A quantitative trait locus on chromosome 5p influences d-dimer levels in the san antonio family heart study.

Background. D-dimer is associated with increasing severity of atherosclerosis and with increased risk of a cardiovascular disease (CVD). Methods and Results. To better understand this risk factor, we performed a genome scan on 803 (301 males and 502 females) Mexican Americans in the San Antonio Family Heart Study (SAFHS). The SAFHS is ideal for the discovery of quantitative trait loci (QTLs) influencing CVD because CVD risk factors are prevalent in Mexican Americans of San Antonio and because the study design involves large families, which is optimal for QTL discovery. D-dimer levels were normalized in our study. We found that D-dimer levels were heritable, at about 23% heritability (P ≈ .00001). In a linkage analysis employing 432 microsatellite markers, we found strong evidence of a QTL on chromosome 5p with a lod score of 3.32 at 21 centiMorgans (cM). We also found suggestive evidence of a QTL on chromosome 2q with a lod score of 2.33 at 207 cM. Conclusions. To our knowledge, the putative QTL on chromosome 5p is novel. The possible QTL on chromosome 2q is discussed in relation to a recent report of linkage of a related hemostatic factor to the same location. These results warrant further investigation.

Quantitative trait locus on chromosome 12q14.1 influences variation in plasma plasminogen levels in the San Antonio Family Heart Study.

Plasminogen is a hemostasis-related phenotype and is commonly implicated in thrombotic and bleeding disorders. In the San Antonio Family Heart Study (SAFHS), we performed to our knowledge the first genomewide linkage scan for quantitative trait loci (QTLs) that influence the level of plasminogen. The subset of the SAFHS population used for this study consists of 629 individuals distributed across 26 extended Mexican American families. Pedigree-based variance component linkage analyses were performed using SOLAR. The mean plasminogen level was 114.94% +/- 17.8 (range, 42-195). The heritability (h2) of plasminogen was 0.43 +/- 0.08 (p < 6.3 x 10(-13)). One region on chromosome 12 (12q14.1) showed suggestive evidence of linkage (LOD = 2.73, nominal p < 0.0002, genomewide p = 0.0786) near marker D12S1609. Because plasminogen has important effects in many human health problems, such as cancer and atherosclerosis, the role of this putative QTL in the regulation of plasminogen variability needs to be studied further.

Evaluation of tight junction protein 1 encoding zona occludens 1 as a candidate gene for albuminuria in a Mexican American population.

Albuminuria, a hallmark of diabetic nephropathy, has been shown to be significantly heritable in multiple studies. Therefore, the identification of genes that affect susceptibility to albuminuria may lead to novel avenues of intervention. Current evidence suggests that the podocyte and slit diaphragm play a key role in controlling the selective sieve of the glomerular filtration barrier, and podocyte-specific genes have been identified that are necessary for maintaining its integrity. We therefore investigated the role of gene variants of tight junction protein (TJP1) which encodes another slit diaphragm-associated protein zona occludens 1 as risk factors for albuminuria in the San Antonio Family Diabetes/Gallbladder Study (SAFDGS), which consists of extended Mexican-American families with a high prevalence of type 2 diabetes. Albuminuria, defined as an albumin (mg/dl) to creatinine (mg/dl) ratio (ACR) of 0.03, which is approximately equivalent to a urinary albumin excretion (UAE) >30 mg/day, was present in a total of 14.9% of participants, and 31% had type 2 diabetes. The TJP1 exons, flanking intronic sequence, and putative proximal promoter regions were investigated in this population. Twentynine polymorphisms, including 7 nonsynonymous SNPs, were identified and genotyped in all subjects of this study for association analysis. Three sets of correlated SNPs, which include 3 exonic SNPs, were nominally associated with ACR (p value range 0.007-0.049); however, the association with the discrete trait albuminuria was not significant (p value range 0.094-0.338). We conclude that these variants in TJP1 do not appear to be major determinants for albuminuria in the SAFDGS; however, they may play a minor role in its severity in this Mexican-American population. Further examination of the TJP1 gene region in this and other cohorts will be useful to determine whether ZO-1 plays a significant role in glomerular permselectivity.

Association between variants in the genes for adiponectin and its receptors with insulin resistance syndrome (IRS)-related phenotypes in Mexican Americans.

AIMS/HYPOTHESIS: The aim of this study was to examine whether genetic variation in ADIPOQ, ADIPOR1 and ADIPOR2 may contribute to increased susceptibility to components of the insulin resistance syndrome (IRS). MATERIALS AND METHODS: We genotyped single-nucleotide polymorphisms (SNPs) in ADIPOQ, ADIPOR1 and ADIPOR2 in Mexican American subjects (N=439) and performed an association analysis of IRS-related traits. RESULTS: Of the eight SNPs examined in the ADIPOQ gene, rs4632532 and rs182052 exhibited significant associations with BMI (p=0.029 and p=0.032), fasting specific insulin (p=0.023 and p=0.026), sum of skin folds (SS) (p=0.0089 and p=0.0084) and homeostasis model assessment of insulin sensitivity (HOMA-%S) (p=0.015 and p=0.016). Two other SNPs, rs266729 and rs2241767, were significantly associated with SS (p=0.036 and p=0.013). SNP rs7539542 of ADIPOR1 was significantly associated with BMI, SS and waist circumference (p=0.025, p=0.047 and p=0.0062). Fourteen of the ADIPOR2 SNPs were found to be significantly (p<0.05) associated with fasting plasma triglyceride concentrations. Four of these SNPs (rs10848569, rs929434, rs3809266 and rs12342) were in high pairwise linkage disequilibrium (r (2)=0.99) and were strongly associated with fasting triglyceride levels (p=0.00029, p=0.00016, p=0.00027 and p=0.00021). Adjusting for the effects of BMI and HOMA-%S on triglyceride concentrations increased significance to p=0.000060 for SNP rs929434. Bayesian quantitative trait nucleotide analysis was used to examine all possible models of gene action. Again, SNP rs929434 provided the strongest statistical evidence of an effect on triglyceride concentrations. CONCLUSIONS/INTERPRETATION: These results provide evidence for association of SNPs in ADIPOQ and its receptors with multiple IRS-related phenotypes. Specifically, several genetic variants in ADIPOR2 were strongly associated with decreased triglyceride levels.

Impact of parental smoking on diabetes, hypertension and the metabolic syndrome in adult men and women in the San Antonio Heart Study.

AIMS/HYPOTHESIS: In the San Antonio Heart Study (SAHS) we investigated the effects of exposure to parental smoking on diabetes, hypertension and the metabolic syndrome in adult offspring aged 25-64 years. SUBJECTS, MATERIALS AND METHODS: In a retrospective cohort study the parental smoking status during childhood, obtained through a postal questionnaire, determined a person's exposure status. Logistic regression models were used to calculate odds ratios for diabetes, hypertension and the metabolic syndrome at the baseline SAHS examination in relation to parental smoking status. All models were adjusted for age, sex, ethnicity, education years, personal smoking status (current, former or never-smoker), BMI and, in the case of diabetes, a family history of diabetes. RESULTS: Of the 2,371 participants who returned the mailing, 44.5, 5.4, 20.0 and 30.1% reported that their father, mother, both or neither parent smoked, respectively. Participants reporting that both parents smoked were 1.60 (95% CI: 0.95-2.69) times more likely to have diabetes, 1.55 (95% CI: 1.05-2.28) times more likely to have hypertension, and 1.46 (95% CI: 1.01-2.10) times more likely to have the metabolic syndrome than participants reporting that neither parent smoked during their childhood. Odds ratios, after limiting the population to younger participants (i.e.

Association between polymorphisms of the atrial natriuretic peptide gene and proteinuria: a population-based study.

AIMS/HYPOTHESIS: In case-control studies, polymorphisms at the atrial natriuretic peptide gene (ANP) locus have been associated with presence of albuminuria in Type 1 and Type 2 diabetes. We evaluated the relationship between the ScaIand BstxI polymorphisms and albuminuria in the general population of the Mexico City Diabetes Study. METHODS: Allele/genotype frequencies were analysed by PCR-RFLP analysis using ScaI (wild, A(2) vs mutated, A(1)) and BstxI (wild, C(708) vs mutated, T(708)) enzyme. RESULTS: Among 1288 subjects, hypertension was present in 112 subjects, Type 2 diabetes in 191 and impaired glucose tolerance in 136; microalbuminuria was present in 464 subjects, and clinical proteinuria in 199. General frequencies were 0.93 and 0.96 for the wild alleles, and 0.07 and 0.04 for the mutated alleles, respectively for ScaI and BstxI. Frequency of A(1)was 0.08 in normoalbuminuric, 0.05 in microalbuminuric, and 0.05 in proteinuric patients (chi(2)=7.3, p=0.025). Frequency of T(708) was 0.06 in normoalbuminuric and 0.03 microalbuminuric and 0.03 in proteinuric subjects (chi(2)=8.1, p=0.017). By multivariate analysis, the associations between A(1)or T(708) allele and albuminuria were independent of age, sex, BMI, diabetes, and hypertension, (odds ratio (OR) 0.60, p=0.01, (OR) 0.51, p=0.004, respectively). CONCLUSION/INTERPRETATION: In the general population of Mexico City, both polymorphisms of ANP are associated with albuminuria independently of hypertension, and could play a role in protecting subjects against development of albuminuria.

Was the historic contribution of Spain to the Mexican gene pool partially responsible for the higher prevalence of type 2 diabetes in mexican-origin populations? The Spanish Insulin Resistance Study Group, the San Antonio Heart Study, and the Mexico City Diabetes Study.

OBJECTIVE: Mexican-American populations in San Antonio, Texas (SA-MA) and Mexico have a higher prevalence of type 2 diabetes than non-Hispanic whites in San Antonio (SA-NHW). However, the higher prevalence of type 2 diabetes in Mexican-origin populations might be related, in part, not to Native American genetic admixture but to Spanish genetic admixture. RESEARCH DESIGN AND METHODS: Four population-based epidemiological surveys conducted with Mexican-origin and European-origin samples provided data relevant to this question. In all four surveys, type 2 diabetes was defined as fasting plasma glucose > or =7.0 mmol/l or 2-h glucose > or =11.1 mmol/l or use of antidiabetic agents. RESULTS: A comparison of the two Mexican-origin populations showed that the age- and sex-adjusted prevalence of type 2 diabetes was lower in Mexico than in SA-MA (15.1 vs. 17.9%, P = 0.032). Between the two European-origin populations, the prevalence of type 2 diabetes was lower in SA-NHW than in Spain (6.2 vs. 9.1%, P < 0.0001), but differences were attenuated by adjustment for BMI or after stratification by education. In logistic regression analyses, type 2 diabetes was associated with Mexican ethnic origin after adjusting for age, education, BMI, and waist-to-hip ratio. CONCLUSIONS: The prevalence of type 2 diabetes in Spain was intermediate between that in Mexican-origin populations and SA-NHW. Although the higher degree of Native American admixture is a major contributor to the higher rates of type 2 diabetes, we cannot completely rule out a partial contribution of Spanish admixture to diabetes susceptibility among Mexican- origin populations.

Elevated incidence of type 2 diabetes in San Antonio, Texas, compared with that of Mexico City, Mexico.

OBJECTIVE: To compare the incidence of type 2 diabetes between low-income Mexican-Americans residing in San Antonio, Texas, and low-income residents in Mexico City, Mexico. RESEARCH DESIGN AND METHODS: Using data from the San Antonio Heart Study and the Mexico City Diabetes Study, we compared the incidence of type 2 diabetes in 35- to 64-year-old low-income Mexican-American residents of San Antonio with similarly aged low-income residents of Mexico City. Because of the different follow-up times in the two studies, Poisson regression was used to compare the rates of diabetes. Potential risk factors for diabetes were also analyzed to determine whether they explained or contributed to a difference in incidence. RESULTS: The age- and sex-adjusted incidence of type 2 diabetes was significantly higher in San Antonio (RR 2.01) compared with Mexico City. This difference was seen primarily in the oldest age group (55-64 years of age) and remained statistically significant after adjusting for a number of diabetes risk factors, including demographic, anthropometric, and metabolic variables. Follow-up rates were similar in both cities. CONCLUSIONS: We conclude that there was a higher incidence of type 2 diabetes in San Antonio than in Mexico City, and that difference occurred primarily in individuals in the oldest age group. The potential mediating factors we examined did not account for this difference. Other factors, such as exercise and diet, which were not available for analysis in this study, in addition to a cohort effect, may have contributed to the difference in incidence of type 2 diabetes in the two cities. In addition, there was no evidence of a higher case fatality among diabetic individuals from Mexico City compared with San Antonio.

A major locus for fasting insulin concentrations and insulin resistance on chromosome 6q with strong pleiotropic effects on obesity-related phenotypes in nondiabetic Mexican Americans.

Insulin resistance and hyperinsulinemia are strong correlates of obesity and type 2 diabetes, but little is known about their genetic determinants. Using data on nondiabetics from Mexican American families and a multipoint linkage approach, we scanned the genome and identified a major locus near marker D6S403 for fasting "true" insulin levels (LOD score 4.1, empirical P<.0001), which do not crossreact with insulin precursors. Insulin resistance, as assessed by the homeostasis model using fasting glucose and specific insulin (FSI) values, was also strongly linked (LOD score 3.5, empirical P<.0001) with this region. Two other regions across the genome were found to be suggestively linked to FSI: a location on chromosome 2q, near marker D2S141, and another location on chromosome 6q, near marker D6S264. Since several insulin-resistance syndrome (IRS)-related phenotypes were mapped independently to the regions on chromosome 6q, we conducted bivariate multipoint linkage analyses to map the correlated IRS phenotypes. These analyses implicated the same chromosomal region near marker D6S403 (6q22-q23) as harboring a major gene with strong pleiotropic effects on obesity and on lipid measures, including leptin concentrations (e.g., LOD(eq) for traits-specific insulin and leptin was 4.7). A positional candidate gene for insulin resistance in this chromosomal region is the plasma cell-membrane glycoprotein PC-1 (6q22-q23). The genetic location on chromosome 6q, near marker D6S264 (6q25.2-q26), was also identified by the bivariate analysis as exerting significant pleiotropic influences on IRS-related phenotypes (e.g., LOD(eq) for traits-specific insulin and leptin was 4.1). This chromosomal region harbors positional candidate genes, such as the insulin-like growth factor 2 receptor (IGF2R, 6q26) and acetyl-CoA acetyltransferase 2 (ACAT2, 6q25.3-q26). In sum, we found substantial evidence for susceptibility loci on chromosome 6q that influence insulin concentrations and other IRS-related phenotypes in Mexican Americans.

Genome-wide linkage analysis of blood pressure in Mexican Americans.

The genetic mechanisms that control variation in blood pressure level are largely unknown. One of the first steps in understanding those mechanisms is the localization of the genes that have a significant effect on blood pressure. We performed genome scans of systolic (SBP) and diastolic blood pressure (DBP) on a population-based sample of families in the San Antonio Family Heart Study. A likelihood-based Mendelian model incorporating genotype-specific effects of sex, age, age(2), BMI, and blood pressure (SBP or DBP, as appropriate) as covariates was used to perform two-point lodscore (Z) linkage on 399 polymorphic markers. Results showed that the genotype-specific covariate effects were highly significant for both SBP and DBP. Linkage results showed that a quantitative trait locus (QTL) influencing DBP was significantly linked to D2S1790 (Z = 3.92, theta = 0.00) and showed suggestive linkage to D8S373 (Z = 1.92, theta = 0.00). A QTL influencing SBP showed suggestive linkage to D21S1440 (Z = 2.82, theta = 0.00) and D18S844 (Z = 2.09, theta = 0.11). Without the genotype-specific effects in the model, the linkage to D2S1790 was not even suggestive (Z = 1.33, theta = 0.09); thus genotype-specific modeling was crucial in detecting this linkage. A comparison with linkage studies based in other populations showed that the significant linkage to D2S1790 has been replicated at the same marker in the Quebec Family Study. The replicated significant linkage at D2S1790 may begin to establish the locations of the genes that significantly affect blood pressure across several human ethnic groups.

Genome-wide linkage analysis of pulse pressure in Mexican Americans.

Pulse pressure, a measure of aortic stiffness, is a strong predictor of cardiovascular mortality. To locate genes that affect pulse pressure, we performed genetic analysis on randomly ascertained families in the San Antonio Family Heart Study. Pulse pressure was defined as the difference between systolic and diastolic blood pressures. Likelihood methods were used to construct a model that had both single-locus and polygenic components for 46 families (1308 individuals). The single-locus component included sex-specific and genotype-specific effects of both age and body mass index. Using this model, we then performed 2-point linkage analysis in 10 families (440 individuals) that were among the largest of the 46 families and that had been genotyped for 399 polymorphic markers. The model that contained only the polygenic component and simple effects of the covariates showed pulse pressure heritability of 0.21. When the single-locus component was added, the sex-specific and genotype-specific effects of age and body mass index were highly significant (P<0.002). The full model accounted for 73% of the total variation of pulse pressure. Linkage analysis using this model with each marker revealed 4 markers with lod scores >1.9, which is the Lander-Kruglyak suggestive linkage standard. D21S1440 had a lod score of 2.78 with a recombination fraction (theta) of 0.02. D7S1799 had a lod score of 2.04 (theta=0.01), D8S1100 had a lod score of 1.98 (theta=0.08), and D18S844 had a lod score of 1.95 (theta=0.11). These results are highly correlated with results involving systolic blood pressure, indicating that pulse pressure may not be genetically distinct from systolic blood pressure.

High incidence of cardiovascular events in a rheumatoid arthritis cohort not explained by traditional cardiac risk factors.

OBJECTIVE: To compare the incidence of cardiovascular (CV) events in persons with rheumatoid arthritis (RA) with that in people from the general population, adjusting for traditional CV risk factors. METHODS: Two hundred thirty-six consecutive patients with RA were assessed for the 1-year occurrence of 1) CV-related hospitalizations, including myocardial infarction, stroke or other arterial occlusive events, or arterial revascularization procedures, or 2) CV deaths. Both outcomes were ascertained by medical records or death certificates. For comparison, we used CV events that occurred during an 8-year period among participants in an epidemiologic study of atherosclerosis and CV disease who were ages 25-65 years at study entry. We calculated the age- and sex-stratified incidence rate ratio (IRR) of CV events between the 2 cohorts and used Poisson regression to adjust for age, sex, smoking status, diabetes mellitus, hypercholesterolemia, systolic blood pressure, and body mass index. RESULTS: Of the 236 RA patients, 234 were observed for 252 patient-years, during which 15 CV events occurred. Of these, 7 incident events occurred during the 204 patient-years contributed by patients ages 25-65 years, for an incidence of 3.43 per 100 patient-years. In the comparison cohort, 4,635 community-dwelling persons were followed up for 33,881 person-years, during which 200 new events occurred, for an incidence of 0.59 per 100 person-years. The age- and sex-adjusted IRR of incident CV events associated with RA was 3.96 (95% confidence interval [95% CI] 1.86-8.43). After adjusting for CV risk factors using Poisson regression, the IRR decreased slightly, to 3.17 (95% CI 1.33-6.36). CONCLUSION: The increased incidence of CV events in RA patients is independent of traditional CV risk factors. This suggests that additional mechanisms are responsible for CV disease in RA. Physicians who provide care to individuals with RA should be aware of their increased risk of CV events and implement appropriate diagnostic and therapeutic measures.

Rising trend in obesity in Mexican Americans and non-Hispanic whites: is it due to cigarette smoking cessation?

OBJECTIVE: Several studies have examined the influence of smoking cessation on weight gain. However, to date no study has examined this association in Mexican Americans (MA). DESIGN: Using data collected from the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease, we examined the association between smoking cessation and weight gain in 1930 Mexican Americans and 1126 non-Hispanic whites (NHW). Smoking cessation was defined as self-reported smoking at baseline but not at follow-up. RESULTS: Although there was no significant ethnic difference in the prevalence of smoking at baseline (27.2% in MA and 25.4% in NHW, P = 0.309), a greater proportion of MA smoked at follow-up compared to NHW (19.7% vs 16.5%, P = 0.037). However, there was no significant ethnic difference in the percentage of individuals who stopped smoking during the follow-up period. A two-fold greater percentage of MA quitters than NHW quitters became overweight or obese, defined as a body mass index greater than or equal to 25 kg/m2 (7.4% vs 3.1%). However, this difference did not quite reach statistical significance (P = 0.072). Using linear regression to predict change in weight or body mass index from baseline to follow-up, smoking cessation was predictive of either weight gain or BMI gain in both ethnic groups. However, smoking status accounted for only 1.0% of the variance in these outcomes, and the estimated risk of becoming overweight or obese attributable to smoking cessation was only 7.4% in MA and 3.1% in NHW. CONCLUSION: We conclude that there is an ethnic difference in the influence of smoking cessation on weight gain in MA and NHW. However, in both ethnic groups this effect is quite small and makes only a slight contribution to the overall increase in prevalence of obesity in this population.

Association among 5-year changes in weight, physical activity, and cardiovascular disease risk factors in Mexican Americans.

Recent changes in lifestyle have led to a global epidemic of obesity. To determine the associations of these changes with cardiovascular disease (CVD) risk, the authors correlated changes in CVD risk factors with changes in weight and physical activity in a population-based sample of 539 Mexican Americans in the San Antonio Heart Study in 1992-1999 who were examined twice approximately 5 years apart. Average weight change during that interval was 2.7 kg. While change in physical activity (expressed as percent change) was associated modestly only with change in low density lipoprotein cholesterol median diameter (p = 0.017), weight change was strongly and positively associated with unfavorable changes in lipid and lipoprotein traits, insulin levels, and blood pressure, explaining 2-10% of the variation in the risk factor changes during the interval. The unfavorable associations with weight gain tended to be more pronounced in lean compared with obese individuals and in men compared with women. However, the associations were significant for most CVD risk factors in all groups. In Mexican Americans, a population at high risk for obesity, weight change was positively correlated with metabolic variables associated with risk of CVD. Therefore, increasing adiposity in this population may tend to slow, or even reverse, the decline in CVD morbidity and mortality.

Molecular scanning for mutations in the insulin receptor substrate-1 (IRS-1) gene in Mexican Americans with Type 2 diabetes mellitus.

BACKGROUND: Insulin receptor substrate-1 (IRS-1) is an endogenous substrate for the insulin receptor tyrosine kinase, which plays an important role in insulin signaling. Mutations in the IRS-1 gene are associated in some populations with obesity and Type 2 diabetes. METHODS: To determine whether variation in the IRS-1 gene contributes to genetic susceptibility to insulin resistance and Type 2 diabetes in Mexican Americans, the entire coding region of the IRS-1 gene was screened for variation in 31 unrelated subjects with Type 2 diabetes using single-stranded conformational polymorphism analysis (SSCP) and dideoxy sequence analysis. Variants encoding amino acid substitutions were genotyped in 27 unrelated nondiabetic Mexican Americans and in all family members of subjects containing these variants, and association analyses were performed. To trace the ancestral origins of the variants, Iberian Caucasians and Pima Indians were also genotyped. RESULTS: Eight single base changes were found: four silent polymorphisms and four missense mutations (Ala94Thr, Ala512Pro, Ser892Gly and Gly971Arg). Allele frequencies were 0.009, 0.017, 0.017 and 0.043, respectively. There were no significant associations of any of these variants with diabetes, glucose or insulin levels during an oral glucose tolerance test, or with body mass index (BMI) in Mexican American families except for a modest association between the Ala94Thr variant and decreased BMI (30.4 kg/m(2) vs 24.0 kg/m(2); p=0.035). None of these four missense mutations were detected in Pima Indians. In Iberian Caucasians, neither Ala94Thr nor Ser892Gly were detected, and Ala512Pro was detected in only 0/60 diabetic patients and 1/60 nondiabetic controls. Gly971Arg was relatively more common in Iberian Caucasians with 12/58 diabetic patients and 7/60 nondiabetic controls being heterozygous for this variant (p=0.21 for comparison between diabetic and nondiabetic subjects). CONCLUSIONS: Ala94Thr, Ala512Pro and Ser892Gly mutation are rare in the populations studied. Gly971Arg, is more common in Mexican Americans and Caucasians, but is not a major contributor to genetic susceptibility to Type 2 diabetes.

Linkage exclusion analysis of the chromosome 11 region containing UCP2 and UCP3 with obesity-related phenotypes in Mexican Americans.

OBJECTIVE: To investigate whether the region of chromosome 11 (11q13) containing the genes UCP2 and UCP3 could be excluded for linkage with a variety of obesity-related phenotypes in humans. DESIGN: Exclusion mapping using a variance component approach in extended pedigrees. SUBJECTS: Four-hundred and fifty eight individuals (195 females, 263 males) distributed in 10 Mexican American families of probands randomly ascertained with respect to any disease state and who are participating in the San Antonio Family Heart Study. Ages range from 18 to 87 (mean age 35 y). MEASUREMENTS: Serum leptin levels, fat mass (FM), body mass index (BMI), and waist circumference. RESULTS: We were able to exclude the chromosomal region containing UCP2/UCP3 as having an effect on this set of obesity-related phenotypes at relative effect sizes of 10% or greater (P-values<0.05). CONCLUSIONS: These results suggest that variation in these genes is unlikely to have a substantial effect on the expression of obesity-related phenotypes in the Mexican American population.

Genetic basis of acanthosis nigricans in Mexican Americans and its association with phenotypes related to type 2 diabetes.

Acanthosis nigricans (AN) is a skin condition associated with hyperinsulinemia and insulin resistance and has been shown to be a risk factor for type 2 diabetes. The influence of genetic factors on AN and the basis of its association with type 2 diabetes and its risk factors are unknown. Using data from 397 participants from two Mexican American family studies, we investigated the heritability of AN and its genetic correlation with other diabetes risk factors. AN was examined as both a continuous trait and a dichotomous trait by means of a previously described validated scale. The results indicated that the heritability (h2) for AN, when examined as a continuous trait, was high (0.58+/-0.10) and statistically significant (P<0.001). The h2 for AN as a dichotomous trait was estimated to be moderate (0.23+/-0.05) and was also significant (P=0.018). The additive genetic correlations between AN (either as a continuous trait or a dichotomous trait) and type 2 diabetes and its risk factors, including body mass index and fasting insulin, were high or moderately high and statistically significant. The random environmental correlations, by contrast, were low and statistically insignificant. These data suggest that genes that influence AN have pleiotropic effects on diabetes and its risk factors.

Low fasting plasma glucose level as a predictor of cardiovascular disease and all-cause mortality.

BACKGROUND: Although medical textbooks usually classify fasting plasma glucose <70 or 80 mg/dL (<3.89 or 4.44 mmol/L) as abnormal, the prognosis for patients with low fasting plasma glucose is unclear. METHODS AND RESULTS: We conducted prospective cohort studies among 40 069 men and women to investigate the association between fasting plasma glucose levels and cardiovascular disease and all-cause mortality. We documented a U-shaped relation between fasting plasma glucose and mortality. In addition to diabetes and impaired fasting glucose levels, low fasting plasma glucose levels were also associated with high mortality. After multivariate adjustment for age, sex, study population, ethnicity, current smoking status, high blood pressure, total cholesterol, body mass index, triglycerides, history of cardiovascular disease and cancer, and a family history of cardiovascular disease, patients with fasting plasma glucose <70 mg/dL (<3.89 mmol/L) had a 3.3-fold increased risk of cardiovascular disease mortality, and patients with fasting plasma glucose 70 to 79 mg/dL (3.89 to 4.43 mmol/L) had a 2.4-fold increased risk compared with the risk in patients with fasting plasma glucose 80 to 109 mg/dL (4.44 to 6.05 mmol/L) (tests for trend P<0.0001). Participants with low fasting plasma glucose levels also had increased risk of all-cause mortality (test for trend P<0.0001). CONCLUSIONS: Participants with low fasting plasma glucose levels had a high risk of cardiovascular disease and all-cause mortality.