Gordon Gong

A Mutation in the LDL Receptor–Related Protein 5 Gene Results in the Autosomal Dominant High–Bone-Mass Trait

Osteoporosis is a complex disease that affects >10 million people in the United States and results in 1.5 million fractures annually. In addition, the high prevalence of osteopenia (low bone mass) in the general population places a large number of people at risk for developing the disease. In an effort to identify genetic factors influencing bone density, we characterized a family that includes individuals who possess exceptionally dense bones but are otherwise phenotypically normal. This high-bone-mass trait (HBM) was originally localized by linkage analysis to chromosome 11q12-13. We refined the interval by extending the pedigree and genotyping additional markers. A systematic search for mutations that segregated with the HBM phenotype uncovered an amino acid change, in a predicted beta-propeller module of the low-density lipoprotein receptor-related protein 5 (LRP5), that results in the HBM phenotype. During analysis of >1,000 individuals, this mutation was observed only in affected individuals from the HBM kindred. By use of in situ hybridization to rat tibia, expression of LRP5 was detected in areas of bone involved in remodeling. Our findings suggest that the HBM mutation confers a unique osteogenic activity in bone remodeling, and this understanding may facilitate the development of novel therapies for the treatment of osteoporosis.

The Association of Bone Mineral Density with Vitamin D Receptor Gene Polymorphisms

Abstract: A recent meta-analysis of 16 publications suggested that bone mineral density (BMD) is not associated with vitamin D receptor (VDR) gene polymorphism (VDRGP) at the 0.05 significance level when a study with genotyping mistakes is excluded. We wished to determine whether ‘positive’ findings supporting the BMD–VDRGP association may be explained by chance, and what factors affect the outcomes of these studies. Seventy-five articles and abstracts on the association of VDRGP with BMD and related skeletal phenotypes published before January 1997 were identified. Twenty-three of 67 (34.3%) studies on spinal BMD and 22 of 51 (43.1%) on femoral neck BMD had found a BMD–VDRGP association at p<0.05, significantly (p= 7 × 10–14 for spinal BMD, p= 9 × 10–16 for hip BMD) higher than the expected 5% false positive rate under the null hypothesis of ‘no association’. ‘Positive’ results were more frequently observed in studies on females before the menopause than those on females after the menopause (p<0.02) or on male and female subjects combined (p<0.05) when skeletal phenotypes at any bone sites were considered. The ‘positive rate’ among studies was also influenced by the age range of subjects studied and by the inclusion of subjects with osteoporosis. It is concluded that: (1) BMD is associated with VDRGP with high levels of confidence and (2) non-genetic factors and genetic heterogeneity interfere with the detection of the effects of VDRGP on bone phenotypes.

Phenotypic and genotypic heterogeneity in the Lynch syndrome: diagnostic, surveillance and management implications

Lynch syndrome is the most common form of hereditary colorectal cancer (CRC). This review covers the cardinal features of Lynch syndrome with particular emphasis upon its diagnostic criteria, molecular genetics, natural history, genetic counseling, surveillance and management. Considerable attention has been given to the etiologic role of mismatch repair (MMR) genes as well as low penetrance alleles and modifier genes. The American founder mutation, a deletion of exons 1–6 of MSH2, is discussed in some detail, owing to its high frequency in the US (19 000–30 000 carriers). Genetic counseling is essential prior to patients’ undergoing DNA testing and again when receiving their test results. Families with a lower incidence of CRC and extracolonic cancers, in the face of being positive for Amsterdam I criteria but who do not have MMR deficiency by tumor testing, are probably not Lynch syndrome, and thereby should preferably be designated as familial CRC of undetermined type. Patients who are either noncompliant or poorly compliant with colonoscopy, and who are MMR mutation positive, may be candidates for prophylactic colectomy, while MMR mutation-positive women who are noncompliant with gynecologic surveillance may be candidates for prophylactic hysterectomy and bilateral salpingo-oophorectomy.

Change of bone mass in postmenopausal Caucasian women with and without hormone replacement therapy is associated with vitamin D receptor and estrogen receptor genotypes

Our purpose is to assess whether genotypes of the vitamin D receptor (VDR) and estrogen receptor (ER) and their interaction influence changes in bone mass in postmenopausal Caucasian women with and without hormone replacement therapy (HRT). A population of 108 US Mid-West women who participated in a study of low-dose continuous estrogen/progestin was genotyped at the VDR BsmI site and the ER XbaI and PvuII sites. Adequate vitamin D and calcium nutritional intakes were assured in all the study subjects. For the 3.5-year duration of the study, we analyzed changes in bone mineral density (BMD) at the spine, femoral neck, distal radius, and the total body (total body bone mineral content, tbBMC). We adjusted for confounding factors, such as age and weight, in the analysis. We found that VDR and/or ER genotypes and/or their interaction generally had significant effects on the changes in the bone mass measurements in both the placebo and HRT groups. When a significant gene-by-gene interaction exists between VDR and ER genotypes, failure to account for them in analyses may yield nonsignificant results, even if significant genotypic effects exist. The amount of variation in changes in bone mass measurements explained by the total genotypic effects of the VDR and ER loci varies from ∼1.0% (for the tbBMC changes in combined placebo and HRT groups) to ∼18.7% (for the spine BMD changes in the HRT group). These results suggest that individual genotypes are important factors in determining changes in bone mass in the elderly with and without HRT and thus may need to be considered with respect to the treatment to preserve bone mass in elderly Caucasian women.

Association of VDR and estrogen receptor genotypes with bone mass in postmenopausal Caucasian women: different conclusions with different analyses and the implications.

Abstract: Much work has been done on the association between vitamin D receptor (VDR) genotypes and bone mineral density (BMD). Despite considerable effort, the results are inconsistent. While the VDR association remains unresolved, studies have expanded to other candidate genes (i.e., estrogen receptor (ER) genotypes), also yielding inconsistent results. A few studies have suggested that interaction effects between VDR and ER genotypes significantly affect BMD. We assessed associations of BMD with VDR BsmI genotypes, and ER XbaI and PvuII polymorphisms (denoted as ERX and ERP respectively) with spine, femoral neck, distal radius BMD, and with total body bone mineral content (tbBMC) in 108 US Mid-western postmenopausal Caucasian women. We statistically controlled for confounding factors such as height, weight, etc., in the analysis. No significant association was detected for ER genotypes with spine and radius BMD, or for VDR genotypes with femoral neck and radius BMD and tbBMC. No significant interaction between VDR and ER genotypes was detected in our sample. However, the VDR genotypes are significantly (p = 0.004) associated with *5.8% spine BMD variation. Both ERX and ERP genotypes are significantly (p = 0.02) associated with *3.5% femoral neck BMD variation. ERX genotypes are significantly (p = 0.03) associated with *2.4% tbBMC variation. However, if the data were analyzed by simple ANOVA as in some previous studies, without adjusting statistically for confounding factors, all the significant results we found here would have gone undetected. Our findings suggest that: (1) VDR and ER genotypes may have different effects on BMD at different sites and on tbBMC; and (2) if significant factors influencing bone are not appropriately controlled, true significant associations can easily be missed. These findings may offer a partial explanation for some of the earlier inconsistent results of association studies on BMD with VDR and ER genotypes.

Origins and prevalence of the American Founder Mutation of MSH2.

Large germline deletions within the mismatch repair gene MSH2 account for a significant proportion (up to 20%) of all deleterious mutations of this gene which are associated with Lynch syndrome. An exons 1 to 6 deletion of MSH2, originally reported in nine families, has been associated with a founding event within the United States, which genealogic studies had previously dated to 1727, and the number of present day carriers was estimated to be 18,981. Here, we report the development of a robust multiplex PCR which has assisted in the detection of 32 new families who carry the MSH2 American Founder Mutation (AFM). By offering testing to family members, 126 carriers of the AFM have been identified. Extensive genealogic studies have connected 27 of the 41 AFM families into seven extended pedigrees. These extended families have been traced back to around the 18th century without any evidence of further convergence between them. Characterization of the genomic sequence flanking the deletion and the identification of a common disease haplotype of between 0.6 and 2.3 Mb in all probands provides evidence for a common ancestor between these extended families. The DMLE+2.2 software predicts an age of approximately 500 years (95% confidence interval, 425-625) for this mutation. Taken together, these data are suggestive of an earlier founding event than was first thought, which likely occurred in a European or a Native American population. The consequences of this finding would be that the AFM is significantly more frequent in the United States than was previously predicted.

American founder mutation for lynch syndrome : Prevalence estimates and implications

Recently, a new founder mutation, an exon 1–6 deletion in a mismatch repair gene (MMR), MSH2, in nine kindreds with Lynch syndrome was reported. In 3 of the kindreds this mutation was traced by genealogy through 11–12 generations to a common founder, and thus termed the American Founder Mutation (AFM). Since then, 13 additional ‘unrelated’ kindreds with AFM were detected by a recently designed single polymerase chain reaction. This test might serve as first‐line screening for Lynch syndrome mutations, provided AFM was prevalent, which is assessed in the current study.

Family information service participation increases the rates of mutation testing among members of families with BRCA1/2 mutations.

Abstract:  Some members of hereditary breast‐ovarian cancer (HBOC) families may not participate in BRCA testing to determine their mutation status in part because they are unaware of their cancer risk and the availability of BRCA testing. Participation in a family information service (FIS), of which we have provided more than 100 sessions during the past 30 years, has been seen to effectively allow family members to be educated regarding their cancer genetic risk and potential benefits from cancer control measures such as mutation testing. However, the effect of the FIS on the rate of mutation testing has not been studied. One thousand five hundred seventy‐four eligible (>18‐year old, at a 25% or higher pedigree risk) members from 60 extended HBOC families with BRCA1/2 mutations were invited to attend a FIS to learn about their risk and undergo genetic testing. The rates of mutation testing were compared between those who had attended an FIS, and those who had not with chi‐squared test and logistic regression analysis. Seventy five percent (334/444) of FIS attendees had undergone mutation testing following or during an FIS which was significantly higher than the 33.8% (382/1130) rate among nonattendees (p < 0.0001). Logistic regression analysis showed that FIS attendance, breast‐ovarian cancer history, gender, and age were significant variables for undertaking a mutation test. FIS attendance significantly increased the rate of mutation testing among high‐risk family members.

Impact of BRCA mutation test results in members of hereditary breast ovarian cancer (HBOC) families

1014 Background: Disclosure of BRCA mutation results may cause distress and in turn affect patient’s behavior, work and decision on cancer screening and management. Methods: Members (n=898) from 84 HBOC families who received their result and genetic counseling provided responses to their BRCA mutation test result. Findings from 395 responders (78 with breast cancer and a BRCA mutation; 20 with cancer but without a mutation; 90 without cancer but with a BRCA mutation, and 207 without cancer and without a mutation) were analyzed by Kruskal-Wallis, Dunn and Fisher’s exact tests. Results: Mutation-carriers regardless of their cancer status gave statistically higher emotionally laden scores than comparable non-carriers without cancer. Following mutation disclosure, 23% (36/154) underwent prophylactic bilateral mastectomy as compared to 5.5% (36/660) before mutation test disclosure (p<0.001). After mutation disclosure 51.5% (88/171) underwent prophylactic bilateral oophorectomy as compared to 26% (171/660) befo...