Genome-wide linkage of plasma adiponectin reveals a major locus on chromosome 3q distinct from the adiponectin structural gene: the IRAS family study.

Adiponectin (APM1) is an adipocyte-derived peptide that contributes to glucose, lipid, and energy homeostasis. We assessed the genetic basis of plasma adiponectin in Hispanic-American and African-American families enrolled through the Insulin Resistance Atherosclerosis Study Family Study. A 10-cM genome scan was performed in two batches: an original set (set 1) consisting of 66 families (45 Hispanic American and 21 African American) and a replication set (set 2) consisting of 66 families (45 Hispanic American and 21 African American). Adiponectin levels were measured by radioimmunoassay in 1,727 individuals from 131 of 132 families. Linkage analysis was carried out in Hispanic Americans and African Americans separately in set 1, set 2, and the pooled set (set 1 plus set 2), with and without diabetic subjects. A major gene was mapped to 3q27 with a logarithm of odds (LOD) score of 8.21 in the Hispanic-American sample. Ninety-six unrelated individuals were screened for polymorphisms in the APM1 gene, and 18 single nucleotide polymorphisms (SNPs) were genotyped in the Hispanic-American sample. Plasma adiponectin level was modestly associated with two SNPs and their accompaning haplotypes. Incorporating each or both SNPs in the linkage analysis, however, did not significantly reduce the LOD score. Therefore, a quantitative trait locus at 3q27, likely distinct from the APM1 gene, contributes to the variation of plasma adiponectin levels in the Hispanic-American population.

Cosegregation of albuminuria and blood pressure: the Insulin Resistance Atherosclerosis (IRAS) family study.

BACKGROUND: Albuminuria was shown to be heritable and to share common genetic determinants with blood pressure (BP) in individuals of white ethnicity. Our aim in this study was to examine the familial aggregation of albuminuria and its phenotypic, genetic, and environmental correlations with BP in nondiabetic individuals of Hispanic (HA) and African American (AA) ethnicity. METHODS: The study included 129 large HA and AA families, providing 1405 nondiabetic individuals; those on antihypertensive medications were excluded. The albumin/creatinine ratio (ACR) in a random urine sample was used as a measure of albuminuria. A variance component approach was used in the analysis. RESULTS: After adjusting for age, sex, and body mass index (BMI), the heritabilities of ACR, systolic BP (SBP) and diastolic BP (DBP) were 11%, 26%, and 28%. The phenotypic correlations between ACR and each of SBP and DBP in HA (r = 0.17 and r = 0.16 respectively) and AA (r = 0.26 and r = 0.16) were significant. When partitioned into genetic and environmental factors, the genetic correlations between ACR and each of SBP and DBP were significant in HA (r(g) = 0.49 for each), whereas the environmental correlations were not. Conversely, the genetic correlations between ACR and SBP/DBP were not significant in AA (although with DBP it was not significantly different from that of HA), whereas a significant environmental correlation was observed between ACR and SBP (r(e) = 0.28, P < .001). CONCLUSIONS: Both albuminuria and BP exhibit familial aggregation in nondiabetic HA and AA. In HA, but not in AA, ACR and especially SBP share common genetic determinants. The mechanism of this ethnic heterogeneity is unclear but merits further investigation.

Racial/ethnic differences in hypertension and hypertension treatment and control in the multi-ethnic study of atherosclerosis (MESA).

BACKGROUND: Most previous studies investigating the association between ethnicity and hypertension focused on differences between African Americans and whites and did not include other racial/ethnic groups such as Chinese or Hispanics. METHODS: We used data from the Multi-Ethnic Study of Atherosclerosis (MESA), a population-based study of 6814 adults without clinical cardiovascular disease, to examine the association between ethnicity and hypertension and hypertension treatment among white, African American, Chinese, and Hispanic ethnic groups. RESULTS: The prevalence of hypertension, defined as systolic blood pressure (BP) <140 mm Hg and diastolic BP <90 mm Hg or self-reported treatment for hypertension, was significantly higher in African Americans compared to whites (60% v 38%; P < .0001), whereas prevalence in Hispanic (42%) and Chinese participants (39%) did not differ significantly from that in whites. After adjustment for age, body mass index, prevalence of diabetes mellitus, and smoking, African American (odds ratio [OR] 2.21; 95% confidence interval [95% CI] 1.91-2.56) and Chinese (OR 1.30; 95% CI 1.07-1.56) ethnicity were significantly associated with hypertension compared to whites. Among hypertensive MESA participants, the percentage of treated but uncontrolled hypertension in whites (24%) was significantly lower than in African Americans (35%, P < .0001), Chinese (33%, P = .003), and Hispanics (32%, P = .0005), but only African-American race/ethnicity remained significantly associated with treated but uncontrolled hypertension after controlling for socioeconomic factors (OR 1.35; 95% CI 1.07-1.71). Diuretic use was lowest in the Chinese (22%) and Hispanic participants (32%) and was significantly lower in these groups compared with white participants (47%; P < .0001 for both comparisons). CONCLUSIONS: Programs to improve hypertension treatment and control should focus on a better understanding of differences in the prevalence of hypertension and hypertension control among minority groups in the United States, especially African Americans, compared with whites, and on techniques to prevent hypertension and improve control in high-risk groups.

Insulin resistance and hypertension: the Insulin Resistance Atherosclerosis study.

The association between insulin resistance and insulinemia and hypertension is controversial. We examined the relation between insulin resistance and hypertension in 564 non-Hispanic whites (NHW), 505 Hispanics (H), and 413 African Americans (AA) who participated in the Insulin Resistance Atherosclerosis Study (IRAS). Insulin sensitivity was measured with a frequently sampled intravenous glucose tolerance test with minimal model analysis. The prevalence of hypertension was 32.5%, 49.4%, and 32.3% in NHW, AA, and H, respectively (P<0.001). When subjects without diabetes in all ethnic groups were combined, age, male sex, race (AA), body mass index (BMI), and insulin resistance, but not fasting insulin, were significantly associated with hypertension. When each ethnic group was analyzed separately, insulin resistance was significantly associated with hypertension in NHW and H, but not AA. After excluding subjects taking antihypertensive medications, male sex, BMI, fasting glucose, and insulin resistance, but not fasting insulin, were significant determinants of blood pressure. When the 3 ethnic groups were analyzed separately, insulin resistance was significantly associated with blood pressure in H, but not NHW, or AA. Neither insulin resistance nor fasting insulin was significantly associated with hypertension or blood pressure in subjects with diabetes of the 3 ethnic groups after adjusting for age, sex, BMI, and waist. In conclusion, insulin resistance, but not insulinemia, was related to hypertension and blood pressure in subjects without diabetes, but ethnic differences in these relations appear to exist. Neither insulin resistance nor insulinemia was related to hypertension or blood pressure in patients with type 2 diabetes in the 3 ethnic groups.

Evaluation of insulin sensitivity and beta-cell function indexes obtained from minimal model analysis of a meal tolerance test.

Modeling analysis of glucose, insulin, and C-peptide following a meal has been proposed as a means to estimate insulin sensitivity (S(i)) and beta-cell function from a single test. We compared the model-derived meal indexes with analogous indexes obtained from an intravenous glucose tolerance test (IVGTT) and hyperglycemic clamp (HGC) in 17 nondiabetic subjects (14 men, 3 women, aged 50 +/- 2 years [mean +/- SE], BMI 25.0 +/- 0.7 kg/m(2)). S(i) estimated from the meal was correlated with S(i) estimated from the IVGTT and the HGC (r = 0.59 and 0.76, respectively; P < 0.01 for both) but was approximately 2.3 and 1.4 times higher (P < 0.05 for both). The meal-derived estimate of the beta-cell's response to a steady-state change in glucose (static secretion index) was correlated with the HGC second-phase insulin response (r = 0.69; P = 0.002), but the estimated rate-of-change component (dynamic secretion index) was not correlated with first-phase insulin release from either the HGC or IVGTT. Indexes of beta-cell function obtained from the meal were significantly higher than those obtained from the HGC. In conclusion, insulin sensitivity and beta-cell indexes derived from a meal are not analogous to those from the clamp or IVGTT. Further work is needed before these indexes can be routinely used in clinical and epidemiological studies.

Insulin regulates plasma ghrelin concentration.

Ghrelin is a novel gastric peptide which stimulates growth hormone and has orexigenic and adipogenic properties. Plasma ghrelin is influenced by nutritional status and is thought to play a role in regulating food intake and body weight. We examined the effect of infusing insulin (40 mU/m(2)/min) for 2 hours while maintaining euglycemia on plasma ghrelin in 8 subjects (5 M, 3 F) aged 46 +/- 4 yrs (mean +/- SEM). Plasma insulin increased from 78 +/- 9 to 564 +/- 23 pmol/L during and returned rapidly to basal values after stopping the insulin infusion. Plasma ghrelin decreased from 85 +/- 28 to 61 +/- 18 pmol/L (p < 0.01) by 90 minutes of and continued to be suppressed for 15 minutes after the insulin infusion was discontinued. Subsequently, plasma ghrelin rose rapidly to near-basal values (81 +/- 23 pmol/L) within 60 minutes. The reciprocal relation between insulin and ghrelin was observed consistently in all subjects with the maximum insulin-induced suppression of ghrelin ranging from 19 to 64% (mean 32 +/- 5) and occurring 90-135 minutes after starting the insulin infusion (median 120). These findings indicate that insulin is a physiological and dynamic modulator of plasma ghrelin and that insulinemia possibly mediates the effect of nutritional status on its concentration.