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January 10, 1986, Vol 255, No. 2 >
ARTICLE | January 10, 1986

Evidence That Men With Familial Hypercholesterolemia Can Avoid Early Coronary Death: Title and subTitle BreakAn Analysis of 77 Gene Carriers in Four Utah Pedigrees FREE

Roger R. Williams, MD; Sandra J. Hasstedt, PhD; Dana E. Wilson, MD; K. Owen Ash, PhD; Frank F. Yanowitz, MD; Gayle E. Reiber, RN, MPH; Hiroshi Kuida, MD
[+] Author Affiliations

Reprint requests to Division of Cardiology, University of Utah Medical Center, 50 N Medical Dr, Salt Lake City, UT 84132 (Dr Williams).


JAMA. 1986;255(2):219-224. doi:10.1001/jama.1986.03370020065029
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References

To study the genetic influence on serum cholesterol levels and early coronary heart disease, 1,134 individuals were screened from 18 Utah pedigrees. In most pedigrees, serum cholesterol appeared to be a purely polygenic trait, with 54% heritability. In four pedigrees with dominant familial hypercholesterolemia, male heterozygotes had a mean serum cholesterol level of 352 mb/dL, myocardial infarction at an average age of 42 years, and coronary death at an average age of 45 years. An informative pedigree structure allowed the identification of four ancestral males born before 1880 who carried this lethal gene and survived to ages 62, 68, 72, and 81 years. This suggests that some healthy life-style factors protected these men against the expression of a gene that has led to coronary disease by age 45 years in all of their heterozygous great-grandsons. One heterozygote showed a drop in serum cholesterol level from 426 to 248 mg/dL, with strict adherence to a low-fat diet without drugs. These observations should help encourage physicians to try harder to identify and help such individuals.

(JAMA 1986;255:219-224)

REFERENCES

1 +
Williams RR:  The role of genes in coronary atherosclerosis , in Hurst JW (ed): Update IV: The Heart . New York, McGraw-Hill Book Co, 1979;, pp 89-118.
2 +
Goldstein JL, Dana SD, Brunschede GY, et al:  Genetic heterogeneity in familial hypercholesterolemia: Evidence for two different mutations affecting functions of low-density lipoprotein receptor . Proc Natl Acad Sci USA 1975;; 72:1092.
3 +
Williams RR, Hunt SC, Kuida H, et al:  Sodium-lithium countertransport in erythrocytes of hypertension prone families in Utah . Am J Epidemiol 1983;;118:338-344.
4 +
Williams RR, Dadone M, Hunt SC, et al:  The genetic epidemiology of hypertension: A review of past studies and current results in 948 persons in 48 Utah pedigrees , in Rao DC, Carter C (eds): Genetic Epidemiology of Coronary Heart Disease . New York, Academic Press Inc, in press.
5 +
Williams RR, Skolnick M, Carmelli D, et al:  Utah pedigree studies: Design and preliminary data for premature male CHD deaths , in Sing CF, Skolnick M (eds): The Genetic Analysis of Common Diseases . New York, Alan R Liss Inc, 1979;.
6 +
Williams RR:  A population perspective of early and familial coronary heart disease , in Proceedings of the Conference on Human Health Data From Defined Populations, Banbury report 4. New York, Cold Spring Harbor Laboratory, 1980 , pp 333-350.
7 +
Hopkins PN, Hunt SC, Williams RR:  Magnified risks from cigarette smoking for Utah families prone to coronary disease . West J Med 1984;;141:196-202.
8 +
Levine JB, Zak B:  Automated determination of serum total cholesterol . Clin Chim Acta 1964;;10:381-384.
9 +
Wahlefeld AW:  Triglycerides: Determination after enzymatic hydrolysis , in Bergmeyer HU (ed): Methods of Enzymatic Analysis . New York, Academic Press Inc, 1974;, pp 1831-1835.
10 +
Rautela GS, Liedtke RJ:  Automated enzymic measurement of total cholesterol in serum . Clin Chem 1978;;24:108-114.
11 +
Eggstein M, Kreutz FH:  Eine neue Bestimmung der neutralfette im Blutserum und Gewebe . Klin Wochschr 1966;;44:262-273.
12 +
Maclean CJ, Morton NE, Elston RC, et al:  Skewness in commingled distributions . Biometrics 1976;;32:695-699.
13 +
Elston RC, Stewart J:  A general model for the genetic analysis of pedigree data . Hum Hered 1971;;21:523-542.
14 +
Cannings C, Thompson EA, Skolnick M:  Pedigree functions on complex pedigrees . Adv Appl Prob 1978;;10:26-61.
15 +
Hasstedt SJ, Cartwright PE: PAP: Pedigree Analysis Package , technical report 13. Salt Lake City, University of Utah Department of Medical Biophysics and Computing, 1981;.
16 +
Hasstedt SJ, Cartwright PE, Skolnick MH, et al: PAP:  A Fortran program for pedigree analysis . Am J Hum Genet 1979;;31:135A.
17 +
Lalouel JM: GEMINI: A Computer Program for Optimization of General Nonlinear Functions , technical report 14. Salt Lake City, University of Utah Department of Medical Biophysics and Computing, 1979;.
18 +
Morton NE, MacLean CJ:  Analysis of family resemblance: III. Complex segregation of quantitative traits . Am J Hum Genet 1974;; 26:489-503.
19 +
Hasstedt SJ:  A mixed-model likelihood approximation on large pedigrees . Comput Biomed Res 1982;;15:295-307.
20 +
Thompson EA, Cannings C:  Sampling schemes and ascertainment , in Sing CF, Skolnick M (eds): Genetic Analysis of Common Diseases: Applications to Predictive Factors in Coronary Disease . New York, Alan R Liss Inc, 1979;.
21 +
Goldstein JL, Schrott HG, Hazzard WR, et al:  Hyperlipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia . J Clin Invest 1973;; 52:1544-1568.
22 +
Carter CO, Slack J, Myant NB:  Genetics of hyperlipoproteinemias . Lancet 1971;;1:400-401.
23 +
Moll PP, Powsner R, Sing CF:  Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan: V. Variance components estimated from pedigrees . Ann Hum Genet 1979;;42:343-354.
24 +
Rao DC, Morton NE, Gulbrandsen CL, et al:  Cultural and biological determinants of lipoprotein concentrations . Ann Hum Genet 1979;; 42:467-477.
25 +
Iselius L:  Analysis of family resemblance for lipids and lipoproteins . Clin Genet 1979;; 15:300-306.
26 +
Christian JC, Feinleib M, Hulley SB, et al:  Genetics of plasma cholesterol and triglycerides: A study of adult male twins . Acta Genet Med Gemellol 1976;;25:145-149.
27 +
Smoking and Health: 1979 Report of the Surgeon General, Dept of Health, Education, and Welfare publication (PHS) 79-50066. Government Printing Office, 1979, pp 2-11-2-12.
28 +
Schettler G, Nussel E, Bucholz L:  Epidemiological research in Western Europe . Atherosclerosis Rev 1978;;3:201-211.
29 +
Lipid Research Clinics Program:  The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease . JAMA 1984;;251:351-374.

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1 +
Williams RR:  The role of genes in coronary atherosclerosis , in Hurst JW (ed): Update IV: The Heart . New York, McGraw-Hill Book Co, 1979;, pp 89-118.
2 +
Goldstein JL, Dana SD, Brunschede GY, et al:  Genetic heterogeneity in familial hypercholesterolemia: Evidence for two different mutations affecting functions of low-density lipoprotein receptor . Proc Natl Acad Sci USA 1975;; 72:1092.
3 +
Williams RR, Hunt SC, Kuida H, et al:  Sodium-lithium countertransport in erythrocytes of hypertension prone families in Utah . Am J Epidemiol 1983;;118:338-344.
4 +
Williams RR, Dadone M, Hunt SC, et al:  The genetic epidemiology of hypertension: A review of past studies and current results in 948 persons in 48 Utah pedigrees , in Rao DC, Carter C (eds): Genetic Epidemiology of Coronary Heart Disease . New York, Academic Press Inc, in press.
5 +
Williams RR, Skolnick M, Carmelli D, et al:  Utah pedigree studies: Design and preliminary data for premature male CHD deaths , in Sing CF, Skolnick M (eds): The Genetic Analysis of Common Diseases . New York, Alan R Liss Inc, 1979;.
6 +
Williams RR:  A population perspective of early and familial coronary heart disease , in Proceedings of the Conference on Human Health Data From Defined Populations, Banbury report 4. New York, Cold Spring Harbor Laboratory, 1980 , pp 333-350.
7 +
Hopkins PN, Hunt SC, Williams RR:  Magnified risks from cigarette smoking for Utah families prone to coronary disease . West J Med 1984;;141:196-202.
8 +
Levine JB, Zak B:  Automated determination of serum total cholesterol . Clin Chim Acta 1964;;10:381-384.
9 +
Wahlefeld AW:  Triglycerides: Determination after enzymatic hydrolysis , in Bergmeyer HU (ed): Methods of Enzymatic Analysis . New York, Academic Press Inc, 1974;, pp 1831-1835.
10 +
Rautela GS, Liedtke RJ:  Automated enzymic measurement of total cholesterol in serum . Clin Chem 1978;;24:108-114.
11 +
Eggstein M, Kreutz FH:  Eine neue Bestimmung der neutralfette im Blutserum und Gewebe . Klin Wochschr 1966;;44:262-273.
12 +
Maclean CJ, Morton NE, Elston RC, et al:  Skewness in commingled distributions . Biometrics 1976;;32:695-699.
13 +
Elston RC, Stewart J:  A general model for the genetic analysis of pedigree data . Hum Hered 1971;;21:523-542.
14 +
Cannings C, Thompson EA, Skolnick M:  Pedigree functions on complex pedigrees . Adv Appl Prob 1978;;10:26-61.
15 +
Hasstedt SJ, Cartwright PE: PAP: Pedigree Analysis Package , technical report 13. Salt Lake City, University of Utah Department of Medical Biophysics and Computing, 1981;.
16 +
Hasstedt SJ, Cartwright PE, Skolnick MH, et al: PAP:  A Fortran program for pedigree analysis . Am J Hum Genet 1979;;31:135A.
17 +
Lalouel JM: GEMINI: A Computer Program for Optimization of General Nonlinear Functions , technical report 14. Salt Lake City, University of Utah Department of Medical Biophysics and Computing, 1979;.
18 +
Morton NE, MacLean CJ:  Analysis of family resemblance: III. Complex segregation of quantitative traits . Am J Hum Genet 1974;; 26:489-503.
19 +
Hasstedt SJ:  A mixed-model likelihood approximation on large pedigrees . Comput Biomed Res 1982;;15:295-307.
20 +
Thompson EA, Cannings C:  Sampling schemes and ascertainment , in Sing CF, Skolnick M (eds): Genetic Analysis of Common Diseases: Applications to Predictive Factors in Coronary Disease . New York, Alan R Liss Inc, 1979;.
21 +
Goldstein JL, Schrott HG, Hazzard WR, et al:  Hyperlipidemia in coronary heart disease: II. Genetic analysis of lipid levels in 176 families and delineation of a new inherited disorder, combined hyperlipidemia . J Clin Invest 1973;; 52:1544-1568.
22 +
Carter CO, Slack J, Myant NB:  Genetics of hyperlipoproteinemias . Lancet 1971;;1:400-401.
23 +
Moll PP, Powsner R, Sing CF:  Analysis of genetic and environmental sources of variation in serum cholesterol in Tecumseh, Michigan: V. Variance components estimated from pedigrees . Ann Hum Genet 1979;;42:343-354.
24 +
Rao DC, Morton NE, Gulbrandsen CL, et al:  Cultural and biological determinants of lipoprotein concentrations . Ann Hum Genet 1979;; 42:467-477.
25 +
Iselius L:  Analysis of family resemblance for lipids and lipoproteins . Clin Genet 1979;; 15:300-306.
26 +
Christian JC, Feinleib M, Hulley SB, et al:  Genetics of plasma cholesterol and triglycerides: A study of adult male twins . Acta Genet Med Gemellol 1976;;25:145-149.
27 +
Smoking and Health: 1979 Report of the Surgeon General, Dept of Health, Education, and Welfare publication (PHS) 79-50066. Government Printing Office, 1979, pp 2-11-2-12.
28 +
Schettler G, Nussel E, Bucholz L:  Epidemiological research in Western Europe . Atherosclerosis Rev 1978;;3:201-211.
29 +
Lipid Research Clinics Program:  The Lipid Research Clinics Coronary Primary Prevention Trial results: I. Reduction in incidence of coronary heart disease . JAMA 1984;;251:351-374.

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