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Biomedical subjects

Jean W MacCluer

Publications and source records attributed to Jean W MacCluer.

At least 19 recordsLinked to original sources
PubMed2007

Sex-specific QTL effects on variation in paraoxonase 1 (PON1) activity in Mexican Americans.

Paraoxonase 1 (PON1), a high-density lipoprotein-associated enzyme known to protect against cellular damage from toxic agents, may also have antioxidant properties. PON1 activity levels have been reported to differ by sex in human and animal studies with females exhibiting higher basal levels. We measured PON1 activity frozen serum for 1,406 individuals in over 40 extended pedigrees from the San Antonio Family Heart Study (SAFHS). We used a maximum likelihood-based, variance decomposition approach implemented in SOLAR to test for genotype-by-sex (G x S) interaction on variation in PON1 activity and to determine if any of the four PON1 quantitative trait loci (QTL) previously reported by us for this population might account for sex differences in PON1 activity levels. The residual additive genetic correlation (rho(G) = 0.82) between males and females is significantly different from 1 (P = 0.009), suggesting that some of the genes that influence PON1 activity act differently in females and males or, possibly, that a different combination of genes influences this trait in each sex. In addition to the QTL at or near the PON structural locus on 7q21-22, three other potential QTLs were evaluated for sex-specific effects: one each on chromosomes 12, 17 and 19. The QTL on chromosome 17 (LOD = 2.32, P = 0.0003; flanked by microsatellite marker loci D17S974 and D17S969) shows a significant (P = 0.005) sex-specific effect on PON1 activity; accounting for 6% of the additive genetic variance in males and 20% in females. This study represents the first formal statistical genetic test for G x S interactions on normal quantitative variation in PON1 activity in humans.

Adult↗
PubMed2006

Quantitative trait locus on Chromosome 19 for circulating levels of intercellular adhesion molecule-1 in Mexican Americans.

Circulating soluble intercellular adhesion molecule-1 (sICAM-1) is a biochemical marker of inflammation. We performed variance-components-based quantitative genetic analyses in SOLAR of sICAM-1 in 1170 individuals from Mexican American families in the San Antonio Family Heart Study. The trait is heritable (h(2)=0.50+/-0.06, P<10(-6)). Multipoint linkage analysis using a approximately 10-cM microsatellite map revealed a region on Chromosome 19p near marker D19S586 showing strong evidence of linkage for sICAM-1 (empirically adjusted univariate-equivalent LOD=4.95), coincident with the structural gene ICAM1. This region has been identified previously as a QTL for inflammatory, autoimmune, and metabolic syndrome traits. There is significant evidence (P=0.0023) of locus heterogeneity for sICAM-1 in this sample: a subset of pedigrees contributes most of the linkage signal for sICAM-1 on Chromosome 19, suggesting a logical focus for future genetic dissection of the trait.

Adult↗
PubMed2006

A quantitative trait loci-specific gene-by-sex interaction on systolic blood pressure among American Indians: the Strong Heart Family Study.

Age-adjusted systolic blood pressure is higher in males than females. Genetic factors may account for this sex-specific variation. To localize sex-specific quantitative trait loci (QTL) influencing blood pressure, we conducted a genome scan of systolic blood pressure, in males and females, separately and combined, and tested for aggregate and QTL-specific genotype-by-sex interaction in American Indian participants of the Strong Heart Family Study. Blood pressure was measured 3 times and the average of the last 2 measures was used for analyses. Systolic blood pressure was adjusted for age and antihypertensive treatment within study center. We performed variance component linkage analysis in the full sample and stratified by sex among 1168 females and 726 males. Marker allele frequencies were derived using maximum likelihood estimates based on all individuals, and multipoint identity-by-descent sharing was estimated using Loki. We detected suggestive evidence of a QTL influencing systolic blood pressure on chromosome 17 at 129 cM between markers D17S784 and D17S928 (logarithm of odds [LOD] = 2.4). This signal substantially improved when accounting for QTL-specific genotype-by-sex interaction (P = 0.04), because we observed an LOD score of 3.3 for systolic blood pressure in women on chromosome 17 at 136 cM. The magnitude of the linkage signal on chromosome 17q25.3 was slightly attenuated when participants taking antihypertensive medications were excluded, although suggestive evidence for linkage was still identified (LOD = 2.8 in women). Accounting for interaction with sex improved our ability to detect QTLs and demonstrated the importance of considering genotype-by-sex interaction in our search for blood pressure genes.

Adult↗
PubMed2006

Association of genetic variation within UBL5 with phenotypes of metabolic syndrome.

The BEACON gene was initially identified using the differential display polymerase chain reaction on hypothalamic mRNA samples collected from lean and obese Psammomys obesus, a polygenic animal model of obesity. Hypothalamic BEACON gene expression was positively correlated with percentage of body fat, and intracerebroventricular infusion of the Beacon protein resulted in a dose-dependent increase in food intake and body weight. The human homolog of BEACON, UBL5, is located on chromosome 19p in a region previously linked to quantitative traits related to obesity. Our previous studies showed a statistically significant association between UBL5 sequence variation and several obesity- and diabetes-related quantitative physiological measures in Asian Indian and Micronesian cohorts. Here we undertake a replication study in a Mexican American cohort where the original linkage signal was first detected. We exhaustively resequenced the complete gene plus the putative promoter region for genetic variation in 55 individuals and identified five single nucleotide polymorphisms (SNPs), one of which was novel. These SNPs were genotyped in a Mexican American cohort of 900 individuals from 40 families. Using a quantitative trait linkage disequilibrium test, we found significant associations between UBL5 genetic variants and waist-to-hip ratio (p = 0.027), and the circulating concentrations of insulin (p = 0.018) and total cholesterol (p = 0.023) in fasted individuals. These data are consistent with our earlier published studies and further support a functional role for the UBL5 gene in influencing physiological traits that underpin the development of metabolic syndrome.

Adult↗
PubMed2006

Fasting insulin and obesity-related phenotypes are linked to chromosome 2p: the Strong Heart Family Study.

To localize quantitative trait loci for insulin metabolism and obesity, genome scans/linkage analyses were performed on >900 members of 32 extended families participating in phase 3 of the Strong Heart Study, an investigation of the genetic and environmental determinants of cardiovascular disease in American-Indian populations from Arizona, Oklahoma, and North and South Dakota. Linkage analyses of fasting insulin and two obesity-related phenotypes, BMI and percent fat mass, were performed independently in each of the three populations. For log fasting insulin, we found a genome-wide maximum, robust logarithm of odds (LOD) score of 3.42 at 51 cM on chromosome 2p in the Dakotas. Bivariate linkage analyses of log fasting insulin with both BMI and fat mass indicate a situation of incomplete pleiotropy, as well as several significant bivariate LOD scores in the Dakotas.

Adolescent↗
PubMed2006

Recruitment and community interactions in the GOCADAN study.

OBJECTIVES: To study heart and vascular disease in Alaskan Eskimos. To identify risk factors for CVD in Norton Sound Eskimos. STUDY DESIGN: Participatory research. In this paper, procedures for selection and enrollment and providing feedback and referrals are described. Our working relationships with the Norton Sound Health Corporation (NSHC) Board, the village councils, individuals, and communities are also described. METHODS: This study was conducted in the Norton Sound region of Alaska. The participants were members of Alaskan Eskimo families. RESULTS: Procedures were formed for selecting and enrolling extended families into the study and for working with the NSHC Board, the village councils, and individual participants. The average participation was 82.6% of the age-eligible villagers in seven villages. A four-level referral system was designed. Test results were provided to participants in the form of letters, with duplicates sent to health care providers and medical records. A senior researcher returned to the village to explain the results to the participants. CONCLUSIONS: Principles of participatory research applied and developed in this study led to successful screening of 1214 Eskimos in nine villages between October 2000 and June 2004. This partnership developed into a relationship with the community, in which researchers and the communities mutually participated in the study, from the initiation of the design to the return of the data to the individuals, communities, and health care providers.

Adult↗
PubMed2005

Genetic variation in selenoprotein S influences inflammatory response.

Chronic inflammation has a pathological role in many common diseases and is influenced by both genetic and environmental factors. Here we assess the role of genetic variation in selenoprotein S (SEPS1, also called SELS or SELENOS), a gene involved in stress response in the endoplasmic reticulum and inflammation control. After resequencing SEPS1, we genotyped 13 SNPs in 522 individuals from 92 families. As inflammation biomarkers, we measured plasma levels of IL-6, IL-1beta and TNF-alpha. Bayesian quantitative trait nucleotide analysis identified associations between SEPS1 polymorphisms and all three proinflammatory cytokines. One promoter variant, -105G --> A, showed strong evidence for an association with each cytokine (multivariate P = 0.0000002). Functional analysis of this polymorphism showed that the A variant significantly impaired SEPS1 expression after exposure to endoplasmic reticulum stress agents (P = 0.00006). Furthermore, suppression of SEPS1 by short interfering RNA in macrophage cells increased the release of IL-6 and TNF-alpha. To investigate further the significance of the observed associations, we genotyped -105G --> A in 419 Mexican American individuals from 23 families for replication. This analysis confirmed a significant association with both TNF-alpha (P = 0.0049) and IL-1beta (P = 0.0101). These results provide a direct mechanistic link between SEPS1 and the production of inflammatory cytokines and suggest that SEPS1 has a role in mediating inflammation.

Adult↗
PubMed2005

Atherosclerotic risk genotypes and recurrent coronary events after myocardial infarction.

The association of a group of prespecified atherosclerotic risk genotypes with recurrent coronary events (coronary-related death, nonfatal myocardial infarction, or unstable angina) was investigated in a cohort of 1,008 patients after infarction during an average follow-up of 28 months. We used a carrier-ship approach with time-dependent survivorship analysis to evaluate the average risk of each carried genotype. Contrary to expectation, the hazard ratio for recurrent coronary events per carried versus noncarried genotype was 0.89 (95% confidence interval 0.80 to 0.99, p = 0.03) after adjustment for relevant genetic, clinical, and environmental covariates. This hazard ratio, derived from the 7 prespecified genotypes, indicated an average 11% reduction in the risk of recurrent coronary events per carried versus noncarried genotype. At 1 year after hospital discharge, the cumulative probability of recurrent coronary events was 26% in those who carried < or =1, 20% for those with 2 to 4, and 13% for those with > or =5 of these genotypes (p = 0.02). This unexpected risk reversal is a likely consequence of changes in the mix of risk factors in pre- and postinfarction populations. In conclusion, this under appreciated, population-based, risk-reversal phenomenon may explain the inconsistent associations of genetic risk factors with outcome events in previous reports involving coronary populations with different risk attributes.

Aged↗
PubMed2005

Linkage analysis of factors underlying insulin resistance: Strong Heart Family Study.

In previous work in non-diabetic participants of the Strong Heart Family Study, we identified three heritable principal components of nine insulin resistance (IR) phenotypes: 1) a glucose/insulin/obesity factor, 2) a blood pressure factor, and 3) a dyslipidemia factor. To localize quantitative trait loci (QTL) potentially influencing these factors, we conducted a genome scan of factor scores in Strong Heart Family Study participants. Approximately 599 men and women, >or=18 years of age, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota), were examined between 1997 and 1999. We used variance components linkage analysis to identify QTLs for the IR factors. With age, sex, and study center as covariates, we detected linkage of the glucose/insulin/obesity factor to chromosome 4 (robust logarithm of the odds (LOD) = 2.2), the dyslipidemia factor to chromosome 12 (robust LOD = 2.7), and the blood pressure factor to chromosome 1 (robust LOD = 1.6). The peak linkage signals identified for these IR factors support several positive findings from other studies and occur in regions harboring interesting candidate genes. The corroboration of existing QTLs will bring us closer to the identification of the functional genes that predispose to IR.

Aged↗
PubMed2005

Kidney disease among the Zuni Indians: the Zuni Kidney Project.

BACKGROUND: There is an epidemic of kidney disease among the Zuni Indians. In collaboration with health care providers and research institutions, the Zuni Pueblo established the Zuni Kidney Project to reduce the burden of kidney disease. METHODS: The Zuni Kidney Project conducted a population-based, cross-sectional survey to estimate the prevalence of albuminuria, hematuria, and related risk factors. Neighborhood household clusters served as the sampling frame. Participants completed a questionnaire, donated blood and urine samples, and had blood pressure, height, and weight measured. This survey provided the foundation for ongoing studies to identify genetic and environmental risk factors for disease susceptibility and progression. RESULTS: Age and gender distributions among survey participants were similar to those in the eligible Zuni population. Prevalence of incipient albuminuria (IA) (0.03< or = urine albumin:creatinine ratio, UACR <0.3) and overt albuminuria (OA) (UACR < 0.3) were higher among diabetics [IA 34.3% (28.3, 40.4%); OA 18.6% (13.7, 23.6%)] than nondiabetics [IA 11.1% (9.3, 12.8%); OA 1.7% (1.0, 2.5%)]. Nondiabetics comprised 58.6% (52.2, 65.0%) and 30.9% (19.9, 41.9%) of participants with IA and OA, respectively. The prevalence of hematuria was higher among diabetics [> or = trace 47.0% (40.7, 53.4); > or =50 red blood cell/microL 25.8% (20.3, 31.4%)] than nondiabetics [> or = trace 31.1% (28.5, 33.7%); > or =50 red blood cell/microL 16.6% (14.5, 18.7%)]. Hypertension was associated with albuminuria among diabetic and nondiabetic participants. Hypercholesterolemia was associated with albuminuria among nondiabetic participants. Diabetes and alcohol use were associated with hematuria. CONCLUSION: The high prevalences of albuminuria among nondiabetics and of hematuria among diabetics and nondiabetics are consistent with high rates of nondiabetic kidney disease among Zuni Indians with and without diabetes.

Adult↗
PubMed2005

Joint linkage and association analysis of the hepatic lipase promoter polymorphism and lipoprotein size phenotypes.

The hepatic lipase gene (LIPC) has been implicated as a potential regulator of HDL-cholesterol concentration and HDL and LDL particle size. Studies have centered on a C to T transition in the promoter region of LIPC, 514 base pairs upstream from the transcription initiation site. We performed a genome-wide linkage screen for several lipoprotein size phenotypes and tested for association of these traits with LIPC -514C-T in 798 individuals from the San Antonio Family Heart Study. Median diameters were measured for HDL particles stained for apoA1 (A1), apoA2 (A2), unesterified cholesterol (UC), and esterified cholesterol (EC) and for LDLs stained for EC. The median diameter of all phenotypes exhibited evidence of linkage to the LIPC region of chromosome 15 (LODs of 1.78 to 3.79). Linkage was also observed for HDL-EC size on chromosome 5p (LOD = 3.50). Association with the LIPC -514C-T polymorphism was detected for HDL-A1, HDL-A2, HDL-UC, and HDL-EC median diameters (p < 0.001) but not for LDL-EC size. Linkage analyses of HDL sizes conditional on the -514C-T polymorphism reduced the LOD scores in the LIPC region only slightly, suggesting that this polymorphism does not explain the observed linkage of lipoprotein sizes to chromosome 15. These results indicate the presence of a lipoprotein size locus in the LIPC region but suggest that -514C-T is not the primary functional variant in this region, implying that additional functional mutations influencing HDL and potentially LDL size variation occur in or near LIPC.

Cholesterol, HDL↗
PubMed2005

Heritability of hemostasis phenotypes and their correlation with type 2 diabetes status in Mexican Americans.

Hypercoagulation often occurs in type 2 diabetes, suggesting pleiotropy of the genes that influence disease liability and hemostasis-related phenotypes. To better understand the relationship between hemostasis and diabetes, we first used maximum-likelihood methods to estimate the relative contribution of additive genetic, measured environmental, and shared household effects to the normal variance of 16 hemostasis-related traits in 813 individuals participating in the San Antonio Family Heart Study. We estimated moderate to high heritabilities (0.20-0.60) for each phenotype. Von Willebrand factor (VWF), thrombin activatable fibrinolysis inhibitor, activated protein C (APC) ratio, factor V, and prothrombin time had heritabilities greater than 0.50. The correlation between type 2 diabetes status and the hemostasis-related traits was then partitioned into genetic and environmental components using bivariate variance-components methods. Significant (p < or = 0.05) positive genetic correlations (0.37-0.51) occurred with factors II and VIII, VWF, total protein S (tPS), and tissue factor pathway inhibitor. Significant negative genetic correlations were estimated for activated partial thromboplastin time (-0.49) and APC ratio (-0.38). By contrast, significant environmental correlations occurred only with factor II (-0.40) and tPS (-0.31). Our results suggest that genes are important contributors to the normal variation in hemostasis-related traits and that genes influencing hemostasis-related traits pleiotropically influence diabetes risk.

Adolescent↗
PubMed2005

A genetic and epidemiologic study of cardiovascular disease in Alaska natives (GOCADAN): design and methods.

This article is a report of the design and methods of the Genetics of Coronary Artery Disease in Alaska Natives (GOCADAN) Study. This longitudinal, population-based study was initiated to investigate the genetic determinants of cardiovascular disease and its risk factors. Between October 2000 and April 2004, this family study enrolled 1,214 Eskimos from several coastal villages in the Norton Sound region of Western Alaska. Examinations included a physical, laboratory determinations, and measures of subclinical disease. This study will generate a genome-wide scan for loci influencing cardiovascular disease-related traits. Relations between subclinical atherosclerosis and markers of inflammation will be examined using historic and newly drawn samples. The study will provide data on CVD prevalence, risk factors and the relative contribution of genetic and environmental determinants in Alaska Native peoples. Data from this study will contribute to the delivery of health-care and prevention of CVD in Alaska Eskimos and other populations.

Adult↗
PubMed2004

Prospective analysis of mannose-binding lectin genotypes and coronary artery disease in American Indians: the Strong Heart Study.

BACKGROUND: Mannose-binding lectin (MBL) is a circulating immune factor responsible for opsonization of pathogens and directly activating complement. Common variations in the MBL gene are responsible for an opsonic deficiency that affects 5% to 7% of whites and are associated with increased susceptibility to infections. After a preliminary report associating these variations with coronary artery disease (CAD), we determined MBL genotypes in 3 American Indian communities experiencing an increased mortality and morbidity from CAD. METHODS AND RESULTS: We examined DNA from 434 participants in a population-based cohort, the Strong Heart Study. Genotypes for 3 common MBL coding variations and 1 promoter polymorphism were determined. The frequency of a composite genotype that conferred low MBL levels was 20.7% in 217 cases and 11.1% in matched controls without CAD. A conditional logistic regression model indicated a univariate OR for CAD of 2.3 (95% CI 1.3 to 4.2, P=0.005) for the variant genotypes. After adjustment for demographic and CAD risk factors, including type 2 diabetes mellitus, fibrinogen, triglycerides, and hypertension, the OR was 3.2 (95% CI 1.5 to 7.0, P=0.004). CONCLUSIONS: Variant MBL genotypes coding for markedly diminished levels of MBL are predictive of CAD. After adjustment for multiple traditional risk factors for ischemic heart disease, this association remains significant. A high prevalence of variant MBL alleles and CAD in this population suggests that potentially important public health benefits may accrue from future interventions based on these genotypes.

Cohort Studies↗
PubMed2004

Two quantitative trait loci affect ACE activities in Mexican-Americans.

Angiotensin-converting enzyme (ACE) activity is highly heritable and has been associated with cardiovascular disease. We are studying the effects of genes and environmental factors on hypertension and related phenotypes, such as ACE activity, in Mexican-American families. In the current study, we performed multipoint linkage analysis to search for quantitative trait loci (QTLs) that affect ACE activities on data from 793 individuals from 29 pedigrees from the San Antonio Family Heart Study. As expected, we obtained strong evidence (maximum log of the odds [LOD]=4.57, genomic P=0.003) that a QTL for ACE activity is located on chromosome 17 near the ACE structural locus. We subsequently performed linkage analyses conditional on the effect of this QTL and obtained strong evidence (LOD=3.34) for a second QTL on chromosome 4 near D4S1548. We next incorporated the ACEIns/Del genotypes in our analyses and removed the evidence for the chromosome 17 QTL (maximum LOD=0.60); however, we retained our evidence for the QTL on chromosome 4q. We conclude that the QTL on chromosome 17 is tightly linked to ACE and is in strong disequilibrium with the insertion/deletion polymorphism, which is consistent with other reports. We also have evidence that an additional QTL affects ACE activity. Identification of this additional QTL might lead to alternate means of prophylaxis.

Adolescent↗
PubMed2004

A quantitative trait locus influences coordinated variation in measures of ApoB-containing lipoproteins.

Lipoprotein phenotypes are known to be strongly intercorrelated. These intercorrelations are due to genetic and environmental effects on common metabolic pathways. The purpose of this study was to determine if we could localize genes that exert pleiotropic effects on multiple related lipoprotein traits in humans. Using data from the San Antonio Family Heart Study, we extracted principal components from a set of 12 intercorrelated lipoprotein traits that included phenotypes reflecting lipid and protein concentrations and size distributions for LDLs and HDLs. Five principal components were extracted from the data and all were significantly heritable (h(2) = 0.41-0.57). When subjected to linkage analyses, only one, Component 5, returned a LOD score > or = 3 (LOD score was 3.0 at 38cM on chromosome 15; genome-wide P-value = 0.039). LDL median diameter (-0.529), non-HDLC (-0.422), and ApoB (-0.403) concentrations were the only traits with loadings (absolute value) >0.4, suggesting Component 5 is related to LDL size or perhaps more generally to beta-lipoprotein metabolism. Surprisingly, none of the 12 original lipoprotein traits had a LOD >1 in this region of chromosome 15. These data provide evidence for a novel gene, influencing beta-lipoprotein phenotypes, whose effect(s) is detected only when several lipoprotein traits are considered together.

Adult↗
PubMed2004

Bivariate linkage between acylation-stimulating protein and BMI and high-density lipoproteins.

OBJECTIVE: Given the importance of visceral adiposity in the metabolic syndrome, whether levels of adipokines have shared genetic effects (pleiotropy) with aspects of the metabolic syndrome should be addressed. Acylation-stimulating protein (ASP), an adipose-derived protein, influences lipid metabolism, obesity, and glucose use. Therefore, our objective was to examine the genetic regulation of ASP and associated pleiotropic effects. RESEARCH METHODS AND PROCEDURES: We assayed serum ASP levels in 435 Mexican Americans participating in the San Antonio Family Heart Study and performed univariate and bivariate variance components analysis. RESULTS: Additive genetic heritability of ASP was 26% (p = 0.0004). Bivariate genetic analysis detected significant genetic correlations between ASP and several lipid measures but not between ASP and adiposity or diabetes measures. We detected two potential quantitative trait loci influencing ASP levels. The strongest signal was on chromosome 17 near marker D17S1303 [log of the odds ratio (LOD) = 2.7]. The signal on chromosome 15 reached its peak near marker D15S641 (LOD = 2.1). Both signals localize in regions reported to harbor quantitative trait loci influencing obesity and lipid phenotypes in this population. Bivariate linkage analysis yielded LODs of 4.7 for ASP and BMI on chromosome 17 and 3.2 for ASP and high-density lipoprotein2a on chromosome 15. DISCUSSION: Given these findings, there seems to be a significant genetic contribution to variation in circulating levels of ASP and an interesting pattern of genetic correlation (i.e., pleiotropy) with other risk factors associated with the metabolic syndrome.

Adolescent↗