The Arg59Trp variant in ANGPTL8 (betatrophin) is associated with total and HDL-cholesterol in American Indians and Mexican Americans and differentially affects cleavage of ANGPTL3.

We previously identified a locus linked to total cholesterol (TC) concentration in Pima Indians on chromosome 19p. To characterize this locus, we genotyped >2000 SNPs in 1838 Pimas and assessed association with log(TC). We observed evidence for association with log(TC) with rs2278426 (3.5% decrease/copy of the T allele; P=5.045×10(-6)) in the ANGPTL8 (angiopoietin-like 8) gene. We replicated this association in 2413 participants of the San Antonio Mexican American Family Study (SAMAFS: 2.0% decrease per copy of the T allele; P=0.005842). In a meta-analysis of the combined data, we found the strongest estimated effect with rs2278426 (P=2.563×10(-7)). The variant T allele at rs2278426 predicts an Arg59Trp substitution and has previously been associated with LDL-C and HDL-C. In Pimas and SAMAFS participants, the T allele of rs2278426 was associated with reduced HDL-C levels (P=0.000741 and 0.00002, respectively), and the combined estimated effect for the two cohorts was -3.8% (P=8.526×10(-8)). ANGPTL8 transcript and protein levels increased in response to both glucose and insulin. The variant allele was associated with increased levels of cleaved ANGPTL3. We conclude that individuals with the variant allele may have lower TC and HDL-C levels due to increased activation of ANGPTL3 by ANGPTL8.

Epidemiologic investigation of tuberculosis in a Mexican population from Chihuahua State, Mexico: a pilot study.

Tuberculosis (TB) and its co-morbid conditions have become a burden on global health economies. It is well understood that susceptibility of the host to TB infection/disease is influenced by both genetic and environmental factors and their interactions. The aims of this pilot case-control study are to characterize the sociodemographic and environmental factors related to active TB disease (TB/case) and latent TB infection (LTBI/control) status, and to identify risk factors associated with progression from LTBI to TB. We recruited 75 cases with TB (mean age=46.3y; females=41%) and 75 controls with LTBI (mean age=39.0y; females=37%), from the Mestizo population of Cuidad Juárez, Mexico. In addition to the determination of case/control status, information on environmental variables was collected (e.g., socioeconomic status, smoking, alcohol consumption, substance abuse, nutritional status, household demographics, medical histories and presence of type 2 diabetes [T2DM]). The data were analyzed to identify the environmental correlates of TB and LTBI using univariate and multivariate statistical approaches. Following multivariate logistic regression analysis, TB was associated with poor nutrition, T2DM, family history of TB, and non-Chihuahua state of birth. These preliminary findings have relevance to TB control at the Mexico-United States border, and contribute to our future genetic study of TB in Mexicans.

The Gly(972)Arg variant of human IRS1 gene is associated with variation in glomerular filtration rate likely through impaired insulin receptor signaling.

The objective of this study is to identify and characterize the genetic variants related to the glomerular filtration rate (GFR) linkage on 2q37. Of the positional candidate genes, we selected IRS1 and resequenced its 2-kb promoter region and exons for sequence variants in 32 subjects. A total of 11 single nucleotide polymorphisms (SNPs) were identified. To comprehensively cover the 59-kb-long intron-1, eight additional tagging SNPs were selected from the HapMap. All the 19 SNPs were genotyped by TaqMan Assay in the entire data set (N = 670; 39 families). Association analyses between the SNPs and GFR and type 2 diabetes-related traits were performed using the measured genotype approach. Of the SNPs examined for association, only the Gly(972)Arg variant of IRS1 exhibited a significant association with GFR (P = 0.0006) and serum triglycerides levels (P = 0.003), after accounting for trait-specific covariate effects. Carriers of Arg972 had significantly decreased GFR values. Gly(972)Arg contributed to 26% of the linkage signal on 2q. Expression of IRS1 mutant Arg972 in human mesangial cells significantly reduced the insulin-stimulated phosphorylation of IRS1 and Akt kinase. Taken together, the data provide the first evidence that genetic variation in IRS1 may influence variation in GFR probably through impaired insulin receptor signaling.

Autosomal genome-wide linkage analysis to identify loci for gallbladder wall thickness in Mexican Americans.

The significance of gallbladder wall thickness (GBWT) in regard to gallbladder disease (GBD) is not completely understood. Thickening of the gallbladder wall has been observed in patients with acute calculous and acalculous cholecystitis and chronic cholecystitis. However, various pathologic processes, such as gallbladder cancer and nonbiliary disorders such as liver cirrhosis and viral hepatitis, could also cause thickening of the gallbladder wall. To date, there is no report available on the genetic factors influencing GBWT. Therefore we sought to estimate the heritability (h2) of GBWT and to perform a genome-wide search to identify the susceptibility genes for GBWT, using data from the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), a family study of Mexican Americans. GBWT was measured by ultrasound. After adjusting for the significant effects of age, sex, GBD (i.e., asymptomatic gallstones), metabolic syndrome, and duration of type 2 diabetes (T2DM), GBWT was found to be under significant and appreciable additive genetic influences (h2 +/- SE = 0.38 +/- 0.09, P < 0.0001). The strongest evidence for linkage occurred between markers D11S912 and D11S968 on chromosome 11q24-q25 (LOD = 2.7), where we have already shown suggestive evidence for linkage of GBD (LOD = 2.7) in a subset of our SAFDGS data. Potential evidence for linkage occurred at markers D1S1728 (1p31.1; LOD = 1.4) and D16S748 (16p13.1; LOD = 1.4), respectively. In conclusion, our study provides suggestive evidence for linkage of GBWT on chromosome 11q in Mexican Americans, and future tasks of mapping susceptibility gene(s) for GBD and its related traits, such as GBWT, in this chromosomal region can be fruitful.

A genome-wide linkage scan for genes controlling variation in renal function estimated by serum cystatin C levels in extended families with type 2 diabetes.

We performed a variance components linkage analysis of renal function, measured as glomerular filtration rate (GFR), in 63 extended families with multiple members with type 2 diabetes. GFR was estimated from serum concentrations of cystatin C and creatinine in 406 diabetic and 428 nondiabetic relatives. Results for cystatin C were summarized because they are superior to creatinine results. GFR aggregates in families with significant heritability (h(2)) in diabetic (h(2) = 0.45, P < 1 x 10(-5)) and nondiabetic (h(2) = 0.36, P < 1 x 10(-3)) relatives. Genetic correlation (r(G) = 0.35) between the GFR of diabetic and nondiabetic relatives was less than one (P = 0.01), suggesting that genes controlling GFR variation in these groups are different. Linkage results supported this interpretation. In diabetic relatives, linkage was strong on chromosome 2q (logarithm of odds [LOD] = 4.1) and suggestive on 10q (LOD = 3.1) and 18p (LOD = 2.2). In nondiabetic relatives, linkage was suggestive on 3q (LOD = 2.2) and 11p (LOD = 2.1). When diabetic and nondiabetic relatives were combined, strong evidence for linkage was found only on 7p (LOD = 4.0). In conclusion, partially distinct sets of genes control GFR variation in relatives with and without diabetes on chromosome 2q, possibly on 10q and 18p in the former, and on 7p in both. None of these genes overlaps with genes controlling variation in urinary albumin excretion.

A genomewide search finds major susceptibility loci for gallbladder disease on chromosome 1 in Mexican Americans.

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.