Objective:Arachidonate 12-lipoxygenase (ALOX12) is a member of the lipoxygenase superfamily, which catalyzes the incorporation of molecular oxygen into polyunsaturated fatty acids. The products of ALOX12 reactions serve as endogenous ligands for peroxisome proliferator-activated receptor γ (PPARG). The activation of the PPARG pathway in marrow-derived mesenchymal progenitors stimulates adipogenesis and inhibits osteoblastogenesis. Our objective was to determine whether polymorphisms in the ALOX12 gene were associated with variations in peak bone mineral density (BMD) and obesity phenotypes in young Chinese men.Methods:All six tagging single-nucleotide polymorphisms (SNPs) in the ALOX12 gene were genotyped in a total of 1215 subjects from 400 Chinese nuclear families by allele-specific polymerase chain reaction. The BMD at the lumbar spine and hip, total fat mass (TFM) and total lean mass (TLM) were measured using dual-energy X-ray absorptiometry. The pairwise linkage disequilibrium among SNPs was measured, and the haplotype blocks were inferred. Both the individual SNP markers and the haplotypes were tested for an association with the peak BMD, body mass index, TFM, TLM and percentage fat mass (PFM) using the quantitative transmission disequilibrium test (QTDT).Results:Using the QTDT, significant within-family association was found between the rs2073438 polymorphism in the ALOX12 gene and the TFM and PFM (P=0.007 and 0.012, respectively). Haplotype analyses were combined with our individual SNP results and remained significant even after correction for multiple testing. However, we failed to find significant within-family associations between ALOX12 SNPs and the BMD at any bone site in young Chinese men.Conclusions:Our present results suggest that the rs2073438 polymorphism of ALOX12 contributes to the variation of obesity phenotypes in young Chinese men, although we failed to replicate the association with the peak BMD variation in this sample. Further independent studies are needed to confirm our findings.

Alendronate is an antiosteoporotic drug that targets the mevalonate pathway. To investigate whether the genetic variations in this pathway affect the clinical efficacy of alendronate in postmenopausal Chinese women with osteopenia or osteoporosis, 23 single-nucleotide polymorphisms (SNPs) in 7 genes were genotyped in 500 patients treated with alendronate for 12 months. Bone mineral density (BMD) was measured at baseline and after 12 months. The rs10161126 SNP in the 3' flanking region of MVK and the GTCCA haplotype in FDFT1 were significantly associated with therapeutic response. A 6.6% increase in BMD in the lumbar spine was observed in the GG homozygotes of rs10161126; AG heterozygotes and AA homozygotes experienced a 4.4 and 4.5% increase, respectively. The odds ratio (95% confidence interval) of G allele carriers to be responders in lumbar spine BMD was 2.06 (1.08-6.41). GTCCA haplotype in FDFT1 was more frequently detected in the group of responders than in the group of non-responders at the total hip (2.6 vs 0.5%, P=0.009). Therefore, MVK and FDFT1 polymorphisms are genetic determinants for BMD response to alendronate therapy in postmenopausal Chinese women.

No abstract

Exposure to Clopidogrel Through Modulation of P-Glycoprotein but Does Not Alter Its Antithrombotic Activity" by Oh et al., which elucidated the effect of aspirin coadministration on the pharmacokinetics/ pharmacodynamics of clopidogrel in healthy subjects. 1 The results of their study demonstrated that the clopidogrel area under the concentration-time curve (AUC) significantly decreased, but the AUC of H4 remained unchanged and RPI increased after aspirin administration. In addition, the plasma level of miR-27a, a microRNA involved in regulation of P-glycoprotein (P-gp) expression, was significantly increased after aspirin administration. However, no change in plasma MDR1 mRNA or miR-451 was observed. The authors proposed that coadministration of low-dose aspirin decreased the systemic exposure to clopidogrel, but the antithrombotic effect of clopidogrel was not affected.Previous study has indicated that prolonged use of aspirin may reduce the intestinal absorption of clopidogrel by inducing P-gp expression in human and rat intestinal cells. 2 And a similar trend in the PK profile of clopidogrel was also observed in the study of Oh et al., but the decrements were not statistically significant due to an insufficient dose of aspirin. Although the exposure to clopidogrel was lowered, the level of H4 was not changed after aspirin administration. For these seemingly contradictory results, the authors give two explanations. One is that the decrement in exposure to clopidogrel might not be sufficient to alter the exposure to H4. The other is bioactivation of effluxed clopidogrel to H4 in the intestine by CYP3A4. But we consider that there is another more reasonable explanation for this phenomenon. In a study presented previously, we demonstrated that low-dose aspirin significantly increased the activity of CYP2C19 and CYP3A4 in healthy volunteers. 3 As 15% of the clopidogrel converted to the biologically active thiol metabolite via a two-step CYP-dependent oxidative pathway, even small changes in activities of CYP isoenzymes seem to influence formation of its active metabolite. 4 Given the fact that oxidation of clopidogrel is catalyzed by CYP2C19, CYP3A4, and CYP3A5, 5 increased CYP2C19 and CYP3A4 activity by low-dose aspirin likely increases the activation of clopidogrel, thus enhancing the efficacy of this antiplatelet prodrug. So aspirin coadministration eventually does not alter the exposure of H4 by the combined two effects of aspirin. Further studies are needed to confirm the clinical significance regarding aspirin-increased CYP2C19 and CYP3A4 activity on clopidogrel activation. ACKNOWLEDGMENTS

No abstract