doi: 10.1161/hc3601.096729
(Circulation. 2001;104:1255.)
© 2001 American Heart Association, Inc.
Clinical Investigation and Reports |
Coincident Linkage of Fasting Plasma Insulin and Blood Pressure to Chromosome 7q in Hypertensive Hispanic Families
From the Division of Medical Genetics (L.S.-C.C., L.J.R., S.P., J.I.R.), Steven Spielberg Pediatric Research Center, Cedars-Sinai Medical Center; the Departments of Pediatrics (L.S.-C.C., L.J.R., S.P., J.I.R.), Medicine (R.C.D., N.W., M.Q., P.-Z.W., W.A.H., J.I.R.), and Human Genetics (J.I.R.), UCLA School of Medicine; and the Departments of Medicine (A.H.X., E.T., J.D., P.C.H., T.A.B.) and Preventive Medicine (A.H.X., S.P.A.), University of Southern California Keck School of Medicine, Los Angeles, Calif.
Correspondence to Li Shu-Chuan Cheng, Department of Biostatistics, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010 (E-mail lcheng{at}coh.org). Reprint requests to Jerome I. Rotter, Division of Medical Genetics, SSB 378, Cedars-Sinai Medical Center, 8723 Alden Drive, Los Angeles, CA 90048 (E-mail jrotter@xchg.peds.csmc.edu).
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Abstract |
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Background— Insulin resistance (IR) and hyperinsulinemia are phenotypically associated with hypertension. We have previously provided evidence that blood pressure (BP) and IR cosegregate in Hispanic families, suggesting that this association has a genetic component. In the present study, we provide further support for the hypothesis of a genetic basis for the BP-IR relationship from a genetic linkage study.
Methods and Results— A 10-cM genome scan was conducted in 390 Hispanic family members of 77 hypertensive probands. Detailed measurements of BP, glucose, insulin levels, and insulin sensitivity (euglycemic clamp) were performed in adult offspring of probands. Multipoint variance component linkage analysis was used. A region on chromosome 7q seemed to influence both IR and BP. The greatest evidence for linkage was found for fasting insulin (lod score=3.36 at 128 cM), followed by systolic BP (lod score=2.06 at 120 cM). Fine mapping with greater marker density in this region increased the maximum lod score for fasting insulin to 3.94 at 125 cM (P=0.00002); lod score for systolic BP was 2.51 at 112 cM. Coincident mapping at this locus also included insulin sensitivity measured by the homeostasis assessment model (HOMA) and serum leptin concentrations. Insulin sensitivity by euglycemic clamp did not map to the same locus.
Conclusions— Our results demonstrate that a major gene determining fasting insulin is located on chromosome 7q. Linkage of BP, HOMA, and leptin levels to the same region suggests this locus may broadly influence traits associated with IR and supports a genetic basis for phenotypic associations in IR syndrome.
Key Words: hypertension • insulin • genetics
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Introduction |
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Insulin resistance (IR) has been proposed as a potential intermediate phenotype for hypertension. Cross-sectional studies have shown correlations between IR and blood pressure (BP) in several ethnic groups.1,2 Clustering of IR-associated clinical diseases (ie, diabetes, hypertension, and obesity) as well as quantitative traits (IR and BP) has been observed in twins,3 suggesting a genetic component to the phenotypic associations. These findings are consistent with the now well-described IR or metabolic syndrome, in which hyperinsulinemia, hypertension, dyslipidemia, elevated plasminogen activator inhibitor-1, and intra-abdominal obesity occur together.4 Studies by Williams et al5 identified a closely related syndrome termed "familial dyslipidemic hypertension," which involves a clustering of central obesity, lipid abnormalities, hypertension, and elevated fasting insulin.6
Physiological studies have revealed several potential mechanistic links between IR and elevated BP,5,7 but cause-effect relationships remain to be established. Animal models have demonstrated that IR and hyperinsulinemia do not result from hypertension.8,9 In humans, IR, as defined by hyperinsulinemia, may precede and predict the development of hypertension.1 Additionally, insulin sensitivity identified by euglycemic clamp studies have been reported to exhibit major gene effects in at least 3 ethnic groups.10–12 Together, these findings provide strong support for the hypothesis that IR is a genetically regulated intermediate phenotype for hypertension.
In our previous studies of BP and IR in hypertensive Hispanic families,13 path analysis suggested a pleiotropic genetic effect controlling BP and IR, only a portion of which could be accounted for by body mass index (BMI)-related genetic factors. In the present study, we used detailed phenotyping of IR-related traits, including the oral glucose tolerance test (OGTT) and euglycemic clamp measurements, together with a genome scan approach to localize chromosomal regions likely to contain genes for various measures of IR and BP.
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Methods |
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Subjects
All study subjects were Hispanic, of Mexican, Salvadoran, or Guatemalan ancestry. Probands had primary hypertension (sitting BP
140/90 mm Hg) without evidence of a secondary cause. Additionally, they had either (1) a spouse and at least 2 adult offspring or (2) 2 adult siblings and both parents available for study. Subjects were recruited through the Hypertension Clinics at Los Angeles County-University of Southern California Medical Center. They gave written informed consent for the protocol, which was approved by the Institutional Review Board. Subjects who had fasting glucose >140 mg/dL, systolic/diastolic blood pressure (SBP/DBP) >200/115 mm Hg, or significant cardiac disease were excluded from phenotyping procedures. A total of 77 families containing 390 members were included in the genome scan. The mean age of probands (21 men and 50 women) was 55.7±8.6 years. Genotype information from all available family members was used to calculate identity-by-descent allele-sharing probabilities. Only phenotypes of offspring or siblings of probands were used for the linkage analyses.
Phenotyping
SBP and DBP were measured in the sitting position using a Dinamap system (Critikon, Inc). A total of 3 BP readings were taken at 5-minute intervals and were averaged for analysis. No measurement was discarded. The coefficients of variation of 3 sets of SBP and DBP were 4.7% and 5.1%, respectively. Measurements in this analysis were taken on the day of the OGTT or on the first day of screening. At least 5 minutes of rest was required before the measurement was taken. Mean arterial pressure (MAP) was calculated as MAP=[(SBP+2) x DBP]/3. BMI was calculated as weight/height2 (kg/m2). Glucose and insulin levels were measured after an 8-hour overnight fast and 2 hours after ingestion of 75 g of glucose. Glucose was measured by glucose oxidase (Beckman Glucose Analyzer, Beckman Instruments), and insulin by a radioimmunoassay that provided <0.2% crossreactivity with proinsulin (Linco Research). Serum leptin after overnight fast was measured by radioimmunoassay (Linco Research).
For the steady-state euglycemic clamp,14 a primed infusion (60 mU/m2 surface area per minute) of human insulin (Novolin R, Novo Nordisk) was administered for 120 minutes. Blood was sampled at 5-minute intervals, and dextrose was infused to maintain plasma glucose concentrations at 
100 mg/dL. Insulin was infused at a constant rate calculated to maintain plasma insulin at 140 µU/mL. Potassium chloride was infused at 5 mEq/h to prevent hypokalemia. Blood samples were drawn for glucose and insulin measurement at -30, -20, -10, +160, +170, and +180 minutes. Whole-body insulin sensitivity was calculated as the ratio of the glucose infusion rate (GINF) required to maintain euglycemia during the final 30 minutes of insulin infusion to the increment in plasma insulin over basal levels, corrected by body surface area. The homeostasis model assessment (HOMA), defined as HOMA=fasting insulin level (µU/mL) x fasting glucose level (mmol/L)/22.5,15 was calculated as an additional measure of insulin sensitivity.
Genotyping
A 10-cM genome scan was carried out using 387 fluorescently tagged microsatellite markers (Marshfield Version 9, Marshfield Medical Research Foundation). Amplified DNA fragments from multiplex polymerase chain reaction (2 to 5 co-amplified markers) using a "touchdown" polymerase chain reaction protocol16 were resolved by polyacrylamide gel electrophoresis and detected using a scanning fluorescence detector.17 Gel image files were analyzed using Imager and Scorer software programs, kindly provided by J.L. Weber, PhD (Center for Medical Genetics, Marshfield Medical Research Foundation, Marshfield, Wis).
Statistical Analysis
For correlations among BPs and IR-related traits, simple linear correlation was performed for unrelated individuals. For genetic markers, PedCheck18 was used to detect inconsistencies in mendelian segregation. One complete pedigree and 1 individual in a second pedigree were removed from analysis because their genotypes were inconsistent with mendelian inheritance. Markers with random inconsistencies (genotyping errors) were also deleted.
Two-point linkage analysis using sib-pair regression analysis as described by Haseman and Elston19 was performed to correlate quantitative trait data with the probability of siblings being genetically identical by descent. This analysis was carried out in the SIBPAL program, which is part of the the SAGE software package (Case Western Reserve University).20
For multipoint linkage analysis, we applied variance component (VC) approach using the computer program SOLAR (Sequential Oligogenic Linkage Analysis Routines; Southwest Foundation for Biomedical Research).21 VC partitions the variability of a trait into effects caused by a quantitative trait locus (QTL), random polygenic effects, and residual nongenetic effects. We used SOLAR both to confirm the significant findings from SIBPAL and to search other possible regions that were not detected in the SIBPAL analysis. SOLAR uses a Monte Carlo procedure to estimate the identity-by-descent matrix for pedigrees. We compared the likelihood of no linkage with that of a model in which the variance is caused by the ith QTL. The difference between the 2 log10 likelihoods produces a lod score equivalent to the classic lod score of linkage analysis.
The values of SBP, DBP, and MAP were adjusted for sex, and their residual values were used in SIBPAL analysis. Age, sex, and agexsex were allowed in the SOLAR models and were adjusted for when significant. Log-transformed trait values were used when needed to obtain normal distributions.
A permutation procedure was used to obtain the empirical P value by generating a marker unlinked to the trait and then calculating a 2-point lod score.22 This step was repeated for 100 000 replicates, and thus, an empirical distribution of the lod score was obtained.
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Results |
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Phenotypic Traits
Table 1 shows distributions of BPs and IR-related traits for all offspring of probands. Although the data shown came from family members, the observed distributions are not significantly different from those obtained using independent, unrelated individuals (data not shown). The correlations among IR-related traits also showed significance, as would be expected. Fasting insulin levels were strongly correlated with OGTT 2-hour insulin (r=0.66, P=0.0001), fasting glucose (r=0.39, P=0.009), HOMA (r=0.97, P=0.0001), and clamp GINF (r=-0.60, P=0.0001). The correlation coefficient for the latter is similar to that reported by Hanson et al,23 although the correlation is not actually linear.
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Genome Scan
The chromosomal locations where maximal linkage was observed are shown in Table 2. Several regions demonstrated suggestive or significant linkage with BPs and IR-related traits. In particular, fasting insulin was linked to chromosome 7q at 128 cM using both multipoint (lod 3.36) or SIBPAL 2-point analysis (P=0.00001). Fasting insulin also mapped to chromosome 16 at 68 cM, with a multipoint lod of 1.77 and SIBPAL P of 0.001. For SBP, 3 chromosomal regions showed evidence for linkage: chromosome 1 at 4 cM (lod 2.48, P=0.004); chromosome 2 at 242 cM (lod 1.57, P=0.001); and chromosome 7 at 120 cM (lod 2.06, P=0.02). DBP and MAP also seemed to be linked to the same region of chromosome 2, with lod scores of 1.6 to 1.7. Although several regions, including chromosomes 7, 9, 17, and 18, showed moderate evidence of linkage for HOMA by multipoint analysis, most were not significant by 2-point analysis. For plasma leptin, several interesting regions were found on chromosomes 7, 9, and 15, whereas BMI demonstrated linkage to regions on chromosomes 1, 2, and 10. Clamp GINF gave moderately high lod scores (1.5 to 2.0) on chromosomes 1q and 7p.
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The region between D7S821 (109 cM) and D7S3070 (163 cM) on chromosome 7q was particularly interesting, with evidence of linkage for fasting insulin, SBP, MAP, HOMA, and leptin. Detailed 2-point and multipoint analyses are shown in Table 3, and complete genome scan results for these traits are provided in Online Table I (available at http://www.circulationaha.org).
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Fine Mapping
To better define this candidate region and to more stringently test linkage, fine mapping studies were carried out. An additional 9 markers (D7S2212, D7S518, D7S523, D7S680, D7S500, D7S495, D7S2513, D7S798, and D7S550), spanning the region from 95 cM to 178 cM, increased the marker density to 2 to 5 cM.
The maximal lod score for fasting insulin increased to 3.94 (P=0.00002) at 126 cM, between markers D7S523 and D7S3061 (95% CI, 117 cM to 135 cM) (Table 3 and Figure 1). Improved evidence for cosegregation was also seen for SBP (lod=2.51), MAP (lod=1.78), and HOMA (lod=1.95), whereas evidence of linkage for leptin persisted (lod=1.85) (Table 3). Although maximal lod scores for these traits vary by 10 to 15 cM, the CIs are overlapping, suggesting that there may be a single genetic locus on chromosome 7q contributing to their common variation. Permutation analysis showed that only 19 times among 100 000 replicates resulted in a lod score >3.0, and only 1 lod score >3.94, giving an empirical P of 0.00001 for this linkage result.
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Discussion |
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The present study has demonstrated a QTL controlling fasting plasma insulin levels, SBP, and related traits mapping to chromosome 7q in hypertensive Hispanic families. This locus was identified using 2 different statistical analyses of genome scan data and was further confirmed by fine mapping (lod increased to 3.94).
Criteria for interpretation of lod-score significance in linkage analysis is currently a topic of much discussion, with the most stringent criterion having been proposed by Lander and Kruglyak.24 On the basis of that criterion (lod score>3.6, P<2x10-5), our results have achieved significant linkage for fasting insulin on chromosome 7q. Importantly, the locus on 7q coincides with the "diabesity" locus reported in the Pima Indians25,26 and may overlap with the obesity region reported in Mexican Americans,27 thus adding confirmatory evidence that this region contains a gene or genes with important impact on factors regulating insulin and glucose metabolism in people of Native American heritage, including the Mexican-American population. Two candidate genes have been identified in the region. Protein phosphatase 1 regulatory subunit 3 (PPP1R3) located at 135 cM is a glycogen and sarcoplasmic reticulum-binding subunit in skeletal muscle that has been proposed to regulate glycogenesis and to have a role in type 2 diabetes.28 Leptin, located at approximately 126 cM, is produced by adipose tissue and has a well-known role as a signaling molecule in lipid homeostasis.29 Both these genes will be tested as candidates in our families by association studies after further mapping and expansion of sample size.
Further review of recent genome scan results for IR-related traits suggests that our 7q locus may well be coincident with a locus for SBP variation in a sample of white patients30 and a locus for pulse pressure in a sample of Mexican-American patients31 (see Online Table II at http://www.circulationaha.org). The former study found a suggestive signal at D7S530 at 130 cM (lod 2.26), and the latter study observed suggestive linkage for pulse pressure at D7S1799, located at 114 cM (lod 2.04). This suggests that the present QTL for fasting insulin may play an important role in the IR blood pressure pathophysiological pathway. Although we did not find a significant linkage for euglycemic clamp in the 7q region, a suggestive linkage was detected in another region on chromosome 7 (71 cM) for this trait. This latter locus seems to overlap with one reported by Watanabe et al32 in Finland-United States Investigation Of Non-insulin-dependent diabetes mellitus genetics (FUSION) study. The FUSION study observed several regions for IR-related traits, including a locus responsible for both C-peptide and C-peptide/glucose ratio at 75 cM on chromosome 7.
The present study did not provide support for linkage between fasting insulin and chromosome 3p, as described by Mitchell et al33 in a genome-wide linkage study of Mexican Americans. This may be attributed to several factors. First, the Hispanic population is heterogeneous, with a varying admixture of Native American, Spanish, and African populations.34 Migration patterns from Mexico to southern California and to Texas may also be different. The majority of Mexican-American families in southern California come from the western portions of Mexico, whereas migration to Texas more often occurs from the eastern portions of Mexico.34 Second, subjects in the present study were offspring of hypertensive probands. Although they were largely free of hypertension (10% were found to be hypertensive at screening; none had received antihypertensive medications), and none had clinically apparent cardiovascular diseases, the presence of hypertension in a parent placed them at increased risk for developing hypertension and related diseases. Because plasma insulin levels in these individuals represent an intermediate phenotype that seems to predispose them to hypertension,1 the locus we identified is likely to contain one of the genes involved in development of hypertension and related diseases. On the other hand, the QTL identified by Mitchell et al33 may represent a gene controlling basal insulin levels in the normal, nonhypertensive population. Third, unlike the present study, children were included in the study by Mitchell et al.33 Even though age correction was performed, the differing age distributions between studies might mean that different loci are responsible for the regulation of insulin levels at different ages.
Several studies have suggested fasting insulin levels as a surrogate to assess ß-cell function and IR.23,35 Interestingly, insulin sensitivity, as measured by euglycemic clamp, did not show linkage to the same chromosomal locations as fasting insulin despite significant correlation between the 2 traits in our subjects. Although a region on chromosome 7 shows suggestive linkage to GINF (lod 1.82), there is no overlap in the 95% CI for this locus and the CI for fasting insulin at 128 cM. Although a type II error cannot be excluded as the reason for failure to find linkage of GINF to chromosome 7q, it is likely that fasting insulin and euglycemic clamp measures are affected by various factors, some of which are common to both but others of which are unique. If so, the chromosome 7q locus may be affecting aspects of IR that are reflected in fasting insulin levels and are of less importance to IR as measured by clamp.
Conclusion
In conclusion, genome-scan linkage analysis confirms that a gene on chromosome 7q contributes to fasting insulin concentrations and also implicates the locus in blood pressure variation. Understanding the basis of this relationship should provide additional insights into the etiologies of hypertension.
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Acknowledgments |
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This work was supported by the National Institutes of Health National Heart, Lung, and Blood Institute (grant HL55005); the National Institutes of Health National Center for Research Resources, General Clinical Research Center (grants RR00425 to RR00430, M01-RR00865, M01-RR00043, M01-RR00425, and CA42710); and the Cedars-Sinai Board of Governors’ Chair in Medical Genetics. SIBPAL analysis used the program SAGE, which is supported by US Public Health Services Resource grant P41 RR03655 from the Division of Research Resources. The authors thank the families for their participation in this study.
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Footnotes |
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Additional material for this article is available in a Data Supplement available Online at http://www.circulationaha.org
Received April 9, 2001; revision received July 2, 2001; accepted July 5, 2001.
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W.-D. Li, C. Dong, D. Li, H. Zhao, and R. A. Price An Obesity-Related Locus in Chromosome Region 12q23-24 Diabetes, March 1, 2004; 53(3): 812 - 820. [Abstract] [Full Text] [PDF]
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N. J. Camp, P. N. Hopkins, S. J. Hasstedt, H. Coon, A. Malhotra, R. M. Cawthon, and S. C. Hunt Genome-Wide Multipoint Parametric Linkage Analysis of Pulse Pressure in Large, Extended Utah Pedigrees Hypertension, September 1, 2003; 42(3): 322 - 328. [Abstract] [Full Text] [PDF]
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R. N. Bergman, D. J. Zaccaro, R. M. Watanabe, S. M. Haffner, M. F. Saad, J. M. Norris, L. E. Wagenknecht, J. E. Hokanson, J. I. Rotter, and S. S. Rich Minimal Model-Based Insulin Sensitivity Has Greater Heritability and a Different Genetic Basis Than Homeostasis Model Assessment or Fasting Insulin Diabetes, August 1, 2003; 52(8): 2168 - 2174. [Abstract] [Full Text] [PDF]
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W.-D. Li, D. Li, S. Wang, S. Zhang, H. Zhao, and R. A. Price Linkage and Linkage Disequilibrium Mapping of Genes Influencing Human Obesity in Chromosome Region 7q22.1-7q35 Diabetes, June 1, 2003; 52(6): 1557 - 1561. [Abstract] [Full Text] [PDF]
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T. A. Lakka, T. Rankinen, S. J. Weisnagel, Y. C. Chagnon, T. Rice, A. S. Leon, J. S. Skinner, J. H. Wilmore, D.C. Rao, and C. Bouchard A Quantitative Trait Locus on 7q31 for the Changes in Plasma Insulin in Response to Exercise Training: The HERITAGE Family Study Diabetes, June 1, 2003; 52(6): 1583 - 1587. [Abstract] [Full Text] [PDF]
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L. D. Monti, C. Barlassina, L. Citterio, E. Galluccio, C. Berzuini, E. Setola, G. Valsecchi, P. Lucotti, G. Pozza, L. Bernardinelli, et al. Endothelial Nitric Oxide Synthase Polymorphisms Are Associated With Type 2 Diabetes and the Insulin Resistance Syndrome Diabetes, May 1, 2003; 52(5): 1270 - 1275. [Abstract] [Full Text] [PDF]
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P. Henry, F. Thomas, A. Benetos, and L. Guize Impaired Fasting Glucose, Blood Pressure and Cardiovascular Disease Mortality Hypertension, October 1, 2002; 40(4): 458 - 463. [Abstract] [Full Text] [PDF]
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S. C. Hunt, R. C. Ellison, L. D. Atwood, J. S. Pankow, M. A. Province, and M. F. Leppert Genome Scans for Blood Pressure and Hypertension: The National Heart, Lung, and Blood Institute Family Heart Study Hypertension, July 1, 2002; 40(1): 1 - 6. [Abstract] [Full Text] [PDF]
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