Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish☆
Introduction
Hip fractures cause significant morbidity and mortality in the elderly, and place a major economic burden on the health care system [1], [2]. The individual and societal burdens from hip fracture are increasing as the population ages. In fact, the number of hip fractures is expected to increase by 50% in the U.S. from 2005 to 2025, if more aggressive efforts are not taken to treat individuals at risk [3]. The factors contributing to fracture risk are incompletely understood, but since osteoporosis is fundamentally a condition characterized by bones that are reduced in mechanical strength and thus susceptible to fracture, the risk factors must act by degrading mechanical strength. Bone mineral density (BMD) is commonly used in the clinical setting as a strength surrogate due to its strong statistical links with fracture risk, but this measure is structurally ambiguous in that any given BMD value can be produced in a range of different and realistic bone dimensions with different mechanical properties. This makes it difficult to identify from BMD the mechanical differences that might lead to reduced strength. Mechanical properties that are related to bone strength include structural stability, axial bone strength and bending strength, represented by the measurable phenotypes buckling ratio (BR), cross-sectional area (CSA) and section modulus (Z) respectively (4). One recent approach, implemented in the Hip Structural Analysis (HSA) program, infers geometric properties from two-dimensional images of bone, and derives structural/mechanical properties from these inferred three dimensional projections.
The HSA program was developed specifically to express the mineral mass from a dual-energy X-ray absorptiometry (DXA) scan of the proximal femur in a structural geometry format that can be interpreted using conventional engineering methods [4], [5], [6]. HSA used in previous studies has shown reduced hip geometry measures of bone strength (lower bending strength, thinner cortical width), in women with hip fracture compared to those without fracture [7]. In addition, aging is known to be associated not only with a reduction in BMD but also with decreases in HSA-derived cortical thickness, femur width and bending strength (section modulus) [8]. Previous studies have shown that hip geometry-derived measures of bone strength are associated with fracture risk and that this association is at least partly independent of differences in BMD [9], [10], [11], [12], [13]).
The significant contributions of genetic factors to osteoporosis and bone mineral density are well accepted [14], [15], [16] though the geometric differences underlying the BMD effect are unclear. There is growing evidence to support the importance of heredity on geometric components of bone strength, including suggestive linkages to quantitative trait loci influencing proximal femur geometry in reports of genome-wide linkage analysis from three different research groups [17], [18], [19], [20], [21], [32]. In the most recent of these reports, the same HSA methods were used as in the current report [21], [22]. In aggregate, these linkage studies suggest that genes distinct from those that influence BMD are determinants of hip geometry traits. In this study, we report heritability and autosome-wide linkage analysis using HSA-derived measures of hip geometric strength in a large family-based cohort of Old Order Amish.
Section snippets
The Amish Family Osteoporosis Study (AFOS)
The AFOS was started in 1997 to identify genetic determinants of osteoporosis [23], [24]. The Old Order Amish (OOA) population is an attractive one for genetic studies of complex traits because it is a closed Caucasian founder population with large families who live in close proximity and have a relatively homogeneous lifestyle. OOA study subjects believed to be at risk for osteoporosis by virtue of fracture history or prior BMD measurements were recruited. The diagnosis of osteoporosis was
Clinical characteristics
The mean age (± SD) of the 879 subjects included in this analysis was 49.6 (± 15.8) years in men and 49.9 (± 16.3) years in women. On average, women had slightly higher (though not statistically significant) body mass indices (BMI) than men (27.9 ± 5.9 kg/m2 vs 26.5 ± 4.2 kg/m2). Approximately 46% of women were post-menopausal. BMD and hip geometry phenotypes obtained from HSA are shown for the neck and shaft regions according to sex and age in Table 1. BMD and geometric measures were higher in men
Discussion
Our study found that hip geometric phenotypes derived from hip structural analysis (HSA) are highly heritable, with genes accounting for 40–84% of the residual variation in these phenotypes after accounting for the effects of age and sex. These heritabilities were found to be largely independent of BMD suggesting distinct genetic influences on these fracture risk factor traits. We found suggestive evidence of linkage to chromosome 17q11.2-12 for NN_CSA for men and women age 50 years and below,
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This work was supported by research grants RO1-AR46838, RO1-AG18728, and RO1-HL69313 awarded by the National Institutes of Health, the University of Maryland General Clinical Research Center, Grant M01 RR 16500 and Hopkins Bayview General Clinical Research Center, Grant M01 RR02719, General Clinical Research Centers Program, National Center for Research Resources (NCRR), NIH, the NHLBI Mammalian Genotyping Service, Marshfield Medical Research Foundation, Marshfield, WI, and the Baltimore Veterans Administration Geriatric Research and Education Clinical Center (GRECC).