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.

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.

Evidence for a major gene affecting postchallenge insulin levels in Mexican-Americans.

Hyperinsulinemia, which is considered a hallmark of insulin resistance, precedes the development of non-insulin-dependent diabetes mellitus (NIDDM). Results of family and twin studies have shown that heredity influences insulin resistance and insulin levels. In Caucasian families ascertained through two or more NIDDM siblings, it has been reported that single genes with large effects, i.e., major genes, influence both fasting and 1-h postchallenge insulin levels. To determine whether a major gene affects 2-h postchallenge insulin levels in Mexican-Americans, we conducted segregation analyses using data collected on 527 pedigreed individuals from 27 families in San Antonio, TX. Probands for the families were randomly ascertained and all first-, second-, and third-degree relatives aged 16 years and older were invited to participate. Subjects received a 2-h oral glucose tolerance test, and diabetes was diagnosed according to World Health Organization criteria. We found that an autosomal dominant major gene best described the inheritance of 2-h insulin levels (ln-transformed) in these 27 families. Of the individuals in the population, 17% were homozygous for the 2-h low-insulin allele (back-transformed mean = 125 pmol/l) and 83% were heterozygous or homozygous for the 2-h high-insulin allele (back-transformed mean = 406 pmol/l). This major gene accounted for 31% of the variance in ln(2-h insulin levels) in this population. Using quantitative trait linkage analyses, we excluded tight linkage between this gene affecting 2-h insulin levels and three candidate loci for insulin levels: the insulin receptor gene, the low-density lipoprotein receptor gene, and the glucokinase gene.(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for linkage of postchallenge insulin levels with intestinal fatty acid-binding protein (FABP2) in Mexican-Americans.

Single genes with large effects may contribute to insulin resistance or influence susceptibility to non-insulin-dependent diabetes mellitus (NIDDM). In the Pima Indians, results from sib-pair analysis have suggested that a gene on chromosome 4q influences both fasting insulin levels and maximal insulin action. We conducted sib-pair and logarithm of odds (LOD)-score linkage analysis to seek evidence for linkage between genes influencing insulin levels and chromosome 4q loci. Analyses were conducted on nondiabetic individuals from 28 different families participating in the San Antonio Family Diabetes Study. All subjects received a 2-h oral glucose tolerance test. Fasting insulin levels were measured in 382 nondiabetic individuals, and 2-h insulin levels were measured in 366 individuals. Initial sib-pair linkage analysis revealed a possible association between 2-h post-glucose challenge insulin levels and the intestinal fatty acid-binding protein (FABP2) locus located in the region of chromosome 4q28-31 (P = 0.006). Subsequent sib-pair linkage analysis of 11 additional chromosome 4q markers supported this hypothesis. We next conducted segregation analyses to estimate allele frequencies and other model parameters for the putative locus influencing 2-h insulin levels. Results of LOD-score linkage analysis indicated possible linkage between the major gene described by the segregation model and FABP2. Using combined segregation and linkage analysis, we obtained a LOD-score of 2.80 at recombination frequency of 0.0 between FABP2 and the putative locus influencing 2-h insulin levels. The maximum likelihood estimate of the allele associated with low insulin levels was 0.21.(ABSTRACT TRUNCATED AT 250 WORDS)

NIDDM in Mexican-American families. Heterogeneity by age of onset.

OBJECTIVE: Heredity has long been known as a risk factor for non-insulin-dependent diabetes mellitus (NIDDM), but the mode of inheritance of NIDDM remains unclear. We examined the distribution of diabetes in 29 Mexican-American families ascertained on a diabetic proband. RESEARCH DESIGN AND METHODS: Probands represented a random sample of diabetic Mexican Americans residing in low-income neighborhoods from San Antonio, TX. A total of 375 family members of these diabetic probands were examined, and diabetes was diagnosed according to the World Health Organization plasma glucose criteria. RESULTS: The prevalence of diabetes decreased from 28.2% in first-degree relatives of the probands to 13.3% in second-degree relatives to 11.1% in third-degree relatives. When compared with Mexican Americans with no parental history of diabetes, this represents an excess of diabetes of 2.0-, 1.3-, and 1.1-fold in first-, second-, and third-degree relatives, respectively. Five of the 29 probands (17%) had an age of diabetes onset < 40 years. In the first-degree relatives of these early-onset probands, diabetes prevalence was 47.0% (16 of 34) compared with only 24.1% (34 of 141) in the first-degree relatives of the 24 late-onset probands. After adjustment for age, this excess represented a fivefold increase in the odds of diabetes among relatives of the early-onset probands compared with relatives of the late-onset probands (P < 0.001). Moreover, the 16 affected family members of the early-onset probands had a mean age of diabetes onset of 42.7 years compared with 49.9 years for the 34 affected members of the late-onset probands, although this difference was not statistically significant (P = 0.13). CONCLUSIONS: NIDDM may be genetically heterogeneous in this Mexican-American population, with family members of early-onset diabetes patients being at higher risk for NIDDM than family members of late-onset diabetes patients.

Correlated expression of atrial myosin heavy chain and regulatory light chain isoforms with pressure overload hypertrophy in the non-human primate.

OBJECTIVE: The aim was to determine the extent to which myosin heavy chain and light chain isoform transitions in atrial myocardium are coordinately regulated under pathological conditions in tissue from normal baboons, hypertensive baboons with myocardial hypertrophy, and baboons in which hypertrophy had regressed. METHODS: Quantitative distributions of myosin heavy chain (MHC) and regulatory myosin light chain (MLC2) isoforms in atrial myocardium from 35 adult baboons were determined by electrophoresis under denaturing conditions and laser densitometry. RESULTS: A significant association was observed between the ratios of MHC and MLC2 isoforms in atrial myocardium (r = 0.73, p < 0.001, n = 69). Expressions of alpha MHC and atrial MLC2 (ALC2) isoforms were correlated in atrial myocardium, as were those of beta MHC and ventricular MLC2 (VLC2) isoforms. In a subset of baboons with experimentally induced renal hypertension (n = 12) both beta MHC and VLC2 isoforms were found at higher levels in left atria than were present in normotensive baboons (p = 0.006, n = 15). Left atria from hypertensive baboons with regressed LVH contained intermediate levels of both beta MHC and VLC2 isoforms. CONCLUSIONS: There is tight coupling between the expression of myosin subunit isoforms under pathological conditions from a primate species closely related to humans. The data suggest that the synthesis of these subunits of myosin may be coordinated at the molecular level.

Selective breeding to develop lines of baboons with high and low blood pressure.

Lines of baboons with high and low blood pressure were developed by selective breeding. Blood pressure was measured in 456 adult feral baboons under ketamine immobilization by direct arterial cannulation. Males with blood pressures two standard deviations and females with blood pressures one standard deviation above and below the cumulative mean were selected as progenitors. High males were mated with high females and low males were mated with low females. We measured blood pressure and plasma renin activity on 100 progeny, 54 males and 46 females, greater than 44 months of age with an abbreviated tether protocol and software program for data collection. Mean systolic and diastolic nighttime pressures for the high line were 126/72 and for the low line were 114/65 mm Hg. Line differences for systolic (12 mm Hg) and for diastolic (7 mm Hg) pressures were significant (p < 0.001). The line difference for plasma renin activity (1.1 [ng/mL]/hr) was not significant. Progeny pressures ranged from 84/49 to 191/126 mm Hg. There was no sex effect on blood pressure or plasma renin activity line differences. Heritability of systolic pressure was 0.46 +/- 0.19 and of diastolic pressure was 0.32 +/- 0.19. These results indicate that, by selective breeding and rigorous measurement of blood pressure, lines of baboons with significant difference in blood pressure can be developed.

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.

Evidence for heritability of biogenic amine levels in the cerebrospinal fluid of rhesus monkeys.

Susceptibility to several human psychopathological disorders is under partial genetic influence, and many of these disorders have biological correlates that may form part of the basis of this vulnerability. In humans, alterations in cerebrospinal fluid (CSF) metabolite levels of the amine transmitters norepinephrine, dopamine, and serotonin have been associated with several forms of psychopathology, and altered levels of these metabolites have been found in healthy probands with a familial history of such illnesses. We report evidence for heritability of CSF levels of biogenic amine measures in rhesus monkeys, Macaca mulatta. In a pilot study of 54 monkeys with known pedigrees, significant differences among sire families were found for CSF levels of norepinephrine (p = 0.04), homovanillic acid (p = 0.02), and 5-hydroxyindoleacetic acid (p = 0.04). These data indicate that variation in bioaminergic measures is associated with pedigree, and that model systems incorporating both genetic and environmental factors can contribute to the understanding of the function of aminergic systems implicated in vulnerability to psychopathology.

A DNA polymorphism for lecithin:cholesterol acyltransferase (LCAT) is associated with high density lipoprotein cholesterol concentrations in baboons.

We investigated the effects of a polymorphic PvuII site in the gene for lecithin:cholesterol acyltransferase (LCAT) on serum high density lipoprotein cholesterol (HDL-C) and apolipoprotein A-I (apo A-I) concentrations in a population of 750 pedigreed baboons. We also tested for genotype by diet interactions using data on HDL-C and apo A-I concentrations on two diets (chow and high-cholesterol, saturated fat). A significant (P < 0.001) association between the LCAT genotypes and HDL-C levels was observed. On both diets, animals homozygous for the less common allele had HDL-C levels that averaged 18-19% lower than animals homozygous for the more common allele. HDL-C levels of the heterozygotes were intermediate. The LCAT RFLP accounted for approximately 5% of the variation in HDL-C levels on the two diets. We observed no strong evidence for an LCAT genotype by diet interaction effect.

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.

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.

Effects of selection for serum cholesterol concentrations on serum lipid concentrations and body weight in baboons.

We examined the results of one generation of selection for serum cholesterol (SC) concentration on low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), and triglyceride concentrations and weight in baboons (Papio cynocephalus). Parents of two lines (high SC response and low SC response) were chosen based on their SC response to a 4-month challenge with a cholesterol and saturated fat enriched diet. Parents of the control line were chosen without regard for SC levels. Expression of SC, LDL-C, and HDL-C concentrations was moderately influenced by additive genetic effects as evidenced by the direct and correlated responses of the serum lipoprotein concentrations of the juvenile offspring of the three lines. Realized heritability of SC and genetic correlations of SC with LDL-C and HDL-C were moderate to high. Sex and age were important factors influencing expression of SC, LDL-C, HDL-C, triglycerides, and weight in both adult baboons and their offspring.