Relative influence of heritability, environment and genetics on serum sclerostin.

SUMMARY: We determined factors associated with serum sclerostin in 446 Afro-Caribbean family members. Age, weight, sex, diabetes and kidney function were associated with sclerostin. Sclerostin was heritable, and nine SNPs in the SOST gene region were associated with sclerostin. Variation in serum sclerostin is a heritable factor that is determined by both genetic and environmental factors. INTRODUCTION: Sclerostin, encoded by the SOST gene, is a Wnt inhibitor that regulates bone mineralization and is a candidate gene locus for osteoporosis. However, little is known about the genetic and non-genetic sources of inter-individual variation in serum sclerostin levels. METHODS: Serum sclerostin was measured in 446 Afro-Caribbean men and women aged 18+ from seven large, multigenerational families (mean family size, 64; 3,840 relative pairs). Thirty-six common single nucleotide polymorphisms (SNP) were genotyped within a 100 kb region encompassing the gene encoding sclerostin (SOST). Genetic and non-genetic factors were tested for association with serum sclerostin. RESULTS: Mean serum sclerostin was 41.3 pmol/l and was greater in men than in women (P < 0.05). Factors associated with higher serum sclerostin were increased age and body weight, male sex, diabetes and decreased glomerular filtration rate, which collectively accounted for 25.4 % of its variation. Residual genetic heritability of serum sclerostin was 0.393 (P < 0.0001). Nine SNPs reached nominal significance with sclerostin. Three of those nine SNPs represented independent association signals (rs851056, rs41455049 and rs9909172), which accounted for 7.8 % of the phenotypic variation in sclerostin, although none of these SNPs surpassed a Bonferroni correction for multiple comparisons. CONCLUSIONS: Serum sclerostin is a heritable trait that is also determined by environmental factors including age, sex, adiposity, diabetes and kidney function. Three independent common SNPs within the SOST region may collectively account for a significant proportion of the variation in serum sclerostin.

Genetic analysis of serum osteocalcin and bone mineral in multigenerational Afro-Caribbean families.

UNLABELLED: Osteocalcin is a major component of bone matrix. Concentrations of total, carboxylated, and uncarboxylated osteocalcin, are highly heritable and genetically correlated with bone mineral content (BMC) within African ancestry families. INTRODUCTION: Osteocalcin (OC) is a protein constituent of bone matrix and a marker of bone formation. We characterized the heritability of serum OC measures and identified genomic regions potentially involved in the regulation of OC via high-density genome-wide linkage analysis in African ancestry individuals. METHODS: African ancestry individuals (n = 459) were recruited, without regard to health status, from seven probands (mean family size = 66; 4,373 relative pairs). Residual heritability of serum OC measures was estimated and multipoint quantitative trait linkage analysis was performed using pedigree-based maximum likelihood methods. RESULTS: Residual heritabilities of total OC, uncarboxylated OC, carboxylated OC and percent uncarboxylated OC were 0.74 ± 0.10, 0.89 ± 0.08, 0.46 ± 0.10 and 0.41 ± 0.09, respectively. All OC measures were genetically correlated with whole body BMC. We obtained strong evidence of bivariate linkage for percent uncarboxylated OC and whole body BMC on chromosome 17 (logarithm of the odds [LOD] = 3.15, 99 cM). CONCLUSIONS: All forms of OC were highly heritable and genetically correlated with total body BMC in these African ancestry families. The identified linkage region contains several candidate genes for bone and energy metabolism including COL1A1 and TNFRSF11A. Further studies of this genomic region may reveal novel insight into the genetic regulation of OC and bone mineralization.

Genetic analysis of vertebral trabecular bone density and cross-sectional area in older men.

We investigated 383 bone candidate genes for associations between single nucleotide polymorphisms and vertebral trabecular volumetric bone mineral density (vBMD) and cross-sectional area (CSA) in 2,018 Caucasian men aged ≥ 65 years. SNPs in TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE were associated with vBMD and SNPs in CYP11B1, DVL2, DLX5, WNT4, and PAX7 were associated with CSA in independent study samples (p < 0.005). INRODUCTION: Vertebral bone mineral density and cross-sectional area are important determinants of vertebral bone strength. Little is known about the specific genetic variants that influence these phenotypes in humans. METHODS: We investigated the potential genetic variants associated with vertebral trabecular volumetric BMD and CSA measured by quantitative computed tomography. We initially tested for association between these phenotypes and 4608 tagging and potentially functional single nucleotide polymorphisms (SNPs) in 383 candidate genes in 862 community-dwelling Caucasian men aged ≥ 65 years in the Osteoporotic Fractures in Men Study. RESULTS: SNP associations were then validated by genotyping an additional 1,156 randomly sampled men from the same cohort. We identified 11 SNPs in 10 genes (TGFBR3, SOST, KL, CALCR, LEP, CSF1R, PTN, GNRH2, FGFR2, and MEPE) that were consistently associated with trabecular vBMD and five SNPs in five genes (CYP11B1, DVL2, DLX5, WNT4, and PAX7) that were consistently associated with CSA in both samples (p < 0.005). CONCLUSION: None of the SNPs associated with trabecular vBMD were associated with CSA. Our findings raise the possibility that at least some of the loci for vertebral trabecular BMD and bone size may be distinct.

Polymorphisms in the platelet-specific collagen receptor GP6 are associated with risk of nonfatal myocardial infarction in Caucasians.

BACKGROUND AND AIMS: Glycoprotein 6 (GP6) is a platelet-specific collagen receptor implicated in the thrombotic pathway to acute myocardial infarction (AMI), but a possible genetic relationship between GP6 and AMI is poorly understood. We tested for the genetic association between AMI and single nucleotide polymorphisms (SNPs) in 24 loci, including GP6. METHODS AND RESULTS: We conducted a case-control study of AMI and GP6 in a community-based population (n = 652 cases, 625 controls). We also examined men and women separately and stratified the latter by use of hormone replacement therapy (HRT). Among both sexes, the strongest association was for a protective missense polymorphism (rs1163662) in the GP6 gene (OR = 0.70; Bonferroni-adjusted p < 0.05). SNPs in GP6 were also strongly associated with AMI among women who reported ever taking HRT, but not among women who never took HRT. Haplotype analyses were consistent with the single-SNP findings. CONCLUSIONS: In this sample of white non-Hispanic men and women, several SNPs in GP6 were significantly related to risk of AMI. Development of pharmacologic therapy directed towards platelet activity and thrombosis may reduce the incidence of AMI among at-risk groups.

Association analysis of 33 lipoprotein candidate genes in multi-generational families of African ancestry.

African ancestry individuals have a more favorable lipoprotein profile than Caucasians, although the mechanisms for these differences remain unclear. We measured fasting serum lipoproteins and genotyped 768 tagging or potentially functional single nucleotide polymorphisms (SNPs) across 33 candidate gene regions in 401 Afro-Caribbeans older than 18 years belonging to 7 multi-generational pedigrees (mean family size 51, range 21-113, 3,426 relative pairs). All lipoproteins were significantly heritable (P<0.05). Gender-specific analysis showed that heritability for triglycerides was much higher (P<0.01) in women than in men (women, 0.62+/-0.18, P<0.01; men, 0.13+/-0.17, P>0.10), but the heritability for LDL cholesterol (LDL-C) was higher (P<0.05) in men than in women (men, 0.79+/-0.21, P<0.01; women, 0.39+/-0.12, P<0.01). The top 14 SNPs that passed the false discovery rate threshold in the families were then tested for replication in an independent population-based sample of 1,750 Afro-Caribbean men aged 40+ years. Our results revealed significant associations for three SNPs in two genes (rs5929 and rs6511720 in LDLR and rs7517090 in PCSK9) and LDL-C in both the family study and in the replication study. Our findings suggest that LDLR and PCSK9 variants may contribute to a variation in LDL-C among African ancestry individuals. Future sequencing and functional studies of these loci may advance our understanding of genetic factors contributing to LDL-C in African ancestry populations.

Association of a common G6PC2 variant with fasting plasma glucose levels in non-diabetic individuals.

BACKGROUND/AIMS: Fasting plasma glucose (FPG) levels correlate with cardiovascular disease and mortality in both diabetic and non-diabetic subjects. G6PC2 encodes a pancreatic islet-specific glucose-6-phosphatase-related protein and G6pc2-null mice were reported to exhibit decreased blood glucose levels. Two recent genome-wide association studies have implicated a role for G6PC2 in regulation of FPGlevels in the general European population and reported the strongest association with the rs560887 SNP. The purpose of this study was to replicate this association in our independent epidemiological samples. METHODS: DNA samples from non-Hispanic white Americans (NHWs; n = 623), Hispanic Americans (n = 410) and black Africans (n = 787) were genotyped for rs560887 using TaqMan allelic discrimination. RESULTS: While no minor allele A of rs560887 was observed among blacks, its frequency was 33% in NHWs and 17.5% in Hispanics. The rs560887 minor allele was associated with reduced FPG levels in non-diabetic NHWs (p = 0.002 under an additive model). A similar trend of association was observed in non-diabetic Hispanics (p = 0.076 under a dominant model), which was more pronounced in normoglycemic subjects (p = 0.036). CONCLUSIONS: Our results independently confirm the robust association of G6PC2/rs560887 with FPG levels in non-diabetic NHWs. The observed evidence for association in Hispanics warrants further studies in larger samples.

Genetic influences on bone loss in the San Antonio Family Osteoporosis study.

UNLABELLED: The genetic contribution to age-related bone loss is not well understood. We estimated that genes accounted for 25-45% of variation in 5-year change in bone mineral density in men and women. An autosome-wide linkage scan yielded no significant evidence for chromosomal regions implicated in bone loss. INTRODUCTION: The contribution of genetics to acquisition of peak bone mass is well documented, but little is known about the influence of genes on subsequent bone loss with age. We therefore measured 5-year change in bone mineral density (BMD) in 300 Mexican Americans (>45 years of age) from the San Antonio Family Osteoporosis Study to identify genetic factors influencing bone loss. METHODS: Annualized change in BMD was calculated from measurements taken 5.5 years apart. Heritability (h(2)) of BMD change was estimated using variance components methods and autosome-wide linkage analysis was carried out using 460 microsatellite markers at a mean 7.6 cM interval density. RESULTS: Rate of BMD change was heritable at the forearm (h(2) = 0.31, p = 0.021), hip (h(2) = 0.44, p = 0.017), spine (h(2) = 0.42, p = 0.005), but not whole body (h(2) = 0.18, p = 0.123). Covariates associated with rapid bone loss (advanced age, baseline BMD, female sex, low baseline weight, postmenopausal status, and interim weight loss) accounted for 10% to 28% of trait variation. No significant evidence of linkage was observed at any skeletal site. CONCLUSIONS: This is one of the first studies to report significant heritability of BMD change for weight-bearing and non-weight-bearing bones in an unselected population and the first linkage scan for change in BMD.

Genetic markers for ancestry are correlated with body composition traits in older African Americans.

UNLABELLED: Individual-specific percent European ancestry was assessed in 1,277 African Americans. We found significant correlations between proportion of European ancestry and several musculoskeletal traits, indicating that admixture mapping may be a useful strategy for locating genes affecting these traits. INTRODUCTION: Genotype data for admixed populations can be used to detect chromosomal regions influencing disease risk if allele frequencies at disease-related loci differ between parental populations. We assessed evidence for differentially distributed alleles affecting bone and body composition traits in African Americans. METHODS: Bone mineral density (BMD) and body composition data were collected for 1,277 African and 1,790 European Americans (aged 70-79). Maximum likelihood methods were used to estimate individual-specific percent European ancestry for African Americans genotyped at 37 ancestry-informative genetic markers. Partial correlations between body composition traits and percent European ancestry were calculated while simultaneously adjusting for the effects of covariates. RESULTS: Percent European ancestry (median = 18.7%) in African Americans was correlated with femoral neck BMD in women (r = -0.18, p < 10(-5)) and trabecular spine BMD in both sexes (r = -0.18, p < 10(-5)) independently of body size, fat, lean mass, and other covariates. Significant associations of European ancestry with appendicular lean mass (r = -0.19, p < 10(-10)), total lean mass (r = -0.12, p < 10(-4)), and total body fat (r = 0.09, p < 0.002) were also observed for both sexes. CONCLUSIONS: These results indicate that some population differences in body composition may be due to population-specific allele frequencies, suggesting the utility of admixture mapping for identifying susceptibility genes for osteoporosis, sarcopenia, and obesity.

Linkage mapping and physical localization of the major histocompatibility complex region of the marsupial Monodelphis domestica.

We used genetic linkage mapping and fluorescence in situ hybridization (FISH) to conduct the first analysis of genic organization and chromosome localization of the major histocompatibility complex (MHC) of a marsupial, the gray, short-tailed opossum Monodelphis domestica. Family based linkage analyses of two M. domestica MHC Class I genes (UA1, UG) and three MHC Class II genes (DAB, DMA, and DMB) revealed that these genes were tightly linked and positioned in the central region of linkage group 3 (LG3). This cluster of MHC genes was physically mapped to the centromeric region of chromosome 2q by FISH using a BAC clone containing the UA1 gene. An interesting finding from the linkage analyses is that sex-specific recombination rates were virtually identical within the MHC region. This stands in stark contrast to the genome-wide situation, wherein males exhibit approximately twice as much recombination as females, and could have evolutionary implications for maintaining equality between males and females in the ability to generate haplotype diversity in this region. These analyses also showed that three non-MHC genes that flank the MHC region on human chromosome 6, myelin oligodendrocyte glycoprotein (MOG), bone morphogenetic protein 6 (BMP6), and prolactin (PRL), are split among two separate linkage groups (chromosomes) in M. domestica. Comparative analysis with eight other vertebrate species suggests strong conservation of the BMP6-PRL synteny among birds and mammals, although the BMP6-PRL-MHC-ME1 synteny is not conserved.

Bone mineral density, carotid artery intimal medial thickness, and the vitamin D receptor BsmI polymorphism in Mexican American women.

Low bone mineral density (BMD) is a predictor of cardiovascular mortality, suggesting that osteoporosis and cardiovascular disease may share common risk factors. We assessed the relationship between BMD and intimal medial thickening (IMT) of the common carotid artery, a marker of sub-clinical atherosclerosis, in 471 women examined as part of the San Antonio Family Osteoporosis Study, a population-based study of osteoporosis risk conducted in Mexican American families. Because of the documented role of vitamin D metabolism in bone metabolism and its possible role in cardiovascular function, we further evaluated whether allelic variation at the vitamin D receptor locus (VDR) influenced joint variation in BMD and IMT. The association of BMD with IMT depended on age, with low BMD being correlated with high IMT in older women, but with low IMT in younger women [age by IMT interaction effects significant at the spine (P = 0.042), radius ultradistal (P = 0.010), and hip (P = 0.006)]. In all women, the VDR BsmI BB genotype was associated with significantly higher forearm BMD (P = 0.005 for both radius ultradistal and midpoint), higher IMT (P = 0.05), and higher spine BMD in older women (P = 0.06), but not with hip BMD. The association of the VDR genotype with IMT was independent of its association with BMD. Although a functional consequence of the BsmI polymorphism on vitamin D metabolism has not been established, these findings support a possible biological relationship among VDR, bone metabolism, and atherosclerosis. We conclude that VDR polymorphisms may be one of multiple factors influencing the joint risk of atherosclerosis and osteoporosis.

Sodium-lithium countertransport activity is linked to chromosome 5 in baboons.

The genes involved in the regulation of cellular sodium transport characteristics, which are correlated with some forms of essential hypertension, have not yet been identified. We are studying the genes and environmental factors that affect red blood cell sodium-lithium countertransport (SLC) activity and intracellular sodium (ICNa) concentration in 634 baboons that comprise 11 pedigrees of 2 and 3 generations each. To detect and locate possible quantitative trait loci (QTLs) that affect SLC activity and ICNa concentration, we performed a genome screen by using a maximum likelihood-based variance-components linkage analysis program (SOLAR). SLC and ICNa phenotypes as well as genotypes on 281 microsatellite loci were available for all pedigreed animals. Both SLC and ICNa traits were highly heritable (residual heritability 0.593+/-0.083 [P<0.0001] and 0.739+/-0.082 [P<0.0001], respectively). We obtained evidence that a possible QTL for SLC activity is located on the baboon homologue of human chromosome 4 between D4S2456 and D4S2365 with a maximum multipoint lod score of 9.3 (P<10(-)(10)) near D4S1645. This QTL accounts for approximately two thirds of the total additive genetic variation in SLC activity in baboons. Although ICNa concentration was highly heritable, we found no evidence for linkage to a QTL with use of this methodology. Thus, we have evidence that a gene located on the baboon homologue of human chromosome 4 (baboon chromosome 5) affects cell sodium transport in baboons.

Evidence that multiple genes influence baseline concentrations and diet response of Lp(a) in baboons.

We investigated the response of lipoprotein(a) [Lp(a)] levels to dietary fat and cholesterol in 633 baboons fed a series of 3 diets: a basal diet low in cholesterol and fat, a high-fat diet, and a diet high in fat and cholesterol. Measurement of serum concentrations in samples taken while the baboons were sequentially fed the 3 diets allowed us to analyze 3 Lp(a) variables: Lp(a)(Basal), Lp(a)(RF) (response to increased dietary fat), and Lp(a)(RC) (response to increased dietary cholesterol in the high-fat environment). On average, Lp(a) concentrations significantly increased 6% and 28%, respectively, when dietary fat and cholesterol were increased (P<0.001). As expected, most of the variation in Lp(a)(Basal) was influenced by genes (h(2)=0.881). However, less than half of the variation in Lp(a)(RC) was influenced by genes (h(2)=0.347, P<0. 0001), whereas the increase due to dietary fat alone was not significantly heritable (h(2)=0.043, P=0.28). To determine whether Lp(a) phenotypic variation was due to variation in LPA, the locus encoding the apolipoprotein(a) [apo(a)] protein, we conducted linkage analyses by using LPA genotypes inferred from the apo(a) isoform phenotypes. All of the genetic variance in Lp(a)(Basal) concentration was linked to the LPA locus (log of the odds [LOD] score was 30.5). In contrast, linkage analyses revealed that genetic variance in Lp(a)(RC) was not linked to the LPA locus (LOD score was 0.036, P>0.5). To begin identifying the non-LPA genes that influence the Lp(a) response to dietary cholesterol, we tested, in bivariate quantitative genetic analyses, for correlation with low density lipoprotein cholesterol [LDLC; ie, non-high density lipoprotein cholesterol less the cholesterol contribution from Lp(a)]. LDLC(Basal) was weakly correlated with Lp(a)(Basal) (rho(P)=0.018). However, LDLC(RC) and Lp(a)(RC) were strongly correlated (rho(P)=0. 382), and partitioning the correlations revealed significant genetic and environmental correlations (rho(G)=0.587 and rho(E)=0.251, respectively). The results suggest that increasing both dietary fat and dietary cholesterol caused significant increases in Lp(a) concentrations and that the response to dietary cholesterol was mediated by a gene or suite of genes that appears to exert pleiotropic effects on LDLC levels as well. The gene(s) influencing Lp(a) response to dietary cholesterol is not linked to the LPA locus.

Lipoprotein Lp(a): effects of allelic variation at the LPA locus.

Concentrations of the lipoprotein Lp(a) vary widely in healthy individuals, but in many studies, high concentrations are strongly associated with cardiovascular disease. On the basis of lipid and protein composition, Lp(a) is a variant of the atherogenic low-density lipoprotein but differs in possessing the unique apolipoprotein(a) [apo(a)]. Lp(a) concentrations are controlled at the level of biosynthesis of the apo(a) protein, which is encoded by the LPA locus, and allelic differences at LPA are responsible for the bulk of variation in Lp(a) phenotype. In this article we describe several aspects of allelic variation at LPA reported in studies of human and baboons, including (1) polymorphisms for protein size, (2) families of alleles having distinct relationships between apo(a) size and Lp(a) concentration, (3) sequence polymorphisms, (4) a group of alleles whose protein products have a multibanded phenotype, and (5) allelic diversity of null phenotype alleles (whose protein products are not detected in the plasma). The data make clear that no single aspect of allelic variation at LPA is sufficient to fully explain the genetic control of Lp(a).

Two major loci control variation in beta-lipoprotein cholesterol and response to dietary fat and cholesterol in baboons.

We explored the genetic control of cholesterolemic responses to dietary cholesterol and fat in 575 pedigreed baboons. We measured cholesterol in beta-lipoproteins (low density lipoprotein cholesterol [LDLC]) in blood drawn from baboons while they were consuming a baseline (low in cholesterol and fat) diet, a high-saturated fat (lard) diet, and a high-cholesterol, high-saturated fat diet. In addition to baseline levels (LDLC(Base)), we analyzed two variables for diet response: LDLC(RF), which represents the LDLC response to increasing dietary fat (ie, high-fat diet minus baseline), and LDLC(RC), which represents the LDLC response to increasing dietary cholesterol level (ie, high-cholesterol, high-fat diet minus high-fat diet). Heritabilities (h2) of the 3 traits were 0.59 for LDLC(Base), 0.14 for LDLC(RF), and 0.59 for LDLC(RC). In addition, LDLC(Base) and LDLC(RC) had a significant genetic correlation (ie, rhoG=0.54), suggesting that 1 or more genes exert pleiotropic effects on the 2 traits. Segregation analyses detected a single major locus that accounted for nearly all genetic variation in LDLC(RC) and some genetic variation in LDLC(Base) and LDLC(RF) and confirmed the presence of a different major locus that influences LDLC(Base) alone. Preliminary linkage analyses indicated that neither locus was linked to the LDL receptor gene, a likely candidate locus for LDLC. Detection of these major loci with large effects on the LDLC response to dietary cholesterol in a nonhuman primate offers hope of detecting and ultimately identifying similar loci that determine LDLC variation in human populations.

Linkage of essential hypertension to the angiotensinogen locus in Mexican Americans.

Essential hypertension has been linked to a highly polymorphic marker at the angiotensinogen locus, and association with a polymorphism in this locus has been found in some populations. We tested the hypothesis that these same polymorphic markers are linked to essential hypertension in Mexican Americans. The data comprised all the affected relative pairs in 46 extended families chosen at random from a low-income barrio in San Antonio. Specifically, we searched for linkage by testing for excessive marker alleles shared identical by descent (IBD) among hypertensive relative pairs. When women taking oral contraceptives or hormones were excluded, the affected relative pairs shared a significant excess of alleles IBD for the highly heterozygous GT repeat polymorphism (P=.038) and were marginally significant for the M235T variant (P=.079), which has a much lower heterozygosity (0.43 versus 0.85 for the GT repeat). We also assayed plasma levels of angiotensinogen and, using likelihood methods, found no significant association (P=.43) between plasma levels of angiotensinogen and M235T genotypes. These results support the linkage of essential hypertension to the angiotensinogen locus but do not indicate a specific role for the M235T variant.

Characterization of the genetic elements controlling lipoprotein(a) concentrations in Mexican Americans. Evidence for at least three controlling elements linked to LPA, the locus encoding apolipoprotein(a).

Analyses of 1163 samples from the San Antonio Family Heart Study revealed several elements of genetic control of lipoprotein(a) (Lp(a)) concentrations in Mexican Americans. Apolipoprotein(a) (apo(a)) isoform size variation was inversely related to Lp(a) concentrations and explained about 22% of total phenotypic variation. Segregation analyses suggested the existence of a major gene that influenced an additional 41% of total Lp(a) variation. A G-->A polymorphism in the LPA promoter was in strong disequilibrium with apo(a) isoform size, but did not contribute a significant amount of additional information about Lp(a) variation. However, about 25% of variation in Lp(a) concentrations was influenced by additive polygenic effects, which include the effects of null phenotype alleles. Altogether, these genetic components explained 89% of Lp(a) variation, similar to heritability estimates made in several other studies. Apo(a) size variation and the major gene (explaining a total of about 62% of Lp(a) variation) were linked to each other and, as expected, to the plasminogen locus. Thus, together with the well-established null phenotype allele, these different genetic factors represent at least three distinct elements of control exerted at the LPA locus, which encodes the apo(a) protein.

Dietary and genetic effects on LDL size measures in baboons.

Genetic and dietary effects on LDL phenotypes, including predominant LDL particle diameter, LDL size distribution, and non-HDL cholesterol and apoB concentrations, were investigated in 150 pedigreed baboons that are members of 19 sire groups. Baboons were fed a sequence of three defined diets differing in levels of fat and cholesterol. Increasing dietary fat had relatively little effect on two measures of LDL particle size. However, increasing the level of cholesterol in the diet resulted in larger increases of the predominant LDL particle diameters and in the proportion of stain on LDLs > 28 nm. As expected, apoB and non-HDL cholesterol concentrations significantly increased when levels of dietary fat and cholesterol were increased. Correlations among the LDL phenotypes suggested that several different aspects of the LDL phenotype were captured by the four LDL measures across the three diets. Genetic effects indicated by sire group membership were significant both for expression of the LDL phenotypes and for response to changes in diet.

Genetic and environmental contributions to cardiovascular risk factors in Mexican Americans. The San Antonio Family Heart Study.

BACKGROUND: The familial aggregation of coronary heart disease can be in large part accounted for by a clustering of cardiovascular disease risk factors. To elucidate the determinants of cardiovascular disease, many epidemiological studies have focused on the behavioral and lifestyle determinants of these risk factors, whereas others have examined whether specific candidate genes influence quantitative variation in these phenotypes. METHODS AND RESULTS: Among Mexican Americans from San Antonio (Tex), we quantified the relative contributions of both genetic and environmental influences to a large panel of cardiovascular risk factors, including serum levels of lipids, lipoproteins, glucose, hormones, adiposity, and blood pressure. Members of 42 extended families were studied, including 1236 first-, second-, and third-degree relatives of randomly ascertained probands and their spouses. In addition to the phenotypic assessments, information was obtained regarding usual dietary and physical activity patterns, medication use, smoking habits, alcohol consumption, and other lifestyle behaviors and medical factors. Maximum likelihood methods were used to partition the variance of each phenotype into components attributable to the measured covariates, additive genetic effects (heritability), household effects, and an unmeasured environmental residual. For the lipid and lipoprotein phenotypes, age, gender, and other environmental covariates accounted in general for < 15% of the total phenotypic variance, whereas genes accounted for 30% to 45% of the phenotypic variation. Similarly, genes accounted for 15% to 30% of the phenotypic variation in measures of glucose, hormones, adiposity, and blood pressure. CONCLUSIONS: These results highlight the importance of considering genetic factors in studies of risk factors for cardiovascular disease.

Apolipoprotein B (apo B) signal peptide length polymorphisms are associated with apo B, low density lipoprotein cholesterol, and glucose levels in Mexican Americans.

We investigated the effects of apolipoprotein (apo) B signal peptide length polymorphisms on low density lipoprotein cholesterol (LDL-C), apo B, and post-challenge (2 h) glucose levels in 686 Mexican Americans from 34 families. The most common allele encoded an apo B signal peptide of 27 amino acids (ins; SP-27), the next most frequent allele encoded a 24 amino acid signal peptide (del; SP-24), and the rarest allele encoded a 29 amino acid signal peptide (ins; SP-29) that has been found only in Mexican Americans. Homozygotes for the SP-24 allele had significantly higher mean levels of apo B. LDL-C, and 2-h glucose than SP-27 homozygotes, and SP-27/SP-24 heterozygotes had intermediate levels (P = 0.01 for apo B, P < 0.001 for LDL-C, and P = 0.04 for 2-h glucose). Heterozygotes for the SP-29 allele had higher apo B and LDL-C levels compared to homozygotes for the SP-27 or SP-24 alleles. Apo B signal peptide length polymorphism accounted for 4.2%, 3.5%, and 3.0% of the residual variation in LDL-C, apo B, and 2-h glucose levels, respectively, among the Mexican American families.