Migraine-Associated Common Genetic Variants Confer Greater Risk of Posterior vs. Anterior Circulation Ischemic Stroke☆.

OBJECTIVE: To examine potential genetic relationships between migraine and the two distinct phenotypes posterior circulation ischemic stroke (PCiS) and anterior circulation ischemic stroke (ACiS), we generated migraine polygenic risk scores (PRSs) and compared these between PCiS and ACiS, and separately vs. non-stroke control subjects. METHODS: Acute ischemic stroke cases were classified as PCiS or ACiS based on lesion location on diffusion-weighted MRI. Exclusion criteria were lesions in both vascular territories or uncertain territory; supratentorial PCiS with ipsilateral fetal posterior cerebral artery; and cases with atrial fibrillation. We generated migraine PRS for three migraine phenotypes (any migraine; migraine without aura; migraine with aura) using publicly available GWAS data and compared mean PRSs separately for PCiS and ACiS vs. non-stroke control subjects, and between each stroke phenotype. RESULTS: Our primary analyses included 464 PCiS and 1079 ACiS patients with genetic European ancestry. Compared to non-stroke control subjects (n=15396), PRSs of any migraine were associated with increased risk of PCiS (p=0.01-0.03) and decreased risk of ACiS (p=0.010-0.039). Migraine without aura PRSs were significantly associated with PCiS (p=0.008-0.028), but not with ACiS. When comparing PCiS vs. ACiS directly, migraine PRSs were higher in PCiS vs. ACiS for any migraine (p=0.001-0.010) and migraine without aura (p=0.032-0.048). Migraine with aura PRS did not show a differential association in our analyses. CONCLUSIONS: Our results suggest a stronger genetic overlap between unspecified migraine and migraine without aura with PCiS compared to ACiS. Possible shared mechanisms include dysregulation of cerebral vessel endothelial function.

Risk factors for Toxoplasma gondii seropositivity in the Old Order Amish.

Toxoplasma gondii (T. gondii) is an important human disease-causing parasite. In the USA, T. gondii infects >10% of the population, accrues economic losses of US$3.6 billion/year, and ranks as the second leading culprit of foodborne illness-related fatalities. We assessed toxoplasmosis risk among the Old Order Amish, a mostly homogenous population with a high prevalence of T. gondii seropositivity, using a questionnaire focusing on food consumption/preparation behaviours and environmental risk factors. Analyses were conducted using multiple logistic regression. Consuming raw meat, rare meat, or unpasteurised cow or goat milk products was associated with increased odds of seropositivity (unadjusted Odds Ratios: 2.192, 1.613, and 1.718 , respectively). In separate models by sex, consuming raw meat, or consuming unpasteurised cow or goat milk products, was associated with increased odds of seropositivity among women; washing hands after touching meat with decreased odds of seropositivity among women (adjusted OR (AOR): 0.462); and cleaning cat litterbox with increased odds of seropositivity among men (AOR: 5.241). This is the first study to assess associations between behavioural and environmental risk factors and T. gondii seropositivity in a US population with high seroprevalence for T. gondii. Our study emphasises the importance of proper food safety behaviours to avoid the risk of infection.

CPT1A methylation is associated with plasma adiponectin.

BACKGROUND AND AIMS: Adiponectin, an adipose-secreted protein that has been linked to insulin sensitivity, plasma lipids, and inflammatory patterns, is an established biomarker for metabolic health. Despite clinical relevance and high heritability, the determinants of plasma adiponectin levels remain poorly understood. METHODS AND RESULTS: We conducted the first epigenome-wide cross-sectional study of adiponectin levels using methylation data on 368,051 cytosine-phosphate-guanine (CpG) sites in CD4+ T-cells from the Genetics of Lipid Lowering Drugs and Diet Network (GOLDN, n = 991). We fit linear mixed models, adjusting for age, sex, study site, T-cell purity, and family. We have identified a positive association (regression coefficient ± SE = 0.01 ± 0.001, P = 3.4 × 10-13) between plasma adiponectin levels and methylation of a CpG site in CPT1A, a key player in fatty acid metabolism. The association was replicated (n = 474, P = 0.0009) in whole blood samples from the Amish participants of the Heredity and Phenotype Intervention (HAPI) Heart Study as well as White (n = 592, P = 0.0005) but not Black (n = 243, P = 0.18) participants of the Bogalusa Heart Study (BHS). The association remained significant upon adjusting for BMI and smoking in GOLDN and HAPI but not BHS. We also identified associations between methylation loci in RNF145 and UFM1 and plasma adiponectin in GOLDN and White BHS participants, although the association was not robust to adjustment for BMI or smoking. CONCLUSION: We have identified and replicated associations between several biologically plausible loci and plasma adiponectin. These findings support the importance of epigenetic processes in metabolic traits, laying the groundwork for future translational applications.

Heritability of young- and old-onset ischaemic stroke.

BACKGROUND AND PURPOSE: Although the genetic contribution to stroke risk is well known, it remains unclear if young-onset stroke has a stronger genetic contribution than old-onset stroke. This study aims to compare the heritability of ischaemic stroke risk between young and old, using common genetic variants from whole-genome array data in population-based samples. METHODS: This analysis included 4050 ischaemic stroke cases and 5765 controls from six study populations of European ancestry; 47% of cases were young-onset stroke (age < 55 years). To quantify the heritability for stroke risk in these unrelated individuals, the pairwise genetic relatedness was estimated between individuals based on their whole-genome array data using a mixed linear model. Heritability was estimated separately for young-onset stroke and old-onset stroke (age ≥ 55 years). RESULTS: Heritabilities for young-onset stroke and old-onset stroke were estimated at 42% (±8%, P < 0.001) and 34% (±10%, P < 0.001), respectively. CONCLUSIONS: Our data suggest that the genetic contribution to the risk of stroke may be higher in young-onset ischaemic stroke, although the difference was not statistically significant.

Determinants of intrathoracic adipose tissue volume and associations with cardiovascular disease risk factors in Amish.

BACKGROUND AND AIM: Hypothesizing that intrathoracic fat might exert local effects on the coronary vasculature, we assessed the association of intrathoracic fat volume and its two subcomponents with coronary artery calcification (CAC) in 909 relatively healthy Amish adults. METHODS AND RESULTS: Intrathoracic fat, which is comprised of fat between the surface of the heart and the visceral epicardium (epicardial fat) and fat around the heart but outside of the fibrous pericardium (pericardial fat), was measured from electron beam CT scans. We examined the association between intrathoracic fat volume and cardiovascular disease risk factors in multivariate regression model. Fat volume in the epicardial and pericardial compartments were highly correlated with each other and with body mass index. Neither CAC extent nor CAC presence (Agatston score > 0) was associated with increased intrathoracic fat volume in sex-stratified models adjusting for age (p > 0.10). Intrathoracic fat volume was significantly correlated with higher systolic/diastolic blood pressure, pulse pressure, fasting glucose, insulin, triglyceride and lower high-density lipoprotein cholesterol in sex-stratified models adjusting for age (p < 0.05). However, associations were attenuated after further adjustment for body mass index. CONCLUSIONS: These data do not provide support for a significant role for intrathoracic fat in the development of CAC.

A major quantitative trait locus determining serum leptin levels and fat mass is located on human chromosome 2.

Obesity is a major predisposing factor for the development of several chronic diseases including non-insulin dependent diabetes mellitus (NIDDM) and coronary heart disease (CHD). Leptin is a serum protein which is secreted by adipocytes and thought to play a role in the regulation of body fat. Leptin levels in humans have been found to be highly correlated with an individual's total adiposity. We performed a genome-wide scan and conducted multipoint linkage analysis using a general pedigree-based variance component approach to identify genes with measurable effects on quantitative variation in leptin levels in Mexican Americans. A microsatellite polymorphism, D2S1788, mapped to chromosome 2p21 (approximately 74 cM from the tip of the short arm) and showed strong evidence of linkage with serum leptin levels with a lod score of 4.95 (P = 9 x 10(-7)). This locus accounted for 47% of the variation in serum leptin levels, with a residual additive genetic component contributing an additional 24%. This region contains several potential candidate genes for obesity, including glucokinase regulatory protein (GCKR) and pro-opiomelanocortin (POMC). Our results show strong evidence of linkage of this region of chromosome 2 with serum leptin levels and indicate that this region could contain an important human obesity gene.

Surgical treatment for combined hemifacial spasm and atypical trigeminal neuralgia caused by a tortuous basilar artery. Case report and review of the literature.

Simultaneous hemifacial spasm (HFS) and trigeminal neuralgia caused by cranial nerve (CN) compression from a tortuous basilar artery (BA) is very rare. We report a case of a 66-year-old man who presented with both HFS and "atypical" trigeminal neuralgia. The patient had a tortuous BA compressing both CN V and VII. The patient underwent microvascular decompression after failing conservative medical management. To the best of our knowledge this is the first reported case of both HFS and "atypical" trigeminal neuralgia that were both successfully treated by surgical intervention. We report the management of this rare combination and review the literature.

Detailed phenotyping of posterior vs. anterior circulation ischemic stroke: a multi-center MRI study.

OBJECTIVE: Posterior circulation ischemic stroke (PCiS) constitutes 20-30% of ischemic stroke cases. Detailed information about differences between PCiS and anterior circulation ischemic stroke (ACiS) remains scarce. Such information might guide clinical decision making and prevention strategies. We studied risk factors and ischemic stroke subtypes in PCiS vs. ACiS and lesion location on magnetic resonance imaging (MRI) in PCiS. METHODS: Out of 3,301 MRIs from 12 sites in the National Institute of Neurological Disorders and Stroke (NINDS) Stroke Genetics Network (SiGN), we included 2,381 cases with acute DWI lesions. The definition of ACiS or PCiS was based on lesion location. We compared the groups using Chi-squared and logistic regression. RESULTS: PCiS occurred in 718 (30%) patients and ACiS in 1663 (70%). Diabetes and male sex were more common in PCiS vs. ACiS (diabetes 27% vs. 23%, p < 0.05; male sex 68% vs. 58%, p < 0.001). Both were independently associated with PCiS (diabetes, OR = 1.29; 95% CI 1.04-1.61; male sex, OR = 1.46; 95% CI 1.21-1.78). ACiS more commonly had large artery atherosclerosis (25% vs. 20%, p < 0.01) and cardioembolic mechanisms (17% vs. 11%, p < 0.001) compared to PCiS. Small artery occlusion was more common in PCiS vs. ACiS (20% vs. 14%, p < 0.001). Small artery occlusion accounted for 47% of solitary brainstem infarctions. CONCLUSION: Ischemic stroke subtypes differ between the two phenotypes. Diabetes and male sex have a stronger association with PCiS than ACiS. Definitive MRI-based PCiS diagnosis aids etiological investigation and contributes additional insights into specific risk factors and mechanisms of injury in PCiS.

Autosome-wide linkage analysis of hip structural phenotypes in the Old Order Amish.

INTRODUCTION: Fracture risk is associated with bone mineral density (BMD) and with other indices of bone strength, including hip geometry. While the heritability and associated fracture risk of BMD are well described, less is known about genetic influences of bone geometry. We derived hip structural phenotypes using the Hip Structural Analysis program (HSA) and performed autosome-wide linkage analysis of hip geometric structural phenotypes. MATERIALS AND METHODS: The Amish Family Osteoporosis Study was designed to identify genes affecting bone health. BMD was measured at the hip using dual X-ray absorptiometry (DXA) in 879 participants (mean age+/-SD=49.8+/-16.1 years, range 18-91 years) from large multigenerational families. From DXA scans, we computed structural measures of hip geometry at the femoral neck (NN) and shaft (S) by HSA, including cross-sectional area (CSA), endocortical or inner diameter (ID), outer diameter (OD) buckling ratio (BR) and section modulus (Z). Genotyping of 731 highly polymorphic microsatellite markers (average spacing of 5.4 cM) and autosome-wide multipoint linkage analysis was performed. RESULTS: The heritability of HSA-derived hip phenotypes ranged from 40 to 84%. In the group as a whole, autosome-wide linkage analysis suggested evidence of linkage for QTLs related to NN_Z on chromosome 1p36 (LOD=2.36). In subgroup analysis, ten additional suggestive regions of linkage were found on chromosomes 1, 2, 5, 6, 11, 12, 14, 15 and 17, all with LOD>2.3 except for our linkage at 17q11.2-13 for men and women age 50 and under for NN_CSA, which had a lower LOD of 2.16, but confirmed a previous linkage report. CONCLUSIONS: We found HSA-derived measures of hip structure to be highly heritable independent of BMD. No strong evidence of linkage was found for any phenotype. Confirmatory evidence of linkage was found on chromosome 17q11.2-12 for NN_CSA. Modest evidence was found for genes affecting hip structural phenotypes at ten other chromosomal locations.

Genetic influences on bone loss in the San Antonio Family Osteoporosis study.

UNLABELLED: The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25-45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosomal regions implicated in bone loss. INTRODUCTION: The contribution of genetics to acquisition of peak bone mass is well documented, but little is known about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. METHODS: Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h(2)) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. RESULTS: Rate of BMD change was heritable at the forearm (h(2) = 0.31, p = 0.021), hip (h(2) = 0.44, p = 0.017), spine (h(2) = 0.42, p = 0.005), but not whole body (h(2) = 0.18, p = 0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. CONCLUSIONS: This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD.

Accounting for relatedness in family based genetic association studies.

OBJECTIVE: Assess the differences in point estimates, power and type 1 error rates when accounting for and ignoring family structure in genetic tests of association. METHODS: We compare by simulation the performance of analytic models using variance components to account for family structure and regression models that ignore relatedness for a range of possible family based study designs (i.e., sib pairs vs. large sibships vs. nuclear families vs. extended families). RESULTS: Our analyses indicate that effect size estimates and power are not significantly affected by ignoring family structure. Type 1 error rates increase when family structure is ignored, as density of family structures increases, and as trait heritability increases. For discrete traits with moderate levels of heritability and across many common sampling designs, type 1 error rates rise from a nominal 0.05 to 0.11. CONCLUSION: Ignoring family structure may be useful in screening although it comes at a cost of a increased type 1 error rate, the magnitude of which depends on trait heritability and pedigree configuration.

Association of plasma nitrite levels with obesity and metabolic syndrome in the Old Order Amish.

OBJECTIVES: Plasma nitrite is a metabolite of nitric oxide and reflects endogenous nitric oxide synthase (NOS) activity. Although plasma nitrites were previously linked with obesity and metabolic syndrome (MetS), the direction of association remains inconsistent, possibly due to sample heterogeneity. In a relatively homogeneous population, we hypothesized that nitrite levels will be positively associated with overweight/obesity and MetS. METHODS: Fasting nitrite levels were measured in 116 Old Order Amish (78% women). We performed age-and-sex-adjusted ancovas to compare nitrite levels between three groups (a) overweight/obese(-)MetS(-), (b) overweight/obese(+)MetS(-) and (c) overweight/obese(+)MetS)(+). Multivariate linear regressions were conducted on nitrite associations with continuous metabolic variables, with successive adjustments for demographics, body mass index, C-reactive protein and neopterin. RESULTS: Nitrite levels were higher in the obese/overweight(+)MetS(+) group than in the other two groups (p < 0.001). Nitrites were positively associated with levels of triglycerides (p < 0.0001), total cholesterol (p = 0.048), high-density lipoprotein/cholesterol ratio (p < 0.0001) and fasting glucose (p < 0.0001), and negatively correlated with high-density lipoprotein-cholesterol (p < 0.0001). These associations were robust to adjustments for body mass index and inflammatory markers. CONCLUSION: Further investigation of the connection between obesity/MetS and plasma nitrite levels may lead to novel dietary and pharmacological approaches that ultimately may contribute to reducing the increasing burden of obesity, MetS and cardiovascular morbidity and mortality.

A paired sibling analysis of the beta-3 adrenergic receptor and obesity in Mexican Americans.

The beta3 adrenergic receptor, located on chromosome 8, is a regulator of energy expenditure and lipolysis. A missense mutation in this gene, characterized by the replacement of tryptophan by arginine at codon 64 (Trp64Arg), is associated with obesity in some studies. We examined the effect of this variant on obesity in Mexican Americans, using a paired sibling design to minimize variability due to genetic background and a previously identified major susceptibility locus for obesity. We identified 45 sib-pairs that were concordant (identical by descent) for a locus on chromosome 2 which we have shown previously to be tightly linked to obesity in this population. The Trp64Arg variant, detected by PCR-restriction fragment length polymorphism analysis, was present in one sibling within each of the 45 sib-pairs. Presence of the variant was associated with significantly higher values in body mass index (P = 0.04), fat mass (P = 0.04), and waist circumference (P = 0.05). We conclude that the Trp64Arg variant is associated with obesity in this Mexican American population. The paired sibling design probably enhanced our ability to detect the effects of this variant by allowing us to account for variation attributable to another obesity susceptibility locus and to background genes.

Betacellulin variants and type 2 diabetes in the Old Order Amish.

Betacellulin is a member of the epidermal growth factor (EGF) family and may play a role in islet neogenesis and regeneration. To evaluate whether polymorphisms in this gene are associated with type 2 diabetes (T2DM) and impaired glucose tolerance (IGT), we genotyped 7 previously identified betacellulin variants in Amish subjects with T2DM (n=150), IGT (n=148) and normal glucose tolerance (NGT) (n=361). There were no significant differences in the allele frequencies of the variants among the 3 groups. In an expanded set of 729 nondiabetic Amish subjects, there was no significant association between the betacellulin variants and levels of glucose or insulin either fasting or during a 3 h oral glucose tolerance test, HOMA or insulin secretion index. These results are consistent with previous studies in Caucasian populations and suggest that variants in the betacellulin gene do not play a major role in the development of T2DM in Caucasian populations.

Prospective Evaluation of Genetic Variation in Platelet Endothelial Aggregation Receptor 1 Reveals Aspirin-Dependent Effects on Platelet Aggregation Pathways.

Genetic variation in the platelet endothelial aggregation receptor 1 (PEAR1) gene, most notably rs12041331, is implicated in altered on-aspirin platelet aggregation and increased cardiovascular event risk. We prospectively tested the effects of aspirin administration at commonly prescribed doses (81, 162, and 324 mg/day) on agonist-induced platelet aggregation by rs12041331 genotype in 67 healthy individuals. Prior to aspirin administration, rs12041331 minor allele carriers had significantly reduced adenosine diphosphate (ADP)-induced platelet aggregation compared with noncarriers (P = 0.03) but was not associated with other platelet pathways. In contrast, rs12041331 was significantly associated with on-aspirin platelet aggregation when collagen and epinephrine were used to stimulate platelet aggregation (P < 0.05 for all associations), but not ADP. The influence of PEAR1 rs12041331 on platelet aggregation is pathway-specific and is altered by aspirin at therapeutic doses, but not in a dose-dependent manner. Additional studies are needed to determine the impact of PEAR1 on cardiovascular events in aspirin-treated patients.

QTL influencing blood pressure maps to the region of PPH1 on chromosome 2q31-34 in Old Order Amish.

BACKGROUND: Hypertension is a major risk factor for coronary heart disease, stroke, congestive heart failure, renal insufficiency, and peripheral vascular disease. Although the genetic contribution to variation in blood pressure is well recognized, the specific genes involved are mostly unknown. We carried out a genome-wide scan to identify loci influencing blood pressure in the Old Order Amish population of Lancaster County, Pennsylvania. METHODS AND RESULTS: Blood pressures were measured in 694 adult participants from families recruited without regard to blood pressure. We performed a quantitative linkage analysis by using 357 microsatellite markers. In multipoint analysis, strong evidence for linkage was observed with both diastolic (lod=3.36; P=0.00004) and to a lesser extent systolic (lod=1.64; P=0.003) blood pressure in the region of chromosome 2q31-34. Peak evidence for linkage occurred at map positions 217 and 221 cM from pter for diastolic and systolic blood pressure, respectively. CONCLUSIONS: A gene linked to familial primary pulmonary hypertension has recently been mapped to this same region, suggesting the intriguing hypothesis that other (attenuated) mutations in this same gene may influence variation in systolic and diastolic blood pressure in this population.

Incidence of type II diabetes in Mexican Americans predicted by fasting insulin and glucose levels, obesity, and body-fat distribution.

Few data exist on predictors of non-insulin-dependent (type II) diabetes mellitus. We examined body mass index (BMI), ratio of subscapular-to-triceps skin fold (centrality index), and fasting glucose and insulin concentrations as predictors of decompensation to type II diabetes in Mexican Americans, a population at high risk for this disorder. Twenty-eight of 474 initially nondiabetic Mexican Americans developed type II diabetes after 8 yr of follow-up. Converters to diabetes were older and had higher BMIs, centrality indices, and fasting glucose and insulin concentrations than nonconverters. Subjects in the highest quartile of the insulin distribution had 6.6 times the risk of developing type II diabetes as subjects in the remaining three quartiles combined (95% confidence interval [CI] = 3.14-13.7). In multivariate analysis, fasting glucose (odds ratio [OR] = 5.80, 95% CI = 2.57-13.1) and insulin (OR = 3.12, 95% CI = 1.36-7.14) remained significantly related to conversion to diabetes. However, BMI and centrality index, which were significantly related to conversion in the univariate analysis, were no longer significant in the multivariate analysis once glucose and insulin concentrations were taken into consideration, suggesting that the effect of these variables may be mediated by insulin resistance. Nearly half of the incident cases developed in a subset of the population who were simultaneously in the highest quartile of both fasting insulin and glucose concentrations (population-attributable risk 44.2%). Our results support the insulin resistance/pancreatic exhaustion theory of type II diabetes.

Genetic and environmental determinants of type II diabetes in Mexico City and San Antonio.

To study genetic and environmental determinants of non-insulin-dependent (type II) diabetes, we compared a random sample of 35- to 64-yr-old Mexican-American men and women living in several low-income barrio neighborhoods of San Antonio to similarly aged Mexicans living in a low-income colonia of Mexico City (Colonia Liberales). A total of 1138 Mexican Americans, representing 64.3% of the original sample, and 646 Mexicans, representing 69.2% of the original sample, participated in the survey. Diabetes was diagnosed using World Health Organization criteria. Genetic susceptibility to type II diabetes was inferred from the percentage of Native American genetic admixture as estimated from skin reflectance measurements. The prevalence of diabetes was 36% higher among San Antonio Mexican Americans than among Mexicans in Mexico City; this difference was highly statistically significant (age- and sex-adjusted prevalence ratio 1.36, P = 0.006). This excess was observed despite the fact that genetic susceptibility, as inferred from the admixture estimates, was similar in the two cities. On the other hand, Mexicans were somewhat leaner as measured by body mass index and skin folds. Mexican women consumed fewer total calories than Mexican-American women, but there was no difference in the caloric intake of men. Mexico City residents ate less fat (18-19% of total calories vs. 31-32% in San Antonio, P less than 0.001), more carbohydrate (64-65 vs. 49%, P less than 0.001), and performed more physical activity than San Antonio Mexican Americans. Mexicans appeared to consume more refined sugar than Mexican Americans.(ABSTRACT TRUNCATED AT 250 WORDS)

Incidence of NIDDM and impaired glucose tolerance in hypertensive subjects. The San Antonio Heart Study.

Hypertension often occurs in association with NIDDM and IGT. We examined the association of hypertension at baseline to the 8-yr incidence of NIDDM and IGT in 1471 subjects who participated in the San Antonio Heart Study. Subjects who were hypertensive at baseline had a higher incidence of NIDDM (8.9 vs. 4.9%, P = 0.041) and IGT (25.2 vs. 10.0%, P < 0.001) than subjects who were normotensive at baseline. After adjusting for age, sex, ethnicity, obesity, body fat distribution, fasting glucose, and insulin, this excess was eliminated for NIDDM, but not for IGT. Specifically, the adjusted OR for NIDDM in hypertensive versus normotensive patients was 0.73 (95% Cl 0.34-1.58), whereas the adjusted OR for IGT was 1.87 (95% Cl 1.08-3.22). The excess risk of NIDDM in hypertensive patients can be explained by their greater age, obesity, more unfavorable body fat distribution, and hyperinsulinemia, whereas the excess risk of IGT is independent of these factors.

Proinsulin and specific insulin concentration in high- and low-risk populations for NIDDM.

Hyperinsulinemia and insulin resistance have been implicated as risk factors for the development of non-insulin-dependent diabetes mellitus (NIDDM). Recent data suggest that proinsulin may comprise a large proportion of immunoreactive insulin in subjects with NIDDM and possibly in those with impaired glucose tolerance (IGT) as well. Increased proinsulin concentrations are thought to be an early indicator of a failing pancreas. We examined proinsulin, insulin (using an assay that does not display appreciable cross-reactivity with proinsulin), and the fasting proinsulin:insulin ratio in 206 nondiabetic Mexican-American (a high-risk population for NIDDM) and 123 nondiabetic non-Hispanic white (a low-risk population for NIDDM) participants in the San Antonio Heart Study, a population-based study of diabetes and cardiovascular disease. Mexican-Americans had significantly higher fasting and 2-h proinsulin and insulin levels but similar fasting proinsulin:insulin ratios compared with non-Hispanic whites. After statistical adjustment for age, body mass index, waist-to-hip ratio, and glucose tolerance status, Mexican-Americans continued to have higher fasting and 2-h insulin and fasting and 2-h proinsulin concentrations but similar proinsulin:insulin ratios compared with non-Hispanic whites. The fasting proinsulin:insulin ratio was higher in 85 subjects with NIDDM compared with subjects with IGT or normal glucose tolerance (0.31, 0.09, and 0.07, respectively). Thus, nondiabetic subjects from a high-risk population for NIDDM are hyperinsulinemic (using an assay that does not cross-react with proinsulin) and, further, do not secrete more proinsulin relative to insulin itself than do nondiabetic subjects from a low-risk population.