Susan H. Stephenson

Predictors of an increased risk of future hypertension in Utah. A screening analysis.

A prospective study on 1,482 adult members of 98 Utah pedigrees was carried out to determine which variables may be associated with an increased risk of hypertension incidence. After an average of 7 years of follow-up, 40 individuals had been placed on antihypertensive medications to lower blood pressure. Baseline study variables included anthropometries, clinical chemistry measurements of blood and urine, socioeconomic and lifestyle variables, and detailed erythrocyte ion transport and concentration measurements. Age (relative risk of 4.28 for a 2 SD difference, p< 0.0001) and baseline systolic and diastolic blood pressures (relative risks of 3.55 and 3.52, respectively, both p< 0.0001) had the strongest associations with hypertension incidence. Controlling for age and baseline blood pressure, the following age- and sex-adjusted variables were associated with an increased risk of future hypertension (relative risks for a 2 SD difference, all /?<0.10): family history of hypertension (2J5); height (1.97); body mass index (2.31); abdominal girth (2.66); subscapular, suprailiac, and triceps skinfold thicknesses (2.79, 2.52, and 2.28, respectively); percent ideal body weight (2.63); log triglyceride concentration (2.02); plasma uric acid (2.16); inorganic phosphate (0.50); and passive erythrocyte sodium permeability (1.59). The final model, which included all of the age- and sex-adjusted variables (p<0.10) in a backward elimination logistic regression analysis, consisted of age (4.78), systolic blood pressure (2.91), subscapular skinfold thickness (2.21), height (1.92), uric acid (2.06), inorganic phosphate (0.50), and family history of hypertension (1.82). None of the ion transport or concentration measurements was associated with an increased risk of hypertension. We conclude that the risk factors of age, body fat and size, plasma uric acid, low plasma inorganic phosphate, and family history of hypertension, previously shown to be significant in crosssectional studies, prospectively increase the risk of hypertension. If other variables have important predictive roles, then they may affect only a subset of this or other large study populations.

Evaluation of Coronary Risk Factors in Patients With Heterozygous Familial Hypercholesterolemia

Age at onset of clinically manifested coronary artery disease (CAD) varies widely among patients with familial hypercholesterolemia (FH). A number of factors in addition to high low-density lipoprotein cholesterol (LDL) have been suggested as predictors of risk among patients with FH, but a comprehensive examination of their utility is lacking. We therefore measured plasma lipids, carotid intima-medial thickness, and a variety of coronary risk factors in 262 patients with FH > or = 30 years old (68 of whom had premature CAD). Age (p < 0.0001) and gender were the most important determinants of premature CAD risk, with men having 5.64 times the risk of women (p < 0.0001). In addition, cigarette smoking (odds ratio [OR] 2.71, p = 0.026), smaller LDL as determined by the LDL cholesterol/LDL apolipoprotein B ratio (OR 2.60, p = 0.014), and white blood cell count (p = 0.014) were also statistically significant risk factors. Lipoprotein(a) and the presence of xanthoma were associated with risk only in very early coronary cases. After correction for age, carotid intima-media thickness was not associated with CAD risk. Insulin, fibrinogen, homocysteine, plasma C-reactive protein, and the angiotensin-converting enzyme insertion/deletion polymorphism were unrelated to risk in this cohort. These results provide little justification for extensive investigation of risk factors among patients with FH, at least for the risk factors examined here. Rather, the inherent high LDL cholesterol of these patients should be the focus of preventive efforts. The novel finding of increased risk with smaller LDL may prove useful but needs further confirmation.

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

AbstractPlasma 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.

A prospective study of sodium-lithium countertransport and hypertension in Utah.

A 7-year prospective study of a cohort of 1,458 normotensive adults from Utah pedigrees, screened from 1980 to 1985, was done to determine whether baseline levels of sodium-lithium countertransport were associated with an increased risk of future hypertension. Subsequent new hypertension (n = 39) was ascertained in 1989 from detailed follow-up medical questionnaires (67% response). Previous segregation analyses on a subset of these pedigree members who responded (n = 342) using family relationships in addition to countertransport levels have shown statistically inferred major gene segregation of sodium-lithium countertransport levels. In the normotensive adults inferred by segregation analysis to carry the recessive major gene for high sodium-lithium countertransport, new-onset hypertension occurred in 18.8% (3 of 16) compared with 3.7% (12 of 326) in the low sodium-lithium countertransport genotype group (relative risk, 4.6 [1.6, 13.9]; p = 0.03). However, an elevated baseline sodium-lithium countertransport level without genotype information from segregation analysis did not increase the risk of future hypertension in the complete cohort of adult pedigree members (relative risk, 1.02 [0.85, 1.22]). Adjustment for other risk factors reduced the relative risk to 0.90 (0.72, 1.11). We conclude that the presence of a major gene for sodium-lithium countertransport or another closely linked gene, rather than the actual level of sodium-lithium countertransport, may increase the risk of hypertension onset. High sodium-lithium countertransport levels do not increase the risk of future hypertension for individuals in whom only polygenic and environmental effects determine sodium-lithium countertransport level.(ABSTRACT TRUNCATED AT 250 WORDS)

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

AbstractLipid 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 ± 19mg/dl, P = 0.0015; LDL-cholesterol: 237 ± 8 vs 155 ± 18mg/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.

Co-segregation of elevated LDL with a novel mutation (D92K) of the LDL receptor in a kindred with multiple lipoprotein abnormalities

AbstractFactors predisposing to the phenotypic features of familial combined hyperlipidemia have not been clearly defined. In the course of investigating familial coronary artery disease in Utah, we identified a three-generation family in which multiple members were affected with type IIa hyperlipoproteinemia (HLP IIa), type IIb hyperlipoproteinemia (HLP IIb), or type IV hyperlipoproteinemia (HLP IV). Because several family members had relatively severe low-density lipoprotein (LDL) cholesterol elevation, in order to dissect the possible contribution to the plasma lipoprotein abnormalities in this pedigree, we identified a novel point mutation in the low-density lipoprotein receptor (LDLR) gene, a G-to-A transition at nucleotide position 337 in exon 4. This change substituted lysine for glutamic acid at codon 92 (D92K) of the LDL receptor. By means of mutant allele-specific amplification we determined that the mutation co-segregated with elevated cholesterol and LDL cholesterol in the plasma of family members with HLP IIa and HLP IIb, but not with the elevated plasma triglycerides seen in HLP IIb and HLP IV patients. Thus, in families with apparent familial combined hyperlipidemia, a defective LDLR allele and other genetic or environmental factors that elevate plasma triglycerides may account for the multiple lipid phenotypes observed in this kindred.

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.

A novel LDLR mutation, H190Y, in a Utah kindred with familial Hypercholesterolemia

AbstractHeterozygous familial hypercholesterolemia (FH) is a serious disorder causing twice normal low-density lipoprotein (LDL) cholesterol levels early in childhood and very early coronary disease in both men and women. Treatment with multiple medications together with diet can normalize cholesterol levels in many persons with FH and prevent or delay the development of coronary atherosclerosis. Previously published blood cholesterol criteria greatly under-diagnosed new cases of FH among members of known families with FH and over-diagnosed FH among participants of general population screening. Thus, there is a need for accurate and genetically validated criteria for the early diagnosis of heterozygous FH. In the course of investigations of coronary artery disease in Utah, we identified a family whose proband showed elevated plasma levels of LDL cholesterol. To carry out molecular genetic diagnosis of the disease, we screened DNA samples for mutations in all 18 exons and the exon-intron boundaries of the LDL receptor gene (LDLR). Novel point mutations were identified in the proband: a C-to-T transversion at nucleotide position 631, causing substitution of tyrosine for histidine at codon 190 in exon 4 of the LDLR gene. The mutant allele-specific amplification method was used to examine 12 members of the family recruited for the diagnosis. This method helped to unequivocally diagnose 7 individuals as heterozygous for this particular LDLR mutation, while excluding the remaining 5 individuals from carrier status with FH.

Benefits of the MEDPED treatment support program for patients with familial hypercholesterolemia.

BACKGROUND Patients with heterozygous familial hypercholesterolemia (FH) patients often have difficultly achieving National Cholesterol Education Program (NCEP) goals. Herein we present an evaluation of a centrally located, nationwide treatment support program that remotely attempted to educate and guide FH patients by monitoring their serum low-density lipoprotein (LDL) cholesterol levels and giving appropriate treatment recommendations through mail contact. All subjects were FH patients registered with the Make Early Diagnosis to Prevent Early Deaths (MEDPED) program. METHODS In this descriptive evaluation, we compared self-reported lipid levels in 386 FH patients participating in our treatment support program with 295 non-participants who had responded to questionnaires. Participants were recruited into the treatment support program if they had not reached their LDL cholesterol goal after at least 1 year of follow-up and were unable to receive specialized lipid care due to location. RESULTS Participants who continued for a longer term in the treatment support program achieved greater total cholesterol reductions (14%) than the comparison group (7%, P=.004). Reductions in total and LDL cholesterol were highly correlated with more aggressive use of statin medications (P <.0001). CONCLUSIONS These results demonstrate the potential benefits and limitations of a centralized program operating remotely to encourage appropriate treatment of severe hypercholesterolemia.

Risk factors for cardiovascular disease predict the development of diabetes among Utah families.

In 1989, we sent a medical follow-up questionnaire to 2,728 members of 98 Utah families originally screened from 1980 to 1983 in the Cardiovascular Genetics Research Clinic. The response rate was 69.9%. Of 1,134 nondiabetic individuals initially age 18 or older who returned the questionnaire, 10 were found to be newly diagnosed with diabetes. The incidence of diabetes was higher among individuals who were found at baseline to have central obesity, lipid abnormalities, especially increased triglyceride levels, and hypertension. Family histories of coronary heart disease and diabetes were not related to the development of diabetes. Our findings that cardiovascular disease risk factors predict the development of diabetes in this relatively young, Caucasian population are consistent with the results of studies from several different populations.