Biomedical subjects

Lan-Juan Zhao

Publications and source records attributed to Lan-Juan Zhao.

At least 19 recordsLinked to original sources

PubMed2006

A genome-wide linkage scan for quantitative trait loci underlying obesity related phenotypes in 434 Caucasian families.

To identify quantitative trait loci (QTLs) that contribute to obesity, we performed a large-scale whole genome linkage scan (WGS) involving 4,102 individuals from 434 Caucasian families. The most pronounced linkage evidence was found at the genomic region 20p11-12 for fat mass (LOD = 3.31) and percentage fat mass (PFM) (LOD = 2.92). We also identified several regions showing suggestive linkage signals (threshold LOD = 1.9) for obesity phenotypes, including 5q35, 8q13, 10p12, and 17q11.

Family↗

PubMed2006

Is a gene important for bone resorption a candidate for obesity? An association and linkage study on the RANK (receptor activator of nuclear factor-kappaB) gene in a large Caucasian sample.

In light of findings that osteoporosis and obesity may share some common genetic determination and previous reports that RANK (receptor activator of nuclear factor-kappaB) is expressed in skeletal muscles which are important for energy metabolism, we hypothesize that RANK, a gene essential for osteoclastogenesis, is also important for obesity. In order to test the hypothesis with solid data we first performed a linkage analysis around the RANK gene in 4,102 Caucasian subjects from 434 pedigrees, then we genotyped 19 SNPs in or around the RANK gene. A family-based association test (FBAT) was performed with both a quantitative measure of obesity [fat mass, lean mass, body mass index (BMI), and percentage fat mass (PFM)] and a dichotomously defined obesity phenotype-OB (OB if BMI > or = 30 kg/m(2)). In the linkage analysis, an empirical P = 0.004 was achieved at the location of the RANK gene for BMI. Family-based association analysis revealed significant associations of eight SNPs with at least one obesity-related phenotype (P < 0.05). Evidence of association was obtained at SNP10 (P = 0.002) and SNP16 (P = 0.001) with OB; SNP1 with fat mass (P = 0.003); SNP1 (P = 0.003) and SNP7 (P = 0.003) with lean mass; SNP1 (P = 0.002) and SNP7 (P = 0.002) with BMI; SNP1 (P = 0.003), SNP4 (P = 0.007), and SNP7 (P = 0.002) with PFM. In order to deal with the complex multiple testing issues, we performed FBAT multi-marker test (FBAT-MM) to evaluate the association between all the 18 SNPs and each obesity phenotype. The P value is 0.126 for OB, 0.033 for fat mass, 0.021 for lean mass, 0.016 for BMI, and 0.006 for PFM. The haplotype data analyses provide further association evidence. In conclusion, for the first time, our results suggest that RANK is a novel candidate for determination of obesity.

Adult↗

PubMed2006

Epistasis between loci on chromosomes 2 and 6 influences human height.

CONTEXT: Human height is a typical and important complex trait, which is determined by both actions and interactions of multiple genes. Although an increasing number of genes or genomic regions have been discovered for their independent effects on height variation, no study has been performed to identify genes or loci that interact to control the trait. OBJECTIVE: This study aimed to search for potential genomic regions that harbor interactive genes underlying human height. METHODS: Here with a sample containing 3726 Caucasians, the largest one ever obtained from a single population of the same ethnicity among genetic linkage studies of human complex traits, we performed variance component linkage analyses of height based on a two-locus epistatic model. We examined pairwise genetic interaction among three regions, 9q22, 6p21, and 2q21, which achieved significant or suggestive linkage signals for height in our recent whole genome scan. RESULTS: Significant genetic interaction between 6p21 and 2q21 was detected, with 2q21 achieving a maximum LOD score of 3.21 (P = 0.0035) under the epistatic model, compared with a maximum LOD score of 1.63 under a two-locus additive model. Interestingly, 6p21 contains a cluster of candidate genes for skeletal growth, suggesting a mechanism whereby 2q21 regulates height through 6p21. CONCLUSION: By providing the first evidence for genetic interaction underlying human height variation, this study further delineated the genetic architecture of human height and contributed to the genetic dissection of human complex traits in general.

Adult↗

PubMed2006

Up-regulation of ERK and p38 MAPK signaling pathways by hepatitis C virus E2 envelope protein in human T lymphoma cell line.

Hepatitis C virus (HCV) infection correlates with human immune disorders characterized by abnormal activation and proliferation of lymphocytes. Interaction of HCV major envelope protein E2 with susceptible cells occurs at an early stage of the viral infection. HCV tropism for susceptible cells may elicit cellular signaling events implicated in the viral pathogenicity, and E2 protein is known to be responsible for the tropism. We documented previously that HCV E2 protein was capable of activating extracellular signal-regulated kinase (ERK) in human hepatoma Huh-7 cells. Here, ERK and p38 mitogen-activated protein kinase (MAPK) signaling pathways were investigated in human T lymphoma cell line Molt-4 in response to HCV E2 protein. Binding of HCV E2 protein to Molt-4 cells was detectable, and such interaction was a determinant for recognition and delivery of the E2 signal to intracellular pathways. Activation of ERK and p38 MAPK was specifically induced following the HCV E2-cell interaction. CD81 and low-density lipoprotein receptor (LDLR), proposed cellular receptors for HCV, were expressed naturally on Molt-4 cells. CD81 and LDLR were shown to mediate HCV E2-induced activation of ERK and p38 MAPK. In CD81-deficient U937 cells, levels of ERK and p38 MAPK activation and cell proliferation induced by HCV E2 protein were lower than those in Molt-4 cells. Furthermore, cell proliferation and secretion of interferon-gamma and interleukin-10 by Molt-4 cells were promoted by HCV E2 protein. Therefore, ERK and p38 MAPK signaling pathways were up-regulated by HCV E2 protein without synergetic stimulation, which was accompanied by alterations of cell behavior.

Antigens, CD↗

PubMed2006

Genetic linkage of human height is confirmed to 9q22 and Xq24.

Human height is an important and heritable trait. Our previous two genome-wide linkage studies using 630 (WG1 study) and an extended sample of 1,816 Caucasians (WG2 study) identified 9q22 [maximum LOD score (MLS)=2.74 in the WG2 study] and preliminarily confirmed Xq24 (two-point LOD score=1.91 in the WG1 study, 2.64 in the WG2 study) linked to height. Here, with a much further extended large sample containing 3,726 Caucasians, we performed a new genome-wide linkage scan and confirmed, in high significance, the two regions' linkage to height. An MLS of 4.34 was detected on 9q22 and a two-point LOD score of 5.63 was attained for Xq24. In an independent sub-sample (i.e., the subjects not involved in the WG1 and WG2 studies), the two regions also achieved significant empirical P values (0.002 and 0.004, respectively) for "region-wise" linkage confirmation. Importantly, the two regions were replicated on a genotyping platform different from the WG1 and WG2 studies (i.e., a different set of markers and different genotyping instruments). Interestingly, 9q22 harbors the ROR2 gene, which is required for growth plate development, and Xq24 was linked to short stature. With the largest sample from a single population of the same ethnicity in the field of linkage studies for complex traits, our current study, together with two previous ones, provided overwhelming evidence substantiating 9q22 and Xq24 for height variation. In particular, our three consecutive whole genome studies are uniquely valuable as they represent the first practical (rather than simulated) example of how significant increase in sample size may improve linkage detection for human complex traits.

Adult↗

PubMed2006

Tests of linkage and association of PTH/PTHrP receptor type 1 gene with bone mineral density and height in Caucasians.

Parathyroid hormone/parathyroid hormone-related peptide receptor type 1 (PTHR1) plays an important role in calcium metabolism. It was previously shown to influence variation in bone mineral density (BMD). To investigate its importance in a typical U.S. Caucasian population, we tested linkage or association of the PTHR1 gene with BMD and height. Altogether, 1873 subjects from 405 Caucasian nuclear families were studied. BMD was measured at the lumbar spine (L1-L4) and total hip (femoral neck, trochanter, and intertrochanter regions). Four single nucleotide polymorphisms (SNPs) in the PTHR1 gene were genotyped. Sixteen haplotypes were reconstructed. Only two major haplotypes had frequencies >3% and were thus used for the analysis. Analyses were performed for BMD and height in the total sample and for peak BMD (PBMD) achieved in offspring subjects aged 20-50 in a subsample of 387 nuclear families. We found suggestive evidence for total association between haplotype 13 (AATG) and hip PBMD (P = 0.031). For height, evidence of within-family association was suggested for SNP1, SNP2, and haplotype 4 (GGCA) (P < or = 0.05). Our findings suggest that the PTHR1 gene may be important for PBMD, height variation, or both, although the significance is dampened by correction for multiple testing.

Absorptiometry, Photon↗

PubMed2006

Genomic regions identified for BMD in a large sample including epistatic interactions and gender-specific effects.

UNLABELLED: A genome-wide linkage scan was conducted using a large white sample to identify QTLs for BMD. We found QTLs in the total sample and the gender-specific subgroups, as well as significant epistatic interactions underlying BMD variations. INTRODUCTION: Low BMD is an important risk factor for osteoporosis and under strong genetic control. MATERIALS AND METHODS: To identify quantitative trait loci (QTLs) for regulation of BMD, we performed a large-scale whole genome linkage scan (WGS) involving 4126 individuals from 451 families. In addition to the conventional linkage analyses in the total combined sample of males and females, we conducted epistatic interaction analyses and gender-specific linkage analyses. RESULTS: Significant linkage was detected on 5q23 for wrist BMD (LOD = 3.39) and 15q13 for female spine BMD (LOD = 4.49). For spine BMD, we revealed significant epistatic interactions between 3p25 and 2q32 (p = 0.0022) and between 3p25 and 11q23 (p = 0.0007). We replicated several genomic regions that showed linkage with BMD in previous studies by others and ours, such as 3p21, 1p36, and Xq27. CONCLUSIONS: This study highlights the importance of large sample size, incorporation of epistatic interaction, and consideration of gender-specific effects in identifying QTLs for BMD variation. The results of this study provide a foundation for the future fine mapping and gene identification in our population.

Bone Density↗

PubMed2006

Robust and comprehensive analysis of 20 osteoporosis candidate genes by very high-density single-nucleotide polymorphism screen among 405 white nuclear families identified significant association and gene-gene interaction.

UNLABELLED: Many "novel" osteoporosis candidate genes have been proposed in recent years. To advance our knowledge of their roles in osteoporosis, we screened 20 such genes using a set of high-density SNPs in a large family-based study. Our efforts led to the prioritization of those osteoporosis genes and the detection of gene-gene interactions. INTRODUCTION: We performed large-scale family-based association analyses of 20 novel osteoporosis candidate genes using 277 single nucleotide polymorphisms (SNPs) for the quantitative trait BMD variation and the qualitative trait osteoporosis (OP) at three clinically important skeletal sites: spine, hip, and ultradistal radius (UD). MATERIALS AND METHODS: One thousand eight hundred seventy-three subjects from 405 white nuclear families were genotyped and analyzed with an average density of one SNP per 4 kb across the 20 genes. We conducted association analyses by SNP- and haplotype-based family-based association test (FBAT) and performed gene-gene interaction analyses using multianalytic approaches such as multifactor-dimensionality reduction (MDR) and conditional logistic regression. RESULTS AND CONCLUSIONS: We detected four genes (DBP, LRP5, CYP17, and RANK) that showed highly suggestive associations (10,000-permutation derived empirical global p < or = 0.01) with spine BMD/OP; four genes (CYP19, RANK, RANKL, and CYP17) highly suggestive for hip BMD/OP; and four genes (CYP19, BMP2, RANK, and TNFR2) highly suggestive for UD BMD/OP. The associations between BMP2 with UD BMD and those between RANK with OP at the spine, hip, and UD also met the experiment-wide stringent criterion (empirical global p < or = 0.0007). Sex-stratified analyses further showed that some of the significant associations in the total sample were driven by either male or female subjects. In addition, we identified and validated a two-locus gene-gene interaction model involving GCR and ESR2, for which prior biological evidence exists. Our results suggested the prioritization of osteoporosis candidate genes from among the many proposed in recent years and revealed the significant gene-gene interaction effects influencing osteoporosis risk.

Adult↗

PubMed2005

Genome-wide scan identified QTLs underlying femoral neck cross-sectional geometry that are novel studied risk factors of osteoporosis.

UNLABELLED: A genome-wide screen was conducted using a large white sample to identify QTLs for FNCS geometry. We found significant linkage of FNCS parameters to 20q12 and Xq25, plus significant epistatic interactions and sex-specific QTLs influencing FNCS geometry variation. INTRODUCTION: Bone geometry, a highly heritable trait, is a critical component of bone strength that significantly determines osteoporotic fracture risk. Specifically, femoral neck cross-sectional (FNCS) geometry is significantly associated with hip fracture risk as well as genetic factors. However, genetic research in this respect is still in its infancy. MATERIALS AND METHODS: To identify the underlying genomic regions influencing FNCS variables, we performed a remarkably large-scale whole genome linkage scan involving 3998 individuals from 434 pedigrees for four FNCS geometry parameters, namely buckling ratio (BR), cross-sectional area (CSA), cortical thickness (CT), and section modulus (Z). The major statistical approach adopted is the variance component method implemented in SOLAR. RESULTS: Significant linkage evidence (threshold LOD = 3.72 after correction for tests of multiple phenotypes) was found in the regions of 20q12 and Xq25 for CT (LOD = 4.28 and 3.90, respectively). We also identified eight suggestive linkage signals (threshold LOD = 2.31 after correction for multiple tests) for the respective geometry traits. The above findings were supported by principal component linkage analysis. Of them, 20q12 was of particular interest because it was linked to multiple FNCS geometry traits and significantly interacted with five other genomic loci to influence CSA variation. The effects of 20q12 on FNCS geometry were present in both male and female subgroups. Subgroup analysis also revealed the presence of sex-specific quantitative trait loci (QTLs) for FNCS traits in the regions such as 2p14, 3q26, 7q21 and 15q21. CONCLUSIONS: Our findings laid a foundation for further replication and fine-mapping studies as well as for positional and functional candidate gene studies, aiming at eventually finding the causal genetic variants and hidden mechanisms concerning FNCS geometry variation and the associated hip fractures.

Adult↗

PubMed2005

Association analysis of estrogen receptor alpha gene polymorphisms with cross-sectional geometry of the femoral neck in Caucasian nuclear families.

Bone geometry is a key factor in bone strength, which is the ultimate intrinsic determinant of fracture risk. Though the heritability of bone geometry is high, little effort has been spent on searching for the underlying genes. In this study, employing a sample of 1,873 subjects from 405 Caucasian nuclear families, we studied seven single nucleotide polymorphisms (SNPs) and their haplotypes of the ER-alpha gene for association with six hip geometric variables, namely, cross-sectional area (CSA), cortical thickness (CT), endocortical diameter (ED), subperiosteal width (W), sectional modulus (Z) and buckling ratio (BR). The major method used was the quantitative transmission disequilibrium test (QTDT). Our major findings were summarized below. The within-family association between SNP4 (rs1801132) in exon 4 with endocortical diameter and subperiosteal width was detected in single locus analyses (P=0.008 and 0.021, respectively) and verified in haplotype analyses (P=0.034 and 0.058, respectively). The total association of SNP4 with these two diameters was also observed in both single locus and haplotype analyses (P=0.005 and 0.031 for ED, plus P=0.003 and 0.070 for W). In addition, the total association between SNP5 (rs932477) in intron 4 with cortical thickness and buckling ratio was detected (single locus analyses: P=0.035 and 0.041, respectively). Haplotype analyses further supported the above association (P=0.010 and 0.004, respectively). Similar patterns of associations with the studied SNPs and their haplotypes were present in subsamples stratified by sex, too. However, after permutation tests, the empirical significance level was set as P<0.011, which renders most associations insignificant. Therefore, we concluded that polymorphisms in the ER-alpha gene were nominally associated with femoral neck (FN) geometry variables estimated from DXA. Such genetic effects on hip geometry were not sex specific.

Adult↗

PubMed2005

Predictive factors for age at menopause in Caucasian females.

OBJECTIVE: Early onset of menopause results in the premature exposure to low estrogen levels and is associated with a number of postmenopausal health problems and higher risk of mortality. The aim of this study was to determine genetic and environmental factors associated with age at natural and surgical menopause. METHODS: Multiple regression analysis using a sample of Caucasians composed of 154 females with surgical and 248 with natural menopause. RESULTS: Breastfeeding is a significant predictor of earlier natural menopause (P<0.05). Use of oral contraceptives and smoking were not significantly associated with age at menopause. Females who did not have history of pregnancies are at significantly higher risk (P<0.001) of getting early surgical menopause than those who did. We also tested the association of seven single nucleotide polymorphisms (SNPs) of the estrogen receptor alpha (ER-alpha) gene with age at menopause. No association was observed with age at menopause but the PvuII p allele was overrepresented in women with surgical menopause and associated with menopause per se (P=0.029; OR=1.8, 95% CI=1.1-3.0). CONCLUSIONS: Breastfeeding and alcohol consumption are significantly associated with earlier natural menopause. No significant effects of the ER-alpha genotypes were observed on the age of menopause. Given the important role of the ER-alpha in estrogen signaling, which directly influences the menopausal process, further studies are required to better define the relationship between this gene and age at menopause.

Age of Onset↗

PubMed2005

Mapping quantitative trait loci for cross-sectional geometry at the femoral neck.

UNLABELLED: A genome-wide linkage scan was performed in a sample of 79 multiplex pedigrees to identify genomic regions linked to femoral neck cross-sectional geometry. Potential quantitative trait loci were detected at several genomic regions, such as 10q26, 20p12-q12, and chromosome X. INTRODUCTION: Bone geometry is an important determinant of bone strength and osteoporotic fractures. Previous studies have shown that femoral neck cross-sectional geometric variables are under genetic controls. To identify genetic loci underlying variation in femoral neck cross-sectional geometry, we conducted a whole genome linkage scan for four femoral neck cross-sectional geometric variables in 79 multiplex white pedigrees. MATERIALS AND METHODS: A total of 1816 subjects from 79 pedigrees were genotyped with 451 microsatellite markers across the human genome. We performed linkage analyses on the entire data, as well as on men and women separately. RESULTS: Significant linkage evidence was identified at 10q26 for buckling ratio (LOD = 3.27) and Xp11 (LOD = 3.45) for cortical thickness. Chromosome region 20p12-q12 showed suggestive linkage with cross-sectional area (LOD = 2.33), cortical thickness (LOD = 2.09), and buckling ratio (LOD = 1.94). Sex-specific linkage analyses further supported the importance of 20p12-q12 for cortical thickness (LOD = 2.74 in females and LOD = 1.88 in males) and buckling ratio (LOD = 5.00 in females and LOD = 3.18 in males). CONCLUSIONS: This study is the first genome-wide linkage scan searching for quantitative trait loci underlying femoral neck cross-sectional geometry in humans. The identification of the genes responsible for bone geometric variation will improve our knowledge of bone strength and aid in development of diagnostic approaches and interventions for osteoporotic fractures.

Absorptiometry, Photon↗

PubMed2005

The (CA)n polymorphism of the TNFR2 gene is associated with peak bone density in Chinese nuclear families.

Low peak bone density (PBD) in adulthood is an important determinant of osteoporotic fracture (OF) in the elderly. The tumor necrosis factor receptor 2 (TNFR2) gene has been considered as an important candidate gene for PBD due to its important role in bone turnover. In this study, we recruited a total of 1,263 subjects from 402 Chinese nuclear families composed of both parents and at least one daughter, and tested the association of the (CA)(n) polymorphism in intron 4 of the TNFR2 gene with PBD using a more contemporary quantitative transmission disequilibrium test (QTDT). Significant within-family association was detected between the CA16 allele and bone mineral density (BMD) at the lumbar spine with the P-value of 0.005 after permutations, which is still significant after correction for multiple testing. Some evidence of total-family association between the CA16 allele and lumbar spine BMD was found (P=0.021), although the significant level did not reach the empirical threshold (P< or =0.007). About 3.14% of lumbar spine BMD variation can be explained by the CA16 allele. In summary, our results suggest that the TNFR2 gene may play an important role in determining lumbar spine BMD variation in Chinese women.

Bone Density↗

PubMed2005

Small interfering RNA inhibits SARS-CoV nucleocapsid gene expression in cultured cells and mouse muscles.

SARS-CoV is a newly identified coronavirus that causes severe acute respiratory syndrome (SARS). Currently, there is no effective method available for prophylaxis and treatment of SARS-CoV infections. In the present study, the influence of small interfering RNA (siRNA) on SARS-CoV nucleocapsid (N) protein expression was detected in cultured cells and mouse muscles. Four siRNA expression cassettes driven by mouse U6 promoter targeting SARS-CoV N gene were prepared, and their inhibitory effects on expression of N and enhanced green fluorescence protein (EGFP) fusion protein were observed. A candidate siRNA was proved to down-regulate N and EGFP expression actively in a sequence-specific manner. The expression vector of this siRNA was constructed and confirmed to reduce N and EGFP expression efficiently in both cultured cells and adult mouse muscles. Our findings suggest that the siRNA should provide the basis for prophylaxis and therapy of SARS-CoV infection in human.

Animals↗

PubMed2005

Hepatitis C virus E2 protein promotes human hepatoma cell proliferation through the MAPK/ERK signaling pathway via cellular receptors.

Dysregulation of mitogen-activated protein kinase (MAPK) signaling pathways by various viruses has been shown to be responsible for viral pathogenicity. The molecular mechanism by which hepatitis C virus (HCV) infection caused human liver diseases has been investigated on the basis of abnormal intracellular signal events. Current data are very limited involved in transmembrane signal transduction triggered by HCV E2 protein. Here we explored regulation of the MAPK/extracellular signal-regulated kinase (MAPK/ERK) signaling pathway by E2 expressed in Chinese hamster oval cells. In human hepatoma Huh-7 cells, E2 specifically activated the MAPK/ERK pathway including downstream transcription factor ATF-2 and greatly promoted cell proliferation. CD81 and low density lipoprotein receptor (LDLR) on the cell surface mediated binding of E2 to Huh-7 cells. The MAPK/ERK activation and cell proliferation driven by E2 were suppressed by blockage of CD81 as well as LDLR. Furthermore, pretreatment with an upstream kinase MEK1/2 inhibitor U0126 also impaired the MAPK/ERK activation and cell proliferation induced by E2. Our results suggest that the MAPK/ERK signaling pathway triggered by HCV E2 via its receptors maintains survival and growth of target cells.

Animals↗

PubMed2005

Immune responses against SARS-coronavirus nucleocapsid protein induced by DNA vaccine.

The nucleocapsid (N) protein of SARS-coronavirus (SARS-CoV) is the key protein for the formation of the helical nucleocapsid during virion assembly. This protein is believed to be more conserved than other proteins of the virus, such as spike and membrane glycoprotein. In this study, the N protein of SARS-CoV was expressed in Escherichia coli DH5alpha and identified with pooled sera from patients in the convalescence phase of SARS. A plasmid pCI-N, encoding the full-length N gene of SARS-CoV, was constructed. Expression of the N protein was observed in COS1 cells following transfection with pCI-N. The immune responses induced by intramuscular immunization with pCI-N were evaluated in a murine model. Serum anti-N immunoglobulins and splenocytes proliferative responses against N protein were observed in immunized BALB/c mice. The major immunoglobulin G subclass recognizing N protein was immunoglobulin G2a, and stimulated splenocytes secreted high levels of gamma interferon and IL-2 in response to N protein. More importantly, the immunized mice produced strong delayed-type hypersensitivity (DTH) and CD8(+) CTL responses to N protein. The study shows that N protein of SARS-CoV not only is an important B cell immunogen, but also can elicit broad-based cellular immune responses. The results indicate that the N protein may be of potential value in vaccine development for specific prophylaxis and treatment against SARS.

Animals↗

PubMed2004

SNPP: automating large-scale SNP genotype data management.

UNLABELLED: To manage high-throughput single nucleotide polymorphism (SNP) genotyping data efficiently, we developed a dynamic general database management system-SNPP (SNP Processor). It provides several functions, including data importing with comparison, Mendelian inheritance check within pedigrees, data compiling and exporting. Furthermore, SNPP may generate files for repeat genotyping and transform them into files that can be executed by a liquid handling system. AVAILABILITY: http://orclinux.creighton.edu/snpp/ CONTACT: lanjuanzhao@creighton.edu

Algorithms↗

PubMed2004

APOE haplotypes influence bone mineral density in Caucasian males but not females.

Low bone mineral density (BMD) is one of the most important risk factors for osteoporosis. Apolipoprotein E (APOE) has been considered as a candidate gene for osteoporosis because of its influence on osteoblast uptake of lipoprotein-borne vitamin K. Using the quantitative transmission disequilibrium test QTDT, we examined linkage and/or association of APOE and BMD at the lumbar spine and the total hip in a sample of 387 Caucasian nuclear families with 715 parents and 953 children. The children were aged 20-50 years and female offspring were premenopausal as well. Four single nucleotide polymorphisms (SNP1-4) in the APOE gene, 4-locus haplotypes and 2-locus haplotypes (epsilon1, epsilon2, epsilon3, epsilon4 isoforms, reconstructed by SNP3 and SNP4) were analyzed. In the whole sample and the female offspring families we found no evidence of linkage or association for either single SNP or haplotype with BMD at the two studied skeletal sites. In the male offspring families, within-family associations were observed at the haplotypes CGTC (P = 0.001), GGTT (P = 0.002), and GATC (P = 0.006) for the lumbar spine BMD, and GATC (P = 0.008) for the total hip BMD. These data suggested that in our studied Caucasian population, APOE may have effects on BMD variation in males but not females. Further studies with a larger sample size are required to confirm such results.

Absorptiometry, Photon↗