Craig L Hanis

University of Texas Health Science Center at Houston, Houston, Texas, United States

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Publications (157)646.83 Total impact

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    ABSTRACT: Staphylococcus aureus is the number one cause of hospital-acquired infections. Understanding host pathogen interactions is paramount to the development of more effective treatment and prevention strategies. Therefore, whole exome sequence and chip-based genotype data were used to conduct rare variant and genome-wide association analyses in a Mexican-American cohort from Starr County, Texas to identify genes and variants associated with S. aureus nasal carriage. Unlike most studies of S. aureus that are based on hospitalized populations, this study used a representative community sample. Two nasal swabs were collected from participants (n = 858) 11-17 days apart between October 2009 and December 2013, screened for the presence of S. aureus, and then classified as either persistent, intermittent, or non-carriers. The chip-based and exome sequence-based single variant association analyses identified 1 genome-wide significant region (KAT2B) for intermittent and 11 regions suggestively associated with persistent or intermittent S. aureus carriage. We also report top findings from gene-based burden analyses of rare functional variation. Notably, we observed marked differences between signals associated with persistent and intermittent carriage. In single variant analyses of persistent carriage, 7 of 9 genes in suggestively associated regions and all 5 top gene-based findings are associated with cell growth or tight junction integrity or are structural constituents of the cytoskeleton, suggesting that variation in genes associated with persistent carriage impact cellular integrity and morphology.
    PLoS ONE 11/2015; 10(11):e0142130. DOI:10.1371/journal.pone.0142130 · 3.23 Impact Factor
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    ABSTRACT: Hypertension in pregnancy is a risk factor for future hypertension and cardiovascular disease. This may reflect an underlying familial predisposition or persistent damage caused by the hypertensive pregnancy. We sought to isolate the effect of hypertension in pregnancy by comparing the risk of hypertension and cardiovascular disease in women who had hypertension in pregnancy and their sisters who did not using the dataset from the Genetic Epidemiology Network of Arteriopathy study, which examined the genetics of hypertension in white, black, and Hispanic siblings. This analysis included all sibships with at least one parous woman and at least one other sibling. After gathering demographic and pregnancy data, BP and serum analytes were measured. Disease-free survival was examined using Kaplan-Meier curves and Cox proportional hazards regression. Compared with their sisters who did not have hypertension in pregnancy, women who had hypertension in pregnancy were more likely to develop new onset hypertension later in life, after adjusting for body mass index and diabetes (hazard ratio 1.75, 95% confidence interval 1.27-2.42). A sibling history of hypertension in pregnancy was also associated with an increased risk of hypertension in brothers and unaffected sisters, whereas an increased risk of cardiovascular events was observed in brothers only. These results suggest familial factors contribute to the increased risk of future hypertension in women who had hypertension in pregnancy. Further studies are needed to clarify the potential role of nonfamilial factors. Furthermore, a sibling history of hypertension in pregnancy may be a novel familial risk factor for future hypertension. Copyright © 2015 by the American Society of Nephrology.
    Journal of the American Society of Nephrology 08/2015; DOI:10.1681/ASN.2015010086 · 9.34 Impact Factor
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    ABSTRACT: To determine whether women who had a hypertensive pregnancy disorder (HPD) have elevated uric acid concentrations decades after pregnancy as compared with women who had normotensive pregnancies. The Genetic Epidemiology Network of Arteriopathy study measured uric acid concentrations in Hispanic (30%), non-Hispanic white (28%), and non-Hispanic black (42%) women (mean age, 60±10 years). This cross-sectional study was conducted between July 1, 2000, and December 31, 2004. Hispanic participants were recruited from families with high rates of diabetes, whereas non-Hispanic participants were recruited from families with high rates of hypertension. This analysis compared uric acid concentrations in women with a history of normotensive (n=1846) or hypertensive (n=408) pregnancies by logistic regression. Women who had an HPD had higher uric acid concentrations (median, 5.7 mg/dL vs 5.3 mg/dL; P<.001) and were more likely to have uric acid concentrations above 5.5 mg/dL (54.4% vs 42.4%; P=.001) than were women who had normotensive pregnancies. These differences persisted after adjusting for traditional cardiovascular risk factors, comorbidities, and other factors that affect uric acid concentrations. A family-based subgroup analysis comparing uric acid concentrations in women who had an HPD (n=308) and their parous sisters who had normotensive pregnancies (n=250) gave similar results (median uric acid concentrations, 5.7 mg/dL vs 5.2 mg/dL, P=0.02; proportion of women with uric acid concentrations >5.5 mg/dL, 54.0% vs 40.3%, P<.001). Decades after pregnancy, women who had an HPD have higher uric acid concentrations. This effect does not appear to be explained by a familial predisposition to elevated uric acid concentrations. Copyright © 2015 Mayo Foundation for Medical Education and Research. Published by Elsevier Inc. All rights reserved.
    Mayo Clinic Proceedings 08/2015; 90(9). DOI:10.1016/j.mayocp.2015.05.020 · 6.26 Impact Factor
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    ABSTRACT: Diabetes in neonates usually has a monogenic aetiology; however, the cause remains unknown in 20-30%. Heterozygous INS mutations represent one of the most common gene causes of neonatal diabetes mellitus. Clinical and functional characterisation of a novel homozygous intronic mutation (c.187+241G>A) in the insulin gene in a child identified through the Monogenic Diabetes Registry ( The proband had insulin-requiring diabetes from birth. Ultrasonography revealed a structurally normal pancreas and C-peptide was undetectable despite readily detectable amylin, suggesting the presence of dysfunctional β cells. Whole-exome sequencing revealed the novel mutation. In silico analysis predicted a mutant mRNA product resulting from preferential recognition of a newly created splice site. Wild-type and mutant human insulin gene constructs were derived and transiently expressed in INS-1 cells. We confirmed the predicted transcript and found an additional transcript created via an ectopic splice acceptor site. Dominant INS mutations cause diabetes via a mutated translational product causing endoplasmic reticulum stress. We describe a novel mechanism of diabetes, without β cell death, due to creation of two unstable mutant transcripts predicted to undergo nonsense and non-stop-mediated decay, respectively. Our discovery may have broader implications for those with insulin deficiency later in life. Published by the BMJ Publishing Group Limited. For permission to use (where not already granted under a licence) please go to
    Journal of Medical Genetics 06/2015; 52(9). DOI:10.1136/jmedgenet-2015-103220 · 6.34 Impact Factor
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    ABSTRACT: Polymorphisms rs6232 and rs6234/rs6235 in PCSK1 have been associated with extreme obesity (e.g. body mass index [BMI]≥40 kg/m(2)), but their contribution to common obesity (BMI≥30 kg/m(2)) and BMI variation in a multi-ethnic context is unclear. To fill this gap, we collected phenotypic and genetic data in up to 331,175 individuals from diverse ethnic groups. This process involved a systematic review of the literature in PubMed, Web of Science, Embase and the NIH GWAS catalog complemented by data extraction from pre-existing GWAS or custom-arrays in consortia and single studies. We employed recently developed global meta-analytic random-effects methods to calculate summary odds ratios (OR) and 95% confidence intervals (CI) or beta estimates and standard errors (SE) for the obesity status and BMI analyses, respectively. Significant associations were found with binary obesity status for rs6232 (OR=1.15, 95% CI 1.06-1.24, P=6.08x10(-6)) and rs6234/rs6235 (OR=1.07, 95% CI 1.04-1.10, P=3.00x10(-7)). Similarly, significant associations were found with continuous BMI for rs6232 (beta=0.03, 95% CI 0.00-0.07; P=0.047) and rs6234/rs6235 (beta=0.02, 95% CI 0.00-0.03; P=5.57x10(-4)). Ethnicity, age and study ascertainment significantly modulated the association of PCSK1 polymorphisms with obesity. In summary, we demonstrate evidence that common gene variation in PCSK1 contributes to BMI variation and susceptibility to common obesity in the largest known meta-analysis published to date in genetic epidemiology. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please email:
    Human Molecular Genetics 03/2015; 24(12). DOI:10.1093/hmg/ddv097 · 6.39 Impact Factor
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    ABSTRACT: Genome wide association studies (GWAS) for fasting glucose (FG) and insulin (FI) have identified common variant signals which explain 4.8% and 1.2% of trait variance, respectively. It is hypothesized that low-frequency and rare variants could contribute substantially to unexplained genetic variance. To test this, we analyzed exome-array data from up to 33,231 non-diabetic individuals of European ancestry. We found exome-wide significant (P<5x10-7) evidence for two loci not previously highlighted by common variant GWAS: GLP1R (p.Ala316Thr, minor allele frequency (MAF)=1.5%) influencing FG levels, and URB2 (p.Glu594Val, MAF = 0.1%) influencing FI levels. Coding variant associations can highlight potential effector genes at (non-coding) GWAS signals. At the G6PC2/ABCB11 locus, we identified multiple coding variants in G6PC2 (p.Val219Leu, p.His177Tyr, and p Tyr207Ser) influencing FG levels, conditionally independent of each other and the non-coding GWAS signal. In vitro assays demonstrate that these associated coding alleles result in reduced protein abundance via proteasomal degradation, establishing G6PC2 as an effector gene at this locus. Reconciliation of single-variant associations and functional effects was only possible when haplotype phase was considered. In contrast to earlier reports suggesting that, paradoxically, glucose-raising alleles at this locus are protective against type 2 diabetes (T2D), the p.Val219Leu G6PC2 variant displayed a modest but directionally consistent association with T2D risk. Coding variant associations for glycemic traits in GWAS signals highlight PCSK1, RREB1, and ZHX3 as likely effector transcripts. These coding variant association signals do not have a major impact on the trait variance explained, but they do provide valuable biological insights.
    PLoS Genetics 01/2015; 11(1). DOI:10.1371/journal.pgen.1004876 · 7.53 Impact Factor
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    ABSTRACT: -Admixture mapping of lipids was followed-up by family-based association analysis to identify variants for cardiovascular disease in African-Americans. -The present study conducted admixture mapping analysis for total cholesterol, high-density lipoprotein cholesterol (HDL-C), low-density lipoprotein cholesterol (LDL-C) and triglycerides. The analysis was performed in 1,905 unrelated African-American subjects from the National Heart, Lung and Blood Institute's Family Blood Pressure Program. Regions showing admixture evidence were followed-up with family-based association analysis in 3,556 African-American subjects from the FBPP. The admixture mapping and family-based association analyses were adjusted for age, age(2), sex, body-mass-index, and genome-wide mean ancestry to minimize the confounding due to population stratification. Regions that were suggestive of local ancestry association evidence were found on chromosomes 7 (LDL-C), 8 (HDL-C), 14 (triglycerides) and 19 (total cholesterol and triglycerides). In the fine-mapping analysis, 52,939 SNPs were tested and 11 SNPs (8 independent SNPs) showed nominal significant association with HDL-C (2 SNPs), LDL-C (4 SNPs) and triglycerides (5 SNPs). The family data was used in the fine-mapping to identify SNPs that showed novel associations with lipids and regions including genes with known associations for cardiovascular disease. -This study identified regions on chromosomes 7, 8, 14 and 19 and 11 SNPs from the fine-mapping analysis that were associated with HDL-C, LDL-C and triglycerides for further studies of cardiovascular disease in African-Americans.
    Circulation Cardiovascular Genetics 12/2014; 8(1). DOI:10.1161/CIRCGENETICS.114.000481 · 4.60 Impact Factor
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    ABSTRACT: Insulin sensitivity, insulin secretion, insulin clearance, and glucose effectiveness exhibit strong genetic components although few studies have examined their genetic architecture or their influence on type 2 diabetes (T2D) risk. We hypothesized that loci affecting variation in these quantitative traits influence T2D. We completed a multi-cohort genome-wide association study to search for loci influencing T2D-related quantitative traits in 4,176 Mexican Americans. Quantitative traits were measured by the frequently-sampled intravenous glucose tolerance test (4 cohorts) or euglycemic clamp (3 cohorts) and random effects models were used to test association between loci and quantitative traits, adjusting for age, gender, and admixture proportions (Discovery). Analysis revealed significant (P<5.00x10(-8)) association at 11q14.3 (MTNR1B) with acute insulin response. Loci with P<0.0001 among the quantitative traits were examined for translation to T2D risk in 6,463 T2D cases and 9,232 controls of Mexican ancestry (Translation). Non-parametric meta-analysis of the Discovery and Translation cohorts identified significant associations at 6p24 (SLC35B3/TFAP2A) with glucose effectiveness/T2D, 11p15 (KCNQ1) with disposition index/T2D, and 6p22 (CDKAL1) and 11q14 (MTNR1B) with acute insulin response/T2D. These results suggest that T2D and insulin secretion and sensitivity have both shared and distinct genetic factors, potentially delineating genomic components of these quantitative traits that drive risk for T2D. © 2014 by the American Diabetes Association. Readers may use this article as long as the work is properly cited, the use is educational and not for profit, and the work is not altered.
    Diabetes 12/2014; 64(5). DOI:10.2337/db14-0732 · 8.10 Impact Factor
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    ABSTRACT: Top signals from genome-wide association studies (GWASs) of type 2 diabetes (T2D) are enriched with expression quantitative trait loci (eQTLs) identified in skeletal muscle and adipose tissue. We therefore hypothesized that such eQTLs might account for a dispropor-tionate share of the heritability estimated from all SNPs interrogated through GWASs. To test this hypothesis, we applied linear mixed models to the Wellcome Trust Case Control Consortium (WTCCC) T2D data set and to data sets representing Mexican Americans from Starr County, TX, and Mexicans from Mexico City. We estimated the proportion of phenotypic variance attributable to the additive effect of all variants interrogated in these GWASs, as well as a much smaller set of variants identified as eQTLs in human adipose tissue, skeletal muscle, and lymphoblastoid cell lines. The narrow-sense heritability explained by all interrogated SNPs in each of these data sets was substantially greater than the heritability accounted for by genome-wide-significant SNPs (~10%); GWAS SNPs explained over 50% of phenotypic variance in the WTCCC, Starr County, and Mexico City data sets. The estimate of heritability attributable to cross-tissue eQTLs was greater in the WTCCC data set and among lean Hispanics, whereas adipose eQTLs significantly explained heritability among Hispanics with a body mass index R 30. These results support an important role for regulatory variants in the genetic component of T2D susceptibility, particularly for eQTLs that elicit effects across insulin-responsive peripheral tissues.
    The American Journal of Human Genetics 10/2014; DOI:10.1016/j.ajhg.2014.10.001 · 10.93 Impact Factor
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    ABSTRACT: Advances of modern sensing and sequencing technologies generate a deluge of high dimensional space-temporal physiological and next-generation sequencing (NGS) data. Physiological traits are observed either as continuous random functions, or on a dense grid and referred to as function-valued traits. Both physiological and NGS data are highly correlated data with their inherent order, spacing, and functional nature which are ignored by traditional summary-based univariate and multivariate regression methods designed for quantitative genetic analysis of scalar trait and common variants. To capture morphological and dynamic features of the data and utilize their dependent structure, we propose a functional linear model (FLM) in which a trait curve is modeled as a response function, the genetic variation in a genomic region or gene is modeled as a functional predictor, and the genetic effects are modeled as a function of both time and genomic position (FLMF) for genetic analysis of function-valued trait with both GWAS and NGS data. By extensive simulations, we demonstrate that the FLMF has the correct type 1 error rates and much higher power to detect association than the existing methods. The FLMF is applied to sleep data from Starr County health studies where oxygen saturation were measured in 22,670 seconds on average for 833 individuals. We found 65 genes that were significantly associated with oxygen saturation functional trait with P-values ranging from 2.40E-06 to 2.53E-21. The results clearly demonstrate that the FLMF substantially outperforms the traditional genetic models with scalar trait.
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    ABSTRACT: Background: The purpose was to describe patterns of home self-monitoring of blood glucose (SMBG) in Mexican Americans with type 2 diabetes mellitus enrolled in a diabetes self-management education protocol. Research questions were as follows: (1) What were the patterns and rates of home glucose self-monitoring over the 6-month course of the study? (2) What were the differences in monitoring rates between experimental and control groups? (3) What were the relationships between rates of monitoring and glycosylated hemoglobin (A1C), gender, and years with diabetes? Subjects and methods: We used a randomized (by group) repeated-measures pretest/posttest control group design. Glucometer data from an experimental group (diabetes self-management education plus nurse case management) and a comparison group (diabetes self-management education only) were analyzed. Data were collected at baseline and at 3 and 6 months. Results: Overall average SMBG rates were low. Experimental and control group monitoring levels were not significantly different. More females than males never monitored glucose values, but more females than males checked at least one time per week. Those participants who checked their glucose levels more than once per week had diabetes for a longer period of time. Rates of monitoring were not strongly associated with A1C levels at 3 and 6 months, but at 6 months A1C levels were statistically significantly different based on whether or not individuals monitored their glucose levels (P=0.03, n=71). Conclusions: SMBG rates were low in this study despite SMBG education and access to free glucometers and test strips. The lower rates of SMBG may reflect the effects of unexpected environmental challenges, but exact causes remain unclear. Reasons for low rates of SMBG need to be explored further, especially in underserved communities.
    Diabetes Technology &amp Therapeutics 10/2014; 17(2). DOI:10.1089/dia.2014.0147 · 2.11 Impact Factor
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    ABSTRACT: Objective To detect novel loci with age-dependent effects on fasting (≥8 h) levels of total cholesterol, high-density lipoprotein, low-density lipoprotein, and triglycerides using 3600 African Americans, 1283 Asians, 3218 European Americans, and 2026 Mexican Americans from the Family Blood Pressure Program (FBPP). Methods Within each subgroup (defined by network, race, and sex), we employed stepwise linear regression (retention p ≤ 0.05) to adjust lipid levels for age, age-squared, age-cubed, body-mass-index, current smoking status, current drinking status, field center, estrogen therapy (females only), as well as antidiabetic, antihypertensive, and antilipidemic medication use. For each trait, we pooled the standardized male and female residuals within each network and race and fit a generalized variance components model that incorporated gene–age interactions. We conducted FBPP-wide and race-specific meta-analyses by combining the p-values of each linkage marker across subgroups using a modified Fisher's method. Results We identified seven novel loci with age-dependent effects; four total cholesterol loci from the meta-analysis of Mexican Americans (on chromosomes 2q24.1, 4q21.21, 8q22.2, and 12p11.23) and three high-density lipoprotein loci from the meta-analysis of all FBPP subgroups (on chromosomes 1p12, 14q11.2, and 21q21.1). These loci lacked significant genome-wide linkage or association evidence in the literature and had logarithm of odds (LOD) score ≥ 3 in the meta-analysis with LOD ≥ 1 in at least two network and race subgroups (exclusively of non-European descent). Conclusion Incorporating gene–age interactions into the analysis of lipids using multi-ethnic cohorts can enhance gene discovery. These interaction loci can guide the selection of families for sequencing studies of lipid-associated variants.
    Atherosclerosis 07/2014; 235(1):84–93. DOI:10.1016/j.atherosclerosis.2014.04.008 · 3.99 Impact Factor
  • Sharon A Brown · Craig L Hanis ·
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    ABSTRACT: PurposeThe purpose is to provide an overview of a 20-year research program aimed at testing diabetes self-management education interventions culturally tailored for Mexican Americans residing in an impoverished rural community on the Texas-Mexico border.Methods The research program involved focus group interviews to obtain community input, pilot testing to refine instruments and interventions, and community-based randomized controlled trials to examine intervention effects. Here the authors summarize lessons learned related to the (1) overall effects of culturally tailored diabetes self-management education; (2) impact of culture on study design, intervention development, health outcomes, and community acceptance; (3) benefits of and findings from multiple focus groups held over time in the community; and (4) personal and cultural motivators for behavioral change that were evident among study participants.ResultsPostintervention reductions in A1C ranged from 1.4 to 1.7 percentage points. Individuals who attended ≥ 50% of intervention sessions achieved a 6-percentage point reduction in A1C. Intervention teams included bilingual Mexican American nurses, dietitians, and promotoras, all recruited from the local community. Focus group interviews indicated that a traditional promotora model was not acceptable to the participants who wanted knowledgeable health professionals, or perceived authority figures, to lead intervention sessions while promotoras provided logistical support. Free glucometers and strips, family participation, and interpersonal dynamics within intervention groups motivated individuals to make healthier lifestyle choices.Conclusions Culturally tailored diabetes interventions are effective in improving the health of socially disadvantaged minorities who bear a disproportional burden of type 2 diabetes, and these interventions are cost-effective.
    The Diabetes Educator 04/2014; 40(4). DOI:10.1177/0145721714531336 · 1.79 Impact Factor
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    ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
    Nature Genetics 03/2014; · 29.35 Impact Factor
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    ABSTRACT: Loss-of-function mutations protective against human disease provide in vivo validation of therapeutic targets, but none have yet been described for type 2 diabetes (T2D). Through sequencing or genotyping of ~150,000 individuals across 5 ancestry groups, we identified 12 rare protein-truncating variants in SLC30A8, which encodes an islet zinc transporter (ZnT8) and harbors a common variant (p.Trp325Arg) associated with T2D risk and glucose and proinsulin levels. Collectively, carriers of protein-truncating variants had 65% reduced T2D risk (P = 1.7 × 10−6), and non-diabetic Icelandic carriers of a frameshift variant (p.Lys34Serfs*50) demonstrated reduced glucose levels (−0.17 s.d., P = 4.6 × 10−4). The two most common protein-truncating variants (p.Arg138* and p.Lys34Serfs*50) individually associate with T2D protection and encode unstable ZnT8 proteins. Previous functional study of SLC30A8 suggested that reduced zinc transport increases T2D risk, and phenotypic heterogeneity was observed in mouse Slc30a8 knockouts. In contrast, loss-of-function mutations in humans provide strong evidence that SLC30A8 haploinsufficiency protects against T2D, suggesting ZnT8 inhibition as a therapeutic strategy in T2D prevention.
    Nature Genetics 03/2014; DOI:10.1038/ng.2915 · 29.35 Impact Factor
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    ABSTRACT: To further understanding of the genetic basis of type 2 diabetes (T2D) susceptibility, we aggregated published meta-analyses of genome-wide association studies (GWAS), including 26,488 cases and 83,964 controls of European, east Asian, south Asian and Mexican and Mexican American ancestry. We observed a significant excess in the directional consistency of T2D risk alleles across ancestry groups, even at SNPs demonstrating only weak evidence of association. By following up the strongest signals of association from the trans-ethnic meta-analysis in an additional 21,491 cases and 55,647 controls of European ancestry, we identified seven new T2D susceptibility loci. Furthermore, we observed considerable improvements in the fine-mapping resolution of common variant association signals at several T2D susceptibility loci. These observations highlight the benefits of trans-ethnic GWAS for the discovery and characterization of complex trait loci and emphasize an exciting opportunity to extend insight into the genetic architecture and pathogenesis of human diseases across populations of diverse ancestry.
    Nature Genetics 03/2014; 46(3):234-244. DOI:10.1038/ng.2897 · 29.35 Impact Factor
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    ABSTRACT: Performing genetic studies in multiple human populations can identify disease risk alleles that are common in one population but rare in others, with the potential to illuminate pathophysiology, health disparities, and the population genetic origins of disease alleles. Here we analysed 9.2 million single nucleotide polymorphisms (SNPs) in each of 8,214 Mexicans and other Latin Americans: 3,848 with type 2 diabetes and 4,366 non-diabetic controls. In addition to replicating previous findings, we identified a novel locus associated with type 2 diabetes at genome-wide significance spanning the solute carriers SLC16A11 and SLC16A13 (P = 3.9 × 10−13; odds ratio (OR) = 1.29). The association was stronger in younger, leaner people with type 2 diabetes, and replicated in independent samples (P = 1.1 × 10−4; OR = 1.20). The risk haplotype carries four amino acid substitutions, all in SLC16A11; it is present at ~50% frequency in Native American samples and ~10% in east Asian, but is rare in European and African samples. Analysis of an archaic genome sequence indicated that the risk haplotype introgressed into modern humans via admixture with Neanderthals. The SLC16A11 messenger RNA is expressed in liver, and V5-tagged SLC16A11 protein localizes to the endoplasmic reticulum. Expression of SLC16A11 in heterologous cells alters lipid metabolism, most notably causing an increase in intracellular triacylglycerol levels. Despite type 2 diabetes having been well studied by genome-wide association studies in other populations, analysis in Mexican and Latin American individuals identified SLC16A11 as a novel candidate gene for type 2 diabetes with a possible role in triacylglycerol metabolism.
    Nature 12/2013; 506(7486). DOI:10.1038/nature12828 · 41.46 Impact Factor
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    ABSTRACT: Neonatal diabetes mellitus is known to have over 20 different monogenic causes. A syndrome of permanent neonatal diabetes along with primary microcephaly with simplified gyral pattern associated with severe infantile epileptic encephalopathy was recently described in two independent reports in which disease-causing homozygous mutations were identified in the immediate early response-3 interacting protein-1 (IER3IP1) gene. We report here an affected male born to a non-consanguineous couple who was noted to have insulin-requiring permanent neonatal diabetes, microcephaly, and generalized seizures. He was also found to have cortical blindness, severe developmental delay and numerous dysmorphic features. He experienced a slow improvement but not abrogation of seizure frequency and severity on numerous anti-epileptic agents. His clinical course was further complicated by recurrent respiratory tract infections and he died at 8 years of age. Whole exome sequencing was performed on DNA from the proband and parents. He was found to be a compound heterozygote with two different mutations in IER3IP1: p.Val21Gly (V21G) and a novel frameshift mutation p.Phe27fsSer*25. IER3IP1 is a highly conserved protein with marked expression in the cerebral cortex and in beta cells. This is the first reported case of compound heterozygous mutations within IER3IP1 resulting in neonatal diabetes. The triad of microcephaly, generalized seizures, and permanent neonatal diabetes should prompt screening for mutations in IER3IP1. As mutations in genes such as NEUROD1 and PTF1A could cause a similar phenotype, next-generation sequencing approaches-such as exome sequencing reported here-may be an efficient means of uncovering a diagnosis in future cases.
    Pediatric Diabetes 10/2013; 15(3). DOI:10.1111/pedi.12086 · 2.57 Impact Factor
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    ABSTRACT: PurposeThe purpose of the study was to (1) characterize leptin in Mexican Americans with poorly controlled type 2 diabetes, (2) examine relationships among leptin and indicators of diabetes status (body mass index and A1C), and (3) explore the effects of a culturally tailored diabetes self-management education intervention on leptin.Methods In Starr County, an impoverished Texas-Mexico border community, 252 Mexican Americans with type 2 diabetes were recruited to test a diabetes self-management education intervention culturally tailored in terms of language, dietary recommendations, social emphasis, family participation, and incorporation of cultural health beliefs. Groups of 8 participants were randomized to experimental or wait-listed control conditions. Outcomes were measured at 3, 6, and 12 months; by 12 months, 109 had complete leptin data.ResultsMost participants were women and, on average, 55 years of age, diagnosed with diabetes for 8 years, obese, and in poor glycemic control. Three variables-body mass index, sex, A1C-explained 36% of the variance in baseline leptin; there were no intervention effects on leptin. Sex, time, and gender × time interaction effects on leptin were statistically significant; greater increases in leptin over time occurred in women compared to men. In women, fasting blood glucose changes from baseline to 12 months significantly predicted leptin changes from baseline to 12 months; in men, body mass index changes predicted leptin change.Conclusions With increasing obesity rates, further research is warranted to determine if leptin is a useful intervention target in type 2 diabetes.
    The Diabetes Educator 09/2013; 39(6). DOI:10.1177/0145721713505153 · 1.79 Impact Factor
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    ABSTRACT: Recently, bi-allelic mutations in the transcription factor RFX6 were described as the cause of a rare condition characterized by neonatal diabetes with pancreatic and biliary hypoplasia and duodenal/jejunal atresia. A male infant developed severe hyperglycemia (446 mg/dL) within 24 h of birth. Acute abdominal concerns by day five necessitated exploratory surgery that revealed duodenal atresia, gallbladder agenesis, annular pancreas and intestinal malrotation. He also exhibited chronic diarrhea and feeding intolerance, cholestatic jaundice, and subsequent liver failure. He died of sepsis at four months old while awaiting liver transplantation. The phenotype of neonatal diabetes with intestinal atresia and biliary agenesis clearly pointed to RFX6 as the causative gene; indeed, whole exome sequencing revealed a novel homozygous RFX6 mutation c.779A>C; p.Lys260Thr (K260T). This missense mutation also changes the consensus 5' splice donor site before intron 7 and is thus predicted to cause disruption in splicing. Both parents, who were not known to be related, were heterozygous carriers. Targeted genetic testing based on consideration of phenotypic features may reveal a cause among the many genes now associated with heterogeneous forms of monogenic neonatal diabetes. Our study demonstrates the feasibility of using modern sequencing technology to identify one such rare cause. Continued research is needed to determine the possible cost-effectiveness of this approach, especially when clear phenotypic clues are absent. Further study of patients with RFX6 mutations should clarify its role in pancreatic, intestinal and enteroendocrine cellular development and explain features such as the diarrhea exhibited in our case.
    Pediatric Diabetes 08/2013; 15(1). DOI:10.1111/pedi.12063 · 2.57 Impact Factor

Publication Stats

7k Citations
646.83 Total Impact Points


  • 1983-2015
    • University of Texas Health Science Center at Houston
      • • Human Genetics Center
      • • School of Public Health
      • • Graduate School of Biomedical Sciences
      Houston, Texas, United States
  • 2011
    • Association of American Geographers
      Washington, Washington, D.C., United States
  • 2007
    • Texas A&M University - Corpus Christi
      Corpus Christi, Texas, United States
    • University of Wisconsin–Madison
      • Department of Ophthalmology and Visual Sciences
      Madison, Wisconsin, United States
    • University of Chicago
      • Department of Medicine
      Chicago, IL, United States
  • 2006
    • Texas A&M University System Health Science Center
      • Department of Epidemiology and Biostatistics
      Bryan, TX, United States
  • 2005
    • Stanford University
      Palo Alto, California, United States
  • 1994-2005
    • University of Houston
      Houston, Texas, United States
  • 2002
    • University of Texas Medical School
      • Department of Psychiatry & Behavioral Sciences
      Houston, TX, United States
    • University of Texas at Austin
      • School of Nursing
      Texas City, TX, United States
  • 2000
    • Mayo Clinic - Rochester
      Rochester, Minnesota, United States
    • Howard Hughes Medical Institute
      Ashburn, Virginia, United States
  • 1998
    • Umeå University
      Umeå, Västerbotten, Sweden
  • 1995
    • Virginia Mason Medical Center
      Seattle, Washington, United States