title: Differential effects of MYH9 and APOL1 risk variants on FRMD3 Association with Diabetic ESRD in African Americans.
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.
authors.affiliation: Section on Nephrology, Department of Internal Medicine, Wake Forest School of Medicine, Winston-Salem, North Carolina, USA. bfreedma@wakehealth.edu
authors.forename: Barry I
authors.initials: BI
authors.lastname: Freedman
authors.forename: Carl D
authors.initials: CD
authors.lastname: Langefeld
authors.forename: Lingyi
authors.initials: L
authors.lastname: Lu
authors.forename: Jasmin
authors.initials: J
authors.lastname: Divers
authors.forename: Mary E
authors.initials: ME
authors.lastname: Comeau
authors.forename: Jeffrey B
authors.initials: JB
authors.lastname: Kopp
authors.forename: Cheryl A
authors.initials: CA
authors.lastname: Winkler
authors.forename: George W
authors.initials: GW
authors.lastname: Nelson
authors.forename: Randall C
authors.initials: RC
authors.lastname: Johnson
authors.forename: Nicholette D
authors.initials: ND
authors.lastname: Palmer
authors.forename: Pamela J
authors.initials: PJ
authors.lastname: Hicks
authors.forename: Meredith A
authors.initials: MA
authors.lastname: Bostrom
authors.forename: Jessica N
authors.initials: JN
authors.lastname: Cooke
authors.forename: Caitrin W
authors.initials: CW
authors.lastname: McDonough
authors.forename: Donald W
authors.initials: DW
authors.lastname: Bowden
mesh_terms: D000328:Adult; D001741:Black or African American / Q000235:genetics*; D000368:Aged; D000075944:Apolipoprotein L1; D001053:Apolipoproteins / Q000235:genetics*; D002892:Chromosomes, Human, Pair 22 / Q000235:genetics; D003924:Diabetes Mellitus, Type 2 / Q000150:complications / Q000235:genetics; D003928:Diabetic Nephropathies / Q000209:etiology / Q000235:genetics*; D005260:Female; D005786:Gene Expression Regulation; D055106:Genome-Wide Association Study; D006239:Haplotypes; D006801:Humans; D007676:Kidney Failure, Chronic / Q000209:etiology / Q000235:genetics*; D008075:Lipoproteins, HDL / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D020409:Molecular Motor Proteins / Q000235:genetics*; D018995:Myosin Heavy Chains / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics* / Q000378:metabolism*; D055815:Young Adult
chemical_list: C108666:APOL1 protein, human; D000075944:Apolipoprotein L1; D001053:Apolipoproteins; C562024:FRMD3 protein, human; D008075:Lipoproteins, HDL; C103814:MYH9 protein, human; D020409:Molecular Motor Proteins; D025521:Tumor Suppressor Proteins; D018995:Myosin Heavy Chains