Clinical Annotations
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Variant Annotations
PharmGKB variant annotations provide information about variant-drug pairs based on individual PubMed publications. Each annotation represents information from a single paper and the goal is to report the information that the author states, not an interpretation of the paper. The PMID for supporting PubMed publications is found in the "Evidence" field.
Information presented, including study size, allele frequencies and statistics is taken directly from the publication. However, if the author does not correct p-values in cases of multiple hypotheses, curators may apply a Bonferroni correction. Curators attempt to report study size based on the actual number of participants used for the calculation of the association statistics, so the number may vary slightly from what is reported in the abstract of the paper. OMB Race Category information is derived from the paper and mapped to standardized categories. Category definitions may be found by clicking on the "OMB Race Category" link.
There are 11 annotations for this variant. Register or sign in to see them.
There are 3 disease-related annotations for this variant. Register or sign in to see them.
VIP Variant in PTGS2
The -765G>C promoter SNP (rs20417) is the most well studied variant in PTGS2 [Article:18085997]. It was reported by Papafili et al in 2002 [Article:12377741] as a modulator of the acute phase inflammatory response. The C variant was associated with lower promoter activity as compared to the G variant [Article:12377741]. The SNP is proposed to effect transcription factor binding to the promoter with the G>C transition eliminating an Sp1 site and creating an E2F site [Articles:16083713, 15316498, 15767339]. This variant has also been referred to as -899G>C and ss5112606 in the literature [Articles:14754878, 18085997].
The C variant occurs at a frequency of 0.145 in Caucasians, 0.219 in Native American/Hispanic and 0.364 in African/African American sample sets from the CEPH Human Diversity Panel and was not significantly different in the SNP500Cancer control sample set from the Coriell collection [Article:16381944]. The -765G>C variant is found in a haplotype with -1195G>A (rs689466) in Pima Indians [Article:12920574], Chinese Asians [Article:16083713] and Australian Caucasians [Article:18489027] (see below for more on this variant) and with -1290A>G (rs689465) in a Caucasian Australian population [Article:18489027].
The epidemiological relevance of rs20417 is unclear despite several studies (see Table 1 of PMID:18085997 for summary up to 2007). The C variant was initially found to be protective against myocardial infarction and stroke in a European Caucasian population [Article:15138244], but the same group was unable to confirm their initial finding [Article:20299798]. Other studies found that the C variant was associated with increased risk of stroke in the Atherosclerosis Risk in Communities Study in African Americans but not White individuals [Articles:17350020, 17495879]. Diabetics homozygous for the C allele of rs20417 had increased carotid calcified plaque [Article:18768181]. Other studies have shown no impact on secondary cardiovascular events [Article:20299798], aortic aneurysm [Article:19625268].
The CC genotype was associated with asthma in Polish women [Article:15316498]. In Australian Caucasians the rs20417 polymorphism was not associated with asthma alone [Article:15544595] but the G variant was associated with a reduced incidence of asthma as part of a haplotype (-1290A/-1195G/-765G) [Article:18489027].
Similarly with risk for different cancers there are conflicting results: meta analyses showed no effect on prostate cancer [Article:19488068], or for breast cancer [Article:20033767], no effect on colorectal cancer [Article:19468846] but the C variant has been associated with oral premalignant lesions (as part of a haplotype [Article:19197984]), risk for gastric cancer [Article:17006983] and was protective for skin cancer [Article:17578436]. In order to try and further clarify the role of rs20417 in disease etiology several studies have looked at dietary interaction [Articles:15150618, 19056642]. In individuals consuming higher than average n-6 polyunsaturated fatty acids, the C allele was associated with risk for colon cancer [Article:15150618]. In a study of Mediterranean-style dietary intervention for reduction of inflammation, PTGS2 -765G>C was associated with inflammatory markers but all genotypes responded favorably to diet [Article:19056642].
A small number of studies have looked at drug interaction with rs20417. In the Atherosclerosis Risk in Communities Study, -765C showed a small non-significant association with higher risk of coronary heart disease (CHD) in aspirin non-users and lower risk of CHD in those reporting aspirin use [Article:17495879]. Lemaitre et al, in 2009 replicated this observation of the interaction of rs20417 with aspirin use on myocardial infarction risk [Article:19046748]. The -765C variant was associated with a higher reduction of thromboxane 11dTxB2 with aspirin treatment in platelets in vitro [Article:15604423]. However Takahashi et al suggest that individual differences in platelet thromboxane production and aspirin resistance cannot be explained by COX protein levels or variants although they did not test -765G>C n their study [Article:17631383]. In a study of rofecoxib vs ibuprofen for pain relief following dental surgery, individuals with GG genotype were more likely to report lower pain intensity with rofecoxib whereas CC individuals were more likely to report lower pain intensity with ibuprofen [Article:16678543]. This variant was also examined in a study of rofecoxib and celecoxib in healthy individuals however all subjects in the study were GG homozygotes [Article:16401468]. In an ex vivo study of celecoxib on monocyte PGE2 production, no effect was attributable to rs20417 [Article:17178263]. It is interesting to note that the studies where an interaction of rs20417 was observed with drugs [Articles:16678543, 17495879, 19046748], the drugs were often more non-isoform selective (aspirin, ibuprofen). Thus variant PTGS2 may be more relevant when COX-1 function is disrupted, at least under some circumstances.
Note: The PTGS2 gene is found on the minus chromosomal strand. Please note that for standardization, the PharmGKB presents all allele base pairs on the positive chromosomal strand, therefore the alleles within our variant annotations will differ (in a complementary manner) from those in this VIP summary that are given on the minus strand as reported in the literature.
| Key Publications: | |
|---|---|
| Drugs / Other Molecules | |
| Diseases | Asthma Colonic Neoplasms Coronary Disease Mouth Neoplasms Neoplasms Pain Skin Neoplasms Stomach Neoplasms |
Appendix
1. PTGS2: (-765)G>C (rs20417)
| Genomic Variant & GenBank ID: | 1228G>C on AY382629.1 |
|---|---|
| DNA Source Containing Homozygous Reference Allele(Coriell Lines): | NA12239 |
| DNA Source Containing Heterozygous Reference Allele(Coriell Lines): | NA07019 |
| DNA Source Containing Homozygous Minor Allele(Coriell Lines): | NA10860 |
Connected Drugs
Connected Drug Classes
Connected Diseases
Publications related to rs20417 at chr1:186650321: 23
Cross-References
- UCSC Golden Path:
- chr1:186650321
- dbSNP:
- rs20417
- HapMap:
- rs20417
- Seattle SNP:
- PTGS2-001228
Platform Availability
- Illumina