Genetic Insights into Aging and Age-Related Diseases among Varied Pedigree Structures.

Older age is associated with decline in many physiological functions that eventually lead to increased susceptibility to diseases. The rate of aging varies among individuals and may be influenced by genes. This dissertation has three aims: 1) define a measure of aging using physiologic traits and determine its heritability among various pedigree structures, 2) investigate genetic associations with the age trait using genome-wide association study analyses, and 3) focus on decline in kidney function by examining its association with known kidney loci and clinical risk factors within the SardiNIA Study on Aging. Using data from five genetic cohorts (30,000+ individuals) with varying pedigree structure (SardiNIA Study on Aging – large pedigrees, Framingham Heart Study offspring – small pedigrees, Atherosclerotic Risk in Communities Study – unrelated, and two twins studies: Twingene and TwinsUK), two aging traits were developed. Both traits employ three physiologic health measures (kidney function, systolic blood pressure, and waist circumference) to estimate an individual’s biologic age and contrast it with actual age. Linear mixed modeling was employed to estimate a predicted age, while Cox models were used to estimate a risk age equivalent to the age of the census population with the same mortality risk. Using Merlin software (Abecasis, 2002), both age traits were found to be heritable in all cohorts with h2 estimates of 0.25 to 0.68, depending on pedigree structure. Meta-analysis revealed a genome-wide significant association (p < 5 x 10-8) within the LRP1B gene on chromosome 2. LRP1B produces low density lipoprotein receptor-related protein 1B and has been previously associated with tumor suppression, metabolic traits, and successful aging. Association analyses were also conducted using a genetic risk score for CKD, adjusting for clinical factors, with CKD prevalence and change in kidney function. One additional allele in the genetic risk score for CKD was significantly associated with CKD prevalence (OR=1.07, p=0.001), decline in eGFR (β=-0.23, p=0.004), and eGFR decline > 1 SD (OR=1.05, p=0.04). These findings further our understanding of the genetics of aging and the CKD risk score results suggest a possible clinical utility. Putting the findings into clinical use should be evaluated.PHDEpidemiological ScienceUniversity of Michigan, Horace H. Rackham School of Graduate Studieshttp://deepblue.lib.umich.edu/bitstream/2027.42/97920/1/jennb_1.pd

A principal component meta-analysis on multiple anthropometric traits identifies novel loci for body shape

Large consortia have revealed hundreds of genetic loci associated with anthropometric traits, one trait at a time. We examined whether genetic variants affect body shape as a composite phenotype that is represented by a combination of anthropometric traits. We developed an approach that calculates averaged PCs (AvPCs) representing body shape derived from six anthropometric traits (body mass index, height, weight, waist and hip circumference, waist-to-hip ratio). The first four AvPCs explain \u3e99% of the variability, are heritable, and associate with cardiometabolic outcomes. We performed genome-wide association analyses for each body shape composite phenotype across 65 studies and meta-analysed summary statistics. We identify six novel loci: LEMD2 and CD47 for AvPC1, RPS6KA5/C14orf159 and GANAB for AvPC3, and ARL15 and ANP32 for AvPC4. Our findings highlight the value of using multiple traits to define complex phenotypes for discovery, which are not captured by single-trait analyses, and may shed light onto new pathways

Body mass index change and estimated glomerular filtration rate decline in a middle-aged population: health check-based cohort in Japan

Background: Obesity is a growing public health problem worldwide. We evaluated the mediators and association between changes in obesity metrics and renal outcomes in the general population. Methods: Using the Japanese nationwide health check-based cohort from April 2011 to March 2019, we selected individuals aged 40–74 years, with a baseline estimated glomerular filtration rate (eGFR) ≥45 mL/min/1.73 m2, whose body mass index (BMI) change was assessed. The primary outcome was combined 30% decline in eGFR, eGFR 4%) mediated by three risk factors (blood pressure, haemoglobin A1c and total cholesterol), was 13.3%. Conclusion: In the middle-aged Japanese population, both, increase and decrease in BMI were associated with subsequent eGFR decline. Changes in risk factors mediated a small proportion of the association between BMI increase and eGFR decline. Our findings support the clinical significance of monitoring BMI as a renal risk factor

The cost of procuring deceased donor kidneys: Evidence from OPO cost reports 2013-2017

Peer Reviewedhttps://deepblue.lib.umich.edu/bitstream/2027.42/154616/1/ajt15669_am.pdfhttps://deepblue.lib.umich.edu/bitstream/2027.42/154616/2/ajt15669.pd

Changes in anemia management and hemoglobin levels following revision of a bundling policy to incorporate recombinant human erythropoietin

In April 2006, Japan's health insurance system instituted a bundling policy that included recombinant human erythropoietin (rHuEPO) in outpatient hemodialysis therapy. To evaluate outcomes of this, we analyzed a prospective cohort of hemodialysis patients in the Japan Dialysis Outcomes and Practice Patterns Study, in 53 facilities using prevalent cross-sections of 1584 patients before and 1622 patients after the rHuEPO reimbursement change. Patient data included hemoglobin levels, iron management profiles, and anemia treatment with rHuEPO and intravenous iron. No significant differences were found in pre- or post-policy cross-sections for hemoglobin distributions or the percentage of patients prescribed rHuEPO. Among patients receiving rHuEPO, the mean dose significantly decreased by 11.8 percent. The percentage of patients prescribed intravenous iron over 4months significantly increased; however, the mean dose of iron did not significantly change. Thus, this bundling policy was associated with reduced rHuEPO doses, increased intravenous iron use, and stable hemoglobin levels in Japanese patients receiving hemodialysis

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS

Patterns of hepatitis B prevalence and seroconversion in hemodialysis units from three continents: The DOPPS.BackgroundHepatitis B (HBV) historically has been a public health issue within hemodialysis units. This study estimates HBV prevalence and seroconversion rates across seven countries and investigates associations with facility level practice patterns.MethodsThe study sample was from the Dialysis Outcomes and Practice Patterns Study (DOPPS), a cross-sectional, prospective, observational study of adult hemodialysis patients randomly selected from 308 dialysis facilities in France, Germany, Italy, Spain, the United Kingdom, Japan, and the United States. Logistic regression was used to model the odds ratio (OR) of HBV prevalence, and Cox regression was used to model time from entry into the study to HBV seroconversion.ResultsIn this sample, mean HBV facility prevalence was 3.0% with a median of 1.9%. The percentage of facilities with an HBV prevalence 0% to 5% was 78.5%. Adjusted HBV prevalence was higher in France, Germany, and Italy and lower in Japan and the United Kingdom. The majority of facilities (78.1%) had a seroconversion rate of 0 conversions per 100 patient-years. Presence of a protocol for HBV-infected patients was significantly associated with HBV seroconversion in the separate practice pattern model [risk ratio (RR) = 0.52, P = 0.03] and in the combined practice pattern model (RR = 0.44, P = 0.01).ConclusionThere are differences in HBV prevalence and rate of seroconversion both at the country and the hemodialysis facility level. Presence of a protocol for HBV-infected patients was strongly and significantly associated with decreased risk for seroconversion. The observed variation suggests opportunities for improved HBV outcomes with further definition of optimal practice patterns at the facility level

A large genome-wide association study of age-related macular degeneration highlights contributions of rare and common variants

Advanced age-related macular degeneration (AMD) is the leading cause of blindness in the elderly with limited therapeutic options. Here, we report on a study of \u3e12 million variants including 163,714 directly genotyped, most rare, protein-altering variant. Analyzing 16,144 patients and 17,832 controls, we identify 52 independently associated common and rare variants (P \u3c 5×10–8) distributed across 34 loci. While wet and dry AMD subtypes exhibit predominantly shared genetics, we identify the first signal specific to wet AMD, near MMP9 (difference-P = 4.1×10–10). Very rare coding variants (frequency \u3c 0.1%) in CFH, CFI, and TIMP3 suggest causal roles for these genes, as does a splice variant in SLC16A8. Our results support the hypothesis that rare coding variants can pinpoint causal genes within known genetic loci and illustrate that applying the approach systematically to detect new loci requires extremely large sample sizes

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS

Nonadherence in hemodialysis: Associations with mortality, hospitalization, and practice patterns in the DOPPS.BackgroundNonadherence among hemodialysis patients compromises dialysis delivery, which could influence patient morbidity and mortality. The Dialysis Outcomes and Practice Patterns Study (DOPPS) provides a unique opportunity to review this problem and its determinants on a global level.MethodsNonadherence was studied using data from the DOPPS, an international, observational, prospective hemodialysis study. Patients were considered nonadherent if they skipped one or more sessions per month, shortened one or more sessions by more than 10 minutes per month, had a serum potassium level openface>6.0mEq/L, a serum phosphate level openface>7.5mg/dL (>2.4mmol/L), or interdialytic weight gain (IDWG)>5.7% of body weight. Predictors of nonadherence were identified using logistic regression. Survival analysis used the Cox proportional hazards model adjusting for case-mix.ResultsSkipping treatment was associated with increased mortality [relative risk (RR) = 1.30, P = 0.01], as were excessive IDWG (RR = 1.12, P = 0.047) and high phosphate levels (RR = 1.17, P = 0.001). Skipping also was associated with increased hospitalization (RR = 1.13, P = 0.04), as were high phosphate levels (RR = 1.07, P = 0.05). Larger facility size (per 10 patients) was associated with higher odds ratios (OR) of skipping (OR = 1.03, P = 0.06), shortening (OR = 1.03, P = 0.05), and IDWG (OR = 1.02, P = 0.07). An increased percentage of highly trained staff hours was associated with lower OR of skipping (OR = 0.84 per 10%, P = 0.02); presence of a dietitian was associated with lower OR of excessive IDWG (OR = 0.75, P = 0.08).ConclusionNonadherence was associated with increased mortality risk (skipping treatment, excessive IDWG, and high phosphate) and with hospitalization risk (skipping, high phosphate). Certain patient/facility characteristics also were associated with nonadherence

Exploring reasons for state-level variation in incidence of dialysis-requiring acute kidney injury (AKI-D) in the United States

Background: There is considerable state-level variation in the incidence of dialysis-requiring acute kidney injury (AKI-D). However, little is known about reasons for this geographic variation. Methods: National cross-sectional state-level ecological study based on State Inpatient Databases (SID) and the Behavioral Risk Factor Surveillance System (BRFSS) in 2011. We analyzed 18 states and six chronic health conditions (diabetes mellitus [diabetes], hypertension, chronic kidney disease [CKD], arteriosclerotic heart disease [ASHD], cancer (excluding skin cancer), and chronic obstructive pulmonary disease [COPD]). Associations between each of the chronic health conditions and AKI-D incidence was assessed using Pearson correlation and multiple regression adjusting for mean age, the proportion of males, and the proportion of non-Hispanic whites in each state. Results: The state-level AKI-D incidence ranged from 190 to 1139 per million population. State-level differences in rates of hospitalization with chronic health conditions (mostly \u3c 3-fold difference in range) were larger than the state-level differences in prevalence for each chronic health condition (mostly \u3c 2.5-fold difference in range). A significant correlation was shown between AKI-D incidence and prevalence of diabetes, ASHD, and COPD, as well as between AKI-D incidence and rate of hospitalization with hypertension. In regression models, after adjusting for age, sex, and race, AKI-D incidence was associated with prevalence of and rates of hospitalization with five chronic health conditions - diabetes, hypertension, CKD, ASHD and COPD - and rates of hospitalization with cancer. Conclusions: Results from this ecological analysis suggest that state-level variation in AKI-D incidence may be influenced by state-level variations in prevalence of and rates of hospitalization with several chronic health conditions. For most of the explored chronic conditions, AKI-D correlated stronger with rates of hospitalizations with the health conditions rather than with their prevalences, suggesting that better disease management strategies that prevent hospitalizations may translate into lower incidence of AKI-D