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Susceptibility gene search for nephropathy and related traits in Mexican-Americans.

ABSTRACT: The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican-Americans. Mexican-Americans with type 2 diabetes (T2DM) are three times more likely to develop microalbuminuria, and four times more likely to develop clinical proteinuria compared to non-Hispanic whites. Furthermore, Mexican-Americans have a sixfold increased risk of developing renal failure secondary to T2DM compared to Caucasians. Prevention and better treatment of DN should be a high priority for both health-care organizations and society at large. Pathogenesis of DN is multi-factorial. Familial clustering of DN-related traits in MAs show that DN and related traits are heritable and that genes play a susceptibility role. While, there has been some progress in identifying genes which when mutated influence an individual's risk, major gene(s) responsible for DN are yet to be identified. Knowledge of the genetic causes of DN is essential for elucidation of its mechanisms, and for adequate classification, prognosis, and treatment. Self-identification and collaboration among researchers with suitable genomic and clinical data for meta-analyses in Mexican-Americans is critical for progress in replicating/identifying DN risk genes in this population. This paper reviews the approaches and recent efforts made to identify genetic variants contributing to risk for DN and related phenotypes in the Mexican-American population.

SUBMITTER: Thameem F

PROVIDER: S-EPMC4334565 | biostudies-literature | 2013 Oct

REPOSITORIES: biostudies-literature

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Susceptibility gene search for nephropathy and related traits in Mexican-Americans.

Thameem Farook F Kawalit Issa A IA Adler Sharon G SG Abboud Hanna E HE

Molecular biology reports 20130922 10

The rising global epidemic of diabetic nephropathy (DN) will likely lead to increase in the prevalence of cardiovascular morbidity and mortality posing a serious burden for public health care. Despite greater understanding of the etiology of diabetes and the development of novel treatment strategies to control blood glucose levels, the prevalence and incidence rate of DN is increasing especially in minority populations including Mexican-Americans. Mexican-Americans with type 2 diabetes (T2DM) ar ...[more]

PMID: 24057238

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Project description:Several novel genes that are up-regulated in the kidney in diabetes have been identified including GREM1, which encodes gremlin 1. GREM1 maps to human chromosome 15q12, a region previously found to be linked to albumin to creatinine ratio (ACR) in Mexican Americans. The objective of this study is to investigate whether genetic variants in GREM1, a positional candidate gene, contribute to variation in ACR. By sequencing 32 individuals for both exons and 2-kilobase putative promoter region of GREM1, we identified 19 genetic variants including 5 in the promoter region and 13 in the 3' untranslated region. Of 19 polymorphisms identified, 13 polymorphisms were genotyped in the entire cohort (N = 670, 39 large families) either by restriction fragment length polymorphism or by TaqMan (Applied Biosystems, Foster City, CA) assays. Association analyses between the genotypes and ACR, type 2 diabetes mellitus, and related phenotypes were carried out using a measured genotype approach as implemented in the variance component analytical tools (SOLAR). Of the variants examined for association, none exhibited statistically significant association with ACR after accounting for the effects of covariates such as age, sex, diabetes, duration of diabetes, systolic blood pressure, and antihypertensive medications. However, 2 novel variants at the 3' untranslated region showed significant association with estimated glomerular filtration rate (P = .010 and P = .049) and body mass index (P = .013 and P = .019) after accounting for trait-specific covariate influences. Furthermore, a novel variant located in the promoter exhibited a significant association with systolic (P = .038) and diastolic blood pressure (P = .005) after adjusting for the effects of age, sex, diabetes, and antihypertensive medications. In conclusion, the variants examined at GREM1 are not significant contributors to variation in ACR in Mexican Americans, although they appear to minimally influence risk factors related to ACR.

Project description:Gallbladder disease (GBD) is one of the major digestive diseases. Its risk factors include age, sex, obesity, type 2 diabetes, and metabolic syndrome (MS). The prevalence of GBD is high in minority populations, such as Native and Mexican Americans. Ethnic differences, familial aggregation of GBD, and the identification of susceptibility loci for gallstone disease by use of animal models suggest genetic influences on GBD. However, the major susceptibility loci for GBD in human populations have not been identified. Using ultrasound-based information on GBD occurrence and a 10-cM gene map, we performed multipoint variance-components analysis to localize susceptibility loci for GBD. Phenotypic and genotypic data from 715 individuals in 39 low-income Mexican American families participating in the San Antonio Family Diabetes/Gallbladder Study were used. Two GBD phenotypes were defined for the analyses: (1) clinical or symptomatic GBD, the cases of cholecystectomies due to stones confirmed by ultrasound, and (2) total GBD, the clinical GBD cases plus the stone carriers newly diagnosed by ultrasound. With use of the National Cholesterol Education Program/Adult Treatment Panel III criteria, five MS risk factors were defined: increased waist circumference, hypertriglyceredemia, low high-density lipoprotein cholesterol, hypertension, and high fasting glucose. The MS risk-factor score (range 0-5) for a given individual was used as a single, composite covariate in the genetic analyses. After accounting for the effects of age, sex, and MS risk-factor score, we found stronger linkage signals for the symptomatic GBD phenotype. The highest LOD scores (3.7 and 3.5) occurred on chromosome 1p between markers D1S1597 and D1S407 (1p36.21) and near marker D1S255 (1p34.3), respectively. Other genetic locations (chromosomes 2p, 3q, 4p, 8p, 9p, 10p, and 16q) across the genome exhibited some evidence of linkage (LOD >or=1.2) to symptomatic GBD. Some of these chromosomal regions corresponded with the genetic locations of Lith loci, which influence gallstone formation in mouse models. In conclusion, we found significant evidence of major genetic determinants of symptomatic GBD on chromosome 1p in Mexican Americans.

Project description:To investigate the association of polymorphisms of nur-related receptor 1 (Nurr1) and development of alcohol dependence in Mexican Americans.Peripheral blood samples were collected from 374 alcoholic and 346 nonalcoholic Mexican Americans; these two groups were sex- and age-matched. Sample DNA was extracted and genomic DNA was amplified by polymerase chain reaction. The -2922(C) 2-3 polymerase chain reaction products were digested with Sau96I, alleles of 1345(G/C), and -1198(C/G) in the regulatory region as well as Ex+132 (G/T/A/C) and Ex+715(T/-) in exon 3 were studied by sequencing.The C2/C2, C2/C3, C3/C3 genotype distribution of -2922(C) 2-3 was 34.4%, 38.2% and 27.5% in the nonalcoholic group compared to 23.3%, 51.2% and 25.4% in the alcoholic group (P = 0.001). The C/C, C/G, G/G genotype distribution of -1198(C/G) was 23.5%, 46.1% and 30.3% in the nonalcoholic group compared to 13.9%, 50.9% and 35.3% in the alcoholic group (P = 0.007). However, the -1345 (G/C), Ex3+132(G/T/A/C) and Ex3+715(T/-) alleles were not polymorphic in Mexican Americans, and all those studied had G/G, G/G and T/T genotype for these three alleles, respectively. The -2922(C) 2-3 did not show allele level difference between alcoholic and nonalcoholic individuals, but -1198 (C/G) showed a significant allele frequency difference between alcoholic (39.3%) and nonalcoholic (46.6%) populations (P = 0.005). Excluding obese individuals, significant differences were found at both genotypic and allelic levels for the -2922(C) 2-3 polymorphism (P = 0.000 and P = 0.049) and the -1198 (C/G) polymorphism (P = 0.008 and P = 0.032) between nonobese alcoholics and nonobese controls. Excluding smokers, a significant difference was found only at the genotypic level for the -2922(C) 2-3 polymorphism (P = 0.037) between nonsmoking alcoholics and nonsmoking controls, but only at the allelic level for the -1198(C/G) polymorphism (P = 0.034).Polymorphisms in the regulatory region of Nurr1 are implicated in pathogenesis of alcohol dependence and the Nurr1/dopamine signaling pathway might be important for this dependence development in Mexican Americans.

Project description:Background and objectivesPresumed genetic risk for diabetic and nondiabetic end stage renal disease is strong in African Americans.Design, setting, participants, & measurementsExome sequencing data from African Americans with type 2 diabetic end stage renal disease and nondiabetic, non-nephropathy controls in the T2D-GENES study (Discovery, n=529 patients and n=535 controls) were evaluated, focusing on missense variants in NPHS1. Associated variants were then evaluated in independent type 2 diabetic end stage renal disease (Replication, n=1305 patients and n=760 controls), nondiabetic end stage renal disease (n=1705), and type 2 diabetes-only, non-nephropathy samples (n=503). All participants were recruited from dialysis facilities and internal medicine clinics across the southeastern United States from 1991 to present. Additional NPHS1 missense variants were identified from exome sequencing resources, genotyped, and sequence kernel association testing was then performed.ResultsInitial analysis identified rs35238405 (T233A; minor allele frequency=0.0096) as associated with type 2 diabetic end stage renal disease (adjustment for admixture P=0.042; adjustment for admixture+APOL1 P=0.080; odds ratio, 2.89 and 2.36, respectively); with replication in independent type 2 diabetic end stage renal disease samples (P=0.018; odds ratio, 4.30) and nondiabetic end stage renal disease samples (P=0.016; odds ratio, 4.48). In a combined analysis (all patients with end stage renal disease versus all controls), T233A was associated with all-cause end stage renal disease (P=0.0038; odds ratio, 2.82; n=3270 patients and n=1187 controls). A P-value of <0.001 was obtained after adjustment for admixture and APOL1 in sequence kernel association testing. Two additional variants (H800R and Y1174H) were nominally associated with protection from end stage renal disease (P=0.036; odds ratio, 0.44; P=0.0084; odds ratio, 0.040, respectively) in the locus-wide single-variant association tests.ConclusionsCoding variants in NPHS1 are associated with both risk for and protection from common forms of nephropathy in African Americans.

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Susceptibility gene search for nephropathy and related traits in Mexican-Americans.

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Susceptibility gene search for nephropathy and related traits in Mexican-Americans.

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