A polymorphic variant at the Werner helicase (WRN) gene is associated with bone density, but not spondylosis, in postmenopausal women

Werner syndrome (WS) is a rare autosomal recessive progeroid syndrome characterized by the premature onset of multiple age-related disorders. The gene responsible for WS has been identified as WRN, a member of the RecQ family of helicase genes. Based on the fact that patients with WS exhibit osteoporosis and osteoarthritis, the present study was undertaken to clarify the contribution of the WRN gene to the etiology of these two common age-related disorders in normal postmenopausal women. We investigated the association of a WRN gene polymorphism, namely c.4330 T --> C leading to an amino acid substitution from Cys to Arg, with bone density and lumbar spondylosis score in unrelated Japanese postmenopausal women (n = 377). Genotypic frequencies of T/T, T/C, and C/C were 87.5%, 12.2%, and 0.3%, respectively. Bone density of the lumbar spine (L2-4) was significantly lower in women carrying the minor C allele than in non-carriers (P = 0.037). When bone density was expressed by the Z score after being adjusted by age and weight, carriers of the C allele showed lower values not only in the lumbar spine, but also in the total body (P = 0.015 and 0.042, respectively). The association study with spondylosis in postmenopausal women (n = 221) revealed that this polymorphism was not related to the severity of spondylosis expressed by the Kellgren-Lawrence score at any disk level of the lumbar spine (L2/3-L5/S1). These findings indicate that the WRN gene may be a candidate for the genetic regulation of osteoporosis, but not spondylosis, in normal Japanese postmenopausal women.