A Differential Association of ALOX15 Polymorphisms with Bone Mineral Density in Pre- and Post-Menopausal Women

Abstract

Objective: The 12/15-lipoxygenase gene ALOX15 is reported to be a negative regulator of BMD in knockout mice. Nonetheless results are controversial as over-expression of ALOX15 protects against inflammation-related bone loss. The aim of the present study is to systematically study the relation of ALOX15 polymorphisms in BMD variation in southern Chinese women. Methods: Ten tag single nucleotide polymorphisms (SNP) were genotyped in 942 subjects with either low BMD (defined by a BMD Z score ≤–1.28 at either the hip or spine) or high BMD (Z score ≧+1). Single locus and haplotype associations were performed using logistic regression with adjustment of age, height and weight. Results: The variant ‘G’ allele of rs2619112 was associated with a reduced risk of low BMD at the femoral neck in pre-menopausal women (OR = 0.442, p = 0.007) but an increased risk in post-menopausal women (OR = 1.727, p = 0.042). Haplotype analysis revealed findings similar to the single locus tests. Conclusion: The variant alleles of rs2619112 and rs916055 and their haplotypes of ALOX15 are associated with high BMD in pre-menopausal women but low BMD in post-menopausal women. This suggests that ALOX15 is a dual modulator of BMD variation with opposing effects in pre- and post-menopausal women.

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

“…This appears to support the hypothesis of a pro--inflammatory role of the ALOX15 pathway in humans, although in our cohorts, polymorphisms in ALOX15 do not appear to play a direct role in skeletal integrity in older women, while apparently influencing bone microarchitecture in young women. While other studies have investigated the association between ALOX15 and bone in pre--and post--menopausal women these were in cohorts of different ethnicities and with a focus only on BMD [15,19]. In the present study we aimed at investigating the role of ALOX15 polymorphisms using cohorts with a homogeneous genetic background and investigating phenotypes reflecting skeletal integrity and fracture risk.…”

Association of Low-Density Lipoprotein Receptor-Related Protein 5 (LRP5) Promoter SNP with Peak Bone Mineral Density in Chinese Women

“…Pairwise linkage disequilibrium (LD), based on D value, for all SNP-pair combinations were estimated using the Ldmax program [33] , and displayed as a graphical summary using the GOLD program [33] . A set of informative SNPs were selected by Tagger [31] using aggressive algorithm with r 2 set to be 0.8, and totally 4 SNPs were included in the analysis.…”

“…Subjects were invited to the Osteoporosis Centre at Queen Mary Hospital for assessment. All subjects were interviewed by a trained research assistant using a validated structured questionnaire [30,31] . Low BMD subjects were arbitrarily defined as those with a BMD Z score ^ -1.28 (equivalent to the lowest 10th percentile of the population) at the spine, femoral neck or total hip, while high BMD subjects had BMD Z scores 1 +1 at the corresponding sites (equivalent to the highest 15th percentile of the population).…”

Association of ALOX15 gene polymorphisms with obesity-related phenotypes in Chinese nuclear families with male offspring

“…According to Hapmap, rs11568131 is in high LD with rs916055 (D'=1) (HapMap Data Phase III/Rel#2, Feb09, on NCBIB36 assembly, dbSNP b126), although rs11568131 displays a modest heterozygosity (MAF=0.155). Furthermore, one SNP (rs916055) has been shown to have significant association with bone mineral density (BMD) within the lumbar portion of the spine in postmenopausal women [33] . Because the genomic organization of mammalian ALOX is highly conserved [34] , we speculated that SNP rs916055, which is located within the 3′-UTR of ALOX15 may affect the binding of the transcriptional machinery, which might, in turn, generate potentially functional RNA variants.…”