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

BACKGROUND AND AIMS: Elevated alanine aminotransferase (ALT >40 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.

PNPLA3 polymorphisms and liver aminotransferase levels in a Mexican American population.

PURPOSE: This study examined genetic associations of patatin-like phospholipase domain containing 3 gene (PNPLA3) polymorphisms and liver aminotransferases in an extensively documented, randomly recruited Mexican American population at high risk of liver disease. METHODS: Two single nucleotide polymorphisms (SNP) in the PNPLA3 gene (i.e., rs738409 and rs2281135) were genotyped in 1532 individuals. Population stratification was corrected by the genotyping of 103 ancestry informative markers (AIMs) for Mexican Americans. RESULTS: Both PNPLA3 SNPs showed highly significant association with alanine aminotransferase (ALT) levels, but was also, in males, associated with aspartate aminotransferase (AST) levels. Haplotypic association test of the two SNPs suggested stronger genetic association with rs738409 than rs2281135. Obvious sex effects were observed: rs738409-sex interaction in ALT levels P = 8.37 x 10(-4); rs738409-sex interaction in AST levels P = 5.03 x 10(-3). CONCLUSIONS: This population study highlights a sex-specific association of PNPLA3 polymorphisms and elevated liver enzymes in a population-based study, independent of common pathological factors of the metabolic syndrome. The strong genetic association found in women ≤ 50 years old, but not in women > 50 years old, suggests that sex hormones may mediate the sex effect.

Ancestral effect on HOMA-IR levels quantitated in an American population of Mexican origin.

OBJECTIVE: An elevated insulin resistance index (homeostasis model assessment of insulin resistance [HOMA-IR]) is more commonly seen in the Mexican American population than in European populations. We report quantitative ancestral effects within a Mexican American population, and we correlate ancestral components with HOMA-IR. RESEARCH DESIGN AND METHODS: We performed ancestral analysis in 1,551 participants of the Cameron County Hispanic Cohort by genotyping 103 ancestry-informative markers (AIMs). These AIMs allow determination of the percentage (0-100%) ancestry from three major continental populations, i.e., European, African, and Amerindian. RESULTS: We observed that predominantly Amerindian ancestral components were associated with increased HOMA-IR (ß = 0.124, P = 1.64 × 10(-7)). The correlation was more significant in males (Amerindian ß = 0.165, P = 5.08 × 10(-7)) than in females (Amerindian ß = 0.079, P = 0.019). CONCLUSIONS: This unique study design demonstrates how genomic markers for quantitative ancestral information can be used in admixed populations to predict phenotypic traits such as insulin resistance.

Adiponectin/leptin ratio and metabolic syndrome in a Mexican American population.

OBJECTIVE: Adiponectin and leptin play critical roles in the development of Metabolic Syndrome (MetS). This study was designed to assess the feasibility of using circulating levels of adiponectin and leptin for the early diagnosis of MetS. METHODS: A cross-sectional study was performed using data from 367 participants randomly selected from a well-characterized cohort of Mexican-Americans living at the US-Mexico border. RESULTS: Significant differences in circulating levels of adiponectin and leptin were observed between males and females. Adiponectin/leptin correlated significantly with MetS in this population. A receiver-operator characteristic (ROC) analysis demonstrated that adiponectin/leptin showed a high sensitivity (70.9% for males, 78.9% for females) and specificity (90.2% for males and 69.8% for females) for the diagnosis of MetS, independent of BMI measurements. CONCLUSION: These data support the central role of adiponectin and leptin in MetS, and demonstrated that adiponectin/leptin can be used as a highly sensitive and specific biomarker for MetS.

Decreased expression of ATP6V1H in type 2 diabetes: a pilot report on the diabetes risk study in Mexican Americans.

OBJECTIVE: Previous studies in mice and humans observed down-regulation of the gene expression of ATP6V1H associated with type 2 diabetes. This study identified prospectively changes in ATP6V1H expression before and after overt diabetes. METHODS: Expression of ATP6V1H in peripheral blood was compared pre and post development of diabetes in nine individuals. RESULTS: Considerable variation of ATP6V1H mRNA levels was observed between different individuals. However, within each individual the decrease in expression of ATP6V1H with the development of diabetes was highly statistically significant. CONCLUSIONS: ATP6V1H may represent a critical molecular mechanism involved in the development of type 2 diabetes and its compilations through its important regulatory effect on vacuolar-ATPase activity.

The definition of insulin resistance using HOMA-IR for Americans of Mexican descent using machine learning.

OBJECTIVE: The lack of standardized reference range for the homeostasis model assessment-estimated insulin resistance (HOMA-IR) index has limited its clinical application. This study defines the reference range of HOMA-IR index in an adult Hispanic population based with machine learning methods. METHODS: This study investigated a Hispanic population of 1854 adults, randomly selected on the basis of 2000 Census tract data in the city of Brownsville, Cameron County. Machine learning methods, support vector machine (SVM) and Bayesian Logistic Regression (BLR), were used to automatically identify measureable variables using standardized values that correlate with HOMA-IR; K-means clustering was then used to classify the individuals by insulin resistance. RESULTS: Our study showed that the best cutoff of HOMA-IR for identifying those with insulin resistance is 3.80. There are 39.1% individuals in this Hispanic population with HOMA-IR>3.80. CONCLUSIONS: Our results are dramatically different using the popular clinical cutoff of 2.60. The high sensitivity and specificity of HOMA-IR>3.80 for insulin resistance provide a critical fundamental for our further efforts to improve the public health of this Hispanic population.