Polymorphisms in MYH9 are associated with diabetic nephropathy in European Americans.
ABSTRACT: Polymorphisms in the non-muscle myosin IIA gene (MYH9) are associated with focal segmental glomerulosclerosis (FSGS) and non-diabetic end-stage renal disease (ESRD) in African Americans and FSGS in European Americans. We tested for association of single nucleotide polymorphisms (SNPs) in MYH9 with T2DM-ESRD in European Americans; additionally, three APOL1 gene variants were evaluated.Fifteen MYH9 SNPs and two APOL1 SNPs plus a 6-bp deletion were genotyped in 1963 European Americans, 536 cases with T2DM-ESRD and 1427 non-nephropathy controls (467 with T2DM and 960 without diabetes).Comparing T2DM-ESRD cases with the 467 T2DM non-nephropathy controls, single variant associations trending toward significance were detected with SNPs rs4821480, rs2032487 and rs4281481 comprising part of the major MYH9 E1 risk haplotype [P-values 0.053-0.055 recessive, odds ratio (OR) 6.08-6.14]. Comparing T2DM-ESRD cases to all 1427 non-nephropathy controls, we confirmed evidence of association in these three SNPs as well as in the fourth E1 SNP (rs3752462) (P-values 0.017-0.035, OR 1.41-3.72). APOL1 G1/G2 nephropathy risk variants were rare in individuals of European American heritage, present in 0.28% of chromosomes in T2DM-ESRD cases and 0.32% of controls.MYH9 SNPs rs4821480, rs2032487, rs4281481 and rs3752462 are associated with T2DM-ESRD susceptibility in European Americans. The APOL1 risk variants are not present at appreciable frequency in this cohort with T2DM-ESRD. Therefore, polymorphisms in MYH9 appear to influence nephropathy risk in this sample.
Project description: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.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.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.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.
Project description:MYH9 polymorphisms have been described to be associated with the risk of CKD in non-diabetic nephropathy, HIV nephropathy and FSGS. Predominating in black descendants, MHY9 genetic variants could partially explain the excess risk of CKD associated with African ancestry. However, recent data suggests that APOL1 gene co-segregate with MYH9, and could be the gene truly associated with CKD risk. In this study, we evaluated the role of MYH9 and APOL1 gene polymorphisms in the risk of CKD in Brazilian patients with lupus nephritis (LN). A retrospective analysis of 196 LN patients was done. MYH9 rs4821480, rs2032487, rs4821481 and rs3752462, APOL 1rs73885319, rs16996616, rs60910145, rs71785313, and APOL3 rs11089781 gene polymorphisms were determined. Genetic ancestry was ascertained both by autossomal ancestry and mitochondrial haplogroup. Primary outcome was defined as doubling of serum creatinine (DC) or end stage renal disease (ESRD). Sixty-two patients presented the PO. In our population, MYH9 and APOL1 were not in LD. None APOL polymorphism was associated with the PO, whereas rs3752462 MYH9 polymorphism showed a positive association (HR3.72, 95%CI 1.47-9.38, p?=?0.005). When we analyzed the MYH9 E1 haplotype, the GCCT carriers (1 or 2 alelles present in 29.7% in the PO group vs. 18.5% in controls) showed a significant association to the risk of PO, even after adjustments for baseline estimated creatinine clearance and autossomal ancestry (HR 2.0, 95%CI 1.2-3.4, p?=?0.01). Our results show that in our population MYH9, but not APOL1, gene polymorphisms confer an increased risk of CKD in LN patients, independently of race.
Project description:Single-nucleotide polymorphisms (SNPs) in MYH9-APOL1 gene regions have been reported to be associated with diabetic kidney disease (DKD) in the American population. We examined the association between polymorphisms in MYH9-APOL1 and DKD susceptibility in a Chinese Han population. MYH9 rs3752462 (T>C) and APOL1 rs136161 (C>G) were genotyped in 303 DKD patients and 364 type 2 diabetes mellitus (T2DM) patients without kidney disease using the TaqMan SNP genotyping assay. Chi-squared test and multivariate logistic regression were used to evaluate the association. We observed that only MYH9 rs3752462 was associated with DKD (genotype, P = 0.004; allele, P = 0.002). Genetic model analysis revealed that rs3752462 was associated with increased risk of DKD under a dominant model adjusted by age and sex (adjusted odds ratio (aOR), 1.675; 95% CI 1.225-2.289; P = 0.001) and an additive model (TC versus TT: aOR, 1.649; 95% CI 1.187-2.290; CC versus TT: aOR, 1.817; 95% CI 0.980-3.367; P = 0.005). The combined effect of rs3752462 TC?+?rs136161 CC genotype showed an association of DKD adjusted by age and sex (aOR, 1.732; 95% CI 1.128-2.660; P = 0.012). After a Holm-Bonferroni correction for multiple tests, the C allele frequencies of the rs3752462 and the TC?+?CC genotype in the dominant model were considered statistically significant with a markedly increased risk of DKD (P < 0.00208; P < 0.002). Our results suggest that MYH9 rs3752462 is significantly associated with an increased risk of DKD in Chinese Han individuals.
Project description: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?? 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??). 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.
Project description:Conflicting reports exist as to whether sickle cell trait is a risk factor for the progression of nephropathy. In order to determine whether African Americans with sickle cell trait are at increased risk for kidney disease, we assessed the genetic association between sickle cell trait and end-stage renal disease (ESRD). Hemoglobin S, non-muscle myosin heavy chain 9 (MYH9), and apolipoprotein L1 (APOL1) risk variants were genotyped in 3258 unrelated African Americans: 1085 with non-diabetic ESRD, 996 with type 2 diabetes-associated ESRD, and 1177 controls. Since APOL1 is strongly associated with ESRD in African Americans, interactions between APOL1 and MYH9 risk variants and hemoglobin S were assessed using case-only and case-control centered two-way logistic regression interaction analyses. The sickle cell trait genotype frequencies were 8.7% in non-diabetic ESRD, 7.1% in type 2 diabetes-ESRD, and 7.2% in controls. There was no age-, gender-, and admixture-adjusted significance for sickle cell trait association with non-diabetic ESRD (odds ratio 1.16); type 2 diabetes-ESRD (odds ratio 1.01); or all-cause ESRD (combined non-diabetic and type 2 diabetic-ESRD patients compared to the controls; odds ratio 1.05) in dominant models. In addition, no evidence of APOL1 or MYH9 interactions with sickle cell trait was detected. Hence, sickle cell trait is not associated with diabetic or non-diabetic ESRD in a large sample of African Americans.
Project description:A chromosome 22q13 locus strongly associates with increased risk for idiopathic focal segmental glomerulosclerosis (FSGS), HIV-1-associated nephropathy (HIVAN), and hypertensive ESRD among individuals of African descent. Although initial studies implicated MYH9, more recent analyses localized the strongest association within the neighboring APOL1 gene. In this replication study, we examined the six top-most associated variants in APOL1 and MYH9 in an independent cohort of African Americans with various nephropathies (44 with FSGS, 21 with HIVAN, 32 with IgA nephropathy, and 74 healthy controls). All six variants associated with FSGS and HIVAN (additive ORs, 1.8 to 3.0; P values 3 × 10(-2) to 5 × 10(-5)) but not with IgA nephropathy. In conditional and haplotype analyses, two APOL1 haplotypes accounted for virtually all of the association with FSGS and HIVAN on chromosome 22q13 (haplotype P value = 5.6 × 10(-8)). To assess the role of MYH9 deficiency in nephropathy, we crossbred Myh9-haploinsufficient mice (Myh9(+/-)) with HIV-1 transgenic mice. Myh9(+/-) mice were healthy and did not demonstrate overt proteinuria or nephropathy, irrespective of the presence of the HIV-1 transgene. These data further support the strong association of genetic variants in APOL1 with susceptibility to FSGS and HIVAN among African Americans.
Project description:<h4>Background</h4>MYH9 is a podocyte-expressed gene encoding nonmuscle myosin IIA that is associated with idiopathic and human immunodeficiency virus-associated focal segmental glomerulosclerosis (FSGS) and hypertensive end-stage renal disease in African Americans.<h4>Methods</h4>Four single nucleotide polymorphisms comprising the major MYH9 E1 risk haplotype were tested for association with estimated glomerular filtration rate (eGFR) and urine albumin:creatinine ratio (ACR) in 2,903 HyperGEN participants (1,458 African Americans (AA) in 895 families and 1,445 European Americans (EA) in 859 families) to determine the role of MYH9 in subclinical nephropathy. Association analyses employed general linear models in unrelated probands and generalized estimating equations in families. Adjustment was performed for age, sex, diabetes, BMI, medications, and mean arterial pressure separately in each race.<h4>Results</h4>Mean (SD) eGFR and ACR were 74.3 (16.0) ml/min/1.73 m(2) and 20.3 (119.9) mg/g in EA, and 88.6 (20.9) ml/min/1.73 m(2) and 76.8 (394.5) mg/g in AA (both p < 0.0001 across ethnicities). Urine ACR was associated with rs3752462 (p = 0.01) and rs4821481 (p = 0.05) in unrelated AA and with rs4821481 (p = 0.03), rs2032487 (p = 0.04) and the E1 3224 haplotype (p = 0.013) in AA families. Single nucleotide polymorphisms and the haplotype were not associated with ACR in EA or with eGFR in either ethnic group.<h4>Conclusions</h4>MYH9 variants are associated with albuminuria in hypertensive AA. The strength of the association was weaker than that in FSGS and hypertensive end-stage renal disease. MYH9 risk variants appear to be associated with primary FSGS with secondary hypertension, although nephrosclerosis may develop in response to hypertension in subjects homozygous for the MYH9 E1 risk haplotype.
Project description:Apolipoprotein L1 gene (APOL1) G1 and G2 variants are strongly associated with progressive nondiabetic nephropathy in populations with recent African ancestry. Selection for these variants occurred as a result of protection from human African trypanosomiasis (HAT). Resequencing of this region in 10 genetically and geographically distinct African populations residing in HAT endemic regions identified eight single nucleotide polymorphisms (SNPs) in strong linkage disequilibrium and comprising a novel G3 haplotype. To determine whether the APOL1 G3 haplotype was associated with nephropathy, G1, G2, and G3 SNPs and 70 ancestry informative markers spanning the genome were genotyped in 937 African Americans with nondiabetic ESRD, 965 African Americans with type 2 diabetes-associated ESRD, and 1029 non-nephropathy controls. In analyses adjusting for age, sex, APOL1 G1/G2 risk (recessive), and global African ancestry, the G3 haplotype was not significantly associated with ESRD (P=0.05 for nondiabetic ESRD, P=0.57 for diabetes-associated ESRD, and P=0.27 for all-cause ESRD). We conclude that variation in APOL1 G3 makes a nominal, if any, contribution to ESRD in African Americans; G1 and G2 variants explain the vast majority of nondiabetic nephropathy susceptibility.
Project description:Lupus nephritis (LN) is a severe manifestation of systemic lupus erythematosus (SLE) that exhibits familial aggregation and may progress to end-stage renal disease (ESRD). LN is more prevalent among African Americans than among European Americans. This study was undertaken to investigate the hypothesis that the apolipoprotein L1 gene (APOL1) nephropathy risk alleles G1/G2, common in African Americans and rare in European Americans, contribute to the ethnic disparity in risk.APOL1 G1 and G2 nephropathy alleles were genotyped in 855 African American SLE patients with LN-ESRD (cases) and 534 African American SLE patients without nephropathy (controls) and tested for association under a recessive genetic model, by logistic regression.Ninety percent of the SLE patients were female. The mean ± SD age at SLE diagnosis was significantly lower in LN-ESRD cases than in SLE non-nephropathy controls (27.3 ± 10.9 years versus 39.5 ± 12.2 years). The mean ± SD time from SLE diagnosis to development of LN-ESRD in cases was 7.3 ± 7.2 years. The G1/G2 risk alleles were strongly associated with SLE-ESRD, with 25% of cases and 12% of controls having 2 nephropathy alleles (odds ratio [OR] 2.57, recessive model P = 1.49 × 10(-9)), and after adjustment for age, sex, and ancestry admixture (OR 2.72, P = 6.23 × 10(-6)). The age-, sex-, and admixture-adjusted population attributable risk for ESRD among patients with G1/G2 polymorphisms was 0.26, compared to 0.003 among European American patients. The mean time from SLE diagnosis to ESRD development was ?2 years earlier among individuals with APOL1 risk genotypes (P = 0.01).APOL1 G1/G2 alleles strongly impact the risk of LN-ESRD in African Americans, as well as the time to progression to ESRD. The high frequency of these alleles in African Americans with near absence in European Americans explains an important proportion of the increased risk of LN-ESRD in African Americans.
Project description: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.Seven MYH9 single nucleotide polymorphisms (SNPs) and the E1 risk haplotype were tested for association with LN in three cohorts of AA.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.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.