Leptin receptor genotype at Gln223Arg is associated with body composition, BMD, and vertebral fracture in postmenopausal Danish women.
Leptin is emerging as a key regulator of bone remodeling. In a population-based study of 1306 postmenopausal Danish women, nonsynonymous LEPR SNPs were associated with risk of adiposity, BMD, and vertebral fracture. Smoking exacerbates this LEPR-associated fracture risk.


BACKGROUND
Nonsynonymous single nucleotide polymorphisms (SNPs) in the human LEPR gene have been associated with adiposity in a number of studies, but there have been no large-scale studies of their implications for BMD and osteoporotic fracture risk in postmenopausal women.


METHODS
We carried out a population-based study of 1430 women. Three well-known nonsynonymous leptin receptor (LEPR) SNPs (Lys109Arg, Gln223Arg, and Lys656Asn) were genotyped for qualitative and quantitative association analysis. Phenotype characteristics of main interest were DXA measures of body fat and lean tissue mass, BMD, and radiographic vertebral fractures.


RESULTS
Gln223Arg associated with risk of vertebral fracture (overall OR = 1.76; OR in smokers = 2.31; p = 0.0004), in addition to BMD of the femoral neck and total hip (p = 0.036 and 0.008, respectively). Heterozygote carriers showed lower BMD at both sites. Gln223Arg was also associated with adiposity (p = 0.001 for total fat mass). For adiposity, the at-risk allele was G (resulting in an arginine at position 223).


CONCLUSIONS
Variation in LEPR seemed to contribute to the variation in BMD and fracture risk in Danish postmenopausal women; the heterozygous genotype was associated with increased risk of manifest osteoporosis. Further studies are needed to replicate these data and to clarify the mechanisms involved.
Fairbrother
Una L
UL
Section of Genomic Medicine, Faculty of Medicine, Imperial College London, Hammersmith Hospital, London, UK.
Tankó
László B
LB
Walley
Andrew J
AJ
Christiansen
Claus
C
Froguel
Philippe
P
Blakemore
Alexandra I F
AI
D000368:Aged; D000369:Aged, 80 and over; D001483:Base Sequence; D001823:Body Composition / Q000235:genetics*; D015519:Bone Density / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D003718:Denmark; D005260:Female; D005838:Genotype; D006801:Humans; D008593:Menopause; D008875:Middle Aged; D020641:Polymorphism, Single Nucleotide; D011956:Receptors, Cell Surface / Q000235:genetics*; D054411:Receptors, Leptin; D016103:Spinal Fractures / Q000235:genetics*
D017931:DNA Primers; C515448:LEPR protein, human; D011956:Receptors, Cell Surface; D054411:Receptors, Leptin