PMID 15632380] with 267 ovarian cancer cases and 397 controls as well as 1715 breast cancer cases and 2505 controls association was studied using same haplotypes, with results for ovarian cancer being in same direction for each haplotype group. Both studies suggest that the association could be mostly due to rs608995, included as part of this haplotype, but didn't have enough data for definite conclusion. Further study is no doubt warranted both to validate the results and smooth the risk ratios.
Full SNP list (reverse order from the studies): 1: *rs1870019(T) *rs608995(T) rs561650(C) +rs1042838(G) +rs660541(G) 2: *rs516693(A) rs601040(G) rs572483(C) +rs543215(A) *rs613120(C) *rs565186(T) 3: *rs529359(A) *rs481775(G) rs3740753(C) 4: rs499590(T) rs474320(A) +rs568157(A) * = Exists on 23andMeV3, + = also on FTDNA's new chip
Since this is a gene-spanning haplotype, if one has it, they don't have the risks for the individual SNP's but the combiner risk of the haplotype. This is useful, because there is a tendency to over-estimate the odds ratio when looking at studies done on individual SNP's. For example, since the PROGINS haplotype has always been seen together, it's possible to assign the PROGINS odds ratio to every single mutation contained in the haplotype (In general studies assign the odds ratio to PROGINS allele rs1042838 but state that they believe rs608995 is causal mostly avoiding this problem so far). Someone getting this result has only single risk for progesterone receptor PGR. Unfortunately relatively small studies have been done on the haplotype, so determining odds ratio is still difficult.
Rs11224561(T) which has recently been associated with endometrial cancer occurs 677 bases from rs608995 towards rs1870019. It is in same LD block as the suspected causal variants, but the risk allele doesn't occur in same haplotype as previous risk alleles in OpenSNP data: Rs11224561(T) rs608995(A) rs1042838(G) rs660541(A). In the nomenclature of the original studies this is called haplotype 4C, and was the haplotype of majority of Japanese and native Hawaiians. Note that no quality control beyond the original test companies has been done in OpenSNP data, including checking for relatedness, but the haplotype division is still indicative.
[PMID 21148628] Progesterone receptor gene variants and risk of endometrial cancer.
[PMID 20547493] Genetic variation in the progesterone receptor gene and risk of endometrial cancer: a haplotype-based approach
[PMID 15632380] Clarifying the PROGINS allele association in ovarian and breast cancer risk: a haplotype-based analysis