ABSTRACT
BACKGROUND AND OBJECTIVES: Diabetic nephropathy (DN) is a multifactorial complication characterized by persistent proteinuria in susceptible individuals with type 1 and type 2 diabetes. Disease burden in people of Mexican-American descent is particularly high, but there are only a few studies that characterize genes for DN in this ethnic group. Two genes, carnosine dipeptidase 1 (CNDP1) and engulfment and cell motility 1 (ELMO1) previously showed association with DN in other ethnic groups. CNDP1 and ELMO1 were examined along with eight other genes that are less well characterized for DN in a new study of Mexican-Americans. DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: The target sample was patients of Mexican-American ancestry collected from three centers: 455 patients with DN and 437 controls with long-term diabetes but no incident nephropathy. Forty-two, 227, and 401 single nucleotide polymorphisms (SNPs) in CNDP1, ELMO1, and the other eight genes, respectively, were examined. RESULTS: No region in CNDP1 or ELMO1 showed significant P values. Of the other eight candidate genes, an association of DN with a SNP pair, rs2146098 and rs6659783, was found in hemicentin 1 (HMCN1) (unadjusted P = 6.1 x 10(-5)). Association with a rare haplotype in this region was subsequently identified. CONCLUSIONS: The associations in CNDP1 or ELMO1 were not replicable; however, an association of DN with HMCN1 was found. Additional work at this and other loci will enable refinement of the genetic hypotheses regarding DN in the Mexican-American population to find therapies for this debilitating disease.
Subject(s)
Adaptor Proteins, Signal Transducing/genetics , Diabetic Nephropathies/genetics , Dipeptidases/genetics , Immunoglobulins/genetics , Mexican Americans/genetics , Case-Control Studies , Chi-Square Distribution , Diabetic Nephropathies/ethnology , Genetic Association Studies , Genetic Predisposition to Disease , Haplotypes , Humans , Logistic Models , Pedigree , Phenotype , Polymorphism, Single Nucleotide , Principal Component Analysis , Risk Assessment , Risk Factors , United States/epidemiologyABSTRACT
Diabetic nephropathy is a classic complex trait, whose development in a given individual reflects contributions from multiple genes and whose expression is modulated by environmental factors. Numerous genetic strategies have been used to identify common disease risk loci and genes, including candidate gene analyses, linkage analysis, transmission disequilibrium testing (a family based association test to identify linkage between a genetic marker and a biological trait or disease), and admixture mapping (also referred to as mapping by admixture linkage disequilibrium). Choosing the best genetic strategy to identify susceptibility genes in a disease is dependent on knowing whether the disorder is monogenic (the result of one gene), oligogenic (the result of a few genes), or polygenic (the result of many genes). The likelihood of finding risk loci for a disease with a putative genetic contribution is in part owing to the disease recurrence risk ratio (the risk of expressing the disease phenotype in siblings of the proband divided by the risk observed in the general population), the genotypic risk ratio (the risk of expressing the phenotype if the gene is present divided by the risk if the gene is not present), the number of susceptibility genes, how the susceptibility genes interact, how much of the disease risk is contributed by environmental factors, and the disease penetrance (the likelihood that the phenotype will be expressed if the gene is present).