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A Genomewide Linkage Scan for Abdominal Subcutaneous and Visceral Fat in Black and White Families the HERITAGE Family Study Treva Rice,1 Yvon C

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A Genomewide Linkage Scan for Abdominal Subcutaneous and Visceral Fat in Black and White Families the HERITAGE Family Study Treva Rice,1 Yvon C A Genomewide Linkage Scan for Abdominal Subcutaneous and Visceral Fat in Black and White Families The HERITAGE Family Study Treva Rice,1 Yvon C. Chagnon,4 Louis Pe´russe,5 Ingrid B. Borecki,1,2 Olavi Ukkola,7,8 Tuomo Rankinen,8 Jacques Gagnon,6 Arthur S. Leon,9 James S. Skinner,10 Jack H. Wilmore,11 Claude Bouchard,8 and D.C. Rao1,2,3 Abdominal visceral fat (AVF), abdominal subcutaneous accumulation in the abdominal depot. Additional work fat (ASF), and abdominal total fat (ATF) were mea- in an independent sample is needed to verify the link- sured using a computed tomography scan, both before ages for baseline AVF as well as the response measures. (baseline) and after (post) a 20-week endurance exer- Diabetes 51:848–855, 2002 cise training protocol in the HERITAGE Family Study. Each of the baseline and response (post minus baseline) measures was adjusted for several covariates, including total fat mass, and responses to training were further xcess upper-body adipose tissue is strongly as- adjusted for baseline levels. Multipoint variance com- sociated with insulin resistance (1,2) and clini- ponents linkage analysis using a genomewide scan of cal conditions associated with cardiovascular 344 markers was conducted separately by race using race-specific allele frequencies. Several promising re- Erisk, such as hypertension and dyslipidemia sults (P < 0.0023) were obtained. For baseline AVF, the (3–5). Sex and growth hormones, glucocorticosteroids, best evidence was on 2q22.1 and 2q33.2-q36.3 (includ- and catecholamines all contribute to abdominal fat accu- ing the IRS1 locus) in whites, with suggestive findings mulation within this context (6,7). The relative importance on 7q22.2-q31.3 (including the LEP locus) in blacks. of abdominal visceral fat (AVF) and abdominal subcu- Although several regions were indicated for baseline taneous fat (ASF) in insulin resistance is under debate, ASF, only 4q31.22-q32.2 and 11p15.4-p11.2 replicated with some studies reporting better insulin and glucose the results of another study. For responses to training, homeostasis with AVF (8) and others favoring ASF promising results were limited to ASF and ATF primar- (9,10). ily on 7q36.2 (including NOS3) in blacks, with sugges- tive regions (P < 0.01) on 1q21.2-q24.1 (S100A, Based on results from the Que´bec Family Study (QFS) ATP1A2, and ATP1B1), 10q25.2 (ADRA2A), and 11p15.5 and the HERITAGE Family Study (11,12), it is clear that (IGF2). In summary, the 4q and 11p regions have now abdominal fat depots are strongly influenced by genetic been implicated in two independent studies for ASF; factors, with maximal heritabilities Ͼ55% for AVF and further research is warranted to identify the genes and abdominal total fat (ATF) and Ͼ40% for ASF. Segregation mutations in these regions that are responsible for fat analyses further suggest that the familial effect is primarily attributable to major recessive genes for AVF (13,14). Candidate gene studies have identified regions that may From the 1Division of Biostatistics, Washington University School of Medi- contribute to this variability (15). For example, there are cine, St. Louis, Missouri; 2Department of Genetics, Washington University reports of associations or linkages between AVF and the School of Medicine, St. Louis, Missouri; 3Department of Psychiatry, Washing- ton University School of Medicine, St. Louis, Missouri; 4Physical Activity glucocorticoid receptor gene (16), the ␤-3-adrenergic re- Sciences Laboratory, Laval University, Que´bec, Canada; 5Division of Kinesi- ceptor gene (17,18), and the fatty acid binding proteinϪ2 ology and Department of Preventive Medicine, Laval University, Que´bec, Canada; 6Molecular Endocrinology Laboratory, Laval University, Que´bec, gene (19). The first genomewide scan for abdominal Canada; 7Department of Internal Medicine and Biocenter Oulu, University of adiposity was from the QFS (20), in which linkage was Oulu, Oulu, Finland; 8Pennington Biomedical Research Center, Baton Rouge, found primarily for ASF. As expected for complex traits, LA; 9School of Kinesiology and Leisure Studies, University of Minnesota, Minneapolis, Minnesota; 10Division of Kinesiology, Indiana University, Bloom- multiple linked regions were found, the magnitude of the ington, Indiana; and 11Department of Health and Kinesiology, TexasA&M results was moderate, and replication was needed to University, College Station, Texas. strengthen the credibility of the findings. Address correspondence and reprint requests to Treva Rice, Ph.D., Division of Biostatistics, Washington University School of Medicine, 660 S. Euclid Ave., Other lines of investigation have suggested that adipos- Box 8067, St. Louis, MO 63110. E-mail: [email protected]. ity changes in response to intervention are attributable in Received for publication 26 September 2001 and accepted in revised form 5 December 2001. part to genetic factors (21). For example, a segregation AVF, abdominal visceral fat; ASF, abdominal subcutaneous fat; ATF, analysis of the AVF response to 20 weeks of exercise abdominal total fat; CT, computed axial tomography; FM, total body fat mass; 2 2 training in the HERITAGE Family Study suggested a h g, locus-specific heritability; h r, residual heritability; LOD, logarithm of odds; LRT, likelihood ratio test; QFS, Que´bec Family Study; QTL, quantitative heritability of nearly 20%, which was primarily due to a trait locus. putative recessive locus (22). To date, candidate gene 848 DIABETES, VOL. 51, MARCH 2002 T. RICE AND ASSOCIATES studies of the abdominal fat response phenotypes have form, skewness (Ϫ0.26) and kurtosis (Ϫ0.30) were reduced. All remaining been primarily negative (23), although other dimensions of measures (baseline ASF and ATF, as well as responses to training) approxi- mated a normal distribution without any transforming. Stepwise regression body composition training responses (fat and fat-free analysis was used to remove the effects of several covariates; baseline mass, BMI, and sum of skinfolds) have been linked to measures were adjusted for FM and a polynomial in age (age, age2, and age3), several genomic regions (24). and responses were further adjusted for baseline measures. Adjustments were The objective of the current investigation was to con- performed within sex, generation, and race groups, retaining only those terms that were significant at the 5% level. duct a genomewide search for linkage regions influencing PCR conditions and genotyping methods have been fully outlined by AVF, ASF, and ATF, both in a sedentary state (baseline) Chagnon et al. (30). Automatic DNA sequencers from LICOR (Lincoln, NB) and in response to endurance exercise training, using data were used to detect the PCR products, and genotypes were scored automat- on black and white families participating in the HERI- ically using the software SAGA (R. McIndoe, R. Bumgarner, R. Welti, Univer- TAGE Family Study. A total of 344 markers spanning 22 sity of Washington at Seattle; LICOR). Microsatellite markers and candidate genes were selected mainly from the Marshfield panel version 8a. Map autosomes were typed, including microsatellites as well as locations (Kosambi distance in centimorgans) were taken primarily from the some candidates for adiposity and related cardiovascular location database of Southampton, U.K. (http://cedar.genetics.soton.ac.uk) risk factors. Baseline and response measures were ad- and the Marshfield map (http://www.marshmed.org/genetics). justed for several covariates, including total fat mass, and Linkage analysis was performed using a multipoint variance component model as implemented in SEGPATH (31,32). The additive effects of a trait analyses were conducted separately by race. locus, residual pseudo-polygenic familial background, and residual nonfamil- ial component influence the phenotype. The proportion of phenotypic vari- ance accounted for by the trait locus and pseudo-polygenic component RESEARCH DESIGN AND METHODS 2 2 represents the heritabilities h g (locus specific) and h r (residual). Allele The HERITAGE Family Study was designed to investigate the role of familial sharing probabilities (at each marker location for each sibling pair) were used factors underlying the cardiovascular, metabolic, and hormonal responses to as observed input data and were computed using the program MAPMAKER/ a standardized aerobic exerciseϪtraining program. Several criteria were used SIBS (33). Other parameters included a spouse correlation, additional sibling to screen participants (25). In general, the goal was to obtain sedentary resemblance, and offspring means and variances. families consisting of two parents and at least three biological offspring, Linkage was tested by restricting the locus-specific heritability to zero. A 2 ϭ although family structure/size requirements were relaxed for black families. likelihood ratio test (LRT) contrasting the null hypothesis (h g 0) with the 2 Sedentary was defined as not participating in any regular strenuous exercise, alternative (h g estimated) was used. The LRT was asymptotically distributed Ն ␹2 characterized as exercise lasting 30 min and involving energy expenditure of as a 50:50 mixture of a 1 and a point mass at zero (34), and the correct P Ն Ͻ ␹2 7 (age 50 years) or 8 METS (age 50 years) for more than once a week for value associated with the linkage test was 0.5 of that corresponding to the 1. ␹2 ⅐ Ͻ the previous 6 months. Nonsedentary members in otherwise qualifying The logarithm of odds (LOD) score was computed as /(2 loge10). P families discontinued exercise for at least 6 months before the family was 0.0023 or a LOD score Ն1.75 represents a rate of one false positive result per reconsidered for enrollment in the study. All parents were required to be age scan (on average) for experiments involving ϳ400 markers (35). In the current Յ65 years and offspring to be ages 17–49 years. With a few exceptions study, 12 experiments were conducted (three traits by two dimensions by two approved by a physician, subjects had a BMI Ͻ40 kg/m2 and a resting blood races) using race-specific allele frequencies. pressure Յ159/99 mmHg.
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