|in FDPS gene and may be associated with anti-osteoporosis drug response|rs11264359
|?|| (A;A) (A;G) (G;G) ||28|
is an intronic SNP located 4125 base pairs from the translation start site of the FDPS
(Farnesyl diphosphate synthase) gene.
The FDPS gene encodes an enzyme that converts isopentenyl pyrophosphate and dimethylallyl pyrophosphate into geranyl pyrophosphate and farnesyl pyrophosphate as part of the mevalonate pathway. This pathway is known to be important in cholesterol and sterol biosynthesis [NCBI Gene ID: 2224].
This enzyme is essential in the bone remodeling process. Particularly, it is necessary for the survival and function of osteoclasts, which are bone cells important in the breakdown of bone tissue (bone resorption). This is the first step of the bone remodeling process, where bone tissue is first broken down by osteoclasts and then reformed by osteoblasts. This gene is thought to be the target of amino-biphosphonates, which are drugs shown to increase bone density and decrease risk of fractures [PMID 16009417].
Olmos et al. (2012) conducted a study to estimate the effect of four SNPs in the FDPS gene region on bone mineral density (BMD) [PMID 21151198]. The authors analyzed bone density and genotypes of Spanish women. Rs11264359 was found to have a slight association, which did not reach the multiple test-adjusted threshold for significance, with BMD at the hip (p = 0.043) and spine (p = 0.07) in an analysis of 1186 postmenopausal women not treated with amino-biphosphonates. However, in the same paper the results from an analysis of 191 postmenopausal women treated with amino-bisphosphonates were more intriguing. The authors found a significant association between rs11264359 and hip BMD changes induced by amino-bisphosphonates (p = 0.001). After an average of 2.5 years, individuals with the common rs11264359(A;A) showed an average 1% increase in BMD per year, while women with the rarer rs11264359(G;G) showed an average of 1.6% decrease in BMD per year. Heterozygotes exhibited an intermediate phenotype. However, it is important to note that rs11264359(A) is in strong linkage disequilibrium with rs2297480(A), another SNP in the FDPS region. It is unclear which SNP may be causal, and in vitro studies of the functional effect of the SNPs have not yet been conducted.
Two other studies investigated the correlation of rs2297480 (but not rs11264359) and BMD increase after amino-biphosphonate treatment. Marini et al. (2008) analyzed 234 Danish osteoporotic postmenopausal women treated with amino-bisphosphonates. After two years of treatment, the authors found a significantly greater decrease in the urinary Cross-laps (a marker of bone turnover) in individuals with rs2297480(A;A) and rs2297480(A;C) (-40.41% and -49.18%, respectively) than in individuals with rs2297480(C;C) (-21.7%; p=0.049). However, the authors did not find a significant association with BMD itself. After two years of treatment, the authors found about a 3.5% increase in spine BMD in individuals with the AA and AC genotype and about a 2% increase in individuals with the CC genotype. However, this failed to reach statistical significance (p = 0.60). Similarly, the authors found about a 1.6% increase in femur BMD in individuals with the AA genotype, 1.4% for those with the AC genotype, and about 0.7% for those with the CC genotype (p = 0.59) [PMID 18687167].
Choi et al. (2010) also found the same, not statistically significant, general trend of rs2297480 genotypes and the BMD response after one year of bisphosphonate therapy in 144 Korean women with osteoporosis [PMID 20191015]. In this study, the authors analyzed four SNPs within the FDPS and GGPS1 (geranylgeranyl diphosphate synthase) genes. For the genotypes CC, CA, and AA, the authors found lumbar BMD percentage increases of 7.0 (CI:-0.6-14.6), 6.0 (CI:0.5-11.5), and 8.9 (CI:-0.8-18.6), respectively (p = 0.264). For femoral BMD and the same genotypes, the results were 3.6 (CI:-2.8-10.0), 3.4 (CI:-5.2-12), and 8.5 (CI:-1.5-18.5), respectively (p = 0.059). It is important to note that this study attributed variation in amino-biphosphonate response to variations in the GGPS1 gene, which was not analyzed in the above studies.
The haplotype of FDPS, including rs11264359 was also found to be associated with Alzheimer’s disease in two small samples from Switzerland and Sweden (n = 352 and n = 361, respectively), but this association was not found in other sample populations in the study. Furthermore the haplotype with rs11264359(G) was implicated in Switzerland (p = 0.02), while a haplotype containing rs11264359(A) was implicated in Sweden (p = 0.007) [PMID 17387528]. The AlzGene metaanalysis was negative for the FDPS gene, and therefore rs11264359 as well [PMID: 20580938].
McGovern et al. (2010) conducted a GWAS study with 896 Crohn’s disease cases and 3204 healthy controls, all of Caucasian origin. An expression study of SNPs important in Crohn’s disease pathogenesis indicated a cis effect of rs11264359(A) among other loci (p = 3.3 × 10−8 ) [PMID 20570966].
[PMID 19141583] Phenotypic and molecular evaluation of a chromosome 1q region with linkage and association to type 2 diabetes in humans.