The power of TOPMed imputation for the discovery of Latino-enriched rare variants associated with type 2 diabetes.

AIMS/HYPOTHESIS: The Latino population has been systematically underrepresented in large-scale genetic analyses, and previous studies have relied on the imputation of ungenotyped variants based on the 1000 Genomes (1000G) imputation panel, which results in suboptimal capture of low-frequency or Latino-enriched variants. The National Heart, Lung, and Blood Institute (NHLBI) Trans-Omics for Precision Medicine (TOPMed) released the largest multi-ancestry genotype reference panel representing a unique opportunity to analyse rare genetic variations in the Latino population. We hypothesise that a more comprehensive analysis of low/rare variation using the TOPMed panel would improve our knowledge of the genetics of type 2 diabetes in the Latino population. METHODS: We evaluated the TOPMed imputation performance using genotyping array and whole-exome sequence data in six Latino cohorts. To evaluate the ability of TOPMed imputation to increase the number of identified loci, we performed a Latino type 2 diabetes genome-wide association study (GWAS) meta-analysis in 8150 individuals with type 2 diabetes and 10,735 control individuals and replicated the results in six additional cohorts including whole-genome sequence data from the All of Us cohort. RESULTS: Compared with imputation with 1000G, the TOPMed panel improved the identification of rare and low-frequency variants. We identified 26 genome-wide significant signals including a novel variant (minor allele frequency 1.7%; OR 1.37, p=3.4 × 10-9). A Latino-tailored polygenic score constructed from our data and GWAS data from East Asian and European populations improved the prediction accuracy in a Latino target dataset, explaining up to 7.6% of the type 2 diabetes risk variance. CONCLUSIONS/INTERPRETATION: Our results demonstrate the utility of TOPMed imputation for identifying low-frequency variants in understudied populations, leading to the discovery of novel disease associations and the improvement of polygenic scores. DATA AVAILABILITY: Full summary statistics are available through the Common Metabolic Diseases Knowledge Portal ( https://t2d.hugeamp.org/downloads.html ) and through the GWAS catalog ( https://www.ebi.ac.uk/gwas/ , accession ID: GCST90255648). Polygenic score (PS) weights for each ancestry are available via the PGS catalog ( https://www.pgscatalog.org , publication ID: PGP000445, scores IDs: PGS003443, PGS003444 and PGS003445).

The Mexican Consortium of Epidemiological Studies for the Prevention, Diagnosis, and Treatment of Chronic Kidney Disease: a review of collaborating studies.

OBJECTIVE: To harmonize participants' information from five epidemiological studies. MATERIALS AND METHODS: The Mexican Consortium of Epidemiological Studies for the Prevention, Diagnosis, and Treatment of Chronic Kidney Disease (RenMex, by its Spanish acronym) was established in 2018. RenMex is a consortium of five studies: The Mexican Teachers Cohort Study; the Mexico City Diabetes Study; the Health Workers Cohort Study; the Comitán Study; and the Salt Consumption in Mexico Study, which assessed baseline serum creatinine, albumin, and C-reactive protein, all performed with standardized techniques. RESULTS: RenMex includes 3 133 participants, with a mean age of 44.8 years, 68.8% women, 10.8% with a previous medical diagnosis of type 2 diabetes, and 24.1% living with obesity. CONCLUSIONS: In the future, RenMex will work on more detailed analyses with each cohort allowed to opt in or out for each topic according to their individual data.

Sequence variants in SLC16A11 are a common risk factor for type 2 diabetes in Mexico.

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.

Genome-wide association study of colorectal cancer in Hispanics.

Genome-wide association studies (GWAS) have identified 58 susceptibility alleles across 37 regions associated with the risk of colorectal cancer (CRC) with P < 5×10(-8) Most studies have been conducted in non-Hispanic whites and East Asians; however, the generalizability of these findings and the potential for ethnic-specific risk variation in Hispanic and Latino (HL) individuals have been largely understudied. We describe the first GWAS of common genetic variation contributing to CRC risk in HL (1611 CRC cases and 4330 controls). We also examine known susceptibility alleles and implement imputation-based fine-mapping to identify potential ethnicity-specific association signals in known risk regions. We discovered 17 variants across 4 independent regions that merit further investigation due to suggestive CRC associations (P < 1×10(-6)) at 1p34.3 (rs7528276; Odds Ratio (OR) = 1.86 [95% confidence interval (CI): 1.47-2.36); P = 2.5×10(-7)], 2q23.3 (rs1367374; OR = 1.37 (95% CI: 1.21-1.55); P = 4.0×10(-7)), 14q24.2 (rs143046984; OR = 1.65 (95% CI: 1.36-2.01); P = 4.1×10(-7)) and 16q12.2 [rs142319636; OR = 1.69 (95% CI: 1.37-2.08); P=7.8×10(-7)]. Among the 57 previously published CRC susceptibility alleles with minor allele frequency ≥1%, 76.5% of SNPs had a consistent direction of effect and 19 (33.3%) were nominally statistically significant (P < 0.05). Further, rs185423955 and rs60892987 were identified as novel secondary susceptibility variants at 3q26.2 (P = 5.3×10(-5)) and 11q12.2 (P = 6.8×10(-5)), respectively. Our findings demonstrate the importance of fine mapping in HL. These results are informative for variant prioritization in functional studies and future risk prediction modeling in minority populations.

Incidence of type 2 diabetes in Mexico: results of the Mexico City Diabetes Study after 18 years of follow-up.

OBJECTIVE: To estimate the incidence of type 2 diabetes (T2D) in Mexican population. MATERIALS AND METHODS: Population based prospective study. At baseline (1990), the population at risk (1939 non-diabetic adults 35-64 years) was evaluated with oral glucose tolerance test. Subsequent similar evaluations were done (1994, 1998, 2008). American Diabetes Association diagnostic criteria were applied. RESULTS: The period of observation was 27842 person-years, the cumulative incidence of T2D was 14.4 and 13.7 per 1000 person-years for men and women, respectively. Incidence was 15.8, 15.7 and 12.7 per 1 000 person-years for the second (1994), third (1998) and fourth (2008) follow-up phases, respectively. The mean age at diagnosis was 44 years for prevalent cases and 56 years for incident cases. CONCLUSIONS: This is the first estimate of long-term incidence of T2D in Mexican population. The incidence is among the highest reported worldwide. It remained with few changes throughout the study period.

Risk factors associated to diabetes in Mexican population and phenotype of the individuals who will convert to diabetes.

OBJECTIVE: To describe risk factors associated to the incidence of type 2 diabetes (T2D) in Mexican population and to define phenotypic (clinical, anthropometric, metabolic) characteristics present in the individual who will convert to diabetes, regardless of time of onset. MATERIALS AND METHODS: The Mexico City Diabetes Study began in 1990, with 2 282 participants, and had three subsequent phases: 1994, 1998, and 2008. A systematic evaluation with an oral glucose tolerance test was performed in each phase. For diagnosis of T2D, American Diabetes Association criteria were used. RESULTS: The population at risk was 1939 individuals. Subjects who were in the converter stage (initially non diabetic that eventually converted to T2D) had, at baseline, higher BMI (30 vs 27), systolic blood pressure (119 vs 116 mmHg), fasting glucose (90 vs 82mg/dl), triglycerides (239 vs 196mg/dl), and cholesterol (192 vs 190mg/dl), compared with subjects who remained non converters (p<0.05). CONCLUSION: The phenotype described represents a potentially identifiable phase and a target for preventive intervention.

Association of a low-frequency variant in HNF1A with type 2 diabetes in a Latino population.

IMPORTANCE: Latino populations have one of the highest prevalences of type 2 diabetes worldwide. OBJECTIVES: To investigate the association between rare protein-coding genetic variants and prevalence of type 2 diabetes in a large Latino population and to explore potential molecular and physiological mechanisms for the observed relationships. DESIGN, SETTING, AND PARTICIPANTS: Whole-exome sequencing was performed on DNA samples from 3756 Mexican and US Latino individuals (1794 with type 2 diabetes and 1962 without diabetes) recruited from 1993 to 2013. One variant was further tested for allele frequency and association with type 2 diabetes in large multiethnic data sets of 14,276 participants and characterized in experimental assays. MAIN OUTCOME AND MEASURES: Prevalence of type 2 diabetes. Secondary outcomes included age of onset, body mass index, and effect on protein function. RESULTS: A single rare missense variant (c.1522G>A [p.E508K]) was associated with type 2 diabetes prevalence (odds ratio [OR], 5.48; 95% CI, 2.83-10.61; P = 4.4 × 10(-7)) in hepatocyte nuclear factor 1-α (HNF1A), the gene responsible for maturity onset diabetes of the young type 3 (MODY3). This variant was observed in 0.36% of participants without type 2 diabetes and 2.1% of participants with it. In multiethnic replication data sets, the p.E508K variant was seen only in Latino patients (n = 1443 with type 2 diabetes and 1673 without it) and was associated with type 2 diabetes (OR, 4.16; 95% CI, 1.75-9.92; P = .0013). In experimental assays, HNF-1A protein encoding the p.E508K mutant demonstrated reduced transactivation activity of its target promoter compared with a wild-type protein. In our data, carriers and noncarriers of the p.E508K mutation with type 2 diabetes had no significant differences in compared clinical characteristics, including age at onset. The mean (SD) age for carriers was 45.3 years (11.2) vs 47.5 years (11.5) for noncarriers (P = .49) and the mean (SD) BMI for carriers was 28.2 (5.5) vs 29.3 (5.3) for noncarriers (P = .19). CONCLUSIONS AND RELEVANCE: Using whole-exome sequencing, we identified a single low-frequency variant in the MODY3-causing gene HNF1A that is associated with type 2 diabetes in Latino populations and may affect protein function. This finding may have implications for screening and therapeutic modification in this population, but additional studies are required.

Association between soft drinks intake and low glomerular filtration rate in Mexican adults: Results from RenMex.

BACKGROUND & AIMS: To evaluate the association between soft drinks (SDs) consumption and estimated glomerular filtration rate (eGFR) in a Mexican adult population. METHODS: We used data from the RenMex consortium (n = 2095) that included the Mexican Teachers Cohort Study (34-65 years), the Health Workers Cohort Study (18-90 years), and the Comitán Study (19-91 years). In this cross-sectional study, we assessed SDs consumption (cola and flavored soda) using a food frequency questionnaire (FFQ) and estimated eGFR using the CKD Epidemiology Collaboration equation. Quantile regression was used to assess the association between SDs consumption and eGFR with eGFR as a continuous variable. Multinomial logistic regression models were used for eGFR categories derived from quantile regression (mildly decreased eGFR, ≥72.9-87.9 mL/min/1.73 m2 and moderately decreased eGFR, <72.9 mL/min/1.73 m2). RESULTS: Mean age of study participants was 47.2 years, 67.5% were women, and 12.2% had diabetes. eGFR was <60 mL/min/1.73 m2 in 3.7% of study participants. Mildly decreased eGFR was present in 14.8%, and moderately decreased eGFR was present in 10.1% of study participants. Quantile regression results showed that SDs consumption was associated with lower eGFR at the 10th, 25th, 50th and 75th percentile. Based on the final adjusted multinomial model, ≥7 servings/week was positively associated with moderately decreased eGFR relative to <1 serving/week (Relative Risk Ratio = 1.95; 95% CI: 1.07-3.57). CONCLUSION: Our results suggest that higher SDs consumption is associated with lower eGFR. Encouraging healthy dietary choices should be part of the management and prevention of CKD.

Dietary inflammatory index and lower glomerular filtration rate in Mexican adults.

We hypothesized that higher scores on the dietary inflammatory index (DII) would be associated with a lower glomerular filtration rate (GFR). This cross-sectional study included 2098 participants from Mexican Teachers Cohort Study, the Health Workers Cohort Study, and the Comitán Study belonging to the RenMex consortium. Energy-adjusted DII scores were estimated using a semi-quantitative food frequency questionnaire (FFQ). eGFR was estimated by the CKD Epidemiology Collaboration equation. Quantile regression models and ordered regression models were estimated to assess the associations of interest. Median age of study participants was 47 years, median eGFR was 102.9 mL/min/1.73m2, and the median energy-adjusted DII was 0.89 (range, -2.25, +4.86). The median eGFR was lower in participants in the highest percentile of DII compared to those in the lowest percentile (103.8 vs 101.4). We found that continuous and categorical energy-adjusted DII scores were associated with lower eGFR, especially at the lower percentiles. In adjusted ordered logistic regression, we found that the highest DII category was associated with 1.80 times the odds of belonging to the mildly decreased eGFR category or moderately decreased eGFR category compared lowest DII category (OR: 1.80, 95%CI 1.35, 2.40). A high DII score was associated with a lower eGFR among the Mexican population. Additional studies are crucial to validate these findings and explore potential strategies to reduce the consumption of pro-inflammatory foods as a preventive approach for chronic kidney disease (CKD).

Sweetened beverages intake, hyperuricemia and metabolic syndrome: the Mexico City Diabetes Study.

OBJECTIVE. To determine prevalence of hyperuricemia and its relation with intake of sweetened beverages (SB) and metabolic syndrome (MS) in low income urban Mexican population. MATERIALS AND METHODS. A cross-sectional analysis of The Mexico City Diabetes Study, a prospective population-based investigation (1 173 participants) was performed. We used logistic regression, adjusted by pertinent variables. We determined prevalence of hyperuricemia and explored associations of uric acid levels with MS and intake of SB. RESULTS. Prevalence of hyperuricemia was 26.5 and 19.8% in males and females respectively. In an adjusted multivariate model, body mass index, waist circumference, and triglyceride were higher as uric acid quartiles increased (p<0.005-0.001). The odds ratio for MS was 1.48 for 3rd uric acid quartile and 2.03 for 4th quartile. Higher consumption of SB was associated with higher uric acid levels (p<0.001). CONCLUSION. Prevalence of hyperuricemia is high. Potential association with intake of SB, resulting in metabolic alterations should be considered.

Exome Sequencing Data Analysis and a Case-Control Study in Mexican Population Reveals Lipid Trait Associations of New and Known Genetic Variants in Dyslipidemia-Associated Loci.

Background: Plasma lipid levels are a major risk factor for cardiovascular diseases. Although international efforts have identified a group of loci associated with the risk of dyslipidemia, Latin American populations have been underrepresented in these studies. Objective: To know the genetic variation occurring in lipid-related loci in the Mexican population and its association with dyslipidemia. Methods: We searched for single-nucleotide variants in 177 lipid candidate genes using previously published exome sequencing data from 2838 Mexican individuals belonging to three different cohorts. With the extracted variants, we performed a case-control study. Logistic regression and quantitative trait analyses were implemented in PLINK software. We used an LD pruning using a 50-kb sliding window size, a 5-kb window step size and a r2 threshold of 0.1. Results: Among the 34251 biallelic variants identified in our sample population, 33% showed low frequency. For case-control study, we selected 2521 variants based on a minor allele frequency ≥1% in all datasets. We found 19 variants in 9 genes significantly associated with at least one lipid trait, with the most significant associations found in the APOA1/C3/A4/A5-ZPR1-BUD13 gene cluster on chromosome 11. Notably, all 11 variants associated with hypertriglyceridemia were within this cluster; whereas variants associated with hypercholesterolemia were located at chromosome 2 and 19, and for low high density lipoprotein cholesterol were in chromosomes 9, 11, and 19. No significant associated variants were found for low density lipoprotein. We found several novel variants associated with different lipemic traits: rs3825041 in BUD13 with hypertriglyceridemia, rs7252453 in CILP2 with decreased risk to hypercholesterolemia and rs11076176 in CETP with increased risk to low high density lipoprotein cholesterol. Conclusions: We identified novel variants in lipid-regulation candidate genes in the Mexican population, an underrepresented population in genomic studies, demonstrating the necessity of more genomic studies on multi-ethnic populations to gain a deeper understanding of the genetic structure of the lipemic traits.

Genetic discovery and risk characterization in type 2 diabetes across diverse populations.

Genomic discovery and characterization of risk loci for type 2 diabetes (T2D) have been conducted primarily in individuals of European ancestry. We conducted a multiethnic genome-wide association study of T2D among 53,102 cases and 193,679 control subjects from African, Hispanic, Asian, Native Hawaiian, and European population groups in the Population Architecture Genomics and Epidemiology (PAGE) and Diabetes Genetics Replication and Meta-analysis (DIAGRAM) Consortia. In individuals of African ancestry, we discovered a risk variant in the TGFB1 gene (rs11466334, risk allele frequency (RAF) = 6.8%, odds ratio [OR] = 1.27, p = 2.06 × 10-8), which replicated in independent studies of African ancestry (p = 6.26 × 10-23). We identified a multiethnic risk variant in the BACE2 gene (rs13052926, RAF = 14.1%, OR = 1.08, p = 5.75 × 10-9), which also replicated in independent studies (p = 3.45 × 10-4). We also observed a significant difference in the performance of a multiethnic genetic risk score (GRS) across population groups (pheterogeneity = 3.85 × 10-20). Comparing individuals in the top GRS risk category (40%-60%), the OR was highest in Asians (OR = 3.08) and European (OR = 2.94) ancestry populations, followed by Hispanic (OR = 2.39), Native Hawaiian (OR = 2.02), and African ancestry (OR = 1.57) populations. These findings underscore the importance of genetic discovery and risk characterization in diverse populations and the urgent need to further increase representation of non-European ancestry individuals in genetics research to improve genetic-based risk prediction across populations.

Determinants of penetrance and variable expressivity in monogenic metabolic conditions across 77,184 exomes.

Hundreds of thousands of genetic variants have been reported to cause severe monogenic diseases, but the probability that a variant carrier develops the disease (termed penetrance) is unknown for virtually all of them. Additionally, the clinical utility of common polygenetic variation remains uncertain. Using exome sequencing from 77,184 adult individuals (38,618 multi-ancestral individuals from a type 2 diabetes case-control study and 38,566 participants from the UK Biobank, for whom genotype array data were also available), we apply clinical standard-of-care gene variant curation for eight monogenic metabolic conditions. Rare variants causing monogenic diabetes and dyslipidemias display effect sizes significantly larger than the top 1% of the corresponding polygenic scores. Nevertheless, penetrance estimates for monogenic variant carriers average 60% or lower for most conditions. We assess epidemiologic and genetic factors contributing to risk prediction in monogenic variant carriers, demonstrating that inclusion of polygenic variation significantly improves biomarker estimation for two monogenic dyslipidemias.

The status of diabetes care in Mexican population: are we making a difference? Results of the National Health and Nutrition Survey 2006.

OBJECTIVE: Examine clinical indicators to evaluate diabetes care in Mexico. MATERIAL AND METHODS: Diabetics (self reported, with therapy) were examined with standardized questionnaires, anthropometry, glucose, lipids and glycohemoglobin. Data were analyzed statistically. RESULTS: There were 2 644 patients, 677 cases without access to medical care (73% women), most lived in rural communities and spoke aboriginal dialect. Prevalence of obesity for private access group was 21.2%, for other or non access group was between 31 and 65%. The group without or basic education was most common, 76% of the cases had HDL <40 mg/dl and 36% had hypertriglyceridemia. Only 6.6% of patients had HbA1c <7%. There was no significant difference between HbA1c values observed in the group with or without access. Most patients were treated with oral agents. A significant group was without therapy. Assessments for complications was infrequent. CONCLUSIONS: Current model for diabetes care in Mexico is inefficacious and a paradigm change is necessary.

Applicability of Framingham risk equations for studying a low-income Mexican population.

OBJECTIVE: To compare the predicted risk of coronary heart disease (CHD) and incident myocardial infarction (MI) using Framingham score equations with the observed rate of MI in Mexican subjects. MATERIAL AND METHODS: Longitudinal study that included 1 667 men and women aged 35 to 64 years without MI at baseline. Incident MI was defined by electrocardiogram or death certificate. The predicted risk of fatal MI, non-fatal MI, and both was calculated using Framingham score equations. Predicted to observed risk ratio of MI was estimated. RESULTS: There were 34 incident MI cases and 24 MI deaths (median follow-up 6.2 years). The score equations overestimated the prediction of incident MI and CHD death (ratio 2.27, 95% CI, 1.19-3.34) and incident MI (ratio 2.36, 95% CI, 1.07-3.65) in men. CONCLUSIONS: The Framingham score overestimated incident MI and CHD death risk in men; however, other studies are needed to confirm our results for recalibrating the score for Mexican subjects.

Hypertension and Diabetes Mellitus: Coprediction and Time Trajectories.

Type 2 diabetes mellitus and hypertension overlap in the population. In many subjects, development of diabetes mellitus is characterized by a relatively rapid increase in plasma glucose values. Whether a similar phenomenon occurs during the development of hypertension is not known. We analyzed the pattern of blood pressure (BP) changes during the development of hypertension in patients with or without diabetes mellitus using data from the MCDS (Mexico City Diabetes Study; a population-based study of diabetes mellitus in Hispanic whites) and in the FOS (Framingham Offspring Study, a community-based study in non-Hispanic whites) during a 7-year follow-up. Diabetes mellitus at baseline was a significant predictor of incident hypertension (in FOS, odds ratio, 3.14; 95% confidence interval, 2.17-4.54) independently of sex, age, body mass index, and familial diabetes mellitus. Conversely, hypertension at baseline was an independent predictor of incident diabetes mellitus (in FOS, odds ratio, 3.33; 95% CI, 2.50-4.44). In >60% of the converters, progression from normotension to hypertension was characterized by a steep increase in BP values, averaging 20 mm Hg for systolic BP within 3.5 years (in MCDS). In comparison with the nonconverters group, hypertension and diabetes mellitus converters shared a metabolic syndrome phenotype (hyperinsulinemia, higher body mass index, waist girth, BP, heart rate and pulse pressure, and dyslipidemia). Overall, results were similar in the 2 ethnic groups. We conclude that (1) development of hypertension and diabetes mellitus track each other over time, (2) transition from normotension to hypertension is characterized by a sharp increase in BP values, and (3) insulin resistance is one common feature of both prediabetes and prehypertension and an antecedent of progression to 2 respective disease states.

Risk of progression to hypertension in a low-income Mexican population with prehypertension and normal blood pressure.

BACKGROUND: Blood pressure (BP) levels below the prehypertensive category may be associated with the risk of developing hypertension. We estimated the incidence rates of hypertension in a low-income Mexican population according to several subcategories of baseline BP within normal and prehypertensive categories. METHODS: In total, 1572 nonhypertensive men (n = 632) and nonpregnant women (n = 940), aged 35 to 64 years at baseline, were followed for a median of 5.8 years. Hypertension was defined as systolic blood pressure (SBP) >or=140 mm Hg, diastolic blood pressure (DBP) >or=90 mm Hg, or a self-reported physician's diagnosis with antihypertensive medications. RESULTS: During follow-up, 267 subjects developed hypertension, of whom 83 were men and 184 were women. The age-adjusted incidence rate was higher in women (37.1 per 1000 person-years) than in men (23.7 per 1000 person-years). There was a significant association between BP levels at baseline and incidence of hypertension, even within the normal category. For the upper levels of normal SBP (110 to 119 mm Hg), the hazards ratio (HR) was 2.43 (95% confidence interval [CI], 1.50 to 3.93) in women and 2.44 (95% CI, 1.05 to 5.69) in men, compared with SBP <110 mm Hg. For the upper levels of normal DBP (70 to 79 mm Hg), the HR was 2.33 (95% CI, 1.65 to 3.31) in women and 1.80 (95% CI, 0.92 to 3.52) in men, compared with DBP <70 mm Hg, after adjustment for recognized predictors. CONCLUSIONS: A high risk for the incidence of hypertension was associated with levels of BP, even within the normal category. This information could help define a population at high risk of progression to hypertension, to establish preventive measures.

Design and validation of a population-based definition of the metabolic syndrome.

OBJECTIVE: The National Cholesterol Education Program (NCEP) definition of the metabolic syndrome was modified to be described as a continuous variable and adapted to the characteristics of a Hispanic population. RESEARCH DESIGN AND METHODS: Age/sex population percentiles for every component of the NCEP criteria were included in this approach using population-based data from a Mexican nationwide survey (2,158 subjects). One point was given per decile for every component. The total number of points accumulated was used to classify subjects. The predictive power for incident diabetes was evaluated using the 7-year follow-up results of the Mexico City Diabetes Study. RESULTS: Our population-based method had a significantly better prognostic power compared with the original and the updated NCEP definitions (area under the receiver operating characteristic curve 0.746 vs. 0.697 and 0.723, respectively, P < 0.05). Using individuals with /=39 points) (12.71 [95% CI 5.67-28.49]) compared with that calculated for the original (9.52 [4.69-19.31]) and the updated (11.14 [5.33-23.30]) NCEP criteria. The major advantage of our approach is the detection of subjects at the extremes of the range of diabetes risk and the ability to estimate this risk as a continuum. CONCLUSIONS: Our method adapts the NCEP criteria to the characteristics of a Hispanic population. It improves the predictive power of the NCEP criteria for future diabetes.

Geographic variations of the International Diabetes Federation and the National Cholesterol Education Program-Adult Treatment Panel III definitions of the metabolic syndrome in nondiabetic subjects.

OBJECTIVE: We have carried out international comparisons of the metabolic syndrome using the International Diabetes Federation (IDF) and National Cholesterol Education Program-Adult Treatment Panel III (ATP III) definitions. This analysis could help to discern the applicability of these definitions across populations. RESEARCH DESIGN AND METHODS: Nondiabetic subjects aged 35-64 years were eligible for analysis in population-based studies from San Antonio (Mexican Americans and non-Hispanic whites, n = 2,473), Mexico City (n = 1,990), Spain (n = 2,540), and Peru (n = 346). Kappa statistics examined the agreement between metabolic syndrome definitions. RESULTS: Because of the lower cutoff points for elevated waist circumference, the IDF definition of the metabolic syndrome generated greater prevalence estimates than the ATP III definition. Prevalence difference between definitions was more significant in Mexican-origin and Peruvian men than in Europid men from San Antonio and Spain because the IDF definition required ethnic group-specific cutoff points for elevated waist circumference. ATP III and IDF definitions disagreed in the classification of 13-29% of men and 3-7% of women. In men, agreement between these definitions was 0.54 in Peru, 0.43 in Mexico City, 0.62 in San Antonio Mexican Americans, 0.69 in San Antonio non-Hispanic whites, and 0.64 in Spain. In women, agreement between definitions was 0.87, 0.89, 0.86, 0.87, and 0.93, respectively. CONCLUSIONS: The IDF definition of the metabolic syndrome generates greater prevalence estimates than the ATP III definition. Agreement between ATP III and IDF definitions was lower for men than for women in all populations and was relatively poor in men from Mexico City.

Diabetic by HbA1c, Normal by OGTT: A Frequent Finding in the Mexico City Diabetes Study.

CONTEXT: The agreement between glucose-based and hemoglobin A1c (HbA1c)-based American Diabetes Association criteria in the diagnosis of normal glucose tolerance, prediabetes, or diabetes is under scrutiny. A need to explore the issue among different populations exists. OBJECTIVE: Examine the results obtained with both methods in the diagnosis of the glycemic status. DESIGN: The Mexico City Diabetes Study is a population-based, prospective investigation. SETTING: Low-income elder urban community. PARTICIPANTS: All 854 participants without known diabetes had both oral glucose tolerance test (OGTT) and HbA1c measurements on the same day of the 2008 phase. INTERVENTIONS: Standardized protocol: questionnaires, anthropometry, and biomarkers. MAIN OUTCOME: Diagnostic classification of American Diabetes Association criteria. RESULTS: We found by OGTT normal glucose tolerance (NGT) in 512 (59.9%) participants, prediabetes [impaired fasting glucose (IFG) and/or impaired glucose tolerance (IGT)] in 261 (30.5%), and diabetes in 81 (9.4%). In total, 232 in the NGT group (45.3%) and 158 in the prediabetes group (60.5%) had HbA1c ≥6.5%. Body mass index, waist circumference, and blood pressure were significantly different among OGTT-defined diabetic status groups but not in the HbA1c-diagnosed group. We identified 404 participants in the NGT group with confirmed NGT throughout all phases of the Mexico City Diabetes Study. Of these, 184 (45.5%) had HbA1c ≥6.5%. In a vital/diabetes status follow-up performed subsequently, we found that, of these, 133 remained nondiabetic, 3 had prediabetes, 7 had diabetes, and 13 had died without diabetes; we were unable to ascertain the glycemic status in 5 and vital status in 23. CONCLUSIONS: Normal OGTT coexisting with elevated HbA1c is a common finding in this cohort. It is possible that this finding is not mediated by hyperglycemia. This might occur in similar populations.