Sharon P. Fowler

Fueling the Obesity Epidemic? Artificially Sweetened Beverage Use and Long-term Weight Gain

We have examined the relationship between artificially sweetened beverage (ASB) consumption and long‐term weight gain in the San Antonio Heart Study. From 1979 to 1988, height, weight, and ASB consumption were measured among 5,158 adult residents of San Antonio, Texas. Seven to eight years later, 3,682 participants (74% of survivors) were re‐examined. Outcome measures were incidence of overweight/obesity (OW/OBinc) and obesity (OBinc) (BMI ≥ 25 and ≥ 30 kg/m2, respectively), and BMI change by follow‐up (ΔBMI, kg/m2). A significant positive dose‐response relationship emerged between baseline ASB consumption and all outcome measures, adjusted for baseline BMI and demographic/behavioral characteristics. Consuming >21 ASBs/week (vs. none) was associated with almost‐doubled risk of OW/OB (odds ratio (OR) = 1.93, P = 0.007) among 1,250 baseline normal‐weight (NW) individuals, and doubled risk of obesity (OR = 2.03, P = 0.0005) among 2,571 individuals with baseline BMIs <30 kg/m2. Compared with nonusers (+1.01 kg/m2), ΔBMIs were significantly higher for ASB quartiles 2–4: +1.46 (P = 0.003), +1.50 (P = 0.002), and +1.78 kg/m2 (P < 0.0001), respectively. Overall, adjusted ΔBMIs were 47% greater among artificial sweetner (AS) users than nonusers (+1.48 kg/m2 vs. +1.01 kg/m2, respectively, P < 0.0001). In separate analyses—stratified by gender; ethnicity; baseline weight category, dieting, or diabetes status; or exercise‐change category—ΔBMIs were consistently greater among AS users. These differences, though not significant among exercise increasers, or those with baseline diabetes or BMI >30 kg/m2 (P = 0.069), were significant in all 13 remaining strata. These findings raise the question whether AS use might be fueling—rather than fighting—our escalating obesity epidemic.

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.

Data for Genetic Analysis Workshop 18: human whole genome sequence, blood pressure, and simulated phenotypes in extended pedigrees

Genetic Analysis Workshop 18 (GAW18) focused on identification of genes and functional variants that influence complex phenotypes in human sequence data. Data for the workshop were donated by the T2D-GENES Consortium and included whole genome sequences for odd-numbered autosomes in 464 key individuals selected from 20 Mexican American families, a dense set of single-nucleotide polymorphisms in 959 individuals in these families, and longitudinal data on systolic and diastolic blood pressure measured at 1-4 examinations over a period of 20 years. Simulated phenotypes were generated based on the real sequence data and pedigree structures. In the design of the simulation model, gene expression measures from the San Antonio Family Heart Study (not distributed as part of the GAW18 data) were used to identify genes whose mRNA levels were correlated with blood pressure. Observed variants within these genes were designated as functional in the GAW18 simulation if they were nonsynonymous and predicted to have deleterious effects on protein function or if they were noncoding and associated with mRNA levels. Two simulated longitudinal phenotypes were modeled to have the same trait distributions as the real systolic and diastolic blood pressure data, with effects of age, sex, and medication use, including a genotype-medication interaction. For each phenotype, more than 1000 sequence variants in more than 200 genes present on the odd-numbered autosomes individually explained less than 0.01-2.78% of phenotypic variance. Cumulatively, variants in the most influential gene explained 7.79% of trait variance. An additional simulated phenotype, Q1, was designed to be correlated among family members but to not be associated with any sequence variants. Two hundred replicates of the phenotypes were simulated, with each including data for 849 individuals.

Diet soda intake is associated with long-term increases in waist circumference in a biethnic cohort of older adults: the San Antonio Longitudinal Study of Aging.

To examine the relationship between diet soda (DS) intake (DSI) and long‐term waist circumference (WC) change (ΔWC) in the biethnic San Antonio Longitudinal Study of Aging (SALSA).

Genotype by Diabetes Interaction Effects on the Detection of Linkage of Glomerular Filtration Rate to a Region on Chromosome 2q in Mexican Americans

OBJECTIVE—Glomerular filtration rate (GFR) is used to assess the progression of renal disease. We performed linkage analysis to localize genes that influence GFR using estimated GFR data from the San Antonio Family Diabetes/Gallbladder Study. We also examined the effect of genotype by diabetes interaction (G × DM) on the detection of linkage to address whether genetic effects on GFR differ in diabetic and nondiabetic subjects. RESEARCH DESIGN AND METHODS—GFR (N = 453) was estimated using the recently recalculated Cockcroft-Gault (GFR-CGc) and the simplified Modification of Diet in Renal Disease (GFR-4VMDRD) formulae. Both estimates of GFR exhibited significant heritabilities, but only GFR-CGc showed significant G × DM interaction. We therefore performed multipoint linkage analyses on both GFR measures using models that did not include G × DM interaction effects (Model 1) and that included G × DM interaction effects (Model 2, in the case of GFR-CGc). RESULTS—The strongest evidence for linkage (Model 1) of both GFR-CGc (logarithm of odds [LOD] 2.9) and GFR-4VMDRD (LOD 2.6) occurred between markers D9S922 and D9S1120 on chromosome 9q. However, using Model 2, the strongest evidence for linkage of GFR-CGc on chromosome 2q was found near marker D2S427 (corrected LOD score [LODC] 3.3) compared with the LOD score of 2.7 based on Model 1. Potential linkages (LOD or LODC ≥1.2) were found only for GFR-CGc on chromosomes 3p, 3q, 4p, 8q, 11q, and 14q. CONCLUSIONS—We found a major locus on chromosome 2q that differentially influences GFR in diabetic and nondiabetic environments in the Mexican-American population.

Predicting the development of the metabolically healthy obese phenotype

Objective:The metabolically healthy (MHO) and unhealthy obese (MUHO) differ in terms of cardiovascular risk. However, little is known about predicting the development of these phenotypes and the future stability of the MHO phenotype. Therefore, we examined these two issues in the San Antonio Heart Study.Design:Longitudinal, population-based study of cardiometabolic risk factors among Mexican Americans and non-Hispanic whites in San Antonio.Subjects:The study sample included 2368 participants with neither MUHO nor diabetes at baseline. Median follow-up was 7.8 years. MHO was defined as obesity with ⩽1 metabolic abnormality; MUHO, as obesity with ⩾2 abnormalities.Results:At baseline, 1595 and 498 individuals were non-obese with ⩽1 and ⩾2 metabolic abnormalities, respectively, and 275 were MHO. Among non-obese individuals, independent predictors of incident MHO (odds ratio (OR) for 1 s.d. change (95% confidence interval)) included body mass index (8.12 (5.66–11.7)), triglycerides (0.52 (0.39–0.68)) and high-density lipoprotein cholesterol (HDL-C) (1.41 (1.11–1.81)), whereas independent predictors of incident MUHO included body mass index (5.97 (4.58–7.77)) and triglycerides (1.26 (1.05–1.51)). Among participants with ⩽1 metabolic abnormality, obesity was associated with greater odds of developing multiple metabolic abnormalities (OR 2.26 (1.74–2.95)).Conclusions:Triglycerides and HDL-C may be useful for predicting progression to MHO. MHO may not be a stable condition, because it confers an increased risk of developing multiple metabolic abnormalities.

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.

The late preterm birth rate and its association with comorbidities in a population-based study

We sought to identify rates, associated morbidities, and preventable causes of late preterm birth (LPB) in a defined population. We conducted a retrospective cross-sectional analysis using deidentified delivery data for all who delivered in San Antonio/Bexar County, Texas between 2000 and 2008 (N  = 259,576). LPB was defined as a live birth from 34(0/7) to 36(6/7) weeks. Variables analyzed included age, race/ethnicity, weight gain, hypertensive disease, diabetes, and preterm labor including premature rupture of membranes. From 2000 to 2006, the LPB rate in San Antonio/Bexar County, Texas, was slightly higher than the national average, 9% versus 8.7% (P  < 0.01). From 2000 to 2008, 23,312 LPBs occurred in San Antonio/Bexar County and 53% experienced at least one studied comorbidity. Using logistic regression comparing LPB to term, variables associated with an increased risk of LPB were black race, age < 17, age ≥ 35, gestational hypertension, eclampsia, chronic hypertension, and diabetes. LPB was higher than the national average in our population, and preventable causes of LPB (extremes of age, hypertensive disease, and diabetes) were commonly associated with LPB. We speculate that teenage pregnancy prevention, counseling regarding risks associated with advanced maternal age, and improved management and prevention of hypertensive disease and diabetes should prove beneficial in decreasing the LPB rate.

Metabolic syndrome is linked to chromosome 7q21 and associated with genetic variants in CD36 and GNAT3 in Mexican Americans

The prevalence of metabolic syndrome (MS) has been rising alarmingly worldwide, including in the United States, but knowledge on specific genetic determinants of MS is very limited. Therefore, we planned to identify the genetic determinants of MS as defined by National Cholesterol Education Program/Adult Treatment Panel III (NCEP/ATPIII) criteria. We performed linkage screen for MS using data from 692 Mexican Americans, who participated in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS). We found strong evidence for linkage of MS on chromosome 7q (LOD = 3.6, empirical P = 6.0 × 10−5), between markers D7S2212 and D7S821. In addition, six chromosomal regions exhibited potential evidence for linkage (LOD ≥1.2) with MS. Furthermore, we examined 29 single‐nucleotide polymorphisms (SNPs) from the fatty acid translocase (FAT or CD36, 18 SNPs) gene and guanine nucleotide binding protein, α transducing 3 (GNAT3, 11 SNPs) gene, located within the 1‐LOD support interval region for their association with MS and its related traits. Several SNPs were associated with MS and its related traits. Remarkably, rs11760281 in GNAT3 and rs1194197 near CD36 exhibited the strongest associations with MS (P = 0.0003, relative risk (RR) = 1.6 and P = 0.004, RR = 1.7, respectively) and several other related traits. These two variants explained ∼18% of the MS linkage evidence on chromosome 7q21, and together conferred approximately threefold increase in MS risk (RR = 2.7). In conclusion, our linkage and subsequent association studies implicate a region on chromosome 7q21 to influence MS in Mexican Americans.

Prosaposin is a regulator of progranulin levels and oligomerization

Progranulin (GRN) loss-of-function mutations leading to progranulin protein (PGRN) haploinsufficiency are prevalent genetic causes of frontotemporal dementia. Reports also indicated PGRN-mediated neuroprotection in models of Alzheimers and Parkinsons disease; thus, increasing PGRN levels is a promising therapeutic for multiple disorders. To uncover novel PGRN regulators, we linked whole-genome sequence data from 920 individuals with plasma PGRN levels and identified the prosaposin (PSAP) locus as a new locus significantly associated with plasma PGRN levels. Here we show that both PSAP reduction and overexpression lead to significantly elevated extracellular PGRN levels. Intriguingly, PSAP knockdown increases PGRN monomers, whereas PSAP overexpression increases PGRN oligomers, partly through a protein–protein interaction. PSAP-induced changes in PGRN levels and oligomerization replicate in human-derived fibroblasts obtained from a GRN mutation carrier, further supporting PSAP as a potential PGRN-related therapeutic target. Future studies should focus on addressing the relevance and cellular mechanism by which PGRN oligomeric species provide neuroprotection.