Cholesterol Journal Articles

Record 6441 to 6460

Genetic analysis of cholesterol gallstone formation: searching for Lith (gallstone) genes
Wang, D. Q. and N. H. Afdhal (2004), Curr Gastroenterol Rep 6(2): 140-50.
Abstract: The genetics of cholesterol cholelithiasis is complex because a number of interacting genes regulate biliary cholesterol homeostasis. Quantitative trait locus (QTL) analysis is a powerful method for identifying primary rate-limiting genetic defects and discriminating them from secondary downstream lithogenic effects caused by mutations of the primary genes. The subsequent positional cloning of such genes responsible for QTLs may lead to the discovery of pathophysiologic functions of Lith (gallstone) genes. In this review, we present a map of candidate genes for Lith genes that may determine gallstone susceptibility in mice. The physical-chemical, pathophysiologic, and genetic studies of Lith genes in bile, liver, gallbladder, and intestine will be crucial for elucidating the genetic mechanisms of cholesterol gallstone disease in mice and in humans. Because exceptionally close homology exists between mouse and human genomes, the orthologous human LITH genes can often be recognized after mouse genes are identified.

Genetic analysis of indicators of cholesterol synthesis and absorption: lathosterol and phytosterols in Dutch twins and their parents
Boomsma, D. I., H. M. Princen, et al. (2003), Twin Res 6(4): 307-14.
Abstract: Significant familial aggregation was observed for plasma levels of lathosterol (an indicator of whole-body cholesterol synthesis) and plant sterols campesterol and beta-sitosterol (indicators of cholesterol absorption) in 160 Dutch families consisting of adolescent mono- and dizygotic twin pairs and their parents. For lathosterol a moderate genetic heritability in parents and offspring (29%) was found. In addition, shared environment also contributed significantly (37%) to variation in plasma lathosterol concentrations in twin siblings. However, a model with different genetic heritabilities in the two generations (10% in parents and 68% in offspring) fitted the data almost as well. For plasma plant sterol concentrations high heritabilities were found. For campesterol heritability was 80% and for beta-sitosterol it was 73%, without evidence for differences in heritability between sexes or generations. No influence of common environmental influences shared by family members was seen for either campesterol or beta-sitosterol. Taken together, these results confirm and expand the hypothesis that individual differences in plasma levels of noncholesterol sterols are moderately (lathosterol) to highly (plant sterols) heritable.

Genetic analysis of intestinal cholesterol absorption in inbred mice
Schwarz, M., D. L. Davis, et al. (2001), J Lipid Res 42(11): 1801-11.
Abstract: A genetic mapping strategy was employed to identify chromosomal regions harboring genes that influence the absorption of intestinal cholesterol in the mouse. Analysis of seven inbred strains of male mice (129P3, AKR, BALB/c, C3H/He, C57BL/6, DBA/2, and SJL, all from Jackson Laboratories) revealed substantial differences in their abilities to absorb a bolus of cholesterol delivered by gavage. Crosses between high (AKR, 129) and low (DBA/2, SJL) absorbing strains revealed evidence for the presence of dominant genes that increase and decrease cholesterol absorption. Backcrosses between F1 offspring and parental strains (DBA/2xAKD2F1 and 129xSJL129F1) followed by linkage analyses revealed four quantitative trait loci that influenced cholesterol absorption. Analyses of recombinant inbred strains identified an additional three loci affecting this phenotype. These seven quantitative trait loci, which map to different chromosomes and are termed Cholesterol absorption 1-7 (Chab1-7) loci, together influence the absorption of intestinal cholesterol in mice and are likely to be involved in different steps of this complex pathway.

Genetic and environmental contributions to cholesterol and its subfractions in 11-year-old twins. The Medical College of Virginia Twin Study
Bodurtha, J. N., C. W. Chen, et al. (1991), Arterioscler Thromb 11(4): 844-50.
Abstract: We conducted a cross-sectional analysis of the genetic and environmental contributions to the variance of lipoprotein cholesterol and its subfractions in children during early adolescence. Univariate path analysis was used to determine the relative contributions of genes, individual environment, and family environment to these measures in 233 11-year-old Caucasian twin pairs. For high density lipoprotein, high density lipoprotein2, low density lipoprotein, very low density lipoprotein, and triglycerides, a model that incorporated genes and individual environmental variation but not common environment was sufficient to explain the variation. Different magnitudes of genetic effects were seen for total cholesterol in boys and girls. High density lipoprotein3 showed different magnitudes by sex for genetic and individual environmental effect. Intermediate density lipoprotein was the only cholesterol subfraction in which shared, or common, environment was found to make a statistically significant contribution to the variation.

Genetic and environmental covariance of serum cholesterol and blood pressure in female twins
Williams, P. D., I. B. Puddey, et al. (1993), Atherosclerosis 100(1): 19-31.
Abstract: Blood pressure elevation is frequently associated with elevated cholesterol, triglyceride or low density lipoprotein (LDL-C) or low high density lipoprotein (HDL-C). The relative importance of genetic and environmental factors in these associations is unclear. We examined the relative contribution of genetic and environmental influences to the association between blood pressure and serum lipids in 75 pairs of female twins using path analysis and maximum-likelihood model fitting. Associations between systolic blood pressure and total cholesterol (r = 0.44, P < 0.001), and LDL-C (r = 0.38, P < 0.001), but not HDL-C (r = 0.05, N.S.), remained significant after age and body mass index adjustment. Univariate models suggested genetic effects contributed 60-70% to the variance of total cholesterol, LDL-C, HDL-C and systolic blood pressure. The remaining variance was explained by age and/or unique environmental influences. Using bivariate models, we demonstrated genetic (P = 0.017) and unique environmental covariance (P = 0.011) of cholesterol and systolic blood pressure. Significant genetic covariance (P = 0.038) was observed between LDL-C and systolic blood pressure. The association between blood pressure and total cholesterol in these twins results from shared genetic and similar unique environmental influences. The association between LDL-C and blood pressure is partly due to shared genetic influences. We conclude that both additive genetic and environmental factors unique to the individual are important determinants of the relationships between serum lipids and blood pressure.

Genetic and environmental determinants of plasma high density lipoprotein cholesterol and apolipoprotein AI concentrations in healthy middle-aged men
Talmud, P. J., E. Hawe, et al. (2002), Ann Hum Genet 66(Pt 2): 111-24.
Abstract: The effects of common variants of cholesteryl ester transfer protein (CETP) (TaqIB), hepatic lipase (HL) (-514C>T), lipoprotein lipase (LPL) (S447X) and lecithin cholesterol acyl transferase (LCAT) (S208T) on the determination of high density lipoprotein cholesterol (HDL-C) and apolipoprotein AI (apoAI) levels were examined in 2773 healthy middle-aged men participating in the second Northwick Park Heart Study. The extent of gene:gene, gene:smoking and gene:alcohol interactions were determined. For HDL-C levels, only CETP genotype was associated with significant effects (p&0.0001), with the B2 allele being associated with higher levels in both smokers and non-smokers. This interaction was significant at the lowest tertile of TG, suggesting that TG levels were rate limiting. As previously reported, CETP, LPL and HL genotypes were all associated with significant effects on apoAI levels (all p&0.01), with carriers of the rare alleles having higher levels and with no evidence of heterogeneity of effects in smokers and non-smokers. LCAT genotype was not associated with significant effects on either trait. There was no significant interaction between any of the genotypes and alcohol consumption on either HDL-C or apoAI levels. All genotypic effects were additive for HDL-C and apoAI. Environmental and TG levels explained more than 20% and 5.5% of the variance in HDL-C and apoAI, respectively. The novel aspect of this finding is that genetic variation at these loci explained in total only 2.5% of the variance in HDL-C and 1.89% of the variance in apoAI levels. Thus despite the key roles played by these enzymes in HDL metabolism, variation at these loci, at least as detected by these common genotypes, contributes minimally to the variance in HDL-C and apoAI levels in healthy men, highlighting the polygenic and multifactorial control of HDL-C.

Genetic association of acyl-coenzyme A: cholesterol acyltransferase with cerebrospinal fluid cholesterol levels, brain amyloid load, and risk for Alzheimer's disease
Wollmer, M. A., J. R. Streffer, et al. (2003), Mol Psychiatry 8(6): 635-8.
Abstract: A common polymorphism of the gene encoding acyl-coenzyme A: cholesterol acyltransferase 1 (SOAT1), which is involved in the regulation of beta-amyloid peptide generation, is associated with low brain amyloid load (P=0.03) and with low cerebrospinal fluid levels of cholesterol (P=0.005). This polymorphism of SOAT1 is also associated with reduced risk for Alzheimer's disease in ethnically distinct populations (P=0.0001, odds ratio: 0.6, 95% confidence interval 0.4-0.8).

Genetic background of cholesterol gallstone disease
Kosters, A., M. Jirsa, et al. (2003), Biochim Biophys Acta 1637(1): 1-19.
Abstract: Cholesterol gallstone formation is a multifactorial process involving a multitude of metabolic pathways. The primary pathogenic factor is hypersecretion of free cholesterol into bile. For people living in the Western Hemisphere, this is almost a normal condition, certainly in the elderly, which explains the very high incidence of gallstone disease. It is probably because the multifactorial background genes responsible for the high incidence have not yet been identified, despite the fact that genetic factors clearly play a role. Analysis of the many pathways involved in biliary cholesterol secretion reveals many potential candidates and considering the progress in unraveling the regulatory mechanisms of the responsible genes, identification of the primary gallstone genes will be successful in the near future.

Genetic cholesteryl ester transfer protein deficiency caused by two prevalent mutations as a major determinant of increased levels of high density lipoprotein cholesterol
Inazu, A., X. C. Jiang, et al. (1994), J Clin Invest 94(5): 1872-82.
Abstract: Genetic determinants of HDL cholesterol (HDL-C) levels in the general population are poorly understood. We previously described plasma cholesteryl ester transfer protein (CETP) deficiency due to an intron 14 G(+1)-to-A mutation(Int14 A) in several families with very high HDL-C levels in Japan. Subjects with HDL-C > or = 100 mg/dl (n = 130) were screened by PCR single strand conformational polymorphism analysis of the CETP gene. Two other mutations were identified by DNA sequencing or primer-mediated restriction map modification of PCR products: a novel intron 14 splice donor site mutation caused by a T insertion at position +3 from the exon14/intron14 boundary (Int14 T) and a missense mutation (Asp442 to Gly) within exon 15 (D442G). The Int14 T mutation was only found in one family. However, the D442G and Int14 A mutations were highly prevalent in subjects with HDL-C > or = 60 mg/dl, with combined allele frequencies of 9%, 12%, 21% and 43% for HDL-C 60-79, 80-99, 100-119, and > or = 120 mg/dl, respectively. Furthermore, prevalences of the D442G and Int14 A mutations were extremely high in a general sample of Japanese men (n = 236), with heterozygote frequencies of 7% and 2%, respectively. These two mutations accounted for about 10% of the total variance of HDL-C in this population. The phenotype in a genetic compound heterozygote (Int14 T and Int14 A) was similar to that of Int14 A homozygotes (no detectable CETP and markedly increased HDL-C), indicating that the Int14 T produces a null allele. In four D442G homozygotes, mean HDL-C levels (86 +/- 26 mg/dl) were lower than in Int14 A homozygotes (158 +/- 35 mg/dl), reflecting residual CETP activity in plasma. In 47 D442G heterozygotes, mean HDL-C levels were 91 +/- 23 mg/dl, similar to the level in D442G homozygotes, and significantly greater than mean HDL-C levels in Int14 A heterozygotes (69 +/- 15 mg/dl). Thus, the D442G mutation acts differently to the null mutations with weaker effects on HDL in the homozygous state and stronger effects in the heterozygotes, suggesting dominant expression of a partially defective allele. CETP deficiency, reflecting two prevalent mutations (D442G and Int14 A), is the first example of a genetic deficiency state which is sufficiently common to explain a significant fraction of the variation in HDL-C in the general population.

Genetic contributors to lipoprotein cholesterol levels in an intercross of 129S1/SvImJ and RIIIS/J inbred mice
Lyons, M. A., R. Korstanje, et al. (2004), Physiol Genomics 17(2): 114-21.
Abstract: To determine the genetic contribution to variation among lipoprotein cholesterol levels, we performed quantitative trait locus (QTL) analyses on an intercross between mouse strains RIIIS/J and 129S1/SvImJ. Male mice of the parental strains and the reciprocal F1 and F2 populations were fed a high-cholesterol, cholic acid-containing diet for 8-12 wk. At the end of the feeding period, plasma total, high-density lipoprotein (HDL), and non-HDL cholesterol were determined. For HDL cholesterol, we identified three significant QTLs on chromosomes (Chrs) 1 (D1Mit507, 88 cM, 72-105 cM, 4.8 LOD), 9 (D11Mit149, 14 cM, 10-25 cM, 9.4 LOD), and 12 (D12Mit60, 20 cM, 0-50 cM, 5.0 LOD). These QTLs were considered identical to QTLs previously named Hdlq5, Hdlq17, and Hdlq18, respectively, in crosses sharing strain 129. For total cholesterol, we identified two significant QTLs on Chrs 1 and 9, which were named Chol10 (D1Mit507, 88 cM, 10-105 cM, 3.9 LOD) and Chol11 (D11Mit149, 14 cM, 0-30 cM, 4.4 LOD), respectively. In addition, for total cholesterol, we identified two suggestive QTLs on Chrs 12 (distal) and 17, which remain unnamed. For non-HDL cholesterol, we identified and named one new QTL on Chr 17, Nhdlq3 (D17Mit221, 58 cM, 45-60 cM, 3.4 LOD). Nhdlq3 colocalized with orthologous human QTLs for lipoprotein phenotypes, and with Abcg5 and Abcg8. Overall, we detected eight QTLs for lipoprotein cholesterol concentrations on Chrs 1, 9, 12, and 17 (each two per chromosome), including a new QTL for non-HDL cholesterol, Nhdlq3, on Chr 17.

Genetic control of response to dietary fat and cholesterol
Clifton, P. M. and M. Abbey (1997), World Rev Nutr Diet 80: 1-14.

Genetic defects in postsqualene cholesterol biosynthesis
Moebius, F. F., B. U. Fitzky, et al. (2000), Trends Endocrinol Metab 11(3): 106-14.
Abstract: In humans and mice, four different genetic defects in the nine biosynthetic steps from lanosterol to cholesterol have been identified. They impair the activity of a putative C3-sterol dehydrogenase (Nshdl, X-linked dominant bare patches/striated mutation in mice), the sterol delta 8-delta 7 isomerase/EBP (Ebp, X-linked dominant tattered mutation in mice; chondrodysplasia punctata (CDPX2) in humans), the delta 24-sterol reductase (autosomal recessive desmosterolosis) and the delta 7-sterol reductase (DHCR7 gene, autosomal recessive Smith-Lemli-Opitz syndrome in humans). These inborn errors in postsqualene cholesterol metabolism result in dysmorphogenetic syndromes of variable severity. The X-linked dominant mutations result in mosaicism in females, as a result of X-inactivation, and midgestational lethality in males. The mechanisms by which the depletion of cholesterol or the accumulation of intermediates impair morphogenetic programs are unclear. So far, no cellular processes that require an intact cholesterol biosynthetic pathway have been identified, although the morphogenetic hedgehog-patched signaling cascade is a candidate.

Genetic deletion of tissue-type plasminogen activator (t-PA) in APOE3-Leiden mice reduces progression of cholesterol-induced atherosclerosis
Rezaee, F., M. Gijbels, et al. (2003), Thromb Haemost 90(4): 710-6.
Abstract: During recent years it has become increasingly recognized that the plasmin activation system is involved in the development of atherosclerosis. In this paper, we have studied the contribution of the plasminogen activation system in the development of atherosclerosis by cross-breeding apoE3-Leiden mice, which have a human-like lipid profile, with mice deficient in PAI-1 (plasminogen-activator inhibitor-1), u-PA (urokinase plasminogen activator), and t-PA (tissue plasminogen activator). Genetic compound offspring was used to evaluate the progression of atherosclerotic lesions after they were fed a variant atherogenic diet for 12 weeks. Lesion area of plaques in the aortic valve was not significantly different in apoE3-Leiden:PAI -/- and apoE3-Leiden:u-PA -/- mice as compared to apoE3-Leiden mice. In contrast, a significant 70% reduction of the lesion area was observed in apoE3-Leiden:t-PA -/- mice as compared to control group apoE3-Leiden mice. In addition the early, regular fatty streaks and mild plaques increased in apoE3-Leiden:t-PA -/- mice, whereas the severe plaques (type IV and V) decreased in these animals. A lower deposition of collagen was observed in the atherosclerotic lesions of apoE3-Leiden:t-PA -/- mice as compared with apoE3-Leiden mice. Our results indicate for the first time that t-PA deficiency delayed the atherosclerotic process in this mouse model.

Genetic determination of high-density lipoprotein-cholesterol and apolipoprotein A-1 plasma levels in a family study of cardiac catheterization patients
Prenger, V. L., T. H. Beaty, et al. (1992), Am J Hum Genet 51(5): 1047-57.
Abstract: Plasma levels of two lipoprotein risk factors, high-density lipoprotein-cholesterol (HDL-C) and apolipoprotein A-1 (apo A-1), have been shown to be negatively associated with the risk of developing coronary artery disease, and several reports have examined familial factors in HDL-C and apo A-1 levels. A number of studies suggest that shared genes influence familial resemblance of these lipoprotein levels far more than do shared environments. Possible mechanisms for the inheritance of these two risk factors (HDL-C and apo A-1 plasma levels) are explored using data from 390 individuals in 69 families ascertained through probands undergoing diagnostic cardiac catheterization. Segregation analysis was used to test a series of specific models of inheritance. Evidence for single-locus control of apo A-1 levels, with Mendelian transmission of a dominant allele leading to elevated apo A-1 levels, was seen in these families, although there was additional correlation among sibs present. This locus accounted for 48.6% and 37.2% of the total variation in apo A-1 levels in males and females, respectively. Similar evidence of segregation at a single locus controlling HDL-C levels was not seen in these families.

Genetic diagnosis of familial hypercholesterolemia in a South European outbreed population: influence of low-density lipoprotein (LDL) receptor gene mutations on treatment response to simvastatin in total, LDL, and high-density lipoprotein cholesterol
Chaves, F. J., J. T. Real, et al. (2001), J Clin Endocrinol Metab 86(10): 4926-32.
Abstract: The aims of this study were to examine the presence of mutations in the low-density lipoprotein receptor gene among subjects clinically diagnosed with familial hypercholesterolemia and to analyze whether the molecular diagnosis helps to predict the response to simvastatin treatment in our familial hypercholesterolemia population. Fifty-five probands and 128 related subjects with familial hypercholesterolemia were studied. Genetic diagnosis was carried out following a three-step protocol based on Southern blot and PCR-single strand conformational polymorphism analysis. A randomized clinical trial with simvastatin was conducted in 42 genetically diagnosed subjects with familial hypercholesterolemia classified as carriers of null mutations (n = 22) and of defective mutations (n = 20). A mutation-causing familial hypercholesterolemia was identified in 46 probands (84%). In 41 of them (89%), a total of 28 point mutations were detected, 13 of which have not been previously described. The remaining five probands (11%) were carriers of large rearrangements. Familial hypercholesterolemia with null mutations showed a poor response to simvastatin treatment. The mean percentage reduction of plasma total and low-density lipoprotein cholesterol levels in these subjects were significantly lower (24.8 +/- 10.3 vs. 34.8 +/- 10.9, P = 0.04 and 30.0 +/- 39.8 vs. 46.1 +/- 18.2, P = 0.02, respectively) than in subjects with defective mutations. Baseline and posttreatment high-density lipoprotein cholesterol plasma values were significantly lower in subjects with familial hypercholesterolemia with null mutations (P < 0.001). In an outbreed Caucasian population, a three-step protocol for genetic screening detected a mutation in the low-density lipoprotein receptor gene in a high percentage (84%) of subjects with familial hypercholesterolemia. Subjects with familial hypercholesterolemia with null mutations (class I) showed lower plasma high-density lipoprotein cholesterol values and a poor low-density lipoprotein cholesterol response to simvastatin treatment.

Genetic differences in cholesterol absorption in 129/Sv and C57BL/6 mice: effect on cholesterol responsiveness
Jolley, C. D., J. M. Dietschy, et al. (1999), Am J Physiol 276(5 Pt 1): G1117-24.
Abstract: This study compared the cholesterolemic response of two strains of mice with genetically determined differences in cholesterol absorption. When fed a basal low-cholesterol diet, 129/Sv mice absorbed cholesterol twice as efficiently as did C57BL/6 mice (44% vs. 20%). Total lipid absorption, in contrast, averaged 80-82% in both strains. The higher level of cholesterol absorption in the 129/Sv animals was reflected in an adaptive reduction in hepatic and intestinal sterol synthesis. When fed lipid-enriched diets, the 129/Sv mice became significantly more hypercholesterolemic and had twofold higher hepatic cholesterol concentrations than did the C57BL/6 animals even though the conversion of cholesterol to bile acids was stimulated equally in both strains. The difference in cholesterol absorption between these mouse strains was not the result of physicochemical factors relating to the size and composition of the intestinal bile acid pool but more likely reflects an inherited difference in one or more of the biochemical steps that facilitate the translocation of sterol across the epithelial cell.

Genetic disorders associated with ATP binding cassette cholesterol transporters
Burris, T. P., P. I. Eacho, et al. (2002), Mol Genet Metab 77(1-2): 13-20.
Abstract: Coronary artery disease is the most prevalent form of mortality and morbidity in Western countries. Studies in the last several decades have identified high LDL cholesterol and low HDL cholesterol as major risk factors leading to the disease. Human genetic studies have provided significant insight into the regulation of lipoprotein metabolism. In the last several years, the genes associated with several rare genetic diseases of lipid metabolism have been revealed. These landmark discoveries that identified mutant ABC cholesterol transporters as the underlying causes of these genetic disorders have paved the way for better understanding of the cellular cholesterol transport process and HDL biogenesis. This summary provides an overview and discussion of the most recent progress that includes molecular mechanism and regulation of cholesterol transport mediated by these ABC transporters.

Genetic disorders causing abnormal LDL-cholesterol levels
Murayama, T. (1999), Nippon Rinsho 57(12): 2723-8.
Abstract: Various epidemiological studies and lipid intervention trials have revealed that serum LDL-cholesterol level correlates to the incidence in ischemic heart disease, and decreasing the level can prevent cardiac events. Inherited diseases causing abnormal LDL-cholesterol levels are discussed in this article, including their animal models. Familial hypercholesterolemia, familial ligand-defective apolipoprotein B100, familial combined hyperlipidemia and cholesterol ester storage disease result in elevation of serum LDL-cholesterol. On the other hand, serum LDL-cholesterol is decreased in abetalipoproteinemia and familial hypobetalipoproteinemia. The development of genetic engineering technology has elucidated the mechanism of these genetic disorders and elaborated their animal models. Although most of them cause atherosclerotic or psychoneurological diseases, fundamental therapy remains to be established, such as gene therapy.

Genetic disorders of cholesterol biosynthesis in mice and humans
Nwokoro, N. A., C. A. Wassif, et al. (2001), Mol Genet Metab 74(1-2): 105-19.
Abstract: Over the past few years, the number of identified inborn errors of cholesterol biosynthesis has increased significantly. The first inborn error of cholesterol biosynthesis to be characterized, in the mid 1980s, was mevalonic aciduria. In 1993, Irons et al. (1) (M. Irons, E. R. Elias, G. Salen, G. S. Tint, and A. K. Batta, Lancet 341:1414, 1993) reported that Smith-Lemli-Opitz syndrome, a classic autosomal recessive malformation syndrome, was due to an inborn error of cholesterol biosynthesis. This was the first inborn error of postsqualene cholesterol biosynthesis to be identified, and subsequently additional inborn errors of postsqualene cholesterol biosynthesis have been characterized to various extent. To date, eight inborn errors of cholesterol metabolism have been described in human patients or in mutant mice. The enzymatic steps impaired in these inborn errors of metabolism include mevolonate kinase (mevalonic aciduria as well as hyperimmunoglobulinemia D and periodic fever syndrome), squalene synthase (Ss-/- mouse), 3beta-hydroxysteroid Delta14-reductase (hydrops-ectopic calcification-moth-eaten skeletal dysplasia), 3beta-hydroxysteroid dehydrogenase (CHILD syndrome, bare patches mouse, and striated mouse), 3beta-hydroxysteroid Delta8,Delta7-isomerase (X-linked dominant chondrodysplasia punctata type 2, CHILD syndrome, and tattered mouse), 3beta-hydroxysteroid Delta24-reductase (desmosterolosis) and 3beta-hydroxysteroid Delta7-reductase (RSH/Smith-Lemli-Opitz syndrome and Dhcr7-/- mouse). Identification of the genetic and biochemical defects which give rise to these syndromes has provided the first step in understanding the pathophysiological processes which underlie these malformation syndromes.

Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris
Miquel, J. F., C. Covarrubias, et al. (1998), Gastroenterology 115(4): 937-46.
Abstract: BACKGROUND & AIMS: The etiology of cholesterol gallstones is multifactorial, with interactions of genes and the environment. The hypothesis that aborigine cholesterol lithogenic genes are widely spread among Chileans, a population with a high prevalence of gallstones, was tested. METHODS: Medical history and anthropometric measurements were obtained and abdominal ultrasonography was performed in 182 Mapuche Indians, 225 Maoris of Easter Island, and 1584 Hispanics. Blood groups, DNA, lipids, and glucose were analyzed. The Amerindian Admixture Index and mitochondrial DNA (mtDNA) assessed the ethnicity and degree of racial admixture. RESULTS: Amerindian Admixture Index was 0.8 in Mapuches and 0.4 in Hispanics. All Mapuches, 88% of Hispanics, but none of Maoris had Amerindian mtDNA haplotypes. Age- and sex-adjusted global prevalence of gallstone disease was higher in Mapuches (35%) than in Hispanics (27%) and Maoris (21%). Compared with Hispanics, the youngest group of Mapuches had the greatest corrected risk of gallstones: odds ratios of 6.0 in women and 2.3 in men. In contrast, the gallstone risk in Maoris was lower compared with Hispanics: odds ratios of 0.6 for women and 0.5 for men. CONCLUSIONS: Cholesterol lithogenic genes appear widely spread among Chilean Indians and Hispanics. They could determine the early formation of gallstones and explain the high prevalence of gallbladder diseases among some South American populations.

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