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Biomedical subjects

Nan Laird

Publications and source records attributed to Nan Laird.

17 recordsLinked to original sources
PubMed2006

Polymorphism in maternal LRP8 gene is associated with fetal growth.

Fetal growth restriction (FGR) affects >200,000 pregnancies in the United States annually and is associated with increased perinatal mortality and morbidity, as well as poorer long-term health for infants with FGR compared with infants without FGR. FGR appears to be a complex trait, but the role of genetic factors in the development of FGR is largely unknown. We conducted a candidate-gene association study of birth weight and FGR in two independent study samples obtained at the Boston Medical Center. We first investigated the association between maternal genotypes of 68 single-nucleotide polymorphisms (SNPs) from 41 candidate genes and fetal growth in a sample of 204 black women selected for a previous study of preeclampsia, 92 of whom had preeclampsia (characterized by high blood pressure and the presence of protein in the urine). We found significant association between SNP rs2297660 in the LRP8 gene and birth weight. Subsequently, we replicated the association in a larger independent sample of 1,094 black women; similar association between LRP8 and FGR was observed in this sample. The "A" allele at rs2297660 was associated with a higher standardized birth weight and a lower risk of FGR. Under the additive genetic model, each additional copy of the "A" allele reduced the risk of FGR by 33% (P<.05). In conclusion, results from the two independent samples of black women provide consistent evidence that SNP rs2297660 in LRP8 is associated with fetal growth.

Adult↗
PubMed2006

An efficient family-based association test using multiple markers.

In genetic association studies, multiple markers are usually employed to cover a genomic region of interest for localizing a trait locus. In this report, we propose a novel multi-marker family-based association test (T(LC)) that linearly combines the single-marker test statistics using data-driven weights. We examine the type-I error rate in a numerical study and compare its power to identify a common trait locus using tag single nucleotide polymorphisms (SNPs) within the same haplotype block that the trait locus resides with three competing tests including a global haplotype test (T(H)), a multi-marker test similar to the Hotelling-T(2) test for the population-based data (T(MM)), and a single-marker test with Bonferroni's correction for multiple testing (T(B)). The type-I error rate of T(LC) is well maintained in our numeric study. In all the scenarios we examined, T(LC) is the most powerful, followed by T(B). T(MM) and T(H) are the poorest. T(H) and T(MM) have essentially the same power when parents are available. However, when both parents are missing, T(MM) is substantially more powerful than T(H). We also apply this new test on a data set from a previous association study on nicotine dependence.

Family↗
PubMed2006

Relation of body composition, fat mass, and serum lipids to osteoporotic fractures and bone mineral density in Chinese men and women.

BACKGROUND: Higher fat mass may be an independent risk factor for osteoporosis and osteoporotic fractures. OBJECTIVE: We aimed to determine the independent contribution of fat mass to osteoporosis and to estimate the risk of osteoporotic fractures in relation to body weight, lean mass, and other confounders. DESIGN: This was a community-based, cross-sectional study of 7137 men, 4585 premenopausal women, and 2248 postmenopausal women aged 25-64 y. Total-body and hip bone mineral content (BMC) and bone mineral density (BMD) and body composition were measured by dual-energy X-ray absorptiometry. Serum lipids were measured. Sex- and menopause-specific multiple generalized linear models were applied. RESULTS: Across 5-kg strata of body weight, fat mass was significantly inversely associated with BMC in the whole body and total hip. When we compared the highest quartile with the lowest quartile of percentage fat mass in men, premenopausal women, and postmenopausal women, the adjusted odds ratios (95% CIs) of osteoporosis defined by hip BMD were 5.2 (2.1, 13.2), 5.0 (1.7, 15.1), and 6.9 (4.3, 11.2), respectively. Significant linear trends existed for higher risks of osteoporosis, osteopenia, and nonspine fractures with higher percentage fat mass. Significant negative relations were found between whole-body BMC and cholesterol, triacylglycerol, LDL, and the ratio of HDL to LDL in all groups. CONCLUSIONS: Risks of osteoporosis, osteopenia, and nonspine fractures were significantly higher for subjects with higher percentage body fat independent of body weight, physical activity, and age. Thus, fat mass has a negative effect on bone mass in contrast with the positive effect of weight-bearing itself.

Absorptiometry, Photon↗
PubMed2005

Variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are associated with bone mineral density at different skeletal sites in men.

In order to assess the contribution of polymorphisms in the RANKL (TNFSF11), RANK (TNFRSF11A) and OPG (TNFRSF11B) genes to variations in bone mineral density (BMD), a population-based cohort with 1,120 extreme low hip BMD cases or extreme high hip BMD controls was genotyped on five SNPs. We further explored the associations between these genetic variations and forearm BMDs by genotyping 266 offspring and 309 available parents from 160 nuclear families. A family-based association test was used. Significantly positive associations were found for A163G polymorphisms in the promoter regions of the OPG gene, a missense substitution in exon 7 (Ala192Val) of the RANK gene and rs9594782 SNP in the 5' UTR of the RANKL gene with BMD in men only. Men with TC/CC genotypes of the rs9594782 SNP had a 2.1 times higher risk of extremely low hip BMD (P = 0.004), and lower whole body BMD (P < 0.001). Subjects with the TC genotype of the Ala192Val polymorphism had a 40% reduced risk of having extremely low hip BMD (P < 0.01), and higher whole body BMD (P < 0.01). Subjects with the GG genotype of the A163G polymorphism had a 70% reduced risk of having extremely low hip BMD (P < 0.05), and higher whole body BMD (P < 0.01). Significant gene-gene interactions were also observed among the OPG, RANK and RANKL genes. Our findings suggest that genetic variation in genes involved in the RANKL/RANK/OPG bone remodeling pathway are strongly associated with BMD at different skeletal sites in adult men, but not in women.

Adult↗
PubMed2005

Attempted replication of reported chronic obstructive pulmonary disease candidate gene associations.

Case-control studies have successfully identified many significant genetic associations for complex diseases, but lack of replication has been a criticism of case-control genetic association studies in general. We selected 12 candidate genes with reported associations to chronic obstructive pulmonary disease (COPD) and genotyped 29 polymorphisms in a family-based study and in a case-control study. In the Boston Early-Onset COPD Study families, significant associations with quantitative and/or qualitative COPD-related phenotypes were found for the tumor necrosis factor (TNF)-alpha -308G>A promoter polymorphism (P < 0.02), a coding variant in surfactant protein B (SFTPB Thr131Ile) (P = 0.03), and the (GT)(31) allele of the heme oxygenase (HMOX1) promoter short tandem repeat (P = 0.02). In the case-control study, the SFTPB Thr131Ile polymorphism was associated with COPD, but only in the presence of a gene-by-environment interaction term (P = 0.01 for both main effect and interaction). The 30-repeat, but not the 31-repeat, allele of HMOX1 was associated (P = 0.04). The TNF -308G>A polymorphism was not significant. In addition, the microsomal epoxide hydrolase "fast" allele (EPHX1 His139Arg) was significantly associated in the case-control study (P = 0.03). Although some evidence for replication was found for SFTPB and HMOX1, none of the previously published COPD genetic associations was convincingly replicated across both study designs.

Adult↗
PubMed2005

Weight concerns and weight control behaviors of adolescents and their mothers.

OBJECTIVE: To assess the association between weight concerns and weight control practices of adolescents and their mothers. DESIGN AND PARTICIPANTS: Cross-sectional study of 5331 adolescent girls and 3881 adolescent boys (age range, 11.8-18.4 years) in an ongoing cohort study and their mothers. Participants were included in the analysis if both the adolescent and his or her mother returned a questionnaire mailed in 1999 and provided information on weight, height, and weight concerns. RESULTS: More adolescent girls (33.0%) than boys (8.1%) thought frequently about wanting to be thinner. Compared with adolescent girls who accurately perceived that their thinness was not important to their mother, girls who misperceived (odds ratio [OR] = 1.9; 95% confidence interval [CI], 1.3-2.8) or accurately perceived (OR = 2.85; 95% CI, 1.0-8.4) that it was important to their mother that they be thin were significantly more likely to think frequently about wanting to be thinner. Among the adolescent boys, only those who accurately perceived that it was important to their mother that they not be fat were more likely than their peers to think frequently about wanting to be thinner (OR = 3.8; 95% CI, 2.3-6.2). Adolescents who accurately perceived that it was important to their mother to be thin or not fat were significantly more likely to be frequent dieters than their peers who accurately perceived that their weight was not important to their mother. CONCLUSION: Among adolescents, an accurate perception that weight status is important to their mother is associated with thinking frequently about wanting to be thinner and about frequent dieting.

Adolescent↗
PubMed2005

Exact family-based association tests for biallelic data.

Family-based study designs have an important role in the search for association between disease phenotypes and genetic markers. Unlike traditional case-control methods, family-based tests use within-family data to avoid identification of spurious associations that may result from population admixture. Many family-based association tests have been proposed to accommodate a variety of ascertainment schemes and patterns of missing data. In this report, we describe exact family-based association tests for biallelic data. Specifically, we discuss test of the null hypotheses "no linkage and no association" and "linkage, but no association". These tests, which are valid under various models for inheritance and patterns of missingness, utilize the procedure proposed by Rabinowitz and Laird [2000: Hum Hered 50:211-223] that provides a unified framework for family based association testing (FBAT). The conditioning approach implemented in FBAT makes an exact test conceptually straightforward, but computationally difficult since the minimum sufficient statistics upon which we condition do not have a conventional form. An exact test may be especially critical when accurate computation of the extreme area of the FBAT statistic is needed, such as when the study design necessitates multiple comparisons adjustments. We describe the exact approach as a useful alternative to the asymptotic test and show that the exact tests for biallelic data may be most useful for the recessive disease model.

Algorithms↗
PubMed2004

The transforming growth factor-beta1 (TGFB1) gene is associated with chronic obstructive pulmonary disease (COPD).

Although cigarette smoking is the primary environmental risk factor, genetic risk factors likely influence the development of chronic obstructive pulmonary disease (COPD). Linkage analysis between short-tandem repeat markers on chromosome 19 and COPD phenotypes was followed by association analysis of single nucleotide polymorphisms in a gene on chromosome 19q [transforming growth factor-beta1 (TGFB1)] and COPD phenotypes in a family-based sample and a case-control study (cases with severe COPD and control subjects with significant history of smoking but no COPD). Stratification by smoking status substantially improved the evidence of linkage to chromosome 19q for COPD phenotypes. Among former and current smokers in the Boston Early-Onset COPD Study, there was significant evidence of linkage between chromosome 19q and pre-bronchodilator (pre-BD) FEV(1) (LOD=3.30) and suggestive evidence of linkage between chromosome 19q and other COPD phenotypes. In these families, a SNP in the promoter region of TGFB1 (rs2241712) and two SNPs in the 3' genomic region of TGFB1 (rs2241718 and rs6957) were significantly associated with pre- and post-BD FEV(1) (P<0.05). Among smokers in the COPD cases and control subjects, two SNPs in the promoter region of TGFB1 (rs2241712 and rs1800469) and one SNP in exon 1 of TGFB1 (rs1982073) were significantly associated with COPD (P</=0.02 in all cases). Chromosome 19q likely contains a genetic locus (or loci) that influences COPD through an interaction with cigarette smoking. We hypothesize that genetic variants in or near the TGFB1 gene influence the pathogenesis of COPD among cigarette smokers.

Case-Control Studies↗
PubMed2004

A common haplotype of the nicotine acetylcholine receptor alpha 4 subunit gene is associated with vulnerability to nicotine addiction in men.

Nicotine is the major addictive substance in cigarettes, and genes involved in sensing nicotine are logical candidates for vulnerability to nicotine addiction. We studied six single-nucleotide polymorphisms (SNPs) in the CHRNA4 gene and four SNPs in the CHRNB2 gene with respect to nicotine dependence in a collection of 901 subjects (815 siblings and 86 parents) from 222 nuclear families with multiple nicotine-addicted siblings. The subjects were assessed for addiction by both the Fagerstrom Test for Nicotine Dependence (FTND) and the Revised Tolerance Questionnaire (RTQ). Because only 5.8% of female offspring were smokers, only male subjects were included in the final analyses (621 men from 206 families). Univariate (single-marker) family-based association tests (FBATs) demonstrated that variant alleles at two SNPs, rs1044396 and rs1044397, in exon 5 of the CHRNA4 gene were significantly associated with a protective effect against nicotine addiction as either a dichotomized trait or a quantitative phenotype (i.e., age-adjusted FTND and RTQ scores), which was consistent with the results of the global haplotype FBAT. Furthermore, the haplotype-specific FBAT showed a common (22.5%) CHRNA4 haplotype, GCTATA, which was significantly associated with both a protective effect against nicotine addiction as a dichotomized trait (Z=-3.04, P<.005) and significant decreases of age-adjusted FTND (Z=-3.31, P<.005) or RTQ scores (Z=-2.73, P=.006). Our findings provide strong evidence suggesting a common CHRNA4 haplotype might be protective against vulnerability to nicotine addiction in men.

Adult↗
PubMed2004

A candidate gene association study on preterm delivery: application of high-throughput genotyping technology and advanced statistical methods.

Preterm delivery (PTD) is the leading cause of infant mortality and morbidity worldwide. The etiology of PTD is largely unknown but is believed to be complex, encompassing multiple genetic and environmental determinants. To date, reports of genetic studies on PTD are sparse. We conducted a large-scale case-control study exploring the associations of 426 single-nucleotide polymorphisms with PTD in 300 mothers with PTD and 458 mothers with term deliveries at the Boston Medical Center. Twenty-five candidate genes were included in the final haplotype analysis, and a significant association of F5 gene haplotype with PTD was revealed and remained significant after Bonferroni correction for multiple testing (P=0.025). We applied different statistical algorithms (both Gibbs sampling and expectation-maximization) in reconstructing haplotype phases and different tests (both likelihood ratio test and permutation test) in association analyses, and all yielded similar results. We also performed exploratory ethnicity-specific analyses, which confirmed the consistent findings of the F5 gene across the ethnic groups. Moreover, IL1R2 (P=0.002 in Blacks), NOS2A (P<0.001 in Whites) and OPRM1 (P=0.004 in Hispanics) gene haplotypes were associated with PTD in specific ethnic groups but not at global significance level. In summary, our results underscore the potentially important role of F5 gene variants in the pathogenesis of PTD, and demonstrate the utility of high-throughput genotyping and a haplotype-based approach in dissecting genetic basis of complex traits.

Algorithms↗
PubMed2004

Power estimation of multiple SNP association test of case-control study and application.

At the current stage, a large number of single nucleotide polymorphisms (SNPs) have been deployed in searching for genes underlying complex diseases. A powerful method is desirable for efficient analysis of SNP data. Recently, a novel method for multiple SNP association test using a combination of allelic association (AA) and Hardy-Weinberg disequilibrium (HWD) has been proposed. However, the power of this test has not been systematically examined. In this study, we conducted a simulation study to further evaluate the statistical power of the new procedure, as well as of the influence of the HWD on its performance. The simulation examined the scenarios of multiple disease SNPs among a candidate pool, assuming different parameters including allele frequencies and risk ratios, dominant, additive, and recessive genetic models, and the existence of gene-gene interactions and linkage disequilibrium (LD). We also evaluated the performance of this test in capturing real disease associated SNPs, when a significant global P value is detected. Our results suggest that this new procedure is more powerful than conventional single-point analyses with correction of multiple testing. However, inclusion of HWD reduces the power under most circumstances. We applied the novel association test procedure to a case-control study of preterm delivery (PTD), examining the effects of 96 candidate gene SNPs concurrently, and detected a global P value of 0.0250 by using Cochran-Armitage chi(2)s as "starting" statistics in the procedure. In the following single point analysis, SNPs on IL1RN, IL1R2, ESR1, Factor 5, and OPRM1 genes were identified as possible risk factors in PTD.

Algorithms↗
PubMed2004

IL10 gene polymorphisms are associated with asthma phenotypes in children.

IL10 is an anti-inflammatory cytokine that has been found to have lower production in macrophages and mononuclear cells from asthmatics. Since reduced IL10 levels may influence the severity of asthma phenotypes, we examined IL10 single-nucleotide polymorphisms (SNPs) for association with asthma severity and allergy phenotypes as quantitative traits. Utilizing DNA samples from 518 Caucasian asthmatic children from the Childhood Asthma Management Program (CAMP) and their parents, we genotyped six IL10 SNPs: 3 in the promoter, 2 in introns, and one in the 3' UTR. Using family-based association tests, each SNP was tested for association with asthma and allergy phenotypes individually. Population-based association analysis was performed with each SNP locus, the promoter haplotypes and the 6-loci haplotypes. The 3' UTR SNP was significantly associated with FEV(1) as a percent of predicted (FEV(1)PP) (P=0.0002) in both the family and population analyses. The promoter haplotype GCC was positively associated with IgE levels and FEV(1)PP (P=0.007 and 0.012, respectively). The promoter haplotype ATA was negatively associated with lnPC(20) and FEV(1)PP (P=0.008 and 0.043, respectively). Polymorphisms in IL10 are associated with asthma phenotypes in this cohort. Further studies of variation in the IL10 gene may help elucidate the mechanism of asthma development in children.

3' Untranslated Regions↗
PubMed2004

Weight cycling and the risk of developing type 2 diabetes among adult women in the United States.

OBJECTIVE: To assess the role of weight cycling independent of BMI and weight change in predicting the risk of developing type 2 diabetes. RESEARCH METHODS AND PROCEDURES: A six-year follow-up of 46,634 young and middle-aged women in the Nurses' Health Study II was conducted. Women who had intentionally lost > or = 20 lbs at least three times between 1989 and 1993 were classified as severe weight cyclers. Women who had intentionally lost > or = 10 lbs at least three times were classified as mild weight cyclers. The outcome was physician-diagnosed type 2 diabetes. RESULTS: Between 1989 and 1993, approximately 20% of the women were mild weight cyclers, and 1.6% were severe weight cyclers. BMI in 1993 was positively associated with weight-cycling status (p < 0.001). During 6 years of follow-up (1993 to 1999), 418 incident cases of type 2 diabetes were documented. BMI in 1993 had a strong association with the risk of developing diabetes. Compared with women with a BMI between 17 and 22 kg/m(2), those with a BMI between 25 and 29.9 kg/m(2) were approximately seven times more likely to develop diabetes, and those with a BMI > or = 35 kg/m(2) were 63 times more likely to be diagnosed with type 2 diabetes. After adjustment for BMI, neither mild (relative risk = 1.11, 95% confidence interval, 0.89 to 1.37) nor severe (relative risk = 1.39, 95% confidence interval, 0.90 to 2.13) weight cycling predicted risk of diabetes. DISCUSSION: Weight cycling was strongly associated with BMI, but it was not independently predictive of developing type 2 diabetes.

Adult↗
PubMed2003

Joint models for efficient estimation in proportional hazards regression models.

In survival studies, information lost through censoring can be partially recaptured through repeated measures data which are predictive of survival. In addition, such data may be useful in removing bias in survival estimates, due to censoring which depends upon the repeated measures. Here we investigate joint models for survival T and repeated measurements Y, given a vector of covariates Z. Mixture models indexed as f (T/Z) f (Y/T,Z) are well suited for assessing covariate effects on survival time. Our objective is efficiency gains, using non-parametric models for Y in order to avoid introducing bias by misspecification of the distribution for Y. We model (T/Z) as a piecewise exponential distribution with proportional hazards covariate effect. The component (Y/T,Z) has a multinomial model. The joint likelihood for survival and longitudinal data is maximized, using the EM algorithm. The estimate of covariate effect is compared to the estimate based on the standard proportional hazards model and an alternative joint model based estimate. We demonstrate modest gains in efficiency when using the joint piecewise exponential joint model. In a simulation, the estimated efficiency gain over the standard proportional hazards model is 6.4 per cent. In clinical trial data, the estimated efficiency gain over the standard proportional hazards model is 10.2 per cent.

Algorithms↗
PubMed2003

Which metric of relative weight best captures body fatness in children?

OBJECTIVE: To evaluate the relative merits of BMI (kilograms per meter squared) and age- and gender-adjusted BMI, age- and gender-specific z score of BMI, and age- and gender-specific percentiles of BMI as surrogate measures of body fatness among a sample of youth. RESEARCH METHODS AND PROCEDURES: The sample comprised 596 children and adolescents 5 to 18.7 years old and was 40% male and 55% white. Height and weight were measured by trained research staff. DXA was used to determine body fat mass. BMI, age- and gender-specific percentile of BMI, and age- and gender-specific z scores of BMI were computed, and these metrics were compared with measured body fatness. RESULTS: The BMI values in the sample ranged from 12.9 to 55.0 kg/m(2), with a mean of 24.9 kg/m(2). The Spearman correlations with percentage body fat were similar for all of the BMI metrics (r = 0.82 to 0.88). Linear regression models with age- and gender-specific percentiles of BMI explained significantly less of the variance (65%) than models with log-transformed BMI (81%) or age- and gender-specific z scores of BMI (75% to 79%). z scores were the most accurate at classifying children who were overfat (sensitivity = 0.84, specificity = 0.96 for z score > or = 1). However, using a BMI > or = 85th percentile or a BMI > or = 20 kg/m(2) was also accurate at classifying youth. DISCUSSION: The BMI metrics had similar correlations with body fatness, but age- and gender-specific percentiles of BMI were the least accurate proxy measure of body fatness. However, a BMI z score > or = 1, BMI percentile > or = 85, and BMI> or = 20 kg/m(2) are all useful for identifying children who may be overfat.

Adipose Tissue↗
PubMed2003

Power evaluations for family-based tests of association with incomplete parental genotypes.

While a variety of methods have been developed to deal with incomplete parental genotype information in family-based association tests, sampling design issues with incomplete parental genotype data still have not received much attention. In this article, we present simulation studies with four genetic models and various sampling designs and evaluate power in family-based association studies. Efficiency depends heavily on disease prevalence. With rare diseases, sampling affecteds and their parents is preferred, and three sibs will be required to have close power if parents are unavailable. With more common diseases, sampling affecteds and two sibs will generally be more efficient than trios. When parents are unavailable, siblings need not be phenotyped if the disease is rare, but a loss of power will result with common diseases. Finally, for a class of complex traits where other genetic and environmental factors also cause phenotypic correlation among siblings, little loss of efficiency occurs to rare disease, but substantial loss of efficiency occurs to common disease.

Data Interpretation, Statistical↗