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.

Physical activity and physiological cardiac remodelling in a community setting: the Multi-Ethnic Study of Atherosclerosis (MESA).

OBJECTIVE: To evaluate the association of physical activity with left ventricular structure and function in the general population in a community setting. DESIGN: Cross-sectional study. SETTING: The Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of subclinical atherosclerosis. PARTICIPANTS: A multiethnic sample of 4992 participants (aged 45-84 years; 52% female) free of clinically apparent cardiovascular disease. INTERVENTIONS: Physical activity induces beneficial physiological cardiac remodelling in a cross-sectional study of non-athlete individuals. MAIN OUTCOME MEASURES: Left ventricular mass, volumes and function were assessed by cardiac magnetic resonance imaging. Physical activity, defined as intentional exercise and total moderate and vigorous physical activity, was assessed by a standard semiquantitative questionnaire. RESULTS: Left ventricular mass and end-diastolic volume were positively associated with physical activity (eg, 1.4 g/m(2) (women) and 3.1 g/m(2) (men) greater left ventricular mass in the highest category of intentional exercise compared with individuals reporting no intentional exercise; p = 0.05 and p<0.001, respectively). Relationships were non-linear, with stronger positive associations at lower levels of physical activity (test for non-linearity; p = 0.02 and p = 0.03, respectively). Cardiac output and ejection fraction were unchanged with increased physical activity levels. Resting heart rate was lower in women and men with higher physical activity levels (eg, -2.6 beats/minute lower resting heart rate in the highest category of intentional exercise compared with individuals reporting no intentional exercise; p<0.001). CONCLUSIONS: In a community-based population free of clinically apparent cardiovascular disease, higher physical activity levels were associated with proportionally greater left ventricular mass and end-diastolic volume and lower resting heart rate.

Disability profile of MS did not change over 10 years in a population-based prevalence cohort.

OBJECTIVE: To assess whether the level of multiple sclerosis (MS) -related disability in the Olmsted County population has changed over a decade, and to evaluate how the rate of initial progression to moderate disability impacts further disability. METHODS: The Minimal Record of Disability (MRD) measured impairment, disability, and handicap for the 2000 (n = 201) prevalence cohort. The authors compared these results with the 1991 (n = 162) cohort; 115 patients were in both cohorts. The authors assessed retrospectively intervals at which Expanded Disability Status Scale (EDSS) scores of 3 (moderate disability), 6 (cane), and 8 (wheelchair) were reached. RESULTS: The distribution of the 2000 EDSS and MRD scores were not significantly different from the 1991 distribution. The median time from MS diagnosis, for the entire cohort, to EDSS scores of 3 and 6 was 17 and 24 years, respectively. At 20 years after onset, only 25% of those with relapsing-remitting MS had EDSS scores > or =3. The median time from diagnosis to EDSS score of 6 for the secondary and primary progressive groups was 10 and 3 years, respectively. Rate of progression from onset or diagnosis to EDSS score of 3 did not affect the rate of further disease progression. However, once an EDSS score of 3 was reached, progression of disability was more likely, and rate of progression increased. CONCLUSIONS: The distribution of multiple sclerosis disability in the Olmsted community has remained stable for 10 years. Progression of disability for patients with relapsing-remitting multiple sclerosis or secondary progressive multiple sclerosis may be more favorable than reported previously. Once a clinical threshold of disability is reached, rate of progression increased.

Change in MS-related disability in a population-based cohort: a 10-year follow-up study.

OBJECTIVE: S: To study the change in disability over 10 years in individual patients constituting the 1991 Olmsted County, MN, multiple sclerosis (MS) prevalence cohort. METHODS: The authors reassessed this 1991 cohort in 2001. The authors determined the Expanded Disability Status Scale scores (EDSS) for each patient still alive, and within the year prior to death for those who died. The authors analyzed determinants of potential prognostic significance on change in disability. RESULTS: Follow-up information was available for 161 of 162 patients in the 1991 cohort. Only 15% had received immunomodulatory therapy. The mean change in EDSS for the entire cohort over 10 years was 1 point and 20% worsened by >or=2 points. For patients with EDSS <3 in 1991 (n = 66), 83% were ambulatory without a cane 10 years later. For patients with EDSS of 3 through 5 in 1991 (n = 33), 51% required a cane to ambulate (48%) or worse (3%). For patients with EDSS 6 to 7 in 1991 (n = 39), 51% required a wheelchair or worse in 2001. Gait impairment at onset, progressive disease, or longer duration of disease were associated with more worsening of disability (p < 0.002). The 10-year survival was decreased compared with the Minnesota white population for both men and women. CONCLUSIONS: Although survival was reduced and 30% of patients progressed to needing a cane or wheelchair or worse over the 10-year follow-up period, most remained stable or minimally progressed. Patients within the EDSS 3.0 through 5.0 range are at moderate risk of developing important gait limitations over the 10-year period. The authors did not identify factors strongly predictive of worsening disability in this study.

Incidence and prevalence of multiple sclerosis in Olmsted County, Minnesota, 1985-2000.

BACKGROUND: Epidemiologic data for multiple sclerosis (MS) in Olmsted County, MN, have been recorded for almost 100 years and have indicated that the increasing prevalence rate was likely due in part to an increasing incidence rate. METHODS: All cases of MS diagnosed from 1985 to 2000 were identified using the centralized diagnostic index at the Mayo Clinic and the Rochester Epidemiology Program Project, a shared database of all medical practitioners in the county. Patients were required to have established residency at least 1 year prior to diagnosis of MS. Results were also age- and sex-adjusted to control for shifts in the population structure. RESULTS: The raw prevalence of MS was determined to be 177 per 100,000 on December 1, 2000, and the raw incidence rate was 7.5 per 100,000 person-years at risk from 1985 to 2000. CONCLUSIONS: After age and sex adjustment to a common population, these prevalence and incidence rates of MS appear to have been stable rather than increasing over the past 20 years.