Faculty Bibliography

CONTEXT/BACKGROUND:Inverse associations are reported between circulating 25-hydroxyvitamin D and visceral adiposity. The effects of vitamin D levels on atherosclerosis are unknown. OBJECTIVE:The objective of this study was to test for relationships between vitamin D, adiposity, bone density, and atherosclerosis in African-Americans. DESIGN/METHODS:Circulating 25-hydroxyvitamin D, 1,25 dihydroxyvitamin D, intact PTH, C-reactive protein and computed tomography-derived calcified atherosclerotic plaque (CP), bone density, and fat volumes were measured. SETTING/METHODS:Examinations were performed at a single outpatient general clinical research center visit. SUBJECTS/METHODS:Three hundred forty African-Americans with type 2 diabetes were evaluated. Mean +/- SD age was 55.6 +/- 9.6 yr, diabetes duration 10.6 +/- 8.3 yr, glomerular filtration rate 1.6 +/- 0.5 ml/sec, body mass index 35.6 +/- 8.7 kg/m(2), and 25-hydroxyvitamin D concentration 50.4 +/- 30.5 nmol/liter. MAIN OUTCOME MEASURE/METHODS:Biomarkers were tested for association with pericardial, visceral, im, and sc adipose tissues; thoracic and lumbar vertebral bone density; and aorta, coronary, and carotid artery CP. RESULTS:Adjusting for age, gender, body mass index, glycosylated hemoglobin, and glomerular filtration rate, 25-hydroxyvitamin D was negatively associated with visceral adiposity (P = 0.009) and positively associated with carotid artery CP and aorta CP (P = 0.013 and 0.014, respectively) but not with coronary artery CP or bone density. CONCLUSIONS:We confirmed an inverse association between vitamin D and visceral adiposity in African-Americans with diabetes. In addition, positive associations exist between 25-hydroxyvitamin D and aorta and carotid artery CP in African-Americans. The effects of supplementing vitamin D to raise the serum 25-hydroxyvitamin D level on atherosclerosis in African-Americans are unknown. Prospective trials are needed to determine the cardiovascular effects of supplemental vitamin D in this ethnic group.

We sought to partition the genetic and environmental influences on lipoprotein subclasses and identify genomic regions that may harbor genetic variants that influence serum lipoprotein levels in a sample of Gullah-speaking African-Americans. We genotyped 5,974 SNPs in 979 subjects from 418 pedigrees and used the variance component approach to compute heritability estimates, genetic and environmental correlations, and linkage analyses for selected lipoprotein subclasses. The highest heritability estimate was observed for large VLDL particle concentration (0.56 +/- 0.14). Mean LDL particle size and small LDL particle concentration (-0.94) had the strongest genetic correlation estimate. The highest logarithm of odds (LOD) score detected (3.0) was on chromosome 6p24 for small LDL particle concentration. The strongest signal, obtained with the reduced sample of diabetic individuals only, was observed on chromosome 20p13 for small LDL particle concentration. The highest bivariate linkage signal (LOD 2.4) was observed on chromosome 6p24 for mean LDL particle size and small LDL particle concentration. Our results suggest a significant genetic contribution to multiple lipoprotein subclasses studied in this sample and that novel loci on chromosomes 6, 10, 16, and 20 may harbor genes contributing to small, atherogenic LDL particle concentration and large, triglyceride-rich VLDL particle concentration.

OBJECTIVE:Despite higher rates of nephropathy, calcified atherosclerotic plaque is less prevalent in African Americans with diabetes relative to European Americans. We explored ethnicity-specific relationships between albuminuria and calcified plaque involving the infrarenal aorta, coronary artery, and carotid artery in 835 European American and 393 African American subjects with type 2 diabetes. RESEARCH DESIGN AND METHODS/METHODS:Generalized estimating equations with exchangeable correlation and the sandwich estimator of the variance were used to test for association between the principal component of calcified plaque in the three vascular beds and urine albumin-to-creatinine ratio (ACR). RESULTS:Mean +/- SD ages of African American and European American participants were 56.7 +/- 9.6 and 61.7 +/- 9.1 years, respectively, with diabetes duration of 10.4 +/- 7.4 and 10.0 +/- 7.3 years and median urine ACR of 17.5 and 13.4 mg/g. In African American and European American participants, respectively, median calcified plaque mass scores were 53.5 and 291 for coronary artery, 3 and 35.5 for carotid artery, and 761 and 3,237 for aorta. With adjustment for age, sex, glomerular filtration rate, and BMI, albuminuria was significantly associated with calcified plaque in European Americans (P = 3.4 x 10(-8)) but not in African Americans (P = 0.33), with significant ethnic interaction (P = 0.01). Ethnic differences in this relationship persisted after adjustment for blood pressure, smoking, lipids, and use of ACE inhibitors or angiotensin receptor blockers. CONCLUSIONS:Albuminuria is strongly associated with severity of calcified plaque in European Americans with diabetes but not in African Americans. Disparities in this relationship may contribute to ethnic differences in the rates of cardiovascular disease that are observed in subjects with type 2 diabetes.

PURPOSE OF REVIEW/OBJECTIVE:This paper reviews recent efforts to identify genetic variants conferring risk for chronic kidney disease. A brief overview of methods for identifying gene variants is provided, along with genetic associations and new avenues under exploration. RECENT FINDINGS/RESULTS:The role of renal failure susceptibility genes, including MYH9, ELMO1, UMOD and ACTN4, has become clearer over the past 18 months. The spectrum of MYH9-associated kidney disease, including focal segmental glomerulosclerosis, global glomerulosclerosis and collapsing glomerulopathy, related entities contributing to approximately 43% of end-stage renal disease in African-Americans, has come to light. SUMMARY/CONCLUSIONS:MYH9 will re-categorize focal segmental glomerulosclerosis and related disorders, and has clarified the relationship between hypertension and kidney disease. MYH9 polymorphisms account for much of the excess risk of HIV-associated nephropathy and nondiabetic kidney disease in African-Americans. Kidney disease associations with ELMO1 and UMOD have been replicated and applications of genome-wide association studies based on expression data are providing novel insights on renal protein expression. These breakthroughs will alter our approach to kidney disease surveillance and lead to new therapeutic options.

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterized by increased type I interferons (IFNs) and multiorgan inflammation frequently targeting the skin. IFN-kappa is a type I IFN expressed in skin. A pooled genome-wide scan implicated the IFNK locus in SLE susceptibility. We studied IFNK single nucleotide polymorphisms (SNPs) in 3982 SLE cases and 4275 controls, composed of European (EA), African-American (AA), and Asian ancestry. rs12553951C was associated with SLE in EA males (odds ratio = 1.93, P = 2.5 x 10(-4)), but not females. Suggestive associations with skin phenotypes in EA and AA females were found, and these were also sex-specific. IFNK SNPs were associated with increased serum type I IFN in EA and AA SLE patients. Our data suggest a sex-dependent association between IFNK SNPs and SLE and skin phenotypes. The serum IFN association suggests that IFNK variants could influence type I IFN producing plasmacytoid dendritic cells in affected skin

BACKGROUND:African Americans (AA) disproportionately develop lupus nephritis (LN) relative to European Americans and familial clustering supports causative genes. Since MYH9 underlies approximately 40% of end-stage renal disease (ESRD) in AA, we tested for genetic association with LN. METHODS:Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA. RESULTS:A preliminary analysis revealed that the MYH9 E1 risk haplotype was associated with ESRD in 25 cases with presumed systemic lupus erythematosus (SLE)-associated ESRD, compared to 735 non-SLE controls (odds ratio 3.1; p = 0.010 recessive). Replication analyses were performed in 583 AA with SLE in the PROFILE cohort (318 with LN; 265 with SLE but without nephropathy) and 60 AA from the NIH (39 with LN; 21 with SLE but without nephropathy). Analysis of the NIH and larger PROFILE cohorts, as well as a combined analysis, did not support this association. CONCLUSIONS:These results suggest that AA with ESRD and coincident SLE who were recruited from dialysis clinics more likely have kidney diseases in the MYH9-associated spectrum of focal segmental glomerulosclerosis. PROFILE and NIH participants, recruited from rheumatology practices, demonstrate that MYH9 does not contribute substantially to the development of LN in AA.

Genetic studies in Turkish, Native American, European American, and African American (AA) families have linked chromosome 18q21.1-23 to susceptibility for diabetes-associated nephropathy. In this study, we have carried out fine linkage mapping in the 18q region previously linked to diabetic nephropathy in AAs by genotyping both microsatellite and single nucleotide polymorphisms (SNPs) for linkage analysis in an expanded set of 223 AA families multiplexed for type 2 diabetes associated ESRD (T2DM-ESRD). Several approaches were used to evaluate evidence of linkage with the strongest evidence for linkage in ordered subset analysis with an earlier age of T2DM diagnosis compared to the remaining pedigrees (LOD 3.9 at 90.1 cM, ΔP = 0.0161, NPL P value = 0.00002). Overall, the maximum LODs and LOD-1 intervals vary in magnitude and location depending upon analysis. The linkage mapping was followed up by performing a dense SNP map, genotyping 2,814 SNPs in the refined LOD-1 region in 1,029 AA T2DM-ESRD cases and 1,027 AA controls. Of the top 25 most associated SNPs, 10 resided within genic regions. Two candidate genes stood out: NEDD4L and SERPINB7. SNP rs512099, located in intron 1 of NEDD4L, was associated under a dominant model of inheritance [P value = 0.0006; Odds ratio (95% Confidence Interval) OR (95% CI) = 0.70 (0.57-0.86)]. SNP rs1720843, located in intron 2 of SERPINB7, was associated under a recessive model of inheritance [P value = 0.0017; OR (95% CI) = 0.65 (0.50-0.85)]. Collectively, these results suggest that multiple genes in this region may influence diabetic nephropathy susceptibility in AAs.

BACKGROUND:Although MYH9 is strongly associated with biopsy-proven idiopathic and HIV-associated focal segmental glomerulosclerosis (FSGS) and clinically diagnosed 'hypertension-associated' end-stage renal disease (ESRD) in African Americans, its role in type 2 diabetes mellitus (T2DM)-associated ESRD is unclear. METHODS:To assess whether MYH9 was associated with T2DM-ESRD, 751 African Americans with T2DM-ESRD, 227 with T2DM lacking nephropathy and 925 non-diabetic non-nephropathy controls were genotyped for 14 MYH9 SNPs. Association analyses used SNPGWA and Dandelion. RESULTS:Comparing T2DM-ESRD cases with non-diabetic controls, single SNP associations were detected with 8 of 14 SNPs, gender- and admixture-adjusted P-values 0.047-0.005 [recessive model, odds ratio (OR) range 1.30-1.55]. The previously associated MYH9 E1 and L1 haplotypes were associated with T2DM-ESRD (E1: OR 1.27, 95% CI 1.04-1.56, P = 0.021 recessive and L1: OR 1.43, 95% CI 1.09-1.87, P = 0.009 dominant). Contrasting the 751 T2DM-ESRD cases with 227 T2DM non-nephropathy controls revealed that E1 haplotype SNPs rs4821480, rs2032487 and rs4821481 were associated with kidney failure (OR 1.38-1.40 recessive, all P < 0.048). Among E1 and L1 risk homozygotes, respectively, mean (SD) diabetes duration prior to renal replacement therapy was 16.6 (9.7) and 16.4 (10.0) years, and 65% had diabetic retinopathy. CONCLUSIONS:Genetic dissection of T2DM-associated ESRD reveals that MYH9 underlies a portion of this clinically diagnosed disorder in African Americans. It is likely that a subset of African Americans with T2DM and coincident nephropathy have primary MYH9-related kidney disease (e.g. FSGS or global glomerulosclerosis), although renal biopsy studies need to be performed.

We targeted LYN, a src-tyosine kinase involved in B-cell activation, in case-control association studies using populations of European-American, African-American and Korean subjects. Our combined European-derived population, consisting of 2463 independent cases and 3131 unrelated controls, shows significant association with rs6983130 in a female-only analysis with 2254 cases and 2228 controls (P=1.1 x 10(-4), odds ratio (OR)=0.81 (95% confidence interval: 0.73-0.90)). This single nucleotide polymorphism (SNP) is located in the 5' untranslated region within the first intron near the transcription initiation site of LYN. In addition, SNPs upstream of the first exon also show weak and sporadic association in subsets of the total European-American population. Multivariate logistic regression analysis implicates rs6983130 as a protective factor for systemic lupus erythematosus (SLE) susceptibility when anti-dsDNA, anti-chromatin, anti-52 kDa Ro or anti-Sm autoantibody status were used as covariates. Subset analysis of the European-American female cases by American College of Rheumatology classification criteria shows a reduction in the risk of hematological disorder with rs6983130 compared with cases without hematological disorders (P=1.5 x 10(-3), OR=0.75 (95% CI: 0.62-0.89)). None of the 90 SNPs tested show significant association with SLE in the African American or Korean populations. These results support an association of LYN with European-derived individuals with SLE, especially within autoantibody or clinical subsets

Systemic lupus erythematosus (SLE) is an autoimmune disease with highly variable clinical presentation. Patients suffer from immunological abnormalities that target T-cell, B-cell and accessory cell functions. B cells are hyperactive in SLE patients. An adapter protein expressed in B cells called BANK1 (B-cell scaffold protein with ankyrin repeats) was reported in a previous study to be associated with SLE in a European population. The objective of this study was to assess the BANK1 genotype-phenotype association in an independent replication sample. We genotyped 38 single nucleotide polymorphisms (SNPs) in BANK1 on 1892 European-derived SLE patients and 2652 European-derived controls. The strongest associations with SLE and BANK1 were at rs17266594 (corrected P-value=1.97 x 10(-5), odds ratio (OR)=1.22, 95% CI 1.12-1.34) and rs10516487 (corrected P-value=2.59 x 10(-5), OR=1.22, 95% CI 1.11-1.34). Our findings suggest that the association is explained by these two SNPs, confirming previous reports that these polymorphisms contribute to the risk of developing lupus. Analysis of patient subsets enriched for hematological, immunological and renal ACR criteria or the levels of autoantibodies, such as anti-RNP A and anti-SmRNP, uncovers additional BANK1 associations. Our results suggest that BANK1 polymorphisms alter immune system development and function to increase the risk for developing lupus.