Faculty Bibliography

Apolipoprotein L1 gene (APOL1) G1 and G2 coding variants are strongly associated with chronic kidney disease (CKD) in African Americans (AAs). Here APOL1 association was tested with baseline estimated glomerular filtration rate (eGFR), urine albumin:creatinine ratio (UACR), and prevalent cardiovascular disease (CVD) in 2571 AAs from the Systolic Blood Pressure Intervention Trial (SPRINT), a trial assessing effects of systolic blood pressure reduction on renal and CVD outcomes. Logistic regression models that adjusted for potentially important confounders tested for association between APOL1 risk variants and baseline clinical CVD (myocardial infarction, coronary, or carotid artery revascularization) and CKD (eGFR under 60 ml/min per 1.73 m(2) and/or UACR over 30 mg/g). AA SPRINT participants were 45.3% female with a mean (median) age of 64.3 (63) years, mean arterial pressure 100.7 (100) mm Hg, eGFR 76.3 (77.1) ml/min per 1.73 m(2), and UACR 49.9 (9.2) mg/g, and 8.2% had clinical CVD. APOL1 (recessive inheritance) was positively associated with CKD (odds ratio 1.37, 95% confidence interval 1.08-1.73) and log UACR estimated slope (β) 0.33) and negatively associated with eGFR (β -3.58), all significant. APOL1 risk variants were not significantly associated with prevalent CVD (1.02, 0.82-1.27). Thus, SPRINT data show that APOL1 risk variants are associated with mild CKD but not with prevalent CVD in AAs with a UACR under 1000 mg/g.

BACKGROUND:There is a need to identify patients with diabetic kidney disease (DKD) using noninvasive, cost-effective screening tests. Sudoscan®, a device using electrochemical skin conductance (ESC) to measure sweat gland dysfunction, is valuable for detecting peripheral neuropathy. ESC was tested for association with DKD (estimated glomerular filtration rate (eGFR) <60 ml/min/1.73 m(2)) in 383 type 2 diabetes mellitus (T2D)-affected patients; diagnostic thresholds were determined in 540 patients. METHODS:Relationships between ESC with eGFR and urine albumin:creatinine ratio (UACR) were assessed in 202 European Americans and 181 African Americans with T2D. RESULTS:In 92 European American DKD cases and 110 T2D non-nephropathy controls, respectively, mean (SD) ages were 69 (9.7) and 61 (10.8) years, hemoglobin A1c (HbA1c) 7.4 (1.2) and 7.4 (1.3)%, eGFR 29.6 (12.2) and 87.8 (14.2) ml/min/1.73 m(2), and UACR 1,214 (1,705) and 7.5 (5.8) mg/g. In 57 African American cases and 124 controls, respectively, mean (SD) ages were 64.0 (11.9) and 59.5 (9.7) years, HbA1c 7.4 (1.3) and 7.5 (1.7)%, eGFR 29.6 (13.3) and 90.2 (16.2) ml/min/1.73 m(2), and UACR 1,172 (1,564) and 7.8 (7.1) mg/g. Mean (SD) ESC (μS) was lower in cases than controls (European Americans: case/control hands 49.5 (18.5)/62.3 (16.2); feet 62.1 (17.9)/73.6 (13.8), both p < 1.3 × 10(-6); African Americans: case/control hands 39.8 (19.0)/48.5 (17.1); feet 53.2 (21.3)/63.5 (19.4), both p ≤ 0.01). Adjusting for age, sex, body mass index and HbA1c, hands and feet ESC associated with eGFR <60 ml/min/1.73 m(2) (p ≤ 7.2 × 10(-3)), UACR >30 mg/g (p ≤ 7.0 × 10(-3)), UACR >300 mg/g (p ≤ 8.1 × 10(-3)), and continuous traits eGFR and UACR (both p ≤ 5.0 × 10(-9)). HbA1c values were not useful for risk stratification. CONCLUSIONS:ESC measured using Sudoscan® is strongly associated with DKD in African Americans and European Americans. ESC is a useful screening test to identify DKD in patients with T2D.

BACKGROUND:In African Americans (AAs), APOL1 G1 and G2 nephropathy risk variants are associated with non-diabetic end-stage kidney disease (ESKD) in an autosomal recessive pattern. Additional risk and protective genetic variants may be present near the APOL1 loci, since earlier age ESKD is observed in some AAs with one APOL1 renal-risk variant, and because the adjacent gene MYH9 is associated with nephropathy in populations lacking G1 and G2 variants. METHODS:Re-sequencing was performed across a ∼275 kb region encompassing the APOL1-APOL4 and MYH9 genes in 154 AA cases with non-diabetic ESKD and 38 controls without nephropathy who were heterozygous for a single APOL1 G1 or G2 risk variant. RESULTS:Sequencing identified 3,246 non-coding single nucleotide polymorphisms (SNPs), 55 coding SNPs, and 246 insertion/deletions. No new coding variations were identified. Eleven variants, including a rare APOL3 Gln58Ter null variant (rs11089781), were genotyped in a replication panel of 1,571 AA ESKD cases and 1,334 controls. After adjusting for APOL1 G1 and G2 risk effects, these variations were not significantly associated with ESKD. In subjects with <2 APOL1 G1 and/or G2 alleles (849 cases; 1,139 controls), the APOL3 null variant was nominally associated with ESKD (recessive model, OR 1.81; p = 0.026); however, analysis in 807 AA cases and 634 controls from the Family Investigation of Nephropathy and Diabetes did not replicate this association. CONCLUSION/CONCLUSIONS:Additional common variants in the APOL1-APOL4-MYH9 region do not contribute significantly to ESKD risk beyond the APOL1 G1 and G2 alleles.

Background. Sparse data limit the interpretation of Montreal Cognitive Assessment (MoCA) scores, particularly in minority populations. Additionally, there are no published data on how MoCA scores compare to the widely used Modified Mini Mental State Examination (3MSE). We provide performance data on the MoCA in a large cohort of African Americans and compare 3MSE and MoCA scores, providing a "crosswalk" for interpreting scores. Methods. Five hundred and thirty African Americans with type 2 diabetes were enrolled in African American-Diabetes Heart Study-MIND, a cross-sectional study of cognition and structural and functional brain imaging. After excluding participants with possible cognitive impairment (n = 115), mean (SD) MoCA and 3MSE scores are presented stratified by age and education. Results. Participant mean age was 58.2 years (range: 35-83); 61% were female; and 64.9% had >12 years of education. Mean (SD) 3MSE and MoCA scores were 86.9 (8.2) and 19.8 (3.8), respectively. 93.5% of the cohort had a "positive" screen on the MoCA, scoring <26 (education-adjusted), compared with 47.5% on the 3MSE (cut-point < 88). A 3MSE score of 88 corresponded to a MoCA score of 20 in this population. Conclusion. The present data suggest the need for caution when applying proposed MoCA cutoffs to African Americans.

BACKGROUND:Fibroblast growth factor 23 (FGF23) is a phosphaturic hormone implicated in disorders of serum phosphorus concentration and vitamin D. The role of FGF23 in vascular calcification remains controversial. METHODS:Relationships between FGF23 and coronary artery calcified atherosclerotic plaque (CAC), aortoiliac calcified plaque (CP), carotid artery CP, volumetric bone mineral density (vBMD), albuminuria, and estimated glomerular filtration rate (eGFR) were determined in 545 African Americans with type 2 diabetes (T2D) and preserved kidney function in African American-Diabetes Heart Study participants. Generalized linear models were fitted to test associations between FGF23 and cardiovascular, bone, and renal phenotypes, and change in measurements over time, adjusting for age, gender, African ancestry proportion, body mass index, diabetes duration, hemoglobin A1c, blood pressure, renin-angiotensin-system inhibitors, statins, calcium supplements, serum calcium, and serum phosphate. RESULTS:The sample was 56.7% female with a mean (SD) age of 55.6 (9.6) years, diabetes duration of 10.3 (8.2) years, eGFR 90.9 (22.1) ml/min/1.73 m2, urine albumin:creatinine ratio (UACR) 151 (588) (median 13) mg/g, plasma FGF23 161 (157) RU/ml, and CAC 637 (1,179) mg. In fully adjusted models, FGF23 was negatively associated with eGFR (p < 0.0001) and positively associated with UACR (p < 0.0001) and CAC (p = 0.0006), but not with carotid CP or aortic CP. Baseline FGF23 concentration did not associate with changes in vBMD or CAC after a mean of 5.1 years follow-up. CONCLUSIONS:Plasma FGF23 concentrations were independently associated with subclinical coronary artery disease, albuminuria, and kidney function in the understudied African American population with T2D. Findings support relationships between FGF23 and vascular calcification, but not between FGF23 and bone mineral density, in African Americans lacking advanced nephropathy.

BACKGROUND:Electrocardiographic (ECG) abnormalities are independently associated with poor outcomes in the general population. Their prevalence and determinants were assessed in the understudied African American population with type 2 diabetes. METHODS:Standard 12-lead ECGs were digitally recorded in 635 unrelated African American-Diabetes Heart Study (AA-DHS) participants, automatically processed at a central lab, read, and coded using standard Minnesota ECG Classification. Age- and sex-specific prevalence rates of ECG abnormalities were calculated and logistic regression models were fitted to examine cross-sectional associations between participant characteristics and ECG abnormalities. RESULTS:Participants were 56% women with a mean age of 56 years; 60% had at least one minor or major ECG abnormality [23% ⩾ 1 major (or major plus minor), and 37% ⩾ 1 minor (with no major)]. Men had a higher prevalence of ⩾ 1 minor or major ECG abnormality (66.1% men vs. 55.6% women, p=0.0089). In univariate analysis, age, past history of cardiovascular disease, diabetes duration, systolic blood pressure, sex and statin use were associated with the presence of any (major or minor) ECG abnormalities. In a multivariate model including variables, female sex (OR [95% CI] 0.79 [0.67, 0.93]), statin use (0.79 [0.67, 0.93]) and diabetes duration (1.03 [1.0, 1.05]) remained statistically significant. CONCLUSIONS:Nearly three out of five African Americans with diabetes had at least one ECG abnormality. Female sex and statin use were significantly associated with lower odds of any ECG abnormality and diabetes duration was significantly associated with higher odds of any ECG abnormality in the multivariable model.

The SEARCH for Diabetes in Youth Study prospectively identified youth aged <20 years with physician-diagnosed diabetes. Annual type 1 diabetes (T1D) incidence per 100,000 person-years (95% CI) overall, by age-group, and by sex were calculated for at-risk non-Hispanic white (NHW) youth from 2002 through 2009. Joinpoint and Poisson regression models were used to test for temporal trends. The age- and sex-adjusted incidence of T1D increased from 24.4/100,000 (95% CI 23.9-24.8) in 2002 to 27.4/100,000 (26.9-27.9) in 2009 (P for trend = 0.0008). The relative annual increase in T1D incidence was 2.72% (1.18-4.28) per year; 2.84% (1.12-4.58) per year for males and 2.57% (0.68-4.51) per year for females. After adjustment for sex, significant increases were found for youth aged 5-9 years (P = 0.0023), 10-14 years (P = 0.0008), and 15-19 years (P = 0.004) but not among 0-4-year-olds (P = 0.1862). Mean age at diagnosis did not change. The SEARCH study demonstrated a significant increase in the incidence of T1D among NHW youth from 2002 through 2009 overall and in all but the youngest age-group. Continued surveillance of T1D in U.S. youth to identify future trends in T1D incidence and to plan for health care delivery is warranted.

OBJECTIVE:To describe the prevalence of access and process barriers to health care and to examine their relationship to sociodemographic and disease factors in a large and diverse cohort of US youth with type 1 diabetes. STUDY DESIGN/METHODS:A cross-sectional analysis of 780 youth who participated in the SEARCH for Diabetes in Youth Study and were diagnosed with type 1 diabetes in 2002-2005. Experience of barriers to care was collected from parent report on questionnaires. Analyses included multivariate regression models to predict the presence of specific barriers to care. RESULTS:Overall, 81.7% of participants reported at least one barrier; the 3 most common were costs (47.5%), communication (43.0%), and getting needed information (48.4%). Problems with access to care, not having a regular provider, and receiving contextual care (care that takes into account personal and family context) were associated with poorer glycated hemoglobin levels. Adjusted multivariate models indicated that barriers related to access (regular provider, cost) were most likely for youth with low family income and those without public health insurance. Barriers associated with the processes of quality care (contextual care, communication) were more likely for Hispanic youth and those whose parents had less education. CONCLUSIONS:This study indicates that a large proportion of youth with type 1 diabetes experience substantial barriers to care. Barriers to access and those associated with processes of quality care differed by sociodemographic characteristics. Future investigators should expand knowledge of the systemic processes that lead to disparate outcomes for some youth with diabetes and assess potential solutions.

OBJECTIVE:To examine the longitudinal associations between sex, diabetes self-care, and the health-related quality of life (HRQL) of children and adolescents with type 1 or type 2 diabetes. STUDY DESIGN/METHODS:The sample included 910 participants with type 1 and 241 participants with type 2, ages 10-22 years at baseline, from the SEARCH for Diabetes in Youth Study, a longitudinal observational study. The primary outcome measure was the Pediatric Quality of Life Inventory. Repeated measures, mixed-model regression analysis was conducted with the use of data from baseline and at least one follow-up assessment, spanning approximately 4 years. RESULTS:HRQL was greater among those with type 1 versus type 2 diabetes. Among participants with type 1, greater (better) Pediatric Quality of Life Inventory total scores over time were related to greater parent education (P = .0007), lower glycated hemoglobin values (P < .0001), and greater physical activity during the past 7 days (PÂ = .0001). There was a significant interaction between sex and age (P < .0001); girls' HRQL remained stable or decreased over time, whereas males' HRQL increased. For participants with type 2 diabetes, there was no significant interaction by age and sex, but lower total HRQL was related to being female (P = .011) and greater body mass index z-scores (P = .014). CONCLUSIONS:HRQL in this cohort varied by diabetes type. The interaction between sex and age for type 1 participants, coupled with poorer HRQL among female than male participants with type 2 diabetes, suggests the impacts of diabetes on HRQL differ by sex and should be considered in clinical management. Encouraging physical activity and weight control continue to be important in improving HRQL.

IMPORTANCE/OBJECTIVE:Despite concern about an "epidemic," there are limited data on trends in prevalence of either type 1 or type 2 diabetes across US race and ethnic groups. OBJECTIVE:To estimate changes in the prevalence of type 1 and type 2 diabetes in US youth, by sex, age, and race/ethnicity between 2001 and 2009. DESIGN, SETTING, AND PARTICIPANTS/METHODS:Case patients were ascertained in 4 geographic areas and 1 managed health care plan. The study population was determined by the 2001 and 2009 bridged-race intercensal population estimates for geographic sites and membership counts for the health plan. MAIN OUTCOMES AND MEASURES/METHODS:Prevalence (per 1000) of physician-diagnosed type 1 diabetes in youth aged 0 through 19 years and type 2 diabetes in youth aged 10 through 19 years. RESULTS:In 2001, 4958 of 3.3 million youth were diagnosed with type 1 diabetes for a prevalence of 1.48 per 1000 (95% CI, 1.44-1.52). In 2009, 6666 of 3.4 million youth were diagnosed with type 1 diabetes for a prevalence of 1.93 per 1000 (95% CI, 1.88-1.97). In 2009, the highest prevalence of type 1 diabetes was 2.55 per 1000 among white youth (95% CI, 2.48-2.62) and the lowest was 0.35 per 1000 in American Indian youth (95% CI, 0.26-0.47) and type 1 diabetes increased between 2001 and 2009 in all sex, age, and race/ethnic subgroups except for those with the lowest prevalence (age 0-4 years and American Indians). Adjusted for completeness of ascertainment, there was a 21.1% (95% CI, 15.6%-27.0%) increase in type 1 diabetes over 8 years. In 2001, 588 of 1.7 million youth were diagnosed with type 2 diabetes for a prevalence of 0.34 per 1000 (95% CI, 0.31-0.37). In 2009, 819 of 1.8 million were diagnosed with type 2 diabetes for a prevalence of 0.46 per 1000 (95% CI, 0.43-0.49). In 2009, the prevalence of type 2 diabetes was 1.20 per 1000 among American Indian youth (95% CI, 0.96-1.51); 1.06 per 1000 among black youth (95% CI, 0.93-1.22); 0.79 per 1000 among Hispanic youth (95% CI, 0.70-0.88); and 0.17 per 1000 among white youth (95% CI, 0.15-0.20). Significant increases occurred between 2001 and 2009 in both sexes, all age-groups, and in white, Hispanic, and black youth, with no significant changes for Asian Pacific Islanders and American Indians. Adjusted for completeness of ascertainment, there was a 30.5% (95% CI, 17.3%-45.1%) overall increase in type 2 diabetes. CONCLUSIONS AND RELEVANCE/CONCLUSIONS:Between 2001 and 2009 in 5 areas of the United States, the prevalence of both type 1 and type 2 diabetes among children and adolescents increased. Further studies are required to determine the causes of these increases.