Pharmacogenomic Approaches to Osteoporosis D-H Xiong Et Al 262

genotype was associated with a greater Pharmacogenomic approaches to increase in BMD in response to the vitamin D supplementation in Japa- osteoporosis nese. Furthermore, it was reported in a Japanese study that the TT homozy- D-H Xiong1,2,4, J-R Long1,4, RR Recker1 and H-W Deng1,2,3 gotes benefited from HRT more than the Tt heterozygotes.9 However, the

1 opposite or ‘no association’ conclu- Osteoporosis Research Center, Creighton University Medical Center, Omaha, NE, USA; sions were made in other studies.10–14 2 Department of Biomedical Sciences, Creighton University, Omaha, NE, USA; These discrepancies may be accounted 3 Laboratory of Molecular and Statistical Genetics, College of Life Sciences, Hunan for by many confounding variables Normal University, Changsha, Hunan, People’s Republic of China such as population admixture, epista- sis, gene Â environment interaction, linkage disequilibrium and allele or The Pharmacogenomics Journal (2003) 3, the genetic contribution to interindi- locus heterogeneity across different 261–263. doi:10.1038/sj.tpj.6500199 vidual difference in drug response. populations. Further studies with ro- By means of the population-based bust study designs are needed for a association method, several major better understanding of the relation- Osteoporosis is a common bone dis- candidate genes, such as vitamin D ship between the VDR polymorphisms ease inflicting about 40% of women receptor (VDR), estrogen receptor and the efficacy of anti-osteoporotic and 12% of men at some point during alpha (ER-a) and collagen I alpha 1 therapies. life.1 It is mainly characterized by the (COLIA1) genes, have been investi- Pharmacogenetic studies of the ER-a unbalanced loss of bone mass with gated with regard to osteoporosis drug gene mainly involve two marker loci, decreased density and deteriorated responses. the XbaI and PvuII polymorphisms. bone microarchitecture, leading to The major biological function of Deng et al15 reported a positive asso- osteoporotic fracture. The social eco- VDR is to mediate the multiple and ciation between the XX homozygotes nomic burden of osteoporosis is so complex actions of 1,25-(OH)2 vitamin and the increase of spine BMD in large that its etiology, prevention and D, including its effect on calcium response to HRT treatment in postme- treatment have become an urgent transport and homeostasis and bone nopausal Caucasian women. As for the issue that needs to be coped with resorption. Many association studies PvuII polymorphism, the study of a worldwide. have been conducted on the relation- cohort of Finnish perimenopausal wo- It is generally believed that many ship between various bone phenotypes men showed that the P allele was genetic and environmental factors and and VDR gene polymorphisms, such as significantly associated with the re- the ways in which they interact with the VDR BsmI and TaqI polymorph- duction in the incidence of new each other underlie the development isms. Based on the summarized data, fractures in the group treated with of osteoporosis.2 However, the exact Liu et al5 tentatively concluded that bb HRT. But in the non-HRT group, the genetic pathogenesis remains unclear or TT genotypes were more advanta- PvuII polymorphism was not signifi- although a large number of candidate geous in terms of bone metabolism, cantly associated with fracture risk.16 genes and their proteins are known to calcium homeostasis, bone accrual This result suggests that the gen- be involved in bone metabolism.3 during childhood and bone retention e Â drug interaction may have an in- Anti-osteoporotic pharmacothera- later in life, while BB or tt individuals fluence on the results of association pies mainly involve supplements of might be more likely to develop studies, which might be one of the vitamin D and calcium along with osteoporosis. Data from some pharma- confounding factors underlying the independent or combined use of drugs cogenetic studies provided some sup- outcome of osteoporosis research. like hormones, selective estrogen re- port. In the Framingham study cohort, Ongphiphadhanakul et al17 also found ceptor modulators (eg tamoxifen, ra- dietary calcium intake was positively that the increase in vertebral BMD loxifene), bisphosphonates (eg associated with BMD only among responding to estrogen therapy was alendronate, risedronate) and calcito- those with the bb genotype.6 In a significantly lower in Thai postmeno- nin.4 However, the efficacy of anti- sample of 60 postmenopausal women, pausal women without the P allele osteoporotic treatments may vary sig- the calcium absorption efficiency on compared to those with the P allele, nificantly among individuals. This fact low calcium intake was significantly which partially supported Salmen et encourages the application of pharma- lower in subjects with BB genotype al’s conclusion.16 In addition, BMD cogenetic approaches to osteoporosis than those with bb genotype.7 Mat- changes after HRT were reported to be research, with the aim of dissecting suyama et al8 also reported that the bb associated with another polymorph- Pharmacogenomic approaches to osteoporosis D-H Xiong et al 262

ism in the ER-a gene, a T262C transi- underway ‘HapMap’ project24 holds microarrays. Thus, the study of global tion in exon 1, which may be in promise for the genome-wide associa- gene expression patterns that are linkage disequilibrium with the PvuII tion studies that will use haplotype affected in symphony by specific polymorphism.18 However, no signifi- blocks to unravel some mystery of diseases and drug treatments can be cant difference in BMD change was osteoporosis and provide an ideal regi- greatly facilitated. Moreover, DNA observed between different genotypes men of treatment for osteoporotic microarrays can be used for drug target of either PvuII or XbaI polymorphisms patients according to the complete validation and disease diagnoses. after treatment with selective estrogen genetic evaluations. Yet, a large num- In a recent review, it was also shown receptor modulators.19 ber of SNPs will be required for such that microarrays could be employed For the COLIA1 gene, the Sp1 poly- whole genome association studies. to identify molecular subtypes of morphism was often studied. Cultured Other limitations exist as well, such given disease traits to help find the osteoblasts from ‘Ss’ heterozygotes as the availability of large patient genetic loci specific to each subtype.26 produced increased amount of the populations, the high price of geno- Such an application may provide an collagen a1(I) chain because the s typing and the extent and distribution alternative way to identify genes allele had greater affinity for transcrip- of linkage disequilibrium (LD) in the underlying osteoporosis.27 Yet, the tion factor Sp1 than did the S allele. human genome. Therefore, the candi- DNA microarrays approach is not

The resulted overproduction of a1(I)3 date gene approach is still the most perfect since it only aims at the level in collagen may be responsible for feasible method in the genetic and of RNA alterations. A complementary impaired bone strength.20 In agree- pharmacogenomic studies of osteo- approach is proteomics, which is ment with this theory, many studies porosis at present. the analysis of global changes in showed the association between the Linkage analysis was another protein expression. It deals with Sp1 polymorphism and the risk for prevalent approach to the osteoporosis changes that DNA microarrays cannot osteoporosis or fractures.5 Although genetic research. Our recent review target, which include protein abun- inconsistent association results exist, systematically tabulated the chromo- dance, protein–protein interactions two meta-analyses21,22 supported that some regions, showing evidence of and post-translational modifica- the presence of the s allele was sig- linkage with osteoporosis-related tions.25 Now the proteomics approach nificantly associated with low BMD phenotypes.5 Some of them (2p23-24, is being applied to the discovery of and fracture prevalence though such 1p36, 3q21, 4q31 and 13q34) were new drug targets and the study of drug effect on bone metabolism was mod- replicated to be linked with BMD response, thus leading to the birth of erate and could be easily modified by phenotype, but no region was pharmacoproteomics. The judicious environmental factors. In keeping completely confirmed. However, no use of genetic epidemiology, DNA with this, one pharmacogenetic re- genome-wide linkage scan for microarrays and/or proteomics techni- search demonstrated that the s allele loci influencing the efficacy of ques in the osteoporosis research can negatively influences BMD response to anti-osteoporotic therapies was complement pharmacogenomic meth- the etidronate therapy since femoral launched. Such studies may be only ods for the better understanding of neck BMD obviously increased in the performed in animals because it is osteoporosis. SS group while decreased in the Ss/ss almost impossible to administer a Pharmacogenomic approaches will group.20 This finding also implied the given drug to multiple family mem- have a significant impact on the treat- possible clinical value of using COLIA1 bers of mankind. ment of osteoporosis. It can help map Sp1 polymorphism in targeting etidro- Pharmacogenomic approaches to new anti-osteoporotic drug targets, nate therapy to patients who are most osteoporosis are just in their infancy. improve the efficiency of drug devel- likely to respond, with potential ad- They should be further developed opment and move from ‘one drug fits vantages in terms of cost and clinical and combined with other functional all’ to personalized therapy. In this outcome. genomic approaches to be more way, significant cost savings within Traditional association studies fre- powerful in the genetic dissection the healthcare system can be produced quently analyze one marker indepen- of osteoporosis. Functional genomics and the risk of serious side effects dently of other markers. Haplotypes broadly includes a set of technologies reduced as well. reconstructed by multiple markers in a and strategies focused on finding gene are usually more informative due the function of genes and understand- ACKNOWLEDGEMENTS to the existence of accumulated allelic ing how the genome works together The study was partially supported by grants effects at different loci and/or interac- to generate whole patterns of biologi- from the Health Future Foundation of the tions between these loci.23 In the cal function.25 Currently, DNA USA, grants from the National Institute of osteoporosis research field, although microarrays may be the most powerful Health (K01 AR02170-01, R01 GM60402-01 A1), grants from the State of Nebraska few haplotype analyses were done in of the techniques that address global Cancer and Smoking Related Disease Re- the pharmacogenetic context, some functional genomics questions. search Program (LB595) and the State of haplotypes of certain candidate genes The goal of analyzing the expression Nebraska Tobacco Settlement Fund were already studied and associated of thousands of genes can be achieved (LB692), and US Department of Energy with bone phenotypes.5 Moreover, the in a single experiment using DNA grant (DE-FG03-00ER63000/A00).

The Pharmacogenomics Journal Pharmacogenomic approaches to osteoporosis D-H Xiong et al 263

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