Polymorphisms in ALOX12, but not ALOX15, Are Significantly Associated With BMD in Postmenopausal Women

Abstract

The murine arachidonate 15-lipoxygenase gene (Alox15) has recently been identified as a negative regulator of peak bone mineral density (BMD). The human ALOX15 gene shares significant sequence homology with the murine Alox15 gene; however, the human arachidonate 12-lipoxygenase gene (ALOX12) is functionally more similar to the mouse gene. Multiple single-nucleotide polymorphisms (SNPs) in the human ALOX15 and ALOX12 genes have previously been reported to be significantly associated with BMD in humans. On the basis of these data, we carried out our own investigation of the human ALOX15 and ALOX12 genes and their relationship with hip and spine BMD parameters. The study population consisted of 779 postmenopausal women with a mean (+/- standard deviation) age of 62.5 +/- 5.9 years at BMD measurement and was recruited from a single large general practice in Chingford, northeast London. Three SNPs from ALOX15 and five from ALOX12 were analyzed. None of the SNPs that we analyzed in ALOX15 were significantly associated with any of the BMD parameters or fracture data. However, we found that three SNPs from ALOX12, all previously associated with spine BMD in women, were significantly associated with spine and various hip BMD parameters in our cohort (P = 0.029-0.049). In conclusion, we found no association between polymorphism in ALOX15 and BMD phenotypes but were able to replicate previous findings that genetic variation in ALOX12 seems to play a role in determining bone structure in Caucasian women.

Polymorphisms in inflammation associated genes ALOX15 and IL-6 are associated with bone properties in young women and fracture in elderly

“…Unfortunately, other inflammatory biomarkers were not available and neither fracture nor CRP was available in PEAK--25, which is an undoubted limitation of the study. We found that ALOX12 polymorphisms were associated with BMD only in the young but not the elderly women, contradicting the low BMD and increased vertebral fracture risk among post--menopausal women observed in another study [18]. The much higher age at inclusion of the women in the OPRA cohort leads us to conjecture whether ALOX12 may be most important during critical periods of high bone turnover, for example during bone accrual and menopause.…”

“…The rationale for SNP selection at the time when genotyping was performed is outlined below. SNPs for ALOX12 were selected from the literature as having been previously investigated for BMD [16,18,20]. SNP rs312466…”

Polymorphisms in the human ALOX12 and ALOX15 genes are associated with peak bone mineral density in Chinese nuclear families

“…The rs916055 SNP is located in the 3′ UTR, which has been previously identified as a functional gene region [28,29]. This SNP has a significant association with high BMD in the lumbar spine in premenopausal Hong Kong women [16] but has no association with BMD parameters or fracture data in a British study examining 779 postmenopausal women [13]. Although the QTDT test is less powerful than the population-based association test for the detection of association, we used a large sample size of Chinese nuclear families.…”

“…As candidate genes for susceptibility to osteoporosis, both ALOX15 and ALOX12 single-nucleotide polymorphisms (SNPs) have been found to correlate with BMD in humans [12][13][14][15][16]. Most of these studies were population-based and yielded varying results.…”

“…Most of these studies were population-based and yielded varying results. For example, rs748694 (in the promoter region of ALOX15), which has been found to be associated with the BMD of the whole body and the lumbar spine in a Japanese study [15], had no association with BMD in another study [13] of young Caucasian women. This discrepancy may be due to differences in the studies' populations or sample sizes.…”