Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans.

Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA.
PLoS Genetics (Impact Factor: 8.17). 06/2011; 7(6):e1002150. DOI: 10.1371/journal.pgen.1002150
Source: PubMed

ABSTRACT Single nucleotide polymorphisms (SNPs) in MYH9 and APOL1 on chromosome 22 (c22) are powerfully associated with non-diabetic end-stage renal disease (ESRD) in African Americans (AAs). Many AAs diagnosed with type 2 diabetic nephropathy (T2DN) have non-diabetic kidney disease, potentially masking detection of DN genes. Therefore, genome-wide association analyses were performed using the Affymetrix SNP Array 6.0 in 966 AA with T2DN and 1,032 non-diabetic, non-nephropathy (NDNN) controls, with and without adjustment for c22 nephropathy risk variants. No associations were seen between FRMD3 SNPs and T2DN before adjusting for c22 variants. However, logistic regression analysis revealed seven FRMD3 SNPs significantly interacting with MYH9-a finding replicated in 640 additional AA T2DN cases and 683 NDNN controls. Contrasting all 1,592 T2DN cases with all 1,671 NDNN controls, FRMD3 SNPs appeared to interact with the MYH9 E1 haplotype (e.g., rs942280 interaction p-value = 9.3E⁻⁷ additive; odds ratio [OR] 0.67). FRMD3 alleles were associated with increased risk of T2DN only in subjects lacking two MYH9 E1 risk haplotypes (rs942280 OR = 1.28), not in MYH9 E1 risk allele homozygotes (rs942280 OR = 0.80; homogeneity p-value = 4.3E⁻⁴). Effects were weaker stratifying on APOL1. FRMD3 SNPS were associated with T2DN, not type 2 diabetes per se, comparing AAs with T2DN to those with diabetes lacking nephropathy. T2DN-associated FRMD3 SNPs were detectable in AAs only after accounting for MYH9, with differential effects for APOL1. These analyses reveal a role for FRMD3 in AA T2DN susceptibility and accounting for c22 nephropathy risk variants can assist in detecting DN susceptibility genes.


Available from: Randall C Johnson, May 26, 2015
  • [Show abstract] [Hide abstract]
    ABSTRACT: Membranous glomerulonephritis (MGN) is a common cause of idiopathic nephrotic syndrome in adults end-stage renal disease in 25% of patients. MYH9 gene polymorphisms have been reported to be associated with several types of renal diseases. The objective of this study was to clarify the relationship between MYH9 gene polymorphisms and the pathogenesis of MGN. We investigated MYH9 gene polymorphisms (rs7078 and rs12107) and their association with MGN susceptibility in 400 Taiwanese individuals (135 MGN patients and 265 healthy controls). The results revealed a statistically significant difference in allele frequency distribution at the rs12107 between MGN patients and the control group (p = 0.04). In addition, individuals with the AA genotype at the rs12107 SNP who become MGN patients may have a higher risk of kidney failure than other MGN patients (adjusted odds ratio: 1.63; 95% confidence interval: 1.08-2.48, p = 0.02). A C-A haplotype was susceptible for development of MGN. Our data show that MYH9 (rs12107) polymorphism may be the underlying cause of MGN; hence the polymorphism examined in this study warrant further investigation.
    ScienceAsia 12/2013; 39(6):625. DOI:10.2306/scienceasia1513-1874.2013.39.625 · 0.35 Impact Factor
  • Source
    [Show abstract] [Hide abstract]
    ABSTRACT: Genomic research is one of the tools for elucidating the pathogenesis of diseases of global health relevance and paving the research dimension to clinical and public health translation. Recent advances in genomic research and technologies have increased our understanding of human diseases, genes associated with these disorders, and the relevant mechanisms. Genome-wide association studies (GWAS) have proliferated since the first studies were published several years ago and have become an important tool in helping researchers comprehend human variation and the role genetic variants play in disease. However, the need to expand the diversity of populations in GWAS has become increasingly apparent as new knowledge is gained about genetic variation. Inclusion of diverse populations in genomic studies is critical to a more complete understanding of human variation and elucidation of the underpinnings of complex diseases. In this review, we summarize the available data on GWAS in recent African ancestry populations within the western hemisphere (i.e. African Americans and peoples of the Caribbean) and continental African populations. Furthermore, we highlight ways in which genomic studies in populations of recent African ancestry have led to advances in the areas of malaria, HIV, prostate cancer, and other diseases. Finally, we discuss the advantages of conducting GWAS in recent African ancestry populations in the context of addressing existing and emerging global health conditions.
    Public Health Genomics 11/2014; 18(1). DOI:10.1159/000367962 · 2.46 Impact Factor
  • [Show abstract] [Hide abstract]
    ABSTRACT: Molecular genetics have revolutionized the understanding of susceptibility to the broad spectrum of kidney diseases with light microscopic appearance of FSGS, particularly in populations with recent African ancestry. These disorders include idiopathic FSGS, HIV-associated nephropathy, severe lupus nephritis, sickle cell nephropathy, and the primary kidney disorder focal global glomerulosclerosis, which had historically been ascribed to systemic hypertension. FSGS was once thought to include a multitude of unrelated disorders with similar histologic appearance. However, variation in the apolipoprotein L1 gene locus is now known to account for the vast majority of such cases in African Americans as well as nearly all the excess risk for FSGS and related forms of progressive nondiabetic nephropathy in populations with recent African ancestry, relative to European ancestry. Inheriting two coding apolipoprotein L1 gene nephropathy risk variants is necessary for susceptibility to CKD; however, these variants alone are insufficient to produce disease. This work reviews the evidence supporting second hits or modifying factors that affect risk for apolipoprotein L1 gene-associated nephropathy and produce the protean manifestations of this common and complex syndrome. Targeting modifiable second factors will lead to preventive therapies for slowing progression of nondiabetic nephropathy in many patients possessing two apolipoprotein L1 gene risk variants. This model of genetic risk coupled with modifiable second hits will serve as a paradigm applicable to patients with CKD of various etiologies as well as a host of other complex disorders.
    Clinical Journal of the American Society of Nephrology 06/2014; 9(11). DOI:10.2215/CJN.01330214 · 5.25 Impact Factor