Diabetologia (2005) 48: 661–668 DOI 10.1007/s00125-005-1679-5 ARTICLE B. I. Freedman . S. S. Rich . M. M. Sale . G. Heiss . L. Djoussé . J. S. Pankow . M. A. Province . D. C. Rao . C. E. Lewis . Y. D. I. Chen . S. R. Beck . on behalf of the HyperGEN Investigators Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families Received: 15 July 2004 / Accepted: 7 November 2004 / Published online: 4 March 2005 # Springer-Verlag 2005 Abstract Aims/hypothesis: The heritability of fasting serum insulin and glucose concentrations in non-diabetic members of multiplex hypertensive families is unknown. Methods: We calculated the familial aggregation of fast- ing serum glucose and insulin concentrations and performed a genome-wide scan to assess whether quantitative trait loci contribute to these phenotypes in 2,412 non-diabetic individuals from 1,030 families enrolled in the Hyperten- sion Genetic Epidemiology Network (HyperGEN) in the Family Blood Pressure Program. Results: The heritability (±SE) of fasting serum insulin was 0.47±0.085 in European Americans and 0.28±0.08 in African Americans (p<0.0001 for both), after adjusting for age, sex, and BMI. A genome- wide scan for fasting serum insulin yielded a maximum log of the odds (LOD) score of 2.36 on chromosome 5 at 20 cM (p=0.0004) in European Americans, and an LOD score of 2.28 on chromosome 19 at 11 cM (p=0.0004) in African Americans. The heritability of fasting serum glu- cose was 0.5109±0.08 in the former and 0.29±0.09 in the latter (p<0.0003 for both) after adjusting for age, sex and BMI. A genome-wide scan for fasting serum glucose re- vealed a maximum LOD score of 2.07 on chromosome 5 at 26 cM (p=0.0009) in European Americans. Conclusions/ interpretation: These analyses demonstrate the marked her- itability of fasting serum insulin and glucose concentrations in families enriched for the presence of members with hy- pertension. They suggest that genes associated with fasting serum insulin concentration are present on chromosomes 19 and 5, and that genes associated with fasting serum glucose concentration are on chromosome 5, in families enriched for hypertension. Keywords African Americans . Essential hypertension . Fasting blood sugar . Heritability . Linkage analysis . Serum insulin concentration Abbreviations AA: African American . EA: European American . FBPP: Family Blood Pressure Program . h2: heritability . HOMA: homeostasis model assessment . HyperGEN: Hypertension Genetic Epidemiology B. I. Freedman (*) . M. M. Sale Department of Internal Medicine, Sections on Nephrology and Endocrinology The Wake Forest University School of Medicine, Medical Center Boulevard, Winston-Salem, NC, 27157-1053, USA e-mail: bfreedma@wfubmc.edu Tel.: +1-336-7166192 Fax: +1-336-7164318 S. S. Rich . S. R. Beck Public Health Sciences Wake Forest University School of Medicine, Winston-Salem, NC, USA M. M. Sale Center for Human Genomics Wake Forest University School of Medicine, Winston-Salem, NC, USA G. Heiss Department of Epidemiology, University of North Carolina, Chapel Hill, NC, USA L. Djoussé Evans Department of Medicine, Section of Preventive Medicine and Epidemiology, Boston University, Boston, MA, USA J. S. Pankow Department of Epidemiology, University of Minnesota, Minneapolis, MN, USA M. A. Province . D. C. Rao Division of Biostatistics Washington University School of Medicine, St. Louis, MO, USA C. E. Lewis Department of Preventive Medicine, University of Alabama, Birmingham, AL, USA Y. D. I. Chen Department of Internal Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, USA Network . IBD: Identity-by-descent . LOD: Log of the odds . NHLBI: National Heart, Lung and Blood Institute . SOLAR: Sequential oligogenic linkage analysis routines Introduction Hyperinsulinaemia is a major risk factor for the subsequent development of type 2 diabetes mellitus [1, 2]. Fasting serum insulin concentrations are excellent estimates of insulin re- sistance and the resulting hyperinsulinaemia in population studies, and have been shown to aggregate in families [3]. Insulin resistance is associated with increased serum triglyc- eride levels, reduced high-density lipoprotein concentrations and reduced low-density lipoprotein particle size; these meta- bolic parameters predict increased cardiovascular morbidity and mortality [4, 5]. The heritability (h2) and roles of inherited and envi- ronmental factors in causing hyperglycaemia and elevated serum insulin concentrations among hypertensive subjects remain unknown. In non-hypertensive populations, an ad- justed h2 value of 0.34 for fasting serum glucose [6] and 0.46 for fasting serum insulin concentrations [7] were re- ported in the Framingham Offspring Study. Similar high familial correlations for these prediabetic measures were reported in Amish families [8], the HERITAGE FAMILY study [9], and Caucasian twins [3]. Elevated serum insulin and glucose concentrations represent an increased risk of developing overt type 2 diabetes mellitus, with increased rates of cardiovascular morbidity and mortality [10]. It is likely that both genetic and environmental factors determine fasting serum insulin and glucose concentrations in hypertensive subjects. The Hypertension Genetic Epide- miology Network (HyperGEN) is a family-based consor- tium seeking to identify the genes responsible for elevated blood pressure [11]. We performed maximum likelihood var- iance component linkage analysis of fasting serum glucose and insulin concentrations and homeostasis model assess- ment (HOMA) to identify loci contributing to the variance of these traits in the non-diabetic relatives of families en- riched for the presence of essential hypertension. Subjects and methods Population Participants in the HyperGEN Network of the Family Blood Pressure Program (FBPP), sponsored by the National Heart, Lung and Blood Institute (NHLBI), were evaluated. HyperGEN study methods have previously been reported [11]. In brief, family members were recruited from five clinical centers (Framingham, MA; Minneapolis, MN; Salt Lake City, UT; Forsyth County, NC; and Birmingham, AL). Participants provided written informed consent and the project was approved by the Institutional Review Boards at all of the institutions. A sibship was ascertained if it had two or more siblings with hypertension (defined as blood pres- sure ≥140/90 or the use of anti-hypertensive medications), with an age at diagnosis of less than 60 years. Participants reporting a personal history of diabetes mellitus, having a fasting blood glucose concentration of 6.99 mmol/l or high- er, or being treated with insulin or oral hypoglycaemic agents were excluded from analyses. Phenotyping Morning fasting serum samples from study participants were collected in a resting state and run in du- plicate for insulin concentration on an automated immuno- assay instrument and its ultra-sensitive insulin kit (Beckman Coulter, Fullerton, CA, USA) [12]. The sensitivity of this assay is 0.03 mU/l (0.21 pmol/l) and the dynamic range is 0.03–300 mU/l (0.21–2100 pmol/l). There is zero cross- reactivity with pro-insulin and C-peptide, 30% with bovine insulin, and 97% with porcine insulin. Serum glucose concentrations were measured using Elan Glucose reagent (hexokinase method) [13]. Assay sensitiv- ity is 0.11–24.98 mmol/l and the detection limit 0.11 mmol/l is documented through the repetitive assay of a diluted serum control. The observed detection limit, calculated as two standard deviations of a 30-replicate within-run preci- sion study, is 0.57 mmol/l and is below the claimed limit of 0.11 mmol/l. HOMA was calculated as (fasting serum insulin*fasting serum glucose)/22.5. Genotyping Genotyping was performed by the NHLBI- funded Mammalian Genotyping Service. For additional information regarding the genotyping methods see the website of the Center for Medical Genetics at the Marsh- field Medical Research Foundation http://www.research. marshfieldclinic.org/genetics/). The genome screen was performed by means of an automated technique with the scanning fluorescence detector. The Cooperative Human Linkage Center screening set 8, including 387 microsatellite markers spaced approximately every 9 cM throughout the genome, was used, with an average marker heterozygosity of 0.76. Statistical analysis The distributions of fasting serum in- sulin and glucose concentrations were positively skewed. The natural logarithm transformed both insulin and glucose to approximate normality and was used for all analyses and model building. Any highly influential outliers were exclud- ed from the analyses after adjusting for covariates. Pedigree and genotype data were screened for possible errors using ASPEX software, version 2.2 [14], MAPMAKER/SIBS, version 2.1 [15], PedCheck, version 1.1 [16], and PREST, version 2.01 [17]. The heritability of serum measures was estimated sep- arately in each race and jointly, using variance component modelling as implemented in SOLAR software, version 2.1.2 [18]. Covariates in the model for fasting glucose were age, sex, BMI, age2, and age×sex. Covariates in the model for fasting insulin were age, sex, BMI, age2, age×sex, sex×BMI, and sex×age2. These were selected using a backward elimi- nation approach allowing for re-entry of eliminated covari- ates at each step (significance level=0.10 for backward and forward steps). For both analyses, covariates were selected among age, sex, and BMI, age2, age×sex, age×BMI, sex× BMI, sex×age2, and BMI×age2. Centred values were used to 662 http://research.marshfieldclinic.org/genetics/ http://research.marshfieldclinic.org/genetics/ model the effects of continuous covariates, and indicator variables (0/1) were used for discrete covariates. The heri- tability estimate adjusted for the effects of covariates is re- ported together with corresponding estimates of standard error, p value, and proportion of variance due to covariates. We considered p values of 0.05 or less to be significant. Markov chain Monte Carlo methods were used to esti- mate race-specific multipoint IBD matrices as implemented in the LOKI software package, version 2.4.7 [19]. Variance component multipoint and bivariate linkage analysis as implemented in SOLAR software, version 2.1.2 [18], was performed to detect and localise quantitative trait loci that influence variation in fasting serum insulin and glucose concentrations, using lodadj to account for slight departures from normality. This approach has been described in detail [20–22]. Results Genotype data were available from 2,589 individuals in 805 recruited families who participated in the FBPP. Eight sub- jects were excluded due to fasting serum glucose concentra- tions above 6.99 mmol/l (six AA, two EA). After correcting family relationships based upon the genetic data, 1,030 dis- tinct pedigrees (613 of whom were African American) were used in the analysis. After exclusion of all influential outliers, 2,412 of the genotyped individuals who were nondiabetic had measurements of fasting serum insulin and/or glucose concentrations. The mean age (±SD) of these individuals was 51.0±3.7 years, 59.5% (N=1,435) were women, 53% were AA (N=1,279), and a majority were hypertensive (71.7%) and had a mean BMI (±SD) of 30.70±6.98 kg/m2 (Table 1). Participants had a mean fasting serum glucose concentration Table 1 Demographic charac- teristics of HyperGEN study population Data listed as means±standard deviation (n) for continuous measures and % (n) for dichot- omous measures aDefined as blood pressure >140/90 mmHg or use of antihypertensive medication Characteristic African American Caucasian Race combined Sex Female 65.6 (836) 52.6 (599) 59.5 (1,435) Male 34.4 (438) 47.4 (539) 40.5 (977) Age, years 46.7±12.7 (1,274) 55.8±13.1 (1,138) 51.0±13.7 (2,412) BMI, kg/m2 31.8±7.6 (1,274) 29.5±6.1 (1,138) 30.7±7.0 (2,412) Fasting serum glucose, mmol/l 5.32±1.14 (1,247) 5.42±1.46 (1,109) 5.37±1.30 (2,356) Fasting serum insulin, mU/l 10.8±11.2 (1,093) 8.0±5.7 (1,078) 9.4±9.0 (2,171) Hypertensiona 70.2 (894) 73.6 (838) 71.8 (1,732) Fig. 1 Genome scan plots for fasting serum insulin concentra- tions. Dotted line African Americans; solid line Caucasians 663 T a b le 2 L in k ag e re su lt s: fa st in g in su li n , g lu co se , H O M A an al y si s an d b iv ar ia te an al y si s L o ca ti o n H O M A a F as ti n g in su li n a F as ti n g g lu co se a B iv ar ia te b M ar k er C H R A A E A A A E A A A E A A A E A D 2 S 4 4 1 / D 2 S 1 3 9 4 2 1 .0 8 @ 8 0 .0 0 .5 0 @ 9 8 .0 1 .4 1 @ 7 8 .0 1 .4 2 @ 9 9 .0 1 .9 0 @ 9 6 .0 (8 6 .0 , 1 0 7 .0 ) 0 .0 0 1 4 c 0 .0 0 @ 9 6 .0 1 .2 4 @ 9 6 .0 0 .6 5 @ 9 9 .0 D 2 S 1 7 9 0 2 0 .3 1 @ 1 0 6 .0 1 .0 3 @ 1 0 9 .0 0 .2 2 @ 1 0 2 .0 2 .1 2 @ 1 0 9 .0 (9 5 .0 , 1 3 7 .0 ) 0 .0 0 0 7 c 1 .4 1 @ 1 0 3 .0 0 .0 0 @ 1 0 9 .0 0 .5 5 @ 1 0 6 .0 1 .1 2 @ 1 0 8 .0 D 4 S 3 2 4 3 4 0 .1 2 @ 9 4 .0 2 .4 6 @ 8 1 .0 (7 2 .0 , 1 0 3 .0 ) 0 .0 0 0 3 c 0 .1 7 @ 9 2 .0 2 .3 0 @ 8 1 .0 (7 3 .0 , 1 0 4 .0 ) 0 .0 0 0 4 c 0 .0 0 @ 8 6 .0 0 .0 0 @ 8 1 .0 0 .6 3 @ 9 6 .0 1 .1 7 @ 8 1 .0 D 5 S 8 1 7 / D 5 S 2 8 4 5 5 0 .3 3 @ 2 0 .0 2 .0 0 @ 1 9 .0 (1 1 .0 , 3 8 .0 ) 0 .0 0 1 0 c 0 .5 8 @ 2 0 .0 2 .3 6 @ 2 0 .0 (1 1 .0 , 3 7 .0 ) 0 .0 0 0 4 c 0 .0 0 @ 2 4 .0 2 .0 7 @ 2 6 .0 (2 1 .0 , 3 8 .0 ) 0 .0 0 0 9 c 0 .7 2 @ 2 1 .0 3 .1 1 @ 2 6 .0 (2 1 .0 , 3 8 .0 ) 0 .0 0 0 2 c D 7 S 8 2 1 / D 7 S 1 7 9 9 7 0 .4 1 @ 11 4 .0 0 .6 8 @ 11 5 .0 0 .1 4 @ 11 2 .0 1 .8 8 @ 11 5 .0 (1 0 3 .0 , 1 2 5 .0 ) 0 .0 0 1 5 c 0 .2 0 @ 11 0 .0 0 .0 0 @ 11 1 .0 0 .1 0 @ 11 6 .0 1 .8 6 @ 11 1 .0 (1 0 2 .0 , 1 2 6 .0 ) 0 .0 0 3 4 c D 7 S 5 5 9 7 1 .6 9 @ 1 8 2 .0 (1 5 6 .0 , – ) 0 .0 0 2 4 c 0 .0 9 @ 1 8 0 .0 0 .3 7 @ 1 8 2 .0 0 .0 4 @ 1 8 2 .0 0 .2 7 @ 1 8 0 .0 0 .0 0 @ 1 8 2 .0 0 .1 6 @ 1 8 2 .0 0 .0 0 @ 1 8 2 .0 D 9 S 1 8 3 8 8 1 .6 9 @ 2 5 .0 (6 .0 , 3 6 .0 ) 0 .0 0 2 4 c 0 .3 8 @ 2 4 .0 1 .1 4 @ 2 5 .0 0 .7 3 @ 2 3 .0 0 .0 2 @ 2 4 .0 0 .0 3 @ 2 4 .0 1 .4 0 @ 2 5 .0 0 .2 6 @ 2 4 .0 D 9 S 1 8 3 8 9 0 .0 @ 1 6 4 .0 0 .1 2 @ 1 6 2 .0 0 .0 0 @ 1 6 4 .0 0 .0 0 @ 1 6 4 .0 0 .0 0 @ 1 6 4 .0 1 .8 4 @ 1 6 4 .0 (1 5 2 .0 ,– ) 0 .0 0 1 6 c 0 .2 4 @ 1 6 4 .0 1 .7 9 @ 1 6 4 .0 (1 5 4 .0 ,– ) 0 .0 0 4 1 c D 1 0 S 1 2 1 3 / D 1 0 S 1 2 4 8 1 0 7 3 .0 @ 1 7 1 .0 0 .7 3 @ 1 7 1 .0 0 .3 3 @ 1 6 8 .0 0 .1 7 @ 1 7 0 .0 0 .0 0 @ 1 6 0 .0 1 .5 1 @ 1 6 0 .0 (1 4 6 .0 ,– ) 0 .0 0 4 0 c 0 .2 8 @ 1 7 0 .0 1 .1 4 @ 1 6 1 .0 D 11 S 9 1 2 11 0 .1 1 @ 1 4 6 .0 0 .0 @ 1 3 5 .0 0 .3 4 @ 1 3 6 .0 0 .0 0 @ 1 3 6 .0 0 .6 1 @ 1 4 3 .0 0 .0 0 @ 1 3 6 .0 1 .5 5 @ 1 3 5 .0 (1 2 0 .0 ,– ) 0 .0 0 7 7 c 0 .0 0 @ 1 3 5 .0 D 1 3 S 1 4 9 3 / D 1 3 S 8 9 4 1 3 0 .7 3 @ 1 0 .0 0 .2 6 @ 8 .0 0 .8 2 @ 9 .0 0 .2 5 @ 8 .0 1 .3 0 @ 1 7 .0 0 .1 9 @ 3 0 .0 1 .5 1 @ 1 2 .0 (– ,5 4 .0 ) 0 .0 0 8 4 c 0 .0 2 @ 8 .0 D 1 3 S 3 2 5 / D 1 3 S 7 8 8 1 3 0 .0 2 @ 4 2 .0 0 .0 @ 4 2 .0 0 .0 0 @ 4 2 .0 0 0 .0 0 @ 4 2 .0 1 .8 1 @ 4 2 .0 (– ,5 0 .0 ) 0 .0 0 1 8 c 0 .1 2 @ 3 8 .0 1 .6 2 @ 4 3 .0 (– ,5 0 .0 ) 0 .0 0 6 4 c 0 .0 9 @ 3 6 .0 D 1 3 S 3 1 7 / D 1 3 S 7 9 3 1 3 0 .1 1 @ 7 0 .0 0 .1 0 @ 5 4 .0 0 .0 0 @ 6 4 .0 0 .0 1 @ 6 2 .0 0 .8 2 @ 7 9 .0 1 .6 4 @ 6 4 .0 (5 4 .0 ,7 7 .0 ) 0 .0 0 2 8 c 1 .3 8 @ 8 3 .0 1 .6 5 @ 6 5 .0 (5 5 .0 ,8 0 .0 ) 0 .0 0 5 8 c D 1 8 S 8 7 7 1 8 1 5 .0 @ 3 6 .0 0 .0 0 @ 4 6 .0 0 .0 1 @ 4 6 .0 0 .0 0 @ 4 6 .0 1 .7 0 @ 4 6 .0 (2 8 .0 ,5 9 .0 ) 0 .0 0 2 4 c 0 .0 0 @ 4 6 .0 1 .2 3 @ 4 6 .0 0 .0 0 @ 4 6 .0 D 1 9 S 1 0 3 4 1 9 2 .2 6 @ 11 .0 (– ,2 2 .0 ) 0 .0 0 0 6 c 0 .6 3 @ 0 .0 2 .2 8 @ 11 .0 (– ,2 0 .0 ) 0 .0 0 0 4 c 0 .5 9 @ 2 .0 0 .5 5 @ 5 .0 0 .0 0 @ 1 0 .0 2 .4 6 @ 11 .0 (– ,1 8 .0 ) 0 .0 0 0 8 c 0 .1 3 @ 2 .0 A A A fr ic an A m er ic an , E A E u ro p ea n A m er ic an , C H R ch ro m o so m e a S ig n if ic an t re su lt s re p o rt ed as m ax im u m L O D sc o re @ lo ca ti o n in ce n ti M o rg an s (L O D -1 in te rv al ) em p ir ic al p v al u e b S ig n if ic an t re su lt s re p o rt ed as m ax im u m L O D sc o re @ lo ca ti o n in ce n ti M o rg an s (L O D -1 in te rv al ) p v al u e c L O D -1 su p p o rt in te rv al an d p v al u es fo r m ax im u m L O D sc o re s ab o v e 1 .5 664 of 5.37±1.30 mmol/l and a mean fasting serum insulin con- centration of 9.40±9.0 mU/l. Among these 2,412 individuals, there were 1,329 sibling pairs (513 AA), 610 avuncular pairs (190 AA), 156 half-sibling pairs (144 AA), 185 first cousins (54 AA), and 2 EA monozygotic twins. The mean family size with insulin and/or glucose data was 2.34 members (AA 2.09, EA 2.73). The h2 of serum insulin was 0.47±0.08 in EAs and 0.28± 0.08 in AAs (p<0.0001 for both), after controlling for the significant main and interactive effects of age, sex and BMI. An additional 33% and 31% of the variance in EAs and AAs, respectively, was due to measured covariates. Figure 1 contains the univariate genome-wide scan results for fasting erum insulin concentration in EAs and AAs. A maximum LOD score of 2.36 was observed on chromosome 5 at 20.0 cM (marker D5S817/D5S2845, p=0.0004), with lesser peaks of LOD 2.30 on chromosome 4 (81 cM, marker D4S3243) and 2.12 on chromosome 2 (109 cM, marker D2S1790) in EAs, and 2.28 on chromosome 19 (11 cM, marker D19S1034) in AAs, p<0.0007 for all (Fig. 1). Table 2 contains the re- sults of the genome scan for fasting serum insulin (as well as for HOMA, fasting serum glucose and the bivariate analysis), reporting maximum LOD scores of more than 1.5, position, LOD-1 interval and p value in AAs and EAs (see symbols and footnotes) and maximum LOD scores with position in all other scans in proximity to the sig- nificant results. The results of the HOMA genome scan are presented in Fig. 2 and Table 2. Similar regions of linkage were observed for fasting serum insulin concentrations on chromosomes 4 and 5 in EAs and on chromosome 19 in AAs. The h2 of serum glucose concentration was 0.51±0.08 in EAs and 0.29±0.09 in AAs (p≤0.0003 for both), after controlling for the significant main and interactive effects of age, sex, and BMI. An additional 22% and 20% of the variance in EAs and AAs, respectively, was due to mea- sured covariates. The univariate genome-wide scan results for fasting serum glucose are depicted in Fig. 3. A maxi- mum LOD score of 2.07 was observed on chromosome 5 at 26.0 cM (marker D5S817/D5S2845, p=0.0009) in EAs and a lesser peak was observed on chromosome 2: LOD 1.90 at 96.0 cM (marker D2S441/D2S1394), p<0.0014 in AAs (Fig. 3; Table 2). In AAs, the genetic correlation between fasting serum glucose and insulin was nonsignificant (p=0.37), while the environmental correlation was rE=0.46±0.07 (p<0.0001). In EAs, the genetic correlation between fasting serum glucose and insulin was also nonsignificant (p=0.86), while the environmental correlation was rE=0.35±0.10 (p=0.0007). These data suggest that the primary genetic determinants of fasting serum glucose concentration are different from those that contribute to the variation in fasting serum insulin concentration. A bivariate genome-wide scan for loci con- tributing to both fasting serum glucose and insulin con- centrations in both races demonstrated eight regions with maximum LOD scores above 1.5 (four in AAs and four Fig. 2 Genome scan plots for HOMA. Dotted line African Americans; solid line Caucasians 665 in EAs). These regions are depicted, separately by race, in Fig. 4 and Table 2. Discussion This report is the first to reveal that inherited factors appear to play important roles in the regulation of fasting serum insulin and glucose concentrations in hypertensive, nondia- betic AAs and Caucasians. The heritability of fasting serum insulin and glucose concentrations remained highly signif- icant even after controlling for the effects of significant covariates. The marked heritability of fasting serum glucose and insulin concentrations appears consistent with other reports in Framingham [6, 7], Amish [8], and HERITAGE families [9]. Additionally, the genome scans in AAs and EAs provided suggestive evidence that genes regulating fasting serum insulin concentrations and insulin sensitivity (HOMA) were present on chromosomes 19, 7, 5, 4 and 2, and genes regulating fasting glucose concentration were present on chromosomes 2, 5, 9, 13 and 18. In general, the linkage peaks for fasting insulin, HOMA and fasting glu- cose differed by ethnic group (see Table 2). Race-combined analyses added little, as results were driven by a single eth- nic group (data not shown). Although the bivariate genome scan demonstrated several regions with suggestive evidence for linkage, these results were probably driven by linkage to either fasting serum insulin or fasting serum glucose con- centrations alone, based on the low genetic correlation ob- served between these measures. Several genome-wide scans have been performed in non- diabetic families evaluated for prediabetic phenotypes and in multiplex type 2 diabetes families. Regions of linkage in several reports overlap with those observed in this Hy- perGEN analysis. On chromosome 19, linkage was detected at 18 cM for fasting insulin in Pima Indians (LOD 1.33) [23], and for type 2 diabetes and glucose intolerance in young-onset French families at 36 cM (LOD 1.26) [24]. Linkage with fasting glucose, and combined fasting and non-fasting glucose, was detected on chromosome 5 at 0 cM in the Framingham Offspring Study (LOD 1.09) [6], and Framingham Heart Study (LOD 1.65) [25]. The Hy- perGEN fasting serum glucose scan loci on chromosome 13 are near reported loci for related phenotypes in 580 Finnish families from the FUSION Study [26], i.e., 2-h insulin (LOD 2.86 at 65 cM) and insulin secretion (insulin/ glucose) (LOD 1.37 at 62 cM), and loci for type 2 diabetes in AAs with earlier age at diagnosis (p<0.006 at 76 cM) [27] and Japanese families (LOD 0.94, 79 cM) [28]. Link- age for these phenotypes resides within, or near, the peaks where we found evidence for linkage to fasting insulin (chromosomes 19 and 5) and fasting glucose (5 and 13) in the univariate analyses. Therefore, the regions identified in the HyperGEN genome scan as influencing fasting serum insulin and glucose concentrations may reflect genes that also play major roles in susceptibility to diabetes mellitus Fig. 3 Genome scan plots for fasting serum glucose concen- trations. Dotted line African Americans; solid line Caucasians 666 and/or related phenotypes. Our data are unique, however, in that they are from a biracial population enriched for the presence of essential hypertension. Fasting serum glucose concentrations clearly fluctuate in individuals with insulin resistance and in those with diabe- tes mellitus. In addition, little is known about the natural history of insulin resistance among treated and untreated hypertensive subjects. These difficulties are encountered in all cross-sectional studies. The overlapping regions of link- age observed for the diabetes-related phenotypes in Pima [23] and Finnish [26] families, and the Framingham Off- spring [6] and Heart Studies [25], support the existence of genes affecting fasting serum insulin concentrations on chro- mosomes 19 and 5 and fasting serum glucose on chromo- some 13. In conclusion, this report analysed the heritability of fasting serum insulin and glucose concentrations in non- diabetic members of multiplex hypertensive families. Ele- vated serum insulin concentrations and fasting blood sugars (insulin resistance) are well recognised risk factors for the development of heart attack and stroke. The heritabilities of fasting serum insulin and glucose concentrations were signif- icant after controlling for the main and interactive effects of age, sex, and BMI. Additionally, suggestive evidence for genetic linkage to fasting serum insulin concentrations and insulin sensitivity (HOMA) were detected on chromosomes 19, 5, 4, and 2; and suggestive evidence for linkage to fasting serumglucoseconcentrationswasdetectedonchromosomes2, 5, 9, 13, and 18. These results suggest that the genes regulating susceptibility to insulin resistance, hyperglycaemia and dia- betes-related phenotypes may reside in these regions and play an important role in the observed familial aggregation of cardiovascular disease. It is important that additional large, family-based analyses in hypertensive cohorts attempt to re- produce these results and identify the causative genes. Acknowledgements HyperGEN participating institutions and prin- cipal staff: S.C. Hunt, R.R. Williams (deceased), H. Coon, P.N. Hopkins, J. Hood, L. Wu, J. Skuppin (Network Center/University of Utah Field Center); A. Oberman, C.E. Lewis, M.T. Weaver, P. Johnson, S. Walker, C. Oden (University of Alabama at Birmingham Field Center); R.C. Ellison, R.H. Myers, Y. Zhang, L. Djoussé, J.B. Wilk, G.L. Splansky (Boston University/Framingham Field Center); D. Arnett, A.R. Folsom, M. Miller, J. Pankow, G. Feitl, B. Lux (University of Minnesota Field Center); G. Heiss, B.I. Freedman, K. North, K. Rose, A. Haire (University of North Carolina Field Center); D.C. Rao, M.A. Province, I.B. Borecki, A. Adelman, D. Morgan, K. Schwander, D. Lehner, A. Kraja, S. Mandel (Data Coordinating Center, Washington University); J.H. Eckfeldt, C. Leiendecker-Foster, R.C. McGlennen, G. Rynders, M.Y. Tsai, J. Bucksa (Central Biochemistry Lab, University of Minnesota); M. Leppert, S.C. Hunt, J.M. Lalouel, R. Weiss (Molecular Genetics Laboratory, University of Utah); S.E. Old, M. Higgins (retired), C. Jaquish, M. Lundberg, M. Gerschenson (Na- tional Heart, Lung, and Blood Institute). 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Diabetes 52:209–213 668 http://aspex.sourceforge.net/usage.html http://aspex.sourceforge.net/usage.html Genome-wide scans for heritability of fasting serum insulin and glucose concentrations in hypertensive families Abstract Abstract Abstract Abstract Abstract Introduction Subjects and methods Population Phenotyping Genotyping Statistical analysis Results Discussion References << /ASCII85EncodePages false /AllowTransparency false /AutoPositionEPSFiles true /AutoRotatePages /None /Binding /Left /CalGrayProfile (None) /CalRGBProfile (sRGB IEC61966-2.1) /CalCMYKProfile (ISO Coated) /sRGBProfile (sRGB IEC61966-2.1) /CannotEmbedFontPolicy /Warning /CompatibilityLevel 1.3 /CompressObjects /Off /CompressPages true /ConvertImagesToIndexed true /PassThroughJPEGImages true /CreateJDFFile false /CreateJobTicket false /DefaultRenderingIntent /Perceptual /DetectBlends true /ColorConversionStrategy /sRGB /DoThumbnails true /EmbedAllFonts true /EmbedJobOptions true /DSCReportingLevel 0 /EmitDSCWarnings false /EndPage -1 /ImageMemory 524288 /LockDistillerParams true /MaxSubsetPct 100 /Optimize true /OPM 1 /ParseDSCComments true /ParseDSCCommentsForDocInfo true /PreserveCopyPage true /PreserveEPSInfo true /PreserveHalftoneInfo false /PreserveOPIComments false /PreserveOverprintSettings true /StartPage 1 /SubsetFonts false /TransferFunctionInfo /Apply /UCRandBGInfo /Preserve /UsePrologue false /ColorSettingsFile () /AlwaysEmbed [ true ] /NeverEmbed [ true ] /AntiAliasColorImages false /DownsampleColorImages true /ColorImageDownsampleType /Bicubic /ColorImageResolution 150 /ColorImageDepth -1 /ColorImageDownsampleThreshold 1.50000 /EncodeColorImages true /ColorImageFilter /DCTEncode /AutoFilterColorImages true /ColorImageAutoFilterStrategy /JPEG /ColorACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /ColorImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000ColorACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000ColorImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasGrayImages false /DownsampleGrayImages true /GrayImageDownsampleType /Bicubic /GrayImageResolution 150 /GrayImageDepth -1 /GrayImageDownsampleThreshold 1.50000 /EncodeGrayImages true /GrayImageFilter /DCTEncode /AutoFilterGrayImages true /GrayImageAutoFilterStrategy /JPEG /GrayACSImageDict << /QFactor 0.76 /HSamples [2 1 1 2] /VSamples [2 1 1 2] >> /GrayImageDict << /QFactor 0.15 /HSamples [1 1 1 1] /VSamples [1 1 1 1] >> /JPEG2000GrayACSImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /JPEG2000GrayImageDict << /TileWidth 256 /TileHeight 256 /Quality 30 >> /AntiAliasMonoImages false /DownsampleMonoImages true /MonoImageDownsampleType /Bicubic /MonoImageResolution 600 /MonoImageDepth -1 /MonoImageDownsampleThreshold 1.50000 /EncodeMonoImages true /MonoImageFilter /CCITTFaxEncode /MonoImageDict << /K -1 >> /AllowPSXObjects false /PDFX1aCheck false /PDFX3Check false /PDFXCompliantPDFOnly false /PDFXNoTrimBoxError true /PDFXTrimBoxToMediaBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXSetBleedBoxToMediaBox true /PDFXBleedBoxToTrimBoxOffset [ 0.00000 0.00000 0.00000 0.00000 ] /PDFXOutputIntentProfile (None) /PDFXOutputCondition () /PDFXRegistryName (http://www.color.org?) /PDFXTrapped /False /SyntheticBoldness 1.000000 /Description << /DEU /ENU >> >> setdistillerparams << /HWResolution [2400 2400] /PageSize [2834.646 2834.646] >> setpagedevice