Biomedical subjects

I B Borecki

Publications and source records attributed to I B Borecki.

At least 19 recordsLinked to original sources

PubMed2006

QTL-specific genotype-by-smoking interaction and burden of calcified coronary atherosclerosis: the NHLBI Family Heart Study.

BACKGROUND: Calcified coronary plaque (CCP) is a complex trait influenced by both genes and environment, and plausibly an interaction between the two. Because the familial aggregation of CCP has been demonstrated and smoking is a significant, independent predictor of CCP, we assessed the evidence for genotype-by-smoking interaction and conducted linkage analysis of quantitative Agatston CCP scores in participants of the NHLBI Family Heart Study (FHS). METHODS: During standardized clinical exams smoking habits were ascertained and CCP was quantified with cardiac computed tomography (CT). Among 4387 relationship pairs from 2128 Caucasian examinees variance component analysis was implemented in SOLAR to examine: (1) additive genotype-by-smoking status interaction using a variance component approach; (2) linkage analysis in the full sample and among smoking subsets defined by individual smoking exposure; (3) QTL-specific genotype-by-smoking interaction in the regions that appeared to differentiate between smoking strata. RESULTS: The prevalence of CCP (and median Agatston score) was 75% (184.6) in men and 48% (51.0) in women. We detected four genome-wide significant logarithm of odds (LOD) scores in samples stratified by individual smoking exposure: chromosome 4 at 122cM (nearest marker D4S2297; robust adjusted LOD=3.1; q=0.053), chromosome 6 at 99cM (nearest marker D6S1056; robust adjusted LOD=3.3; q=0.053), chromosome 11 at 19cM (nearest marker D11S199; robust adjusted LOD=4.0; q=0.02) and chromosome 13 at 77cM (nearest marker D13S892; robust adjusted LOD=3.1; q=0.053). Additive and QTL-specific genotype-by-smoking interaction was detected on chromosomes 4, 6, 11 and 13; all P<0.05. Three of the four QTLs identified in this report have been previously linked to atherosclerosis and harbor interesting candidate genes. CONCLUSIONS: These findings demonstrate the importance of considering complex interactions in the search for genes that influence the pathogenesis of CCP.

Adult↗

PubMed2006

Genotype-by-sex interaction in the aetiology of type 2 diabetes mellitus: support for sex-specific quantitative trait loci in Hypertension Genetic Epidemiology Network participants.

AIMS/HYPOTHESIS: While there are sex-related differences in both the prevalence of type 2 diabetes mellitus and disease risk factors, there is only limited research on sex-specific influences on type 2 diabetes aetiology within the same study population. Thus, we assessed genotype-by-sex interaction using a liability threshold model in an attempt to localise sex-specific type 2 diabetes quantitative trait loci (QTLs). SUBJECTS, MATERIALS AND METHODS: Hypertensive siblings and their offspring and/or parents in the Hypertension Genetic Epidemiology Network of the Family Blood Pressure Program were recruited from five field centres. The diabetic phenotype was adjusted for race, study centre, age and non-linear age effects. In total, 567 diabetic individuals were identified in 385 families. Variance component linkage analyses in the combined sample and stratified by sex and race were performed (SOLAR program) using race-specific marker allele frequencies derived from a random sample of participants at each centre. RESULTS: We observed a QTL-specific genotype-by-sex interaction (p=0.009) on chromosome 17 at 31 cM, with females displaying a robust adjusted logarithm of odds (LOD) of 3.0 compared with 0.2 in males and 1.3 in the combined sample. Three additional regions demonstrating suggestive evidence for linkage were detected: chromosomes 2 and 5 in the female sample and chromosome 22 (adjusted LOD=1.9) in the combined sample. CONCLUSIONS/INTERPRETATION: These findings suggest that multiple genes may regulate susceptibility to type 2 diabetes, demonstrating the importance of considering the interaction of genes and environment in the aetiology of common complex traits.

Adult↗

PubMed2005

Sex-specific findings from a genome-wide linkage analysis of human fatness in non-Hispanic whites and African Americans: the HyperGEN study.

OBJECTIVE: To conduct a full genome search for genes potentially influencing two related phenotypes: body mass index (BMI, kg/m2) and percent body fat (PBF) from bioelectric impedance in men and women. DESIGN: A total of 3383 participants, 1348 men and 2035 women; recruitment was initiated with hypertensive sibpairs and expanded to first-degree relatives in a multicenter study of hypertension genetics. MEASUREMENTS: Genotypes for 387 highly polymorphic markers spaced to provide a 10 cM map (CHLC-8) were generated by the NHLBI Mammalian Genotyping Service (Marshfield, WI, USA). Quantitative trait loci for obesity phenotypes, BMI and PBF, were examined with a variance components method using SOLAR, adjusting for hypertensive status, ethnicity, center, age, age2, sex, and age2 x sex. As we detected a significant genotype-by-sex interaction in initial models and because of the importance of sex effects in the expression of these phenotypes, models thereafter were stratified by sex. No genotype-by-ethnicity interactions were found. RESULTS: A QTL influencing PBF in women was detected on chromosome12q (12q24.3-12q24.32, maximum empirical LOD score=3.8); a QTL influencing this phenotype in men was found on chromosome 15q (15q25.3, maximum empirical LOD score=3.0). These QTLs were detected in African-American and white women (12q) and men (15q). QTLs influencing both BMI and PBF were found over a broad region on chromosome 3 in men. QTLs on chromosomes 3 and 12 were found in the combined sample of men and women, but with weaker significance. CONCLUSION: The locations with highest LOD scores have been previously reported for obesity phenotypes, indicating that at least two genomic regions influence obesity-related traits. Furthermore, our results indicate the importance of considering context-dependent effects in the search for obesity QTLs.

Adult↗

PubMed2003

Multivariate and multilocus variance components method, based on structural relationships to assess quantitative trait linkage via SEGPATH.

A general-purpose modeling framework for performing path and segregation analysis jointly, called SEGPATH (Province and Rao [1995] Stat. Med. 7:185-198), has been extended to cover "model-free" robust, variance-components linkage analysis, based on identity-by-descent (IBD) sharing. These extended models can be used to analyze linkage to a single marker or to perform multipoint linkage analysis, with a single phenotype or multivariate vector of phenotypes, in pedigrees. Within a single, consistent approach, SEGPATH models can perform segregation analysis, path analysis, linkage analysis, or combinations thereof. SEGPATH models can incorporate environmental or other measured covariate fixed effects (including measured genotypes), genotype-specific covariate effects, population heterogeneity models, repeated-measures models, longitudinal models, autoregressive models, developmental models, gene-by-environment interaction models, etc., with or without linkage components. The data analyzed can have any missing value structure (assumed missing at random), with entire individuals missing, or missing on one or more measurements. Corrections for ascertainment can be made on a vector of phenotypes and/or other measures. Because of the flexibility of the class of models, the SEGPATH approach can also be used in nongenetic applications where there is a hierarchical structure, such as longitudinal, repeated-measures, time series, or nested models. A variety of specific models are provided, as well as some comparisons with other linkage analysis models. Particular applications demonstrate the importance of correctly accounting for the extraneous sources of familial resemblance, as can be done easily with these SEGPATH models, so as to give added power to detect linkage as well as to protect against spuriously inferring linkage.

Genetic Linkage↗

PubMed2003

A relationship between methylenetetrahydrofolate reductase variants and the development of invasive cervical cancer.

OBJECTIVE: Low red blood cell folate levels have been associated with hypomethylation of DNA in dysplastic tissue and an increased risk for cervical intraepithelial neoplasia in human papillomavirus (HPV)-infected women. Methylenetetrahydrofolate reductase (MTHFR) is a critical enzyme regulating the metabolism of folate and methionine, the important components of DNA synthesis and methylation. Two common genetic polymorphisms, causing reduced MTHFR activity, have been identified. Therefore, the goal of this study was to evaluate these MTHFR variations as risk factors for invasive cervical cancer. METHODS: To overcome the failure to properly match cases and controls that can cause false-positive inferences due to population stratification and unrecognized variables in a traditional case-control study, a family-based transmission/disequilibrium test (TDT) was used. We obtained samples from nuclear families of 102 women with invasive cervical cancer (ICC). One polymorphism was typed by a PCR-RFLP method, while a template-directed dye-terminator assay was developed for the other. RESULTS AND CONCLUSIONS: We were unable to confirm a strong association of MTHFR polymorphisms and ICC using family-based controls and a transmission/disequilibrium test. The overall results of the TDT showed chi(2) (1 df) of 0.28 (P = 0.60) for exon 4, chi(2) (1 df) of 0.81(P = 0.37) for exon 7, and chi(2) (3 df) of 2.56 (P = 0.46) for the haplotype, meaning that there was no transmission of those alleles significantly in excess of Mendelian expectations to affected women. In addition, there was no effect of these variants with increased parity or infection with high-risk-type human papillomavirus.

Adult↗

PubMed2003

Familial aggregation of exercise heart rate and blood pressure in response to 20 weeks of endurance training: the HERITAGE family study.

Changes of heart rate (HR) and blood pressure (BP) relative to baseline levels in response to an extended period of endurance training are indices of cardiovascular adaptability. Familial influences were investigated for HR and BP at work rates of 50 W and 60 % of the maximal oxygen uptake (VO2max) in response to 20 weeks of endurance training. A total of 481 participants from 99 sedentary White nuclear families in the HERITAGE Family Study (HERITAGE) were analyzed using a familial correlation model. Each of these training response phenotypes was adjusted for the effects of age, BMI, cigarette smoking, baseline VO2max, and its baseline values in fathers, mothers, sons and daughters, respectively. We found that maximal heritabilities reached 34 % and 29 % for HR training responses at 50 W and 60 % of VO2 max, respectively. The heritability was 22 % for systolic BP (SBP) training response at 50 W, but negligible at 60 % of VO2max. No significant heritabilities were found for diastolic BP (DBP) training responses at either 50 W or 60 % of VO2max. Familial influences for exercise HR and BP training responses were also assessed in a total of 257 participants from 113 Black family units in HERITAGE. However, there was no significant familial resemblance, which may be attributable to the small sample size. In conclusion, HR and SBP training responses during submaximal exercise in Whites were influenced by a modest, but significant, familial component. These observations are therefore in contrast to substantial familial effects (heritability estimates of about 50 %) previously reported for these variables measured at baseline.

Adaptation, Physiological↗

PubMed2003

Evidence of major genes for exercise heart rate and blood pressure at baseline and in response to 20 weeks of endurance training: the HERITAGE family study.

Major gene effects on exercise heart rate (HR) and blood pressure (BP) measured at 50 W and 80 % maximal oxygen uptake (VO (2)max) were assessed in 99 White families in the HERITAGE Family Study. Exercise HR and BP were measured both before and after 20 weeks of endurance training. The baseline phenotypes were adjusted for the effects of age and BMI, whereas the training responses (post-training minus baseline) were adjusted for the effects of age, BMI and the corresponding baseline values, within four sex-by-generation groups. Baseline exercise HR at 50 W was under the influence of a major recessive gene and a multifactorial component, which accounted for 30 % and 27 % of the variance, respectively. The training response was found to be under the influence of a major dominant gene, which accounted for 27 % of the variance. These significant major gene effects were independent of the effects of cigarette smoking, baseline VO (2)max, and the resting HR levels. No significant interactions were found between genotype and age, sex, or BMI. No major gene effect was found for exercise BP. Instead, we found the baseline exercise BP at 50 W and 80 % VO (2)max and the training response at 50 W were solely influenced by multifactorial effects, which accounted for about 50 %, 40 % and 20 % of the variance, respectively. No familial resemblance was found for training responses in exercise HR or BP at 80 % VO (2)max. Segregation analysis also was carried out for exercise HR in Whites pooled with a small sample of Blacks in HERITAGE. Similar major effects were found, but the transmission from parents to offspring did not follow Mendelian expectations, suggesting sample heterogeneity. In conclusion, submaximal exercise HR at baseline and in response to endurance training was influenced by putative major genes, with no evidence of interactions with sex, age or BMI, in contrast to a multifactorial etiology for exercise BP.

Black People↗

PubMed2002

DGAT1 promoter polymorphism associated with alterations in body mass index, high density lipoprotein levels and blood pressure in Turkish women.

Triglyceride synthesis is catalyzed by acyl CoA:diacylglycerol acyltransferases (DGAT), microsomal enzymes that use diacylglycerol and fatty acyl CoAs as substrates. Because DGAT1 expression is up-regulated during adipocyte differentiation and DGAT1 deficiency is associated with leanness in mice, we hypothesized that alterations in DGAT1 expression may affect human body weight. We identified five polymorphisms in the human DGAT1 promoter and 5' non-coding sequence in a random Turkish population. Functional analysis of one common variant, C79T, revealed reduced promoter activity for the 79T allele in cultured cell lines. In 476 Turkish women, the 79T allele was associated with lower body mass index (BMI) (p = 0.004), conferring an odds ratio of 2.0 (95% CI = 1.30-3.07, p = 0.0001) for BMI </= 20. Interestingly, after controlling for the influence of BMI, the 79T allele was also associated with higher plasma HDL cholesterol levels (p = 0.0006) and lower diastolic blood pressure (p = 0.019) in these women. No association was found in Turkish men (n = 846). Our findings suggest that genetic variation at the DGAT1 locus may influence BMI and other metabolic parameters associated with cardiovascular risk in selected human populations.

Acyltransferases↗

PubMed2002

The hormone-sensitive lipase gene and body composition: the HERITAGE Family Study.

OBJECTIVE: To investigate whether the C-60G polymorphism and other markers in the hormone-sensitive lipase (LIPE) gene are associated with baseline body composition and free-fatty acid (FFA) concentrations measured at rest and during low-intensity exercise in white and black subjects participating in the HERITAGE Family Study. SUBJECTS: Adult sedentary white (245 men and 258 women) and black (91 men and 185 women) subjects. MEASUREMENTS: body mass index (BMI); fat mass (FAT); percentage body fat (%FAT); fat-free mass (FATFR); sum of eight skinfolds (SF8); subcutaneous (ASF), visceral (AVF) and total (ATF) abdominal fat areas assessed by CT scan; plasma FFA concentrations measured at rest (FFAR), at a power output of 50 W (FFA50) and at a relative power output of 60% of VO(2max) (FFA60%); and fasting insulin (INS). STATISTICAL ANALYSIS: Association between the C-60G polymorphism of the LIPE gene and each phenotype was tested separately in men and women using ANCOVA with the effects of age and race as covariates and with further adjustment for FAT for ASF, AVF, ATF, FFAR, FFA50 and FFA60%. Secondly, owing to significant gene-by-race interaction, associations were investigated separately in each of the two race groups. Linkage was tested with the C-60G polymorphism, a dinucleotide repeat polymorphism in the intron 7 of the LIPE gene and two microsatellites markers (D19S178 and D19S903) flanking the LIPE gene. RESULTS: There were no race differences in the allele frequencies of the C-60G polymorphism of the LIPE gene. No association or gene-by-race interaction was observed in men. However, in women, strong gene-by-race interactions were observed for BMI (P=0.0005), FAT (P=0.0007), %FAT (P=0.0003), SF8 (P=0.0001), ASF (P=0.03) and ATF (P=0.01). When the analysis was performed separately in each race, white women carriers of the -60G allele exhibited lower %FAT (P=0.005) and SF8 (P=0.01) than non-carriers, while in black women, the -60G allele was associated with higher BMI (P=0.004), FAT (P=0.009), %FAT (P=0.01) and SF8 (P=0.0009). These associations were no longer significant after adjusting for INS. Evidence of linkage was observed in whites with ATF, FFAR, FFA50 and FFA60%. CONCLUSION: These results suggest that the C-60G polymorphism in the LIPE gene plays a role in determining body composition and that its effect is sex-, race- and insulin-dependent.

Abdomen↗

PubMed2001

Familial and genetic determinants of systemic markers of inflammation: the NHLBI family heart study.

Inflammation is thought to play a central role in the etiology and outcome of atherosclerosis. Animal studies as well as in vitro and in vivo human studies suggest that host factors modulate the magnitude and extent of inflammatory responses. We investigated familial aggregation of three systemic markers of inflammation (C-reactive protein (CRP), white blood cell count (WBC), and albumin) in a large, cross-sectional study conducted in four US communities. We found evidence of substantial heritability (35-40%) for CRP levels as well as for WBC and albumin levels. Negligible spouse correlations suggested little influence of shared household environment on these traits. The combination of sociodemographic factors (age, center, education), behavioral and lifestyle factors (cigarette smoking, alcohol intake, hormone replacement therapy), obesity and fat patterning, and prevalent diabetes explained 13-30% the interindividual variability of these traits. There was no evidence that these inflammation phenotypes were linked to a microsatellite marker in the interleukin-1 gene cluster on chromosome 2q, a region that includes several candidate genes for chronic inflammatory diseases. Our findings suggest that CRP levels, albumin levels, and WBC are determined at least partially by genetic factors. Further efforts to identify gene loci affecting these traits are warranted.

Adult↗

PubMed2001

Evolution of the simulated data problem.

The simulated data problem was designed via an interactive process by the Simulation Problem Organizing Committee and the selected data simulators. Based on discussions at the previous Genetic Analysis Workshop, many of the features of previous simulation problems, such as a complex disease, genome scan, and replication, were retained and in addition, a population genetics model was used to generate the simulated genes. We describe the process that was used to structure the problem and summarize the discussions about many of the scientific issues that were considered.

Chromosome Mapping↗

PubMed2001

Familial resemblance and heritability.

Familial resemblance, which arises when members within families are more similar than are unrelated pairs of individuals, may be estimated in terms of correlations (or covariances) among family members. The magnitudes of such correlations generally reflect both the extent of environmental sharing and the degree of biological relationship between the relatives. Heritability, or more appropriately multifactorial heritability or generalized heritability, quantifies the strength of the familial resemblance and represents the percentage of variance ina trait that is due to all additive familial effects including additive genetic effects and those of the familial environment. However, the traditional concept of heritability, which may be more appropriately called the genetic heritability, represents only the percentage of phenotypic variance due to additive genetic effects. Resolving the sources of familial resemblance entails other issues. For example, there may be major gene effects that may be largely or entirely nonadditive, temporal or developmental trends, and gene-gene (epistasis) and gene-environment interactions. The design of a family study determines which of these sources are resolvable. For example, in intact nuclear families consisting of parents and offspring, the genetic and familial environmental effects are not resolvable because these relatives share both genes and environments. However, extended pedigrees and twin and adoption study designs allow separation of the heritable effects and, possibly, more complex etiologies, including interactions. Various factors affect the estimation and interpretability of heritability, for example, assumptions regarding linearity and additivity of the effects, assortative mating, and the underlying distribution of the data. Nonnormality of the data can lead to errors in hypothesis testing, although it yields reasonably unbiased estimates. Fortunately, these and other complications can be directly modeled in many of the sophisticated software packages available today in genetic epidemiology.

Adoption↗

PubMed2001

Linkage and association: basic concepts.

Many investigators are turning their efforts to dissecting the etiology of complex traits. The primary tools for gene discovery, localization, and functional analysis are linkage and association studies. While the conceptual underpinnings of these approaches have long been known, advances in recent decades in molecular genetics, in the development of efficient computational algorithms, and in computing power have enabled the large-scale application of these methods. Here, we review the biological basis of linkage and association among loci and the common methods used to assess these relationships with respect to observed phenotypes. We further consider the two most common approaches--genome scans and candidate gene studies--especially their respective strengths, weaknesses, and resource requirements. Finally, we highlight some of the major challenges that arise from these investigative approaches and those that are inherent in the nature of complex traits. The chapters that follow elaborate on many of these topics.

Chromosome Mapping↗

PubMed2001

Genome-wide linkage scan to detect loci influencing levels of dehydroepiandrosterones in the HERITAGE Family Study.

A genome-wide linkage scan was performed to identify genomic regions that influence levels of dehydroepiandrosterone (DHEA), DHEA sulfate (DHEAS), and DHEA fatty acid esters (DHEA-FA) at baseline and in response to 20 weeks of endurance exercise training in sedentary white and black participants in the HERITAGE Family Study. The baseline levels were log-transformed and adjusted for the effects of age and sex prior to genetic analysis. The training responses were adjusted for the effects of age, sex, and the baseline values. A total of 509 autosomal component polymorphic markers were used for the genome scan with an average spacing of 6.0 Mb. Multipoint variance components linkage analyses were performed in nuclear families containing 360 white and 106 black sibling pairs. We found 5 genomic regions with significant linkages for baseline DHEA-FA in whites, with log odd (LOD) scores over 3.6 (P < 2 x 10(-5)). They include (1) D1S468 (LOD 4.56, 2.533 Mb, 1p36.22); (2) D2S177 (LOD 5.65, 52.663 Mb, 2p16.3); (3) D4S2397 (LOD 3.98, 32.246 Mb, 4p15.2); (4) the paraoxonase loci (LOD 3.93 approximately 3.99, 101.544 approximately 102.933 Mb, 7q21.3), and D7S821 (LOD 3.88, 104.497 Mb, 7q22.1); and (5) D12S372 (LOD 4.66, 2.129 Mb, 12q13.33). In addition, we obtained evidence of suggestive linkages (2.2 < LOD < 3.6; 2 x 10(-5) < P < 7 x 10(-4)) on chromosomes 3p, 6q, and 8q for baseline DHEAS; on chromosomes 2q, 3p, 9q, 10p, 16q, and 17p for baseline DHEA-FA in whites; and on chromosomes 9q and 11p for baseline DHEA in blacks. This is the first genome-wide linkage scan searching for genomic regions influencing human DHEA levels. Several potential candidate genes are located in these genomic regions, which warrant further studies in HERITAGE and other cohorts.

Adult↗

PubMed2001

Genomic scan for genes affecting body composition before and after training in Caucasians from HERITAGE.

An autosomal genomewide search for genes related to body composition and its changes after a 20-wk endurance-exercise training program has been completed in the HERITAGE Family Study. Phenotypes included body mass index (BMI), sum of eight skinfold thicknesses, fat mass (FM), fat-free mass, percent body fat (%Fat), and plasma leptin levels. A maximum of 364 sib-pairs from 99 Caucasian families was studied with the use of 344 markers with single-point and multipoint linkage analyses. Evidence of significant linkage was observed for changes in fat-free mass with the S100A and the insulin-like growth factor I genes (P = 0.0001). Suggestive evidence (2.0 < or = Lod < 3.0; 0.0001 < P < or = 0.001) was also observed for the changes in FM and %Fat at 1q31 and 18q21-q23, in %Fat with the uncoupling protein 2 and 3 genes, and in BMI at 5q14-q21. At baseline, suggestive evidence was observed for BMI at 8q23-q24, 10p15, and 14q11; for FM at 14q11; and for plasma leptin levels with the low-density lipoprotein receptor gene. This is the first genomic scan on genes involved in exercise-training-induced changes in body composition that could provide information on the determinants of weight loss.

Adipose Tissue↗

PubMed2001

Evidence of LPL gene-exercise interaction for body fat and LPL activity: the HERITAGE Family Study.

Evidence of a gene-exercise interaction for traits related to body composition is limited. Here, the association between the lipoprotein lipase (LPL) S447X polymorphism and changes in body mass index, fat mass, percent body fat, abdominal visceral fat measured by computed tomography, and post-heparin plasma LPL activity in response to 20 wk of endurance training was investigated in 741 adult white and black subjects. Changes were compared between carriers and noncarriers of the X447 allele after adjustment for the effects of age and pretraining values. No evidence of association was observed in men. However, white women carrying the X447 allele exhibited greater reductions of body mass index (P = 0.01), fat mass (P = 0.01), and percent body fat (P = 0.03); in black women, the carriers exhibited a greater reduction of abdominal visceral fat (P = 0.05) and a greater increase in post-heparin LPL activity (P = 0.02). These results suggest that the LPL S447X polymorphism influences the training-induced changes in body fat and post-heparin LPL activity in women but not in men.

Adult↗

PubMed2000

Genome-wide linkage analysis of systolic and diastolic blood pressure: the Québec Family Study.

BACKGROUND: Blood pressure (BP), an important risk factor for coronary heart disease, is a complex trait with multiple genetic etiologies. While some loci affecting BP variation are known (eg, angiotensinogen), there are likely to be novel signals that can be detected with a genome scan approach. METHODS AND RESULTS: A genome-wide scan was performed in 125 random and 81 obese families participating in the Québec Family Study. A multipoint variance-components linkage analysis of 420 markers (353 microsatellites and 67 restriction fragment length polymorphisms) revealed several signals (P:<0.0023) for systolic BP on 1p (D1S551, ATP1A1), 2p (D2S1790, D2S2972), 5p (D5S1986), 7q (D7S530), 8q (CRH), and 19p (D19S247). Suggestive evidence (0.0023<P:<0.01) was found on 3q, 10p, 12p, 14q, and 22q. The results were encouraging for HSD3B1 (P:<0.03), AGT (P:<0.03), ACE (P:<0.02), and adipsin (P:<0.005) but null with regard to other candidates (eg, renin, and glucocorticoid and adrenergic receptors). CONCLUSIONS: Multiple linkage regions support the notion that risk for hypertension is due to multiple (ie, oligogenic) susceptibility loci. Comparisons across the complete, random, and obese samples suggest that some regions are specific to BP and others may involve obesity (eg, pleiotropy, epistasis, or gene-environment interaction). Some of these areas harbor known candidates. Others involve novel regions, some of which replicate previous reports and provide a focus for future studies to identify novel genes that influence interindividual variation in BP.

Age Distribution↗

PubMed2000

Genome-wide search for genes related to the fat-free body mass in the Québec family study.

Fat-free mass (FFM) consists mostly of skeletal muscle and bone tissues, and identification of the genes and molecular mechanisms involved in the control of FFM would have implications for the understanding of sarcopenia and potentially osteoporesis associated with aging, as well as the response to starvation, refeeding, anorexia, and any other conditions in which lean body mass is important. A genome-wide search for genes related to body leanness has been completed in the Quebec Family Study (QFS). Microsatellite markers (N = 292) from the 22 autosomal chromosomes were typed. The mean spacing of the markers was 11.9 centimorgans (cM) (range, <0.1 to 41). FFM was calculated from percent body fat, derived from underwater weighing, and body weight and was adjusted by regression for age and sex effects before analysis. A maximum of 336 sib pairs or 609 pairs of extended relatives were analyzed using single-point Haseman-Elston regression (SIBPAL and RELPAL) and multipoint variance component (SEGPATH) linkage analyses. Significant linkages were observed on chromosomes 15q25-q26 for a CA repeat within the insulin-like growth factor 1 receptor (IGF1R) gene (Lod score = 3.56) and at 18q12 with D18S877 (Lod score = 3.53) and D18S535 (Lod score = 3.58), 2 markers located 10 cM apart. A moderately significant linkage was also observed on chromosome 7p15.3 with the marker D7S1808 (Lod score = 2.72). The most obvious candidate genes within the regions identified by these linkages include the IGF1R on 15q and neuropeptide Y (NPY) and growth hormone-releasing hormone (GHRH) receptor on 7p. On 18q, the melanocortin receptor 4 (MC4R) is not likely the candidate gene for the observed linkage. This study represents the first genome-wide search for genes that may be involved in the regulation of the lean component of body mass in humans.

Adult↗