Population-based risk factors for elevated alanine aminotransferase in a South Texas Mexican-American population

Background and aims: Elevated alanine aminotransferase (ALT \u3e40 IU/mL) is a marker of liver injury but provides little insight into etiology. We aimed to identify and stratify risk factors associated with elevated ALT in a randomly selected population with a high prevalence of elevated ALT (39%), obesity (49%) and diabetes (30%). Methods: Two machine learning methods, the support vector machine (SVM) and Bayesian logistic regression (BLR), were used to capture risk factors in a community cohort of 1532 adults from the Cameron County Hispanic Cohort (CCHC). A total of 28 predictor variables were used in the prediction models. The recently identified genetic marker rs738409 on the PNPLA3 gene was genotyped using the Sequenom iPLEX assay. Results: The four major risk factors for elevated ALT were fasting plasma insulin level and insulin resistance, increased BMI and total body weight, plasma triglycerides and non-HDL cholesterol, and diastolic hypertension. In spite of the highly significant association of rs738409 in females, the role of rs738409 in the prediction model is minimal, compared to other epidemiological risk factors. Age and drug and alcohol consumption were not independent determinants of elevated ALT in this analysis. Conclusions: The risk factors most strongly associated with elevated ALT in this population are components of the metabolic syndrome and point to nonalcoholic fatty liver disease (NAFLD). This population-based model identifies the likely cause of liver disease without the requirement of individual pathological diagnosis of liver diseases. Use of such a model can greatly contribute to a population-based approach to prevention of liver disease

Electrocardiographic abnormalities among Mexican Americans: Correlations with diabetes, obesity, and the metabolic syndrome

Background: Resting ischemic electrocardiographic abnormalities have been associated with cardiovascular mortality. Simple markers of abnormal autonomic tone have also been associated with diabetes, obesity, and the metabolic syndrome in some populations. Data on these electrocardiographic abnormalities and correlations with coronary risk factors are lacking among Mexican Americans wherein these conditions are prevalent. Objective: This study aimed to evaluate the prevalent resting electrocardiographic abnormalities among community-dwelling Mexican Americans, and correlate these findings with coronary risk factors, particularly diabetes, obesity, and the metabolic syndrome. Methods: Study subjects (n=1280) were drawn from the Cameron County Hispanic Cohort comprised of community-dwelling Mexican Americans living in Brownsville, Texas at the United States-Mexico border. Ischemic electrocardiographic abnormalities were defined as presence of ST/T wave abnormalities suggestive of ischemia, abnormal Q waves, and left bundle branch block. Parameters that reflect autonomic tone, such as heart rate-corrected QT interval and resting heart rate, were also measured. Results: Ischemic electrocardiographic abnormalities were more prevalent among older persons and those with hypertension, diabetes, obesity, and the metabolic syndrome. Subjects in the highest quartiles of QTc interval and resting heart rate were also more likely to be diabetic, hypertensive, obese, or have the metabolic syndrome. Conclusions: Among Mexican Americans, persons with diabetes, obesity, and the metabolic syndrome were more likely to have ischemic electrocardiographic abnormalities, longer QTc intervals, and higher resting heart rates. A resting electrocardiogram can play a complementary role in the comprehensive evaluation of cardiovascular risk in this minority population

Comprehensive linkage and linkage heterogeneity analysis of 4344 sibling pairs affected with hypertension from the Family Blood Pressure Program

Linkage analyses of complex, multifactorial traits and diseases, such as essential hypertension, have been difficult to interpret and reconcile. Many published studies provide evidence suggesting that different genes and genomic regions influence hypertension, but knowing which of these studies reflect true positive results is challenging. The reasons for this include the diversity of analytical methods used across these studies, the different samples and sample sizes in each study, and the complicated biological underpinnings of hypertension. We have undertaken a comprehensive linkage analysis of 371 autosomal microsatellite markers genotyped on 4,334 sibling pairs affected with hypertension from five ethnic groups sampled from 13 different field centers associated with the Family Blood Pressure Program (FBPP). We used a single analytical technique known to be robust to interpretive problems associated with a lack of completely informative markers to assess evidence for linkage to hypertension both within and across the ethnic groups and field centers. We find evidence for linkage to a number of genomic regions, with the most compelling evidence from analyses that combine data across field center and ethnic groups (e.g., chromosomes 2 and 9). We also pursued linkage analyses that accommodate locus heterogeneity, which is known to plague the identification of disease susceptibility loci in linkage studies of complex diseases. We find evidence for linkage heterogeneity on chromosomes 2 and 17. Ultimately our results suggest that evidence for linkage heterogeneity can only be detected with large sample sizes, such as the FBPP, which is consistent with theoretical sample size calculations. Genet. Epidemiol . 2007. © 2007 Wiley-Liss, Inc.Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/56011/1/20202_ftp.pd

Genetically Determined Plasma Lipid Levels and Risk of Diabetic Retinopathy: A Mendelian Randomization Study.

Results from observational studies examining dyslipidemia as a risk factor for diabetic retinopathy (DR) have been inconsistent. We evaluated the causal relationship between plasma lipids and DR using a Mendelian randomization approach. We pooled genome-wide association studies summary statistics from 18 studies for two DR phenotypes: any DR (N = 2,969 case and 4,096 control subjects) and severe DR (N = 1,277 case and 3,980 control subjects). Previously identified lipid-associated single nucleotide polymorphisms served as instrumental variables. Meta-analysis to combine the Mendelian randomization estimates from different cohorts was conducted. There was no statistically significant change in odds ratios of having any DR or severe DR for any of the lipid fractions in the primary analysis that used single nucleotide polymorphisms that did not have a pleiotropic effect on another lipid fraction. Similarly, there was no significant association in the Caucasian and Chinese subgroup analyses. This study did not show evidence of a causal role of the four lipid fractions on DR. However, the study had limited power to detect odds ratios less than 1.23 per SD in genetically induced increase in plasma lipid levels, thus we cannot exclude that causal relationships with more modest effect sizes exist

Meta-analysis of lipid-traits in Hispanics identifies novel loci, population-specific effects and tissue-specific enrichment of eQTLs

We performed genome-wide meta-analysis of lipid traits on three samples of Mexican and Mexican American ancestry comprising 4,383 individuals and followed up significant and highly suggestive associations in three additional Hispanic samples comprising 7,876 individuals. Genome-wide significant signals were observed in or near CELSR2, ZNF259/APOA5, KANK2/DOCK6 and NCAN/MAU2 for total cholesterol, LPL, ABCA1, ZNF259/APOA5, LIPC and CETP for HDL cholesterol, CELSR2, APOB and NCAN/MAU2 for LDL cholesterol and GCKR, TRIB1, ZNF259/APOA5 and NCAN/MAU2 for triglycerides. Linkage disequilibrium and conditional analyses indicate that signals observed at ABCA1 and LIPC for HDL cholesterol and NCAN/MAU2 for triglycerides are independent of previously reported lead SNP associations. Analyses of lead SNPs from the European Global Lipids Genetics Consortium (GLGC) dataset in our Hispanic samples show remarkable concordance of direction of effects as well as strong correlation in effect sizes. A meta-analysis of the European GLGC and our Hispanic datasets identified five novel regions reaching genome-wide significance: two for total cholesterol (FN1 and SAMM50), two for HDL cholesterol (LOC100996634 and COPB1) and one for LDL cholesterol (LINC00324/CTC1/PFAS). The top meta-analysis signals were found to be enriched for SNPs associated with gene expression in a tissue-specific fashion, suggesting an enrichment of tissue-specific function in lipid-associated loci

Transancestral fine-mapping of four type 2 diabetes susceptibility loci highlights potential causal regulatory mechanisms.

To gain insight into potential regulatory mechanisms through which the effects of variants at four established type 2 diabetes (T2D) susceptibility loci (CDKAL1, CDKN2A-B, IGF2BP2 and KCNQ1) are mediated, we undertook transancestral fine-mapping in 22 086 cases and 42 539 controls of East Asian, European, South Asian, African American and Mexican American descent. Through high-density imputation and conditional analyses, we identified seven distinct association signals at these four loci, each with allelic effects on T2D susceptibility that were homogenous across ancestry groups. By leveraging differences in the structure of linkage disequilibrium between diverse populations, and increased sample size, we localised the variants most likely to drive each distinct association signal. We demonstrated that integration of these genetic fine-mapping data with genomic annotation can highlight potential causal regulatory elements in T2D-relevant tissues. These analyses provide insight into the mechanisms through which T2D association signals are mediated, and suggest future routes to understanding the biology of specific disease susceptibility loci

Variation in the checkpoint kinase 2 gene is associated with type 2 diabetes in multiple populations

Identification and characterization of the genetic variants underlying type 2 diabetes susceptibility can provide important understanding of the etiology and pathogenesis of type 2 diabetes. We previously identified strong evidence of linkage for type 2 diabetes on chromosome 22 among 3,383 Hypertension Genetic Epidemiology Network (HyperGEN) participants from 1,124 families. The checkpoint 2 (CHEK2) gene, an important mediator of cellular responses to DNA damage, is located 0.22 Mb from this linkage peak. In this study, we tested the hypothesis that the CHEK2 gene contains one or more polymorphic variants that are associated with type 2 diabetes in HyperGEN individuals. In addition, we replicated our findings in two other Family Blood Pressure Program (FBPP) populations and in the population-based Atherosclerosis Risk in Communities (ARIC) study. We genotyped 1,584 African-American and 1,531 white HyperGEN participants, 1,843 African-American and 1,569 white GENOA participants, 871 African-American and 1,009 white GenNet participants, and 4,266 African-American and 11,478 white ARIC participants for four single nucleotide polymorphisms (SNPs) in CHEK2. Using additive models, we evaluated the association of CHEK2 SNPs with type 2 diabetes in participants within each study population stratified by race, and in a meta-analysis, adjusting for age, age2, sex, sex-by-age interaction, study center, and relatedness. One CHEK2 variant, rs4035540, was associated with an increased risk of type 2 diabetes in HyperGEN participants, two replication samples, and in the meta-analysis. These results may suggest a new pathway in the pathogenesis of type 2 diabetes that involves pancreatic beta-cell damage and apoptosis