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Based on the evidence from murine experiments of an association between nonsynonymous coding polymorphisms in Alpl and variations in serum ALP, BMD, and bone mineral strength, we extended our studies to a well-characterized cohort of community-dwelling elderly men. We sequenced the 11 coding regions (exons 2�C12, including intron-exon boundaries) of ALPL in a subset of white men in the MrOS cohort. To increase the probability of identifying functionally relevant ALPL variants, we selected 74 individuals with serum ALP below the clinical cut point for normal ( http://www.selleckchem.com/PD-1-PD-L1.html of the population distribution (72?U/L). A total of 25 sequence variants were identified, with 21 resulting in nonsynonymous changes in amino acid coding and 22 occurring at MAF? http://www.selleckchem.com/products/Adriamycin.html normal ALP group (Table 3; Supplementary Table 1). Seven of these variants were not previously reported in 1000 Genomes or SNP databases. In the low ALP group, 60.8% of men had any of the 25 variants, and in the normal ALP group, 37.1% had at least one of the variants (p for ��2?=?6?��?10?4). The difference in frequency between groups was minimal for variants with MAF �� 1% (37.8% in those with low ALP and 33.1% in those with normal, p for ��2?=?0.49). However, a far greater proportion of men in the low ALP group had a rare variant (36.5%) than did men in the normal ALP group (3.4%, p for Fisher's exact test?=?1.6?��?10?10). To test the hypothesis that nonsynonymous rare variants in ALPL were associated with physiological consequences, we examined the group of men in the low ALP group, in http://www.selleck.cn/products/MK-1775.html which there was a sufficient frequency of rare variants to explore this hypothesis. Beyond direct measure of the circulating enzyme activity, other clinical markers of defective ALP action include increased urinary phosphoethanolamine (PEA) and increased serum phosphate and pyridoxal 5'-phosphate (PLP) levels.17, 40 Neither PEA excretion nor PLP levels were measured in the MrOS cohort, but fasting serum phosphate levels were available for analysis. Although each individual variant occurred in only one, two, or five of the men, 25 men (33.8%) in the low ALP group had at least one rare variant. Therefore, the association with this combined category of ��any rare, nonsynonymous variant�� was examined for serum ALP, serum phosphate, femoral neck BMD, and whole-body BMD. Men with a rare, nonsynonymous variant had 11.2% lower mean serum ALP (p?=?3.9?��?10?4), 6.7% lower femoral neck BMD (p?=?0.03), 6.6% lower whole-body BMD (p?=?0.007), and 11.1% higher serum phosphate (p?=?0.002) than those without such a variant. In contrast, serum ALP, phosphate or BMD did not differ according to the presence of a common nonsynonymous variant or a synonymous variant (Fig. 2).