Biomedical subjects

Steven C Hunt

Publications and source records attributed to Steven C Hunt.

At least 55 records · Page 3Linked to original sources

PubMed2004

Model-fitting and linkage analysis of sodium-lithium countertransport.

Increased sodium-lithium countertransport activity (SLC) associates with hypertension and is highly heritable, yet the underlying genes remain unknown. SLC, measured on 1113 and remeasured 2-3 years later on 675 adult members of 48 Utah pedigrees, was tested for candidate gene association, major locus inheritance, and linkage to genome scan markers using a bivariate model with genotype-specific effects of age, body mass index (BMI), and triglycerides level (TG). No effect of the alpha-adducin Gly460Trp polymorphism on SLC was found. In contrast, SLC increased with age in carriers of apolipoproteinE varepsilon2 (85 individuals; 8.7% of the sample) and decreased in noncarriers. Model-fitting analyses inferred two additional loci with genotype-specific responses to BMI and TG. Using the inferred model, lod scores >2 were obtained for D3S3038, D11S4464, and D10S677 for the BMI-responsive locus, and for D8S1048 for the TG-responsive locus.

Adult↗

PubMed2004

Linkage analysis of diabetes status among hypertensive families: the Hypertension Genetic Epidemiology Network study.

Type 2 diabetes susceptibility is determined by multiple genetic and environmental factors. Genome-wide linkage scans have localized common regions, possibly harboring susceptibility genes on chromosomes 1, 2, 12, and 20. Variability in linkage findings underscores the probable genetic heterogeneity of type 2 diabetes. Thus, we conducted a genome scan of diabetes status using maximum likelihood methods that model affection status by a liability threshold model. Hypertensive sibships and their offspring and/or parents in the Hypertension Genetic Epidemiology Network study were recruited from five field centers. The diabetes phenotype was derived using the World Health Organization criteria and adjusted for race/study center, age, age2, sex, and with and without percent body fat. In total, 567 diabetic participants were identified in 437 families. Variance component linkage analysis was performed among 1,545 Caucasians and 1,608 African Americans using race-specific marker allele frequencies. We detected a quantitative trait loci (QTLs) influencing diabetes variance (logarithm of odds = 3.4) on chromosome 22, which overlaps a positive type 2 diabetes finding among Canadian Oji-Cree Indians. We also observed suggestive evidence for linkage on chromosomes 1, 2, 5, 8, 14, 17, and 19. The identification and replication of type 2 diabetes QTLs will bring us closer to the detection of functional genes that influence diabetes susceptibility.

Chromosome Mapping↗

PubMed2003

Soluble epoxide hydrolase variant (Glu287Arg) modifies plasma total cholesterol and triglyceride phenotype in familial hypercholesterolemia: intrafamilial association study in an eight-generation hyperlipidemic kindred.

Plasma lipid and lipoprotein in general reflect the complex influences of multiple genetic loci, for instance, even familial hypercholesterolemia (FH), a representative example of monogenic hyperlipidemia, often presents with phenotypic heterogeneity. In the course of investigating familial coronary artery disease in Utah, we studied 160 members of an eight-generation extended family of FH in which 69 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and ten with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). Soluble epoxide hydrolase ( EPHX2, sEH) plays a role in disposition of epoxides in plasma lipoprotein particles. Intrafamilial correlation analysis of the modifier effect of Glu287Arg substitution in the EPHX2 gene was carried out among 79 LDLR mutation carriers and 81 noncarriers. In the carriers, plasma cholesterol levels were elevated among carriers of the 287Arg allele (mean +/- SD=358 +/- 72 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=302 +/- 72 mg/dl) (p=0.0087). Similarly, in the LDLR mutation carriers, the plasma triglyceride levels were elevated among carriers of the 287Arg allele (mean +/- SD=260 +/- 100 mg/dl) in comparison with 287Glu homozygotes (mean +/- SD=169 +/- 83 mg/dl) (p=0.020). No such gene-interactive effect was observed among noncarriers of the LDLR mutation. Half of the patients who presented with HLPIIb had inherited a defective LDLR allele as well as an EPHX2-287Arg allele, whereas the majority who presented with HLPIIa had a defective LDLR allele but not an EPHX2-287Arg allele. These results indicate a significant modification of the phenotype of FH with defective LDLR allele by EPHX2-287Arg variation in our studied kindred.

Alleles↗

PubMed2003

Genetic determinants of nonmodulating hypertension.

We sought to determine whether genes of the renin-angiotensin-aldosterone system can predict the nonmodulating intermediate phenotype in essential hypertension. Aldosterone responses to angiotensin II were assessed in 298 subjects with hypertension. Subjects were genotyped at the angiotensinogen M235T, angiotensin-converting enzyme I/D, aldosterone synthase C-344 T, renin, angiotensin II type 1 receptor, and adducin loci. The data were analyzed by Student t test, ANOVA, stepwise linear regression and general linear model or GENMOD regression techniques, and chi2 analysis odds ratios (ORs). Aldosterone response varied by genotype for angiotensin and aldosterone synthase but not for the other loci. The combination of angiotensinogen 235 TT and angiotensin-converting enzyme DD showed further reduction (P=0.0377) when compared with angiotensinogen 235 TT alone, an example of genetic epistasis. When the subject was required also to possess the CYP11B2 -344 TT genotype, there was a further substantial reduction. Of these 3 loci, only angiotensinogen 235 TT significantly increased the OR of predicting the nonmodulating hypertensive phenotype (OR, 2.00; 95% confidence interval, 1.152 to 3.51). However, when angiotensin-converting enzyme DD was combined with angiotensinogen 235 TT, the OR nearly doubled to 3.74, with a further increase to 5.36-fold when the subject possessed all 3 genotypes. Thus, the angiotensinogen, angiotensin-converting enzyme, and aldosterone synthase genotypes identified individuals with the nonmodulating phenotype with an increasing degree of fidelity. For this subclass of essential hypertension, it is likely that genotyping can be substituted for complex phenotyping for therapeutic and preventive decision making.

Age Factors↗

PubMed2003

Genomewide linkage and linkage disequilibrium analyses identify COL6A1, on chromosome 21, as the locus for ossification of the posterior longitudinal ligament of the spine.

Ossification of the posterior longitudinal ligament (OPLL) of the spine is a subset of "bone-forming" diseases, characterized by ectopic ossification in the spinal ligaments. OPLL is a common disorder among elderly populations in eastern Asia and is the leading cause of spinal myelopathy in Japan. We performed a genomewide linkage study with 142 affected sib pairs, to identify genetic loci related to OPLL. In multipoint linkage analysis using GENEHUNTER-PLUS, evidence of linkage to OPLL was detected on chromosomes 1p, 6p, 11q, 14q, 16q, and 21q. The best evidence of linkage was detected near D21S1903 on chromosome 21q22.3 (maximum Zlr=3.97); therefore, the linkage region was extensively investigated for linkage disequilibrium with single-nucleotide polymorphisms (SNPs) covering 20 Mb. One hundred fifty positional candidate genes lie in the region, and 600 gene-based SNPs were genotyped. There were positive allelic associations with seven genes (P<.01) in 280 patients and 210 controls, and four of the seven genes were clustered within a region of 750 kb, approximately 1.2 Mb telomeric to D21S1903. Extensive linkage disequilibrium and association studies of the four genes indicated that SNPs in the collagen 6A1 gene (COL6A1) were strongly associated with OPLL (P=.000003 for the SNP in intron 32 [-29]). Haplotype analysis with three SNPs in COL6A1 gave a single-point P value of.0000007. Identification of the locus of susceptibility to OPLL by genomewide linkage and linkage disequilibrium studies permits us to investigate the pathogenesis of the disease, which may lead to the development of novel therapeutic tools.

Chromosome Mapping↗

PubMed2003

Growth hormone receptor variant (L526I) modifies plasma HDL cholesterol phenotype in familial hypercholesterolemia: intra-familial association study in an eight-generation hyperlipidemic kindred.

Defect of growth hormone receptor (GHR) is classically known to cause Laron syndrome, characterized by short stature, specific facial appearance, elevated serum growth hormone levels, and decreased insulin-like growth factor I levels. In addition, an increased cardiovascular risk due to elevated plasma total and LDL cholesterol levels marks another feature of the disease. Growth hormone (GH) plays an important role in the regulation of lipoprotein metabolism. GH status was found to be an independent determinant of plasma total cholesterol and triglyceride levels in humans. We studied a total of 207 members of eight-generation extended family of familial hypercholesterolemia (FH) in which affected members presented with various lipoprotein phenotypes. Intra-familial correlation analysis of a modifier effect of a Leu526Ile substitution in GHR gene was carried out among 95 carriers for LDL receptor gene (LDLR) mutation and 112 non-carriers. When plasma high-density lipoprotein cholesterol (HDL-c) levels in the LDLR-mutation carriers were compared, a significant lowering effect of HDL-c was observed with the Leu allele; the values were lowest among Leu/Leu homozygotes (mean +/- SD = 37 +/- 2 mg/dl), highest in Ile/Ile homozygotes (50 +/- 4 mg/dl), and intermediate among Leu/Ile heterozygotes (41 +/- 2 mg/dl) (P = 0.0021). The results indicate a significant modification of the phenotype of FH with the defective LDLR allele, by GHR Leu variation in the kindred studied.

Adult↗

PubMed2003

Genome-wide multipoint parametric linkage analysis of pulse pressure in large, extended utah pedigrees.

High pulse pressure, a measure of arterial aging, is an important predictor of cardiovascular and general mortality. It has been suggested that the genetic etiology of pulse pressure is the same as systolic blood pressure. We performed a genome-wide, multipoint, parametric linkage analysis in 26 large, extended Utah pedigrees to locate genes affecting pulse pressure. Four parametric models were considered, including dominant and recessive modes of inheritance involving genes for high and low pulse pressure. Linkage analysis revealed 11 regions with a logarithm of the odds (LOD) >1.5, including 2 regions attaining genome-wide suggestive evidence for linkage after accounting for multiple tests. Inspecting pedigree-specific multipoint linkage evidence suggested that these 2 regions localized to 15.7 cM on chromosome 8p (LOD=2.89), between markers D8S136 and D8S1477, and 20.0 cM on chromosome 12q (LOD=2.59), between D12S1300 and D12S2070. Both regions were identified better by pulse pressure compared with equivalent analyses with systolic or diastolic blood pressure. Results for pulse pressure overlapped favorably with those of others for related blood pressure phenotypes and support the hypothesis that genes with pleiotropic effects on blood pressure phenotypes do exist, but that the genetic etiologies are not identical. In conclusion, our results suggest that pulse pressure might be of use for identifying genes involved in blood pressure phenotypes and arterial aging.

Adolescent↗

PubMed2003

Coronary artery disease risk in familial combined hyperlipidemia and familial hypertriglyceridemia: a case-control comparison from the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: Conventional wisdom suggests that a diagnosis of familial combined hyperlipidemia (FCHL) carries a substantially greater risk of premature coronary artery disease (CAD) than a diagnosis of familial hypertriglyceridemia (FHTG). However, no population-based studies have critically addressed this issue. METHODS AND RESULTS: FCHL and FHTG were diagnosed in 10.2% and 12.3% of 334 random control families and in 16.7% and 20.5% of 293 families with at least one case of premature CAD. The diagnosis of either FCHL or FHTG in an individual was associated with an odds ratio for CAD of 2.0 (P=0.003 and 0.002, respectively). However, odds ratios for premature CAD associated with both lipid disorders decreased substantially and identically with further adjustment for hypertension, diabetes, and especially HDL cholesterol, triglycerides, or apolipoprotein B. Similar results were found for differences in carotid intima-medial thickness and ankle-brachial index. Metabolic syndrome was identified in 65% of FCHL and 71% of FHTG patients compared with 19% in controls without FCHL or FHTG and was associated with an odds ratio of 3.3 (P<0.0001). The increased prevalence of the metabolic syndrome alone could account for the elevated CAD risk associated with both FCHL and FHTG. CONCLUSIONS: FCHL and FHTG appear more alike than dissimilar. Further, the risk of CAD in FCHL and FHTG was strongly related to features of the metabolic syndrome. These findings suggest that the hypertriglyceridemia in FHTG is not benign and may warrant a change in epidemiological, genetic, and clinical approaches to these lipid disorders.

Adult↗

PubMed2003

Family history assessment: strategies for prevention of cardiovascular disease.

Family history assessment can be used to combine population-wide health promotion and risk-reduction efforts with a high-risk, targeted approach to help reduce the burden of cardiovascular disease (CVD). Family history is an independent predictor of CVD, and the upper portion of the family history distribution explains a larger fraction of CVD in the population than can be explained by extreme values of other risk factors (e.g., blood pressure and cholesterol). A positive family history of disease captures the underlying complexities of gene-gene and gene-environment interactions by identifying families with combinations of risk factors, both measured and unmeasured, that lead to disease expression. Family history is a useful tool for identifying most prevalent cases of CVD and for population-wide disease-prevention efforts. A positive family history also identifies the relatively small subset of families in the population at highest risk for CVD who may benefit most from targeted screening and intensive intervention.

Cardiovascular Diseases↗

PubMed2003

A meta-analysis of genome-wide linkage scans for hypertension: the National Heart, Lung and Blood Institute Family Blood Pressure Program.

BACKGROUND: Four multicenter Networks (GenNet, GENOA, HyperGEN, SAPPHIRe) form the National Heart, Lung and Blood Institute Family Blood Pressure Program (FBPP), to search for hypertension/blood pressure (BP) genes. The networks used different family designs and targeted multiple ethnic groups, using standardized protocols and definitions. Linkage genome scans were done on samples within each network (N = 6245 relatives). METHODS: The evidence was synthesized using meta-analysis. RESULTS: Combining ethnic groups, no region reached LOD >2, but several small peaks were identified, including chromosome 2p where two other recent reports find hypertension linkage. CONCLUSIONS: No regions show uniformly large effects on BP/hypertension in all populations.

Chromosome Mapping↗

PubMed2003

Dietary linolenic acid and carotid atherosclerosis: the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: Dietary intake of linolenic acid is associated with a lower risk of cardiovascular disease mortality. However, it is unknown whether linolenic acid is associated with a lower risk of carotid atherosclerosis. OBJECTIVE: The objective was to examine the association between dietary linolenic acid and the presence of atherosclerotic plaques and the intima-media thickness of the carotid arteries. DESIGN: In a cross-sectional design, we studied 1575 white participants of the National Heart, Lung, and Blood Institute Family Heart Study who were free of coronary artery disease, stroke, hypertension, and diabetes mellitus. High-resolution ultrasound was used to assess intima-media thickness and the presence of carotid plaques beginning 1 cm below to 1 cm above the carotid bulb. We used logistic regression and a generalized linear model for the analyses. RESULTS: From the lowest to the highest quartile of linolenic acid intake, the prevalence odds ratio (95% CI) of a carotid plaque was 1.0 (reference), 0.47 (0.30, 0.73), 0.38 (0.22, 0.66), and 0.49 (0.26, 0.94), respectively, in a model that adjusted for age, sex, energy intake, waist-to-hip ratio, education, field center, smoking, and the consumption of linoleic acid, saturated fat, fish, and vegetables. Linoleic acid, fish long-chain fatty acids, and fish consumption were not significantly related to carotid artery disease. Linolenic acid was inversely related to thickness of the internal and bifurcation segments of the carotid arteries but not to the common carotid artery. CONCLUSION: Higher consumption of total linolenic acid is associated with a lower prevalence odds of carotid plaques and with lesser thickness of segment-specific carotid intima-media thickness.

Adult↗

PubMed2003

Dietary linolenic acid is inversely associated with plasma triacylglycerol: the National Heart, Lung, and Blood Institute Family Heart Study.

BACKGROUND: Dietary intake of linolenic acid is associated with a decreased risk of cardiovascular disease mortality. However, the mechanisms by which dietary linolenic acid affects cardiovascular disease risk are not clearly understood. OBJECTIVE: We examined the association between dietary linolenic acid and plasma triacylglycerol concentrations. DESIGN: In a cross-sectional design, we studied 4440 white subjects (2036 men and 2404 women) aged 25-93 y who participated in the National Heart, Lung, and Blood Institute Family Heart Study. We used generalized linear models to estimate adjusted mean triacylglycerol concentrations according to categories of total dietary linolenic acid (alpha- and gamma-linolenic acid) intake. RESULTS: The mean dietary linolenic acid intakes were 0.81 and 0.69 g/d for the men and the women, respectively. High consumption of dietary linolenic acid was associated with young age; high intakes of energy, fat, carbohydrates, fruit, vegetables, and fish; low HDL cholesterol; current smoking; and frequent consumption of creamy salad dressing. High consumption of dietary linolenic acid was also associated with low plasma triacylglycerol concentrations. From the lowest to the highest quintile of linolenic acid intake, the multivariate-adjusted mean triacylglycerol concentrations were 1.75 (95% CI: 1.65, 1.85), 1.74 (1.66, 1.82), 1.69 (1.61, 1.77), 1.66 (1.58, 1.74), and 1.54 (1.44, 1.64) mmol/L, respectively (P for linear trend = 0.007). When linolenic acid was used as a continuous variable, the corresponding regression coefficient was -0.2811 (-0.4922, -0.07001). CONCLUSIONS: Consumption of total linolenic acid is inversely related to plasma triacylglycerol concentrations in both white men and white women. This suggests a pathway by which dietary linolenic acid might reduce cardiovascular disease risk.

Adult↗

PubMed2003

Apolipoprotein H variant modifies plasma triglyceride phenotype in familial hypercholesterolemia: a molecular study in an eight-generation hyperlipidemic family.

In the course of investigating familial coronary artery disease in Utah, we studied 196 members of an eight-generation extended family of familial hypercholesterolemia (FH), in which 73 members were affected with type IIa hyperlipoproteinemia (HLPIIa; high plasma cholesterol) and 11 members with type IIb hyperlipoproteinemia (HLPIIb; high plasma cholesterol as well as plasma triglyceride). A splice-site mutation of the LDL receptor (LDLR) gene (IVS14 + G > A) co-segregated with elevated plasma cholesterol among all the members, but not with the elevated plasma triglyceride and VLDL cholesterol levels seen in HLPIIb patients. The apolipoprotein H (apoH) gene plays a role in plasma triglyceride removal and lipoprotein lipase enhancement. Intra-familial correlation analysis of the modifier effect of Val247Leu substitution in the apoH gene was carried out among 84 LDLR-mutation carriers and 112 non-carriers. When plasma triglyceride levels in the LDLR-mutation carriers were compared, the values were lowest among V/V homozygotes (mean +/- SD = 145 +/- 53 mg/dl), highest in L/L homozygotes (277 +/- 177 mg/dl), and intermediate among V/L heterozygotes (191 +/- 102 mg/dl) (p = 0.0015). All eleven patients who presented with HLPIIb had inherited both the defective LDLR allele and an apoH 247Leu allele, whereas all 45 carriers of the defective LDLR allele not carrying the apoH Leu allele presented with HLPIIa but not HLPIIb (p = 0.0001). These results indicate a significant modification of the phenotype of FH with a defective LDLR allele, by apoH Leu variation in our studied family.

Adolescent↗

PubMed2002

A genome-wide screen reveals evidence for a locus on chromosome 11 influencing variation in LDL cholesterol in the NHLBI Family Heart Study.

A genome scan was performed for low-density lipoprotein cholesterol concentration (LDL-C) in white subjects who were ascertained through the NHLBI Family Heart Study (FHS). The NIH Mammalian Genotyping Service (Marshfield, Wis.) genotyped 401 autosomal markers spaced at approximate 10-cM intervals. Additional FHS families were genotyped by the FHS Molecular Laboratory at the University of Utah for 243 markers; 645 subjects were typed in both laboratories so that a combined map of the 644 markers from the two screening sets (average distance of 5.46 cM) could be produced. Analyses were done on 2,799 genotyped subjects in 500 families where at least two genotyped persons in the family had measured LDL-C levels (average number of genotyped family members=5.95). The variance components method was used as implemented in GeneHunter (Kruglyak et al. 1996). Prior to analysis, each phenotype was adjusted, within sex, for age, age squared, body mass index, waist-hip ratio, alcohol, smoking, medication status for diabetes and hypertension, estrogen use, and field center location. Linkage analyses were performed, first excluding 305 subjects on lipid-lowering medications, then again including the data from these subjects. The highest peak was on chromosome 11 at 56.3-56.4 cM, with a maximum lod score of 3.72. Two genome scans of lipid traits in other populations have found peaks in this region. Other scores at or above 1.9 occurred on chromosomes 5 (lod=1.89 at 1.6 cM), 10 (lod=2.47 at 127.1 cM), 17 (lod=2.33 at 116.3 cM), and 21 (lod=2.74 at 45.2 cM).

Cholesterol, LDL↗

PubMed2002

Gender difference in diastolic function in hypertension (the HyperGEN study).

Although several studies indicate that there are gender differences in left ventricular (LV) systolic function, it remains unclear whether similar differences exist with regard to diastolic function. Accordingly, Doppler echocardiograms were analyzed in 515 male and 839 female, mostly treated (95%) hypertensive participants enrolled in the Hypertension Genetic Epidemiology Network (HyperGEN) study with no evidence of abnormal wall motion or significant valvular heart disease. There was no difference in age between genders, but after adjusting for age and race, men had lower body mass indexes (29.8 +/- 5.2 vs 32.3 +/- 7.6 kg/m(2)) and heart rates (67 +/- 12 vs 69 +/- 11 beats/min) and higher systolic and diastolic blood pressures (BP) than women (134 +/- 20 vs 130 +/- 21 and 80 +/- 11 vs 72 +/- 11 mm Hg, all p <0.001). LV mass/height(2.7) was slightly greater in women than in men (43 +/- 10 vs 42 +/- 9 g/m(2.7), p <0.05). After adjusting for age, race, systolic BP, body mass index, heart rate, and LV hypertrophy, both mitral E-wave (70 +/- 18 vs 77 +/- 19) and A-wave (74 +/- 15 vs 79 +/- 17, both p <0.001) velocities were lower in men than in women, but the mitral E/A ratio and atrial filling fraction were nearly identical in both genders. Deceleration time (221 +/- 55 vs 214 +/- 46 cm/s, p = 0.018) and isovolumic relaxation time (IVRT) were longer in men than in women (85 +/- 18 vs 81 +/- 17 cm/s, p <0.001). Prolonged IVRT was present in more men than women (14% vs 7%, p <0.05). In analyses of covariance, adjusting for age, race, systolic BP, body mass index, heart rate, and medications, male gender remained related to prolonged deceleration time and IVRT. Thus, in this population-based sample of hypertensive adults, men had evidence of slower early diastolic LV filling than women. This gender difference in diastolic function may provide insight into gender differences in congestive heart failure and other specific cardiovascular diseases.

Age Distribution↗

PubMed2002

Angiotensinogen genotype affects renal and adrenal responses to angiotensin II in essential hypertension.

BACKGROUND: Renovascular and adrenal responses to infused angiotensin II (Ang II) are intermediate phenotypes that may indirectly reflect tissue renin-angiotensin system activity. We examine herein angiotensinogen (AGT) as a candidate gene to help elucidate potential mechanisms for previously reported AGT linkage and association studies. METHODS AND RESULTS: Renal plasma flow and plasma aldosterone were measured before and after a 45-minute infusion of Ang II (3 ng x kg(-1) x min(-1)) in 190 hypertensive patients who were on carefully controlled high- and low-salt diets. Reduced renal vascular (P=0.0002) and adrenal (P=0.002) responses to infused exogenous Ang II were associated with the AGT -6A allele. In multiple logistic regression, greater body mass index, lower basal renal plasma flow, and higher diastolic blood pressure together with AGT -6A genotype were associated with lower renal vascular response. In contrast, only male sex and AGT -6A genotype were associated with lower adrenal response. When both the renal and adrenal responses to Ang II were in the lowest tertile, the AGT -6AA genotype was present in 55.6%; in contrast, when both responses were in the upper 2 tertiles, the -6AA genotype was present in only 17.8% (P=0.001). CONCLUSIONS: A clear association between AGT genotype and response to infused Ang II was demonstrated for both the renal vasculature and the adrenal, consistent with the hypothesis that the AGT -6A genotype results in increased tissue expression of angiotensinogen and Ang II.

Adolescent↗

PubMed2002

A major predisposition locus for severe obesity, at 4p15-p14.

Although the predisposition to morbid obesity is heritable, the identities of the disease-causing genes are largely unknown. Therefore, we have conducted a genomewide search with 628 markers, using multigenerational Utah pedigrees to identify genes involved in predisposition to obesity. In the genomewide search, we identified a highly significant linkage to high body-mass index in female patients, at D4S2632, with a multipoint heterogeneity LOD (HLOD) score of 6.1 and a nonparametric linkage (NPL) score of 5.3. To further delineate the linkage, we increased both the marker density around D4S2632 and the size of our pedigree data set. As a result, the linkage evidence increased to a multipoint HLOD score of 9.2 (at D4S3350) and an NPL score of 11.3. Evidence from almost half of the families in this analysis support this linkage, and therefore the gene in this region might account for a significant percentage of the genetic predisposition to severe obesity in females. However, further studies are necessary to clarify the effect that this gene has in males and in the general population.

Body Mass Index↗

PubMed2002

Interaction between the LDL-receptor gene bearing a novel mutation and a variant in the apolipoprotein A-II promoter: molecular study in a 1135-member familial hypercholesterolemia kindred.

Lipid and lipoprotein concentrations in plasma generally reflect complex influences of multiple genetic loci. Even an autosomal dominant disorder, familial hypercholesterolemia (FH), is characterized by phenotypic heterogeneity, as low-density lipoprotein (LDL) levels vary widely within the same pedigree. Molecular screening for LDL receptor ( LDLR) mutations among 75 patients with clinically apparent FH led to identification of a novel splice-site mutation (IVS14+1 G>A) shared by 14 patients. Genealogical research confirmed that all 14 carriers were part of the same 1135-member pedigree with a common ancestor. The mutation resulted in an abruptly truncated LDLR protein, reducing functional LDLR activity by half in heterozygous carriers of the mutant allele. Of the 208 members of the kindred who were screened for the presence of this LDLR mutation, we identified 94 carriers and 114 noncarriers. Nine principal apolipoprotein genes that might affect LDL cholesterol differentially according to LDL-receptor status were examined in this pedigree. Strikingly lower total cholesterol and LDL-cholesterol values were observed among the majority of the LDLR mutation carriers who were simultaneously homozygous for the -265C variant of apoA-II (total cholesterol: 324 +/- 8 vs 244 +/- 19 mg/dl, P = 0.0015; LDL-cholesterol: 237 +/- 8 vs 155 +/- 18 mg/dl, P = 0.0008). In vitro transfection assays showed that transcriptional activity of the apoA-II promoter was reduced by 30% in the -265C variant as compared with the -265T variant. We thus concluded that one variant of the apoA-II gene was associated with reduced plasma LDL cholesterol only in FH patients.

Apolipoproteins↗