Published online before print September 18, 2003, doi: 10.1161/01.ATV.0000095975.35247.9F
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© 2003 American Heart Association, Inc.
Atherosclerosis and Lipoproteins |
Confirmed Locus on Chromosome 11p and Candidate Loci on 6q and 8p for the Triglyceride and Cholesterol Traits of Combined Hyperlipidemia
From the Genomic and Molecular Medicine Group (R.P.N., S.A.B., S.E.-V., H.N.P., B.J., E.L.J., J.A., C.K.Y.N., C.C.S.), Medical Research Council Clinical Sciences Centre, Hammersmith Hospital; Department of Cardiovascular Medicine (M.S.), Charing Cross Hospital; and Genetics and Genomics Research Institute (J.S.), Imperial College London, UK; Departments of Medicine and Human Genetics (S.C., N.J.C., G.I.B.) and Biochemistry and Molecular Biology (G.I.B.), Howard Hughes Medical Institute, University of Chicago, Ill; Department of Medicine (D.J.B.), Royal Free and University College Medical School, University College London, UK; and Departments of Diabetes and Metabolic Medicine (R.A.) and Human Metabolism and Genetics (D.J.G.), St Bartholomew’s Hospital, London, UK.
Correspondence to Dr Carol C. Shoulders or Professor James Scott, Genomic and Molecular Medicine Group, MRC Clinical Sciences Centre, Imperial College London, DuCane Rd, London W12 0NN, UK. E-mail carol.shoulders{at}csc.mrc.ac.uk or j.scott{at}imperial.ac.uk
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Abstract |
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Background— Combined hyperlipidemia is a common disorder characterized by a highly atherogenic lipoprotein profile and increased risk of coronary heart disease. The etiology of the lipid abnormalities (increased serum cholesterol and triglyceride or either lipid alone) is unknown.
Methods and Results— We assembled 2 large cohorts of families with familial combined hyperlipidemia (FCHL) and performed disease and quantitative trait linkage analyses to evaluate the inheritance of the lipid abnormalities. Chromosomal regions 6q16.1-q16.3, 8p23.3-p22, and 11p14.1-q12.1 produced evidence for linkage to FCHL. Chromosomes 6 and 8 are newly identified candidate loci that may respectively contribute to the triglyceride (logarithm of odds [LOD], 1.43; P=0.005) and cholesterol (LOD, 2.2; P=0.0007) components of this condition. The data for chromosome 11 readily fulfil the guidelines required for a confirmed linkage. The causative alleles may contribute to the inheritance of the cholesterol (LOD, 2.04 at 35.2 cM; P=0.0011) component of FCHL as well as the triglyceride trait (LOD, 2.7 at 48.7 cM; P=0.0002).
Conclusions— Genetic analyses identify 2 potentially new loci for FCHL and provide important positional information for cloning the genes within the chromosome 11p14.1-q12.1 interval that contributes to the lipid abnormalities of this highly atherogenic disorder.
Key Words: combined hyperlipidemia • lipid abnormalities • complex genetic disorder • chromosome 11p14.1-q12.1 • metabolic syndrome
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Introduction |
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Combined hyperlipidemia (raised cholesterol and triglyceride levels) affects 1% to 2% of individuals in Western societies. The term familial combined hyperlipidemia (FCHL) was coined by Goldstein et al1 to describe a pattern of lipid abnormalities in 47 Seattle pedigrees, which was simultaneously observed by others in other families.2,3 FCHL was originally considered a dominant disorder with incomplete penetrance until the third decade that primarily affected blood triglyceride levels, with a secondary effect on cholesterol levels.1 This mode of transmission was based on the pattern of serum cholesterol and triglyceride levels in the original Seattle families. The distribution of triglyceride levels in the first-degree relatives of affected probands above the age of 20 years was bimodal, and less than one half of the offspring of affected family members were hyperlipidemic. However, subsequent segregation analyses4–8 and 2 genome-wide studies9,10 have suggested a more complex inheritance pattern.
The etiology of the mixed hyperlipidemia (increases in both cholesterol and triglyceride or in either lipid alone) in FCHL is unknown.4,6,10–12 Stable isotope studies have established a correlation between increased serum triglyceride levels and the production of VLDL and apolipoprotein (apo) B.13,14 FCHL has also been associated with defective catabolism of VLDL and chylomicrons15,16 and increased production of apoCIII and insulin resistance.17–24 The mixed lipid profile of FCHL may also occur in patients with the metabolic syndrome,25 which comprises 3 or more metabolic abnormalities, including hypertriglyceridemia, decreased HDL cholesterol, insulin resistance, hypertension, and abdominal obesity. FCHL and the metabolic syndrome contribute to premature coronary heart disease (CHD) in up to 40% of patients.26–30
In this study, we present an affected sibling and relative pair linkage analysis that identifies chromosomes 6q16.1-q16.3 and 8p23.3-p22 as potential FCHL loci and quantitative trait linkage analyses that suggest that these loci may respectively affect the triglyceride and cholesterol components of this condition. More importantly, we provide independent replication for an FCHL-susceptibility locus on chromosome 11p14.1-q12.19 that affects the triglyceride component of this condition. This interval may also contain a separate quantitative trait locus (QTL) for serum cholesterol levels, giving support to the data of Klos et al.31
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Methods |
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Families
Two cohorts of extended, multigenerational families were assembled. The first comprised 45 families and was assembled between 1988 and 1992 through white British probands attending tertiary referral specialized lipid clinics at Northwick Park Hospital and the Hammersmith Hospital, London, UK. The second, comprising 113 pedigrees, was assembled between 1998 and 2001 through probands attending clinics at Hammersmith Hospital, Charing Cross Hospital, University College London Hospital, and Saint Bartholmews Hospital in London, UK. Based on previous FCHL1,6,9,10,12 studies and PROCAM,28 probands had cholesterol and triglyceride levels greater than age- and sex-specific 95th and 90th percentile values, respectively, and a blood relative with raised plasma cholesterol or triglyceride or both greater than age- and sex-specific 90th percentile values. In the absence of British values, the Lipid Research Clinic’s32 percentile points were used. In this data set, 90th and 95th percentile cut-off values for cholesterol levels for men between 40 to 65 years of age range from 247.4 to 259.1 mg/dL and 265.2 to 274.1 mg/dL, respectively. 90th percentile values for triglyceride levels range from 248.7 to 254.0 mg/dL. In PROCAM (4599 North European men between 40 and 65 years of age), median cholesterol levels were 251.8±47.3 and 222.9±41.0 mg/dL for participants with and without CHD, respectively. Median triglyceride levels were 163.0 and 134.5 mg/dL. In the Lipid Research Clinic’s data set, 75th percentile cut-off values for the same age group are 170.8 to 180.5 mg/dL. Exclusion criteria for participants were age <16 years and other forms of genetic hyperlipidemia (eg, familial hypercholesterolemia) based on molecular diagnosis, standard clinical signs, or diagnostic criteria. Patients with secondary hyperlipidemia (eg, body mass index >30 kg/m2, diabetes mellitus, hypothyroidism, liver and kidney disease, alcohol abuse, or medication influencing lipid metabolism) were also excluded. Ethical committees of all centers approved the study design, and participants gave written informed consent. Fasting levels of total cholesterol, triglycerides, and HDL cholesterol were determined by automated methods using commercial kits and interassay controls. Serum apoB (second cohort only) was measured using an automated immunoturbidimetric assay (Beckman Instruments, Inc). LDL cholesterol levels were calculated from the standard formula, as follows: LDL cholesterol (mg/dL) =total cholesterol-[HDL cholesterol+(triglyceride/5)]. Phenotyping of all individuals was based on lipid levels before the administration of lipid-lowering medication.
Genotyping
The primary screen was performed using the version 9A Weber screening set of microsatellite markers and 45 families, the core of which has been described.6 Follow-up studies were performed in 3 stages as cohort 2 families were assembled and included all family members irrespective of affection status. Fifteen loci (1 to 15), 1q23.3, 2p25.1, 2q32.1-q33.3, 3q24, 4q21.23-q23, 4q35.1, 7q34-q36.2, 9p21.1, 9q21.13-q21.32, 12q24.33, 13q22.3-q31.1, 17p11.2-q11.2, 20p12.2-p12.1, 20q12.1-q13.12, and 21q21.1-q21.2, were evaluated in the first 56 families of cohort 2. In the absence of any evidence for linkage to an FCHL-dichotomised trait (logarithm of odds [LOD] <0.1), these loci were pursued no further. Nine additional loci (16 to 24), 3p21.31-p14.2, 4p16.2-p16.1, 5q34-q35.1, 7p12.1, 8q24.21, 10q26.3, 14q11.2-q12, 15q26.2-q26.3, and 20p11.22, were evaluated in families 1 to 78 of cohort 2. Five loci (25 to 29), 2q35-q36.3, 6q16.1-q16.3, 8p23.3-p22, 10p11.22-q21.1, and 11p14.1-q12.1, produced nominal evidence for linkage to an FCHL-dichotomised trait in the second-stage analysis and were therefore examined in an additional 35 families. Marker details are presented in Table I, available online at http://atvb.ahajournals.org.
Linkage Analysis
Linkages results have been deposited on our website (http://www. csc.mrc.ac.uk/ResearchGroups/GenomicAndMolecularMedicine/Home/home.html). Multipoint and 2-point dichotomised trait analyses were conducted with GENEHUNTER-PLUS33 and GENEHUNTER, respectively. Estimates of allele sharing were based on marker allele frequencies in pedigree founders. The Gaussian distribution was used to approximate the distribution of the NPL+ statistic and nominal probability values. Two-point parametric heterogeneity LODs (HLODs) were computed on data from all family members (ie, including all unaffected individuals) using a dominant model and penetrances of 40% and 90% for carriers with 1 and 2 copies of the disease allele, respectively. The disease allele frequency was set at 0.03, and phenocopies at a frequency of 0.001. This heterogeneity model was used to allow for the possibility that a subset of our families had a significantly higher reoccurrence risk of FCHL and a lower rate of phenocopies than the average reoccurrence risk observed in the total data set (Table 2).
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Quantitative trait linkage analysis was performed with SOLAR34 and MERLIN-REGRESS,35 implemented in Merlin version 0.9.1. For SOLAR, we first removed variation in traits attributable to the covariates, body mass index, age, and sex (as well as their interactions) and then performed 2-point and multipoint linkage analyses. The ascertainment correction option was used for probands only. Estimates for the proportion of variance attributable to covariates were 18.27% for log (triglyceride), 24.65% for log (total cholesterol), and 25.29% for apoB. Log transformation of lipid parameters was performed before the covariate fitting exercise to normalize distributions. Linkage was evaluated by comparing the likelihood of a variance component model that permits a given marker locus (assumed to be tightly linked to a locus influencing the quantitative trait) to account for some of the additive genetic variance to the likelihood of a purely polygenic model. The difference between the two log10 likelihood produces a LOD equivalent to the classical LOD of linkage analysis.36 For MERLIN-REGRESS, the analysis was performed without removing the effects of covariates. The independent variables were defined as trait values and identity by descent alleles as dependent variables because regression coefficient estimates are not biased by sample selection through independent values.35 Cholesterol and triglyceride levels were logged to normalize distributions. Population trait means and variances were computed from the spouses within the families.
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Results |
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Genome-Wide Screen and Identification of Candidate Loci
To evaluate the genetic basis for the lipid abnormalities of FCHL, we screened the human genome of 503 individuals from 45 extended pedigrees (Table 1) with markers at an average map density of 10 cM and evaluated the data using standard and correlated diagnostic criteria for affected status. These were (1) triglyceride trait, triglyceride
90th percentile age- and sex-specific values; (2) combined hyperlipidemia phenotype, raised cholesterol and triglyceride levels and 90th percentile age- and sex-specific values; (3) cholesterol trait, cholesterol 90th percentile age- and sex-specific values; and (4) 95th percentile FCHL lipid trait, cholesterol or triglyceride level 95th percentile age- and sex-specific values. The fourth category was designed to ensure all individuals with a probable genetic cause for hyperlipidemia were included. The number of affected relative pairs in the pedigrees ranged from 77 for the combined hyperlipidemia phenotype to 345 for the cholesterol trait (Table 2). Sibling reoccurrence risk (
s) values ranged from 2.5 for the 95th percentile FCHL lipid trait to 3.5 for the combined hyperlipidemia phenotype (Table 2).
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The analysis of FCHL as a dichotomous trait is consistent with the analysis of Aouizerat et al9 and Pajukanta et al.10 Fifteen genomic regions produced LODs >0.9 (P<0.022) for a FCHL-related lipid trait (Table 3; Figure I, available online at http://atvb.ahajournal.org), and of these, 3 were coincident with regions previously implicated in FCHL (Table 3). All 15 regions were followed up in our second cohort of families, which was recruited by the same strategy as cohort 1 families. The 2 cohorts of families were comparable in most respects, including the proportion of male and female individuals affected with each phenotype and the number of affected sibling and relative pairs per family (Tables 1 and 2
). However, subtle differences were observed between the distributions of lipid abnormalities, which required us to keep the initial analyses of cohort 2 separate from cohort 1. Cohort 2 contained a higher proportion of affected sibling and relative pairs with the combined hyperlipidemia or triglyceride trait compared with the families in cohort 1 (P<0.001 level). In addition, s values were slightly higher (Table 2) in the second cohort, suggesting that familial factors may have played a more important role in determining lipid levels in these families. The differences between cohort 1 and 2 may additionally relate to changes in lifestyle factors that have occurred in the interval between the recruitment of the families in these 2 cohorts.
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The analysis of cohort 2 provided support for 2, 6q16.1-q16.3 (Figure, panel A) and 8p23.3-p22 (Figure, panel B), of the 15 chromosomal regions that had produced evidence for linkage to a FCHL dichotomised trait in the genome-wide screen of cohort 1 (Figure I, Table 1).
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Second-Stage Analyses of Chromosome 6q16.1-q16.3 and 8p23.3-p22
The support for linkage of the chromosome 6q16.1-q16.3 interval to a FCHL-related trait in our second cohort of families was modest but present in all data sets. In the dichotomised trait analyses, the highest nonparametric multipoint LOD (LOD, 0.64; NPL+, 1.72; P=0.043) was obtained for the 95th percentile FCHL lipid trait, near marker D6S1671 at 105.7 cM (Figure, panel A). In the combined data set (ie, cohorts 1 and 2), the LOD increased to 0.79 (NPL+, 1.90; P=0.028) at 107.9 cM (Figure, panel B), attributable to a positive LOD in 49.3% of families with an affected sibling or relative pair with this trait.
In the combined data sets, the highest multipoint LODs for the triglyceride trait combined hyperlipidemia phenotype and cholesterol trait were, respectively, 0.88 (P=0.022) at 107.9 cM, 0.99 (P=0.016) at 99.4 cM, and 0.03 at 97.1 cM (Figure, panel A; Table II, available online at http://atvb.ahajournals.org), suggesting that the candidate linkage of chromosome 6q16.1-q16.3 interval for FCHL might be attributable to the triglyceride component of this condition. This was supported by 2-point parametric and quantitative linkage analyses. In 2-point analyses, the highest HLODs were 0.71 (
=0.30) for the triglyceride trait in cohort 1 with marker D6S1021 at 112.2.cM, compared with 1.91 (=0.25) in cohort 2 with marker D6S1671 at 107.9 cM (Table III, available online at http://atvb.ahajournals.org). A candidate QTL for serum triglyceride at 107.9 cM was also detected by the quantitative trait linkage analyses, implemented in SOLAR. Two-point and multipoint LODs were 1.8 (Table IV, available online at http://atvb.ahajournals.org) and 1.43 (P=0.005), respectively. (Figure, panel A). The corresponding values in MERLIN-REGRESS were more modest, but as in the SOLAR, we obtained the highest LODs for a triglyceride QTL (Tables V and VI, available online at http://atvb.ahajournals.org).
To evaluate the 8p23.3-p22 chromosomal region in our second cohort of families, we used 9 markers spanning a 41-cM interval (Figure, panel B). In the dichotomised trait analyses, the highest nonparametric multipoint LOD (LOD, 1.76; NPL+, 2.85; P=0.0022) was obtained at 28.8 cM for the 95th percentile FCHL lipid trait (Figure, panel B). This was attributable to a positive LOD in 47.8% of affected families. Combining the data with cohort 1 families shifted the peak LOD (LOD, 1.80; NPL+, 2.87; P=0.0022) to 11.1 cM, which coincided with the smaller of the 2 peaks in the cohort 2 families (Figure, panel B). This genomic region also produced the highest LODs for a candidate QTL for serum cholesterol (LOD, 2.20 at 8.3 cM; P=0.0007) and triglyceride (LOD, 1.69 at 0.73 cM; P=0.003) (Figure, panel B; Table VI, available online at http://atvb.ahajournals.org).
Two-point parametric analyses produced some support for linkage of the chromosome 8p23.3-p22 interval to a FCHL-related trait. Cohort 1 produced a HLOD of 1.64 (=0.62) for the combined hyperlipidemia trait with markers D8S1106 at 26.4 cM (data available on our website). Cohort 2 produced HLODs of 1.27 ( 0.26) and 1.69 (=0.55) with markers D8S1721 and D8S549 at 17.0 and 31.7 cM, respectively, for the 95th percentile FCHL lipid trait (online Table III).
Replication of the Chromosome 11p14.1-q12.1 Linkage
We also examined 14 chromosomal regions (1q23.3, 2p25.1, 2q32.1-32.3, 5q34-35.1, 7p12.1, 8q24.21, 10p11.22-10q21.1, 10q26.3, 11p14.1-q12.1, 12q24.33, 13q22.33-31.1, 14q11.2-12, 15q26.1-26.3, 21q21.1-21.2) that had produced evidence of linkage to FCHL in a previous genome-wide scan9,10 but no such evidence in our primary genome-wide screen of 45 white British families (Figure I). Follow-up studies, performed in our second cohort of families, produced multipoint LODs >0.5 for 2 of these 14 chromosomal loci.
The first locus, 10p11.22-10q21.1, produced a multipoint LOD of 0.82 (P=0.026) at 68.8 cM for triglyceride as a dichotomised trait (data available on our website), providing some support for linkage of this locus to the triglyceride trait of FCHL.10 In our combined data set, the highest multipoint LOD was more modest, 0.55 at 70.23 cM (Table II). Modest LODs were also attained when we analyzed the locus as a serum triglyceride QTL. The highest 2-point LODs were 1.40 (SOLAR) and 0.80 (MERLIN-REGRESS) at 75.6 cM (Tables IV and V), compared with multipoint LODs of 0.95 (data available on our website) and 0.67 (Table VI).
The second locus, 11p14.1-q12.1, was evaluated in our second cohort of families using 9 markers spanning a 40-cM interval (ie, 21.5 to 61.8 cM). The highest LODs were obtained for the triglyceride trait of FCHL in all analyses (Figure, panel C, Table 4, and Tables II through VI). The dichotomised trait analyses produced a multipoint nonparametric LOD of 2.9 (NPL+, 3.63; P=0.00014) at 48.9 cM (Figure, panel C) compared with a 2-point parametric HLOD of 3.05 (=0.37) at 47.1 cM (Table III). In the combined data set, the highest multipoint LOD was 2.25 (NPL+, 3.22; P=0.0007) at 49.9 cM (Figure, panel C). This LOD derived from 48.7% of families with an affected sibling or relative pair with the triglyceride trait of FCHL.
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In quantitative analyses, MERLIN-REGRESS produced the highest multipoint LOD (LOD, 2.7; P=0.0002) at 48.7 cM, whereas the SOLAR analyses produced the highest signal (LOD, 2.7; P=0.0002) at 58.4 cM (Figure, panel C). MERLIN-REGRESS additionally detected a candidate QTL (LOD, 2.04; P=0.0011) for cholesterol (Figure, panel C), consistent with the data of Klos et al.31 We conclude that the data for chromosome 11 combined with previous data9,31 readily fulfil the standard criteria proposed for a confirmed linkage37 and indicate that the underlying sequence variant may contribute to the cholesterol component of FCHL as well as the triglyceride trait of this condition.
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Discussion |
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We performed disease and quantitative linkage analyses to evaluate the inheritance of lipid abnormalities in the most common form of hyperlipidemia. The results identify 2 new potential loci (chromosomes 6q16.1-q16.3 and 8p23.3-p22) for FCHL and most importantly provide independent replication for a locus on chromosome 11p14.1-q12.1 that increases the transmission of the lipid abnormalities in this highly atherogenic condition. The refined positional information provided by these studies should markedly accelerate the identification of the FCHL-susceptibility gene associated with this locus.
In our studies, we analyzed lipid and genotype data in all FCHL family members, which enabled us to assess the linkage data for chromosomes 6q16.1-q16.3, 8p23.3-p22, 10p11.22-10q21.1, and 11p14.1-q12.1 using different models. This multipronged approach, which was motivated by the uncertainty of the inheritance of the lipid abnormalities in FCHL,1,4–10 has provided robust data for these loci, suggesting that it may be usefully applied in future studies to identify additional susceptibility loci for this highly atherogenic condition.
A QTL for serum triglyceride or apoCIII levels in the chromosome 6q16.1-q16.3 genomic interval that acts as FCHL susceptibility or modifier locus would be consistent with the modest LODs obtained in the current and previous studies.9,31 In a previous FCHL study, a maximized LOD of 0.8 at 111 cM was obtained for affection status in 18 extended Dutch families.9 This compares with a triglyceride multipoint LOD of 0.88 at 107.9 cM in white British FCHL families and a multipoint LOD of 1.70 at 109 cM for the triglyceride-related trait, apoCIII, in 232 multigenerational pedigrees, ascertained without regard for health through households with 2 schoolchildren.31
The estimated position of a QTL or disease trait locus commonly varies in complex genetic disorders,38 which may be attributable to chance variation around a single locus, the presence of multiple genes, incomplete penetrance, variation in the expression of the phenotype, ascertainment bias, and genetic heterogeneity. In the present study, we used 2 cohorts of families, both of which are likely to be genetically heterogeneous. In addition, we used dichotomised and quantitative trait linkage analyses, which necessarily extracts different genetic information from the families to compute estimates of gene location. Our data for the candidate locus on chromosome 8 produced the most discrepant estimates for gene location and varied according to both the type of analysis performed and the cohort examined. However, reasonable concordance was observed between 2 analyses. The dichotomised trait linkage analysis performed on all 158 FCHL individuals (ie, cohorts 1 and 2) produced a LOD of 1.80 at 11.1 cM for the 95th percentile FCHL lipid trait and was supported by a QTL (LOD, 2.2) for cholesterol levels at 8.4 cM in our second cohort of families (Figure, panel B). In the UK population, the interval, close to marker D8S549 at 31.7 cM, has also been implicated in type 2 diabetes39 (Table 4). Type 2 diabetes was a specific exclusion criterion in the present study. However, because previous studies have indicated that patients with FCHL may have impaired glucose tolerance and insulin resistance,8,19,21,24,40,41 some of the linkage signals we obtained close to this marker in our analyses might relate to a common metabolic abnormality in FCHL and type 2 diabetes.
The data from the present and previous studies (Table 4) provide compelling evidence that the chromosome 11p14.1-q12.1 genomic interval contains a QTL for serum cholesterol and triglyceride, which may act as an FCHL susceptibility or modifier locus. In FCHL, Aouizerat et al9 obtained a maximized nonparametric LOD of 2.6 at 65 cM for affection status (defined by either high cholesterol or triglyceride levels) in 18 extended Dutch FCHL families, which was supported by genotype data in an additional 17 Dutch FCHL families. However, these additional data shifted the estimated position of the causative gene closer to marker D11S1324 at 35.2 cM. In the present study, we used a denser set of markers to evaluate the 11p14.1-q12.1 interval and obtained the highest LODs (2.7 to 3.05) for the triglyceride component of this condition between 48.7 and 58.4 cM. This interval also resides in close proximity to a QTL for impaired glucose intolerance,42 suggesting that a common metabolic abnormality, such as insulin resistance, in FCHL and type 2 diabetes might contribute to the development of the triglyceride abnormalities in these conditions. The results for this interval are unlikely to be attributable to sequence variants at the APOAI/CIII/AIV/AV locus,43 because this gene cluster is located within the 11q23.1 locus at 121 cM, some 73 cM from the peak of the linkage signal for serum triglyceride levels.
We also obtained evidence for a QTL for serum cholesterol at 35.2 cM, which raises the issue of whether the 11p14.1-q12.1 genomic interval might contain separate susceptibility alleles for the different lipid abnormalities (ie, cholesterol and triglyceride) of FCHL. In support of this, Klos et al31 found evidence for a cholesterol QTL (LOD, 1.84) at 35 cM in 232 multigenerational pedigrees, ascertained without regard for health through households with 2 schoolchildren,31 but no such evidence for a serum triglyceride QTL. Instead, the highest LOD (0.13) for this trait was produced at 113 cM, close to the APOAI/CIII/AIV/AV gene cluster. Similarly, 2 additional studies produced evidence for a LDL cholesterol QTL within the 11p14.1-q12.1 genomic interval (Table 4) but no such evidence for a triglyceride QTL.44,45 The first study involved 62 nuclear families, ascertained through 2 obese siblings, whereas the second studied 2799 subjects from the NHLBI Family Heart Study.
The failure to detect linkage of the 11p14.1-q12.1 locus to FCHL in our first cohort of 45 FCHL families does not detract from our replication data. Subtle differences in family structures or the frequency of a disease-causing allele within families can have a substantial impact on the power to detect linkage in genome-wide screen studies, and this is especially true for small data sets.46–48 Indeed, our inability to replicate the evidence for linkage of 11p14.1-q12.1 to FCHL in our first data set has parallels with many genome-wide screens. The Crohn’s chromosome 16 locus, for example,49 produced a NPL score of 3.17 in the original data set, compared with scores of <0.7 in subsequent studies.
A final NPL value of 3.47 in Crohn’s disease proved sufficient for identifying 3 susceptibility alleles for this condition,50 suggesting that the NPL+ value of 3.63 obtained for the 11p14.1-q12.1 chromosomal region in the present study will lead to the identification of sequence variants that impact serum triglyceride levels in FCHL as well as cholesterol levels. This would increase the likelihood of cloning additional genes in this condition through ordered subset analysis and identifying the primary metabolic pathway that is perturbed in FCHL and the associated metabolic syndrome of insulin resistance, which will presumably influence the development of new therapies to treat the substantially increased risk of CHD that is associated with these conditions.
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Electronic Database Information
Family details and data: http://www.csc.mrc.ac.uk/ResearchGroups/GenomicAndMolecularMedicine/Home/home.html; Centre for Medical Genetics, Marshfield Medical Research Foundation: http://research.marshfieldclinic.org/genetics/; Project Ensembl: http://www.ensembl.org/; Genome database: http://www.gdb.org/; MERLIN: http://www.sph.umich.edu/csg/abecasis/merlin; SOLAR: http://www.sfbr.org/sfbr/public/software/solar/index.html; National Public Health Institute of Finland, Department of Human Molecular Genetics: http://www.ktl.fi/molbio/wwwpub/fchl/genomescan
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Acknowledgments |
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Acknowledgments
The authors gratefully acknowledge support from the British Heart Foundation (PG/98159, PG2001015), Medical Research Council, Hammersmith Hospitals NHS Trust, London, UK, and the Marshfield Medical Research Foundation. They are also indebted to all study participants and coinvestigators, including Saro Niththyananthan, Georgina Harrison, Rebecca Francombe, Louise Olofsson, Susan Earl-Mitchell, and John Batty. They also thank Professor Timothy Aitman, Drs Arjen Mensenkamp and Penelope Ritchie for helpful discussion, Dr David Perkins for programming assistance, Professor Pak Sham and Dr David Curtis for guidance on the quantitative and parametric analyses, and Rocio Lale-Montes for excellent secretarial assistance.
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Footnotes |
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Consulting Editor for this article was Goran Hansson, Karolinska Institute, Stockholm, Sweden.
Received August 20, 2003; accepted August 21, 2003.
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References |
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