Olimpia Arellano-Campos

TSH and free thyroxine concentrations are associated with differing metabolic markers in euthyroid subjects

OBJECTIVE To examine the association between thyroid function and the components of the metabolic syndrome and insulin resistance in an Hispanic population. DESIGN Cross-sectional study. METHODS Subjects with no history of thyroid disease or diabetes were included. Thyroid function was stratified as euthyroid or subclinical hypothyroidism (SCH) status and subsequently by free thyroxine (FT(4)) and TSH tertiles. The association of the metabolic syndrome components (defined by 2004 Adult Treatment Panel III criteria) and insulin resistance with thyroid status, TSH, and FT(4) were examined. RESULTS A total of 3148 subjects were analyzed. The prevalence of SCH was 8.3%. The prevalence of the metabolic syndrome was similar in euthyroid and SCH patients (31.6 vs 32.06%, P=0.89). Total cholesterol was higher in patients with SCH (5.51+/-1.19 vs 5.34+/-1.05 mmol/l, P<0.032). Serum TSH values showed a positive correlation (adjusted for age and sex) with total cholesterol, triglycerides, and waist circumference. In contrast, FT(4) showed a positive correlation with high-density lipoprotein cholesterol, and an inverse correlation with waist circumference, insulin, and HOMA-IR. CONCLUSION SCH is not associated with an increased risk for the metabolic syndrome (as conceived as a diagnostic category defined by the National Cholesterol, Education Program, Adult Treatment Panel III criteria). Despite this, low thyroid function (even in the euthyroid state) predisposes to higher cholesterol, glucose, insulin, and HOMA-IR levels. The combined use of TSH and FT(4), compared with the assessment based on only FT(4), is a more convenient approach to evaluate the association between thyroid function and metabolic variables.

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.

A functional ABCA1 gene variant is associated with low HDL-cholesterol levels and shows evidence of positive selection in Native Americans

It has been suggested that the higher susceptibility of Hispanics to metabolic disease is related to their Native American heritage. A frequent cholesterol transporter ABCA1 (ATP-binding cassette transporter A1) gene variant (R230C, rs9282541) apparently exclusive to Native American individuals was associated with low high-density lipoprotein cholesterol (HDL-C) levels, obesity and type 2 diabetes in Mexican Mestizos. We performed a more extensive analysis of this variant in 4405 Native Americans and 863 individuals from other ethnic groups to investigate genetic evidence of positive selection, to assess its functional effect in vitro and to explore associations with HDL-C levels and other metabolic traits. The C230 allele was found in 29 of 36 Native American groups, but not in European, Asian or African individuals. C230 was observed on a single haplotype, and C230-bearing chromosomes showed longer relative haplotype extension compared with other haplotypes in the Americas. Additionally, single-nucleotide polymorphism data from the Human Genome Diversity Panel Native American populations were enriched in significant integrated haplotype score values in the region upstream of the ABCA1 gene. Cells expressing the C230 allele showed a 27% cholesterol efflux reduction (P< 0.001), confirming this variant has a functional effect in vitro. Moreover, the C230 allele was associated with lower HDL-C levels (P = 1.77 x 10(-11)) and with higher body mass index (P = 0.0001) in the combined analysis of Native American populations. This is the first report of a common functional variant exclusive to Native American and descent populations, which is a major determinant of HDL-C levels and may have contributed to the adaptive evolution of Native American populations.

Association of the ATP-Binding Cassette Transporter A1 R230C Variant With Early-Onset Type 2 Diabetes in a Mexican Population

OBJECTIVE—The ATP-binding cassette transporter A1 (ABCA1) R230C variant is associated with low HDL cholesterol levels, obesity, and the metabolic syndrome in Mexican-Mestizos. Because a pivotal role for ABCA1 in pancreatic β-cell function was recently observed in the mouse model, we assessed the association of this variant with type 2 diabetes in this population. RESEARCH DESIGN AND METHODS—The initial group included 446 unrelated Mexican individuals: 244 with type 2 diabetes aged 20–69 years (121 with onset ≤45 years), and 202 nondiabetic control subjects aged >50 years. An independent study group included 242 type 2 diabetic case subjects and 225 control subjects with similar characteristics. RESULTS—R230C/C230C genotypes were significantly more frequent in type 2 diabetic individuals (24.6%) than in control subjects (11.4%) in the initial study group (OR 2.501; P = 0.001). After stratifying by age at diagnosis, the association was significant only in the early-onset group (age at diagnosis ≤45 years) (OR 3.776, P = 3.3 × 10−6). Both associations remained significant after adjusting for admixture (P = 0.0008 and P = 8.1 × 10−6, respectively). Similar trends were observed in the independent study group, and the combined analysis of both populations showed a highly significant association of the R230C variant with type 2 diabetes, particularly with that of early onset (P = 7.6 × 10−6 and 9.4 × 10−8, respectively). CONCLUSIONS—The R230C ABCA1 variant is associated with type 2 diabetes, particularly of early onset, in the Mexican-Mestizo population.

Genomic study in Mexicans identifies a new locus for triglycerides and refines European lipid loci

Background The Mexican population and others with Amerindian heritage exhibit a substantial predisposition to dyslipidemias and coronary heart disease. Yet, these populations remain underinvestigated by genomic studies, and to date, no genome-wide association (GWA) studies have been reported for lipids in these rapidly expanding populations. Methods and findings We performed a two-stage GWA study for hypertriglyceridemia and low high-density lipoprotein cholesterol (HDL-C) in Mexicans (n=4361), and identified a novel Mexican-specific genome-wide significant locus for serum triglycerides (TGs) near the Niemann–Pick type C1 protein gene (p=2.43×10−08). Furthermore, three European loci for TGs (APOA5, GCKR and LPL), and four loci for HDL-C (ABCA1, CETP, LIPC and LOC55908) reached genome-wide significance in Mexicans. We used cross-ethnic mapping to narrow three European TG GWA loci, APOA5, MLXIPL, and CILP2 that were wide and contained multiple candidate variants in the European scan. At the APOA5 locus, this reduced the most likely susceptibility variants to one, rs964184. Importantly, our functional analysis demonstrated a direct link between rs964184 and postprandial serum apoAV protein levels, supporting rs964184 as the causative variant underlying the European and Mexican GWA signal. Overall, 52 of the 100 reported associations from European lipid GWA meta-analysis generalised to Mexicans. However, in 82 of the 100 European GWA loci, a different variant other than the European lead/best-proxy variant had the strongest regional evidence of association in Mexicans. Conclusions This first Mexican GWA study of lipids identified a novel GWA locus for high TG levels; used the interpopulation heterogeneity to significantly restrict three previously known European GWA signals, and surveyed whether the European lipid GWA SNPs extend to the Mexican population.

Total and high molecular weight adiponectin have similar utility for the identification of insulin resistance.

BackgroundInsulin resistance (IR) and related metabolic disturbances are characterized by low levels of adiponectin. High molecular weight adiponectin (HMWA) is considered the active form of adiponectin and a better marker of IR than total adiponectin. The objective of this study is to compare the utility of total adiponectin, HMWA and the HMWA/total adiponectin index (SA index) for the identification of IR and related metabolic conditions.MethodsA cross-sectional analysis was performed in a group of ambulatory subjects, aged 20 to 70 years, in Mexico City. Areas under the receiver operator characteristic (ROC) curve for total, HMWA and the SA index were plotted for the identification of metabolic disturbances. Sensitivity and specificity, positive and negative predictive values, and accuracy for the identification of IR were calculated.ResultsThe study included 101 men and 168 women. The areas under the ROC curve for total and HMWA for the identification of IR (0.664 vs. 0.669, P = 0.74), obesity (0.592 vs. 0.610, P = 0.32), hypertriglyceridemia (0.661 vs. 0.671, P = 0.50) and hypoalphalipoproteinemia (0.624 vs. 0.633, P = 0.58) were similar. A total adiponectin level of 8.03 μg/ml was associated with a sensitivity of 57.6%, a specificity of 65.9%, a positive predictive value of 50.0%, a negative predictive value of 72.4%, and an accuracy of 62.7% for the diagnosis of IR. The corresponding figures for a HMWA value of 4.25 μg/dl were 59.6%, 67.1%, 51.8%, 73.7% and 64.2%.The area under the ROC curve of the SA index for the identification of IR was 0.622 [95% CI 0.554-0.691], obesity 0.613 [95% CI 0.536-0.689], hypertriglyceridemia 0.616 [95% CI 0.549-0.683], and hypoalphalipoproteinemia 0.606 [95% CI 0.535-0.677].ConclusionsTotal adiponectin, HMWA and the SA index had similar utility for the identification of IR and metabolic disturbances.

Amerindian-specific regions under positive selection harbour new lipid variants in Latinos.

Dyslipidemia and obesity are especially prevalent in populations with Amerindian backgrounds, such as Mexican–Americans, which predispose these populations to cardiovascular disease. Here we design an approach, known as the cross-population allele screen (CPAS), which we conduct prior to a genome-wide association study (GWAS) in 19,273 Europeans and Mexicans, in order to identify Amerindian risk genes in Mexicans. Utilizing CPAS to restrict the GWAS input variants to only those differing in frequency between the two populations, we identify novel Amerindian lipid genes, receptor-related orphan receptor alpha (RORA) and salt-inducible kinase 3 (SIK3), and three loci previously unassociated with dyslipidemia or obesity. We also detect lipoprotein lipase (LPL) and apolipoprotein A5 (APOA5) harbouring specific Amerindian signatures of risk variants and haplotypes. Notably, we observe that SIK3 and one novel lipid locus underwent positive selection in Mexicans. Furthermore, after a high-fat meal, the SIK3 risk variant carriers display high triglyceride levels. These findings suggest that Amerindian-specific genetic architecture leads to a higher incidence of dyslipidemia and obesity in modern Mexicans.

Daily Physical Activity, Fasting Glucose, Uric Acid and Body Mass Index are Independent Factors Associated with Serum Fibroblast Growth Factor 21 Levels

OBJECTIVE Fibroblast growth factor 21 (FGF21) levels have been linked with beneficial effects on glucose and lipid metabolism in animals. It is elevated in humans with the metabolic syndrome. This study investigates independent factors associated with serum FGF21 levels. DESIGN Cross-sectional study done in healthy blue-collar workers. METHODS A medical history was taken, and FGF21 (measured using an ELISA commercial kit), glucose, uric acid, plasma lipids, total/high-molecular weight (HMW) adiponectin, and retinal-binding protein 4 (RBP4) were measured in 210 individuals with (n=81) and without (n=129) metabolic syndrome. RESULTS The median of serum FGF21 levels were higher in subjects with metabolic syndrome (339.5 vs 276.4 ng/l, P=0.01). Serum FGF21 levels correlated positively with body mass index (BMI; r=0.23, P=0.001) and age (r=0.17, P=0.01). After adjusting for age and BMI, a significant positive correlation persisted for fasting glucose, uric acid, and physical activity in both males (r=0.21, r=0.11, and r=0.19, all P<0.05) and females (r=0.20, r=0.19, and r=0.14, all P<0.05). In addition, FGF21 also correlates negatively with RBP4 (r=-0.27, P=0.02), total (r=-0.26, P=0.03), and HMW adiponectin (r=-0.30, P=0.01) in women. A multiple linear regression model analysis identified that BMI (standardized beta (SB)=0.247; P=0.008), glucose (SB=0.226; P=0.003), uric acid (SB=0.191; P=0.04), and physical activity (SB=0.223; P=0.004) are independent factors influencing serum FGF21 levels (F=10.05, r(2)=0.19, P<0.001). In addition, fasting hyperglycemia > or =100 mg/dl, excess body weight with BMI > or =25 kg/m(2), and uric acid > or =5.5 mg/dl predicted higher serum FGF21 levels. CONCLUSION Serum FGF21 levels are influenced by BMI, fasting glycemia, uric acid, and physical activity.

Hypoalphalipoproteinemia in populations of Native American ancestry: an opportunity to assess the interaction of genes and the environment.

Purpose of this review Our aim is to review the environmental and genetic factors associated with hypoalphalipoproteinemia in populations of Native American ancestry. We examine the strength of the association and outline the population-specific genetic factors that lead to a higher susceptibilty for this condition. Recent findings Low HDL is the most common lipid abnormality in populations of Native American ancestry. Population-based surveys carried out in Latin America and in Mexican Americans shows that 40–60% of adults have hypoalphalipoproteinemia. The contribution of this trait to the metabolic syndrome is greater in individuals with Native American ancestry than in other ethnic groups. Several environmental factors have contributed to this phenomenon (i.e. high dietary content of carbohydrates and fat due to cultural factors and a growing incidence of obesity). In addition, results from recent genetic studies show that certain hypoalphalipoproteinemia susceptibility alleles are ethnic specific for Native Americans. The variant R230C of the ATP-binding cassette transporter subfamily A member 1 gene (ABC-A1) is common among mestizos (10.9% in Mexican mestizos) and its presence has a significant negative effect on HDL cholesterol levels (−4.2%). An additional noteworthy finding is that the R230C variant appears to be specific for the Amerindian populations. Its allele frequency is 0.28 in Mayans, 0.214 in Purepechas, 0.203 in Yaquis and 0.179 among Teenek. In contrast, the C230 allele has not been found in African, European, Chinese or South Asian populations. Summary The assessment of the genetic and environmental determinants of hypoalphalipoproteinemia in populations of Native American origin provides an opportunity to assess the population-specific interactions between genes and the environment

Association of R230C ABCA1 gene variant with low HDL-C levels and abnormal HDL subclass distribution in Mexican school-aged children

BACKGROUND The effect of ABCA1 genetic variation on HDL-C levels has been widely documented, although studies in children are scarce. We recently found a frequent non-synonymous ABCA1 variant (R230C) exclusive to populations with Native American ancestry, associated with low HDL-C levels and other metabolic traits in adults. METHODS We genotyped R230C variant in 1253 healthy unrelated Mexican school-aged children aged 6-15 years (595 boys and 658 girls) to seek associations with HDL-C levels and other metabolic traits. HDL subclass distribution was analyzed in a subgroup of 81 age, gender and BMI-matched children. RESULTS Individuals carrying the C230 allele showed a significantly lower HDL-C levels (P=2.9x10(-8)), and higher TC/HDL-C ratio, BMI, BMI z-score and percent fat mass (P=0.001, 0.049, 0.032 and 0.039, respectively). HDL size was smaller in R230C heterozygotes as compared to R230R homozygotes (P<0.05). Moreover, the proportion of HDL(2b) was lower, while the proportion of HDL(3a) and HDL(3b) particles was higher in R230C heterozygous and/or C230C homozygous individuals as compared to R230R homozygotes (P<0.05). CONCLUSIONS Our data suggest that the R230C ABCA1 gene variant plays an important role in HDL-C level regulation and HDL subclass distribution in healthy Mexican school-aged children.