Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study

Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study

Replication of genetic loci for ages at menarche and menopause in the multi-ethnic Population Architecture using Genomics and Epidemiology (PAGE) study

STUDY QUESTION: Do genetic associations identified in genome-wide association studies (GWAS) of age at menarche (AM) and age at natural menopause (ANM) replicate in women of diverse race/ancestry from the Population Architecture using Genomics and Epidemiology (PAGE) Study? SUMMARY ANSWER: We replicated GWAS reproductive trait single nucleotide polymorphisms (SNPs) in our European descent population and found that many SNPs were also associated with AM and ANM in populations of diverse ancestry. WHAT IS KNOWN ALREADY: Menarche and menopause mark the reproductive lifespan in women and are important risk factors for chronic diseases including obesity, cardiovascular disease and cancer. Both events are believed to be influenced by environmental and genetic factors, and vary in populations differing by genetic ancestry and geography. Most genetic variants associated with these traits have been identified in GWAS of European-descent populations. STUDY DESIGN, SIZE, DURATION: A total of 42 251 women of diverse ancestry from PAGE were included in cross-sectional analyses of AM and ANM. MATERIALS, SETTING, METHODS: SNPs previously associated with ANM (n = 5 SNPs) and AM (n = 3 SNPs) in GWAS were genotyped in American Indians, African Americans, Asians, European Americans, Hispanics and Native Hawaiians. To test SNP associations with ANM or AM, we used linear regression models stratified by race/ethnicity and PAGE sub-study. Results were then combined in race-specific fixed effect meta-analyses for each outcome. For replication and generalization analyses, significance was defined at P < 0.01 for ANM analyses and P < 0.017 for AM analyses. MAIN RESULTS AND THE ROLE OF CHANCE: We replicated findings for AM SNPs in the LIN28B locus and an intergenic region on 9q31 in European Americans. The LIN28B SNPs (rs314277 and rs314280) were also significantly associated with AM in Asians, but not in other race/ethnicity groups. Linkage disequilibrium (LD) patterns at this locus varied widely among the ancestral groups. With the exception of an intergenic SNP at 13q34, all ANM SNPs replicated in European Americans. Three were significantly associated with ANM in other race/ethnicity populations: rs2153157 (6p24.2/SYCP2L), rs365132 (5q35/UIMC1) and rs16991615 (20p12.3/MCM8). While rs1172822 (19q13/BRSK1) was not significant in the populations of non-European descent, effect sizes showed similar trends. LIMITATIONS, REASONS FOR CAUTION: Lack of association for the GWAS SNPs in the non-European American groups may be due to differences in locus LD patterns between these groups and the European-descent populations included in the GWAS discovery studies; and in some cases, lower power may also contribute to non-significant findings. WIDER IMPLICATIONS OF THE FINDINGS: The discovery of genetic variants associated with the reproductive traits provides an important opportunity to elucidate the biological mechanisms involved with normal variation and disorders of menarche and menopause. In this study we replicated most, but not all reported SNPs in European descent populations and examined the epidemiologic architecture of these early reported variants, describing their generalizability and effect size across differing ancestral populations. Such data will be increasingly important for prioritizing GWAS SNPs for follow-up in fine-mapping and resequencing studies, as well as in translational research. STUDY FUNDING/COMPETING INTEREST(S): The Population Architecture Using Genomics and Epidemiology (PAGE) program is funded by the National Human Genome Research Institute (NHGRI), supported by U01HG004803 (CALiCo), U01HG004798 (EAGLE), U01HG004802 (MEC), U01HG004790 (WHI) and U01HG004801 (Coordinating Center), and their respective NHGRI ARRA supplements. The authors report no conflicts of interest

Casting Metals in Dentistry: Past - Present - Future

This article deals mainly with the development of dental casting techniques and formulation of the different groups of alloys used in the fabrication of ceramo-metal restorations. It is recognized that in order for the quality of dental cast restorations to be improved, having alloys with the proper composition is not enough. Biocompatibility, good mechanical and physical properties, longevity of the restoration, compatibility with porcelain, and a simple manipulative technique are as important. Researchers have contributed to different aspects of dental castings and have made cast restorations what they are today. Unfortunately, much of the original basic research has been overlooked by present investigators, who have duplicated studies conducted in the past without realizing that the study had already been performed and the research had been published. The main reason for this is that abstracts of articles published prior to 1975 are not available through a library computer-search system. To obtain copies of articles published prior to 1975, one has to search the literature to know where they were published. This article provides references for much of the past work in this area. Also, dental libraries do not carry copies of U.S. patents. This places the majority of researchers located at dental schools at a disadvantage. They are not familiar with what the patents claim, what is taught, and why certain elements are added or eliminated from alloys and investment materials. This article also provides the numbers of many U.S. patents. By having the patent number, one can obtain the text of the patent from the U.S. Patent Office in Washington, DC. Since esthetics plays an important role in today's society, emphasis will be given only to alloys designed for fabrication of ceramo-metal restorations. Many ceramo-metal alloys are available today, and they are classified differently by different individuals. In this article, classification will be based on the major components of these alloys, as well as on a chronological introduction of one group leading to the development of the next group. Based on this, one can classify these alloys into six major groups. Chemical composition, properties, and the developers of these alloys, along with their U.S. patents, are given. Recently, two types of all-ceramic restorations have been introduced. The main advantage of the all-ceramic restoration is its superior esthetic quality compared with that of ceramo-metal restorations. Their main disadvantages are low strength and ductility. Their strength, however, is sufficient for single-unit restorations, but not for bridgework. The use of titanium for dental restorations has also been studied, and it has been found to be suitable. Future Studies - Future work should be devoted to the following: (1) the development of stronger and more ductile ceramic materials: (2) further study of the promising palladium alloys from the noble metal group and titanium alloys from the base metal group; (3) the development of easier and less-time-consuming techniques for the fabrication of dental appliances; (4) the development of a powder technique rather than a cast technique for future fabrication methods; and (5) the development of new laboratory equipment, e.g., a single sintering oven capable of sintering both ceramic and metallic particles, which would be accepted if the powder technique is developed.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/67759/2/10.1177_08959374880020011701.pd

Exome sequencing-driven discovery of coding polymorphisms associated with common metabolic phenotypes

Cancer Signaling networks and Molecular Therapeutic