Genetic loci for blood lipid levels identified by linkage and association analyses in Caribbean Hispanics

To identify genetic loci influencing blood lipid levels in Caribbean Hispanics, we first conducted a genome-wide linkage scan in 1,211 subjects from 100 Dominican families on five lipid quantitative traits: total cholesterol (TC), low density lipoprotein cholesterol (LDL-C), high density lipoprotein cholesterol (HDL-C), triglycerides (TG), and LDL-C/HDL-C ratio. We then investigated the association between blood lipid levels and 21,361 single nucleotide polymorphisms (SNP) under the 1-logarithm of odds (LOD) unit down regions of linkage peaks in an independent community-based subcohort (N = 814, 42% Dominican) from the Northern Manhattan Study (NOMAS). We found significant linkage evidence for LDL-C/HDL-C on 7p12 (multipoint LOD = 3.91) and for TC on 16q23 (LOD = 3.35). In addition, we identified suggestive linkage evidence of LOD > 2.0 on 15q23 for TG, 16q23 for LDL-C, 19q12 for TC and LDL-C, and 20p12 for LDL-C. In the association analysis of the linkage peaks, we found that seven SNPs near FLJ45974 were associated with LDL-C/HDL-C with a nominal P < 3.5 × 10(-5), in addition to associations (P < 0.0001) for other lipid traits with SNPs in or near CDH13, SUMF2, TLE3, FAH, ARNT2, TSHZ3, ZNF343, RPL7AL2, and TMC3. Further studies are warranted to perform in-depth investigations of functional genetic variants in these regions.     

Multiple QTLs influencing triglyceride and HDL and total cholesterol levels identified in families with atherogenic dyslipidemia

We conducted a genome-wide scan using variance components linkage analysis to localize quantitative-trait loci (QTLs) influencing triglyceride (TG), high density lipoprotein-cholesterol (HDL-C), low density lipoprotein-cholesterol, and total cholesterol (TC) levels in 3,071 subjects from 459 families with atherogenic dyslipidemia. The most significant evidence for linkage to TG levels was found in a subset of Turkish families at 11q22 [logarithm of the odds ratio (LOD)=3.34] and at 17q12 (LOD=3.44). We performed sequential oligogenic linkage analysis to examine whether multiple QTLs jointly influence TG levels in the Turkish families. These analyses revealed loci at 20q13 that showed strong epistatic effects with 11q22 (conditional LOD=3.15) and at 7q36 that showed strong epistatic effects with 17q12 (conditional LOD=3.21). We also found linkage on the 8p21 region for TG in the entire group of families (LOD=3.08). For HDL-C levels, evidence of linkage was identified on chromosome 15 in the Turkish families (LOD=3.05) and on chromosome 5 in the entire group of families (LOD=2.83). Linkage to QTLs for TC was found at 8p23 in the entire group of families (LOD=4.05) and at 5q13 in a subset of Turkish and Mediterranean families (LOD=3.72). These QTLs provide important clues for the further investigation of genes responsible for these complex lipid phenotypes. These data also indicate that a large proportion of the variance of TG levels in the Turkish population is explained by the interaction of multiple genetic loci.     

Genetic determinants of obesity-related lipid traits

In our ongoing effort to identify genes influencing the biological pathways that underlie the metabolic disturbances associated with obesity, we performed genome-wide scanning in 2,209 individuals distributed over 507 Caucasian families to localize quantitative trait loci (QTLs), which affect variation of plasma lipids. Pedigree-based analysis using a quantitative trait variance component linkage method that localized a QTL on chromosome 7q35-q36, which linked to variation in levels of plasma triglyceride [TG, logarithm of odds (LOD) score = 3.7] and was suggestive of linkage to LDL-cholesterol (LDL-C, LOD = 2.2). Covariates of the TG linkage included waist circumference, fasting insulin, and insulin:glucose, but not body mass index or hip circumference. Plasma HDL-cholesterol (HDL-C) levels were suggestively linked to a second QTL on chromosome 12p12.3 (LOD = 2.6). Five other QTLs with lower LOD scores were identified for plasma levels of LDL-C, HDL-C, and total cholesterol. These newly identified loci likely harbor genetic elements that influence traits underlying lipid adversities associated with obesity.     

Attention-deficit/hyperactivity disorder in a population isolate: linkage to loci at 4q13.2, 5q33.3, 11q22, and 17p11

Attention-deficit/hyperactivity disorder (ADHD [MIM 143465]) is the most common behavioral disorder of childhood. Twin, adoption, segregation, association, and linkage studies have confirmed that genetics plays a major role in conferring susceptibility to ADHD. We applied model-based and model-free linkage analyses, as well as the pedigree disequilibrium test, to the results of a genomewide scan of extended and multigenerational families with ADHD from a genetic isolate. In these families, ADHD is highly comorbid with conduct and oppositional defiant disorders, as well as with alcohol and tobacco dependence. We found evidence of linkage to markers at chromosomes 4q13.2, 5q33.3, 8q11.23, 11q22, and 17p11 in individual families. Fine mapping applied to these regions resulted in significant linkage in the combined families at chromosomes 4q13.2 (two-point allele-sharing LOD score from LODPAL = 4.44 at D4S3248), 5q33.3 (two-point allele-sharing LOD score from LODPAL = 8.22 at D5S490), 11q22 (two-point allele-sharing LOD score from LODPAL = 5.77 at D11S1998; multipoint nonparametric linkage [NPL]-log[P value] = 5.49 at approximately 128 cM), and 17p11 (multipoint NPL-log [P value] >12 at approximately 12 cM; multipoint maximum location score 2.48 [alpha = 0.10] at approximately 12 cM; two-point allele-sharing LOD score from LODPAL = 3.73 at D17S1159). Additionally, suggestive linkage was found at chromosome 8q11.23 (combined two-point NPL-log [P value] >3.0 at D8S2332). Several of these regions are novel (4q13.2, 5q33.3, and 8q11.23), whereas others replicate already-published loci (11q22 and 17p11). The concordance between results from different analytical methods of linkage and the replication of data between two independent studies suggest that these loci truly harbor ADHD susceptibility genes.     

Evidence of QTLs on chromosomes 1q42 and 8q24 for LDL-cholesterol and apoB levels in the HERITAGE family study

Genome-wide multipoint linkage analyses were performed to identify chromosomal regions harboring genes influencing LDL-cholesterol, total apolipoprotein B (apoB), and LDL-apoB levels using 654 markers. They were assessed in a sedentary state (baseline) and after a 20 week endurance training program. Strong evidence for two quantitative trait loci (QTLs) for baseline levels was found. There is linkage evidence in black families on chromosomes 1q41-q44 [at marker D1S2860, 238 centimorgan (cM), with a maximum log of the odds (LOD) score of 3.7 for LDL-apoB] and in white families on chromosome 8q24 (at marker D8S1774, 142 cM, with LOD scores of 3.6, 3.3, and 2.5 for baseline LDL-cholesterol, LDL-apoB, and apoB, respectively). There were no strong signals for the lipoprotein training responses (as computed as the difference in posttraining minus baseline levels). In conclusion, QTLs for baseline apoB and LDL-cholesterol levels on chromosomes 1q41-q44 (in blacks) and 8q24 (in whites) were found. As there are no known strong candidate genes in these regions for lipids, follow-up studies to determine the source of those signals are needed.     

Linkage analysis of LDL cholesterol in American Indian populations: the Strong Heart Family Study

Previous studies have demonstrated that low density lipoprotein cholesterol (LDL-C) concentration is influenced by both genes and environment. Although rare genetic variants associated with Mendelian causes of increased LDL-C are known, only one common genetic variant has been identified, the apolipoprotein E gene (APOE). In an attempt to localize quantitative trait loci (QTLs) influencing LDL-C, we conducted a genome-wide linkage scan of LDL-C in participants of the Strong Heart Family Study (SHFS). Nine hundred eighty men and women, age 18 years or older, in 32 extended families at three centers (in Arizona, Oklahoma, and North and South Dakota) were phenotyped for LDL-C concentration and other risk factors. Using a variance component approach and the program SOLAR, and after accounting for the effects of covariates, we detected a QTL influencing LDL-C on chromosome 19, nearest marker D19S888 at 19q13.41 [logarithm of odds (LOD) = 4.3] in the sample from the Dakotas. This region on chromosome 19 includes many possible candidate genes, including the APOE/C1/C4/C2 gene cluster. In follow-up association analyses, no significant evidence for an association was detected with the APOE*2 and APOE*4 alleles (P = 0.76 and P = 0.53, respectively). Suggestive evidence of linkage to LDL-C was detected on chromosomes 3q, 4q, 7p, 9q, 10p, 14q, and 17q. These linkage signals overlap positive findings for lipid-related traits and harbor plausible candidate genes for LDL-C.     

A genome-wide linkage scan for quantitative trait loci underlying obesity related phenotypes in 434 Caucasian families

To identify quantitative trait loci (QTLs) that contribute to obesity, we performed a large-scale whole genome linkage scan (WGS) involving 4,102 individuals from 434 Caucasian families. The most pronounced linkage evidence was found at the genomic region 20p11-12 for fat mass (LOD = 3.31) and percentage fat mass (PFM) (LOD = 2.92). We also identified several regions showing suggestive linkage signals (threshold LOD = 1.9) for obesity phenotypes, including 5q35, 8q13, 10p12, and 17q11.     

Quantitative trait loci influencing low density lipoprotein particle size in African Americans

Genomic regions that influence LDL particle size in African Americans are not known. We performed family-based linkage analyses to identify genomic regions that influence LDL particle size and also exert pleiotropic effects on two closely related lipid traits, high density lipoprotein cholesterol (HDL-C) and triglycerides, in African Americans. Subjects (n = 1,318, 63.0 +/- 9.5 years, 70% women, 79% hypertensive) were ascertained through sibships with two or more individuals diagnosed with essential hypertension before age 60. LDL particle size was measured by polyacrylamide gel electrophoresis, and triglyceride levels were log-transformed to reduce skewness. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Univariate and bivariate linkage analyses were performed using a variance components approach. LDL particle size was highly heritable (h(2) = 0.78) and significantly (P < 0.0001) genetically correlated with HDL-C (rho(G) = 0.32) and log triglycerides (rho(G) = -0.43). Significant evidence of linkage for LDL particle size was present on chromosome 19 [85.3 centimorgan (cM), log of the odds (LOD) = 3.07, P = 0.0001], and suggestive evidence of linkage was present on chromosome 12 (90.8 cM, LOD = 2.02, P = 0.0011). Bivariate linkage analyses revealed tentative evidence for a region with pleiotropic effects on LDL particle size and HDL-C on chromosome 4 (52.9 cM, LOD = 2.06, P = 0.0069). These genomic regions may contain genes that influence interindividual variation in LDL particle size and potentially coronary heart disease susceptibility in African Americans.     

Genome-wide linkage scans for loci affecting total cholesterol, HDL-C, and triglycerides: the Family Blood Pressure Program

Atherosclerosis accounts for 75% of all deaths from cardiovascular disease and includes coronary heart disease (CHD), stroke, and other diseases of the arteries. More than half of all CHD is attributable to abnormalities in levels and metabolism of lipids. To locate genes that affect total cholesterol, high density lipoprotein cholesterol (HDL-C), and triglycerides, genome-wide linkage scans for quantitative trait loci were performed using variance components methods as implemented in SOLAR on a large diverse sample recruited as part of the Family Blood Pressure Program. Phenotype and genetic marker data were available for 9,299 subjects in 2,953 families for total cholesterol, 8,668 subjects in 2,736 families for HDL, and 7,760 subjects in 2,499 families for triglycerides. Mean lipid levels were adjusted for the effects of sex, age, age², age-by-sex interaction, body mass index, smoking status, and field center. HDL-C and triglycerides were further adjusted for average total alcoholic drinks per week and estrogen use. Significant linkage was found for total cholesterol on chromosome 2 (LOD = 3.1 at 43 cM) in Hispanics and for HDL-C on chromosome 3 (LOD = 3.0 at 182 cM) and 12 (LOD = 3.5 at 124 cM) in Asians. In addition, there were 13 regions that showed suggestive linkage (LOD ≥ 2.0); 7 for total cholesterol, 4 for HDL, and 2 for triglycerides. The identification of these loci affecting lipid phenotypes and the apparent congruence with previous linkage results provides increased support that these regions contain genes influencing lipid levels.Electronic Supplementary Material Supplementary material is available to authorised users in the online version of this article at .     

Genetic control of lipids in the mouse cross DU6i × DBA/2

An F₂ pedigree based on the mouse lines DU6i and DBA/2 with extremely different growth and obesity characteristics was generated to search for QTLs affecting serum concentrations of triglycerides (TG), total cholesterol (CHOL), HDL cholesterol (HDL-C), and LDL cholesterol (LDL-C). Compared with many other studies, we searched for spontaneous genetic variants contributing to high lipid levels under a standard breeding diet. Significant QTLs for CHOL were identified on chromosomes 4 and 6, and a female-specific locus on chromosome 3. QTLs for HDL-C were detected on chromosome 11 for both sexes, and on chromosome 1 for females. These QTLs are located in syntenic human regions that have QTLs that have not been previously confirmed in animal studies. LDL-C QTLs have been mapped for both sexes to chromosome 8 and in males on chromosome 13. Epistatic interactions that significantly accounted for the phenotypic variance of HDL-C, CHOL, and LDL-C serum concentrations were also detected with one interaction between chromosomes 8 and 15, accounting for 22% of the observed variance in LDL-C levels. The identified loci coincide in part with regions controlling growth and obesity. Thus, multiple genes or pleiotropic effects may be assumed. The identified QTLs for cholesterol and its transport proteins as subcomponents of risk for coronary heart disease will further improve our understanding of the genetic net controlling plasma lipid concentrations. Electronic supplementary material The online version of this article (doi: ) contains supplementary material, which is available to authorized users.     

Compendium of genome-wide scans of lipid-related phenotypes: adding a new genome-wide search of apolipoprotein levels

The genetic dissection of complex inherited diseases is a major challenge. Despite limited success in finding genes, substantial data based on genome-wide scan strategies is now available for a variety of diseases and related phenotypes. This can perhaps best be appreciated in the field of lipid and lipoprotein levels, where the amount of information generated is becoming overwhelming. We have created a database containing the results from whole-genome scans of lipid-related phenotypes undertaken to date. The usefulness of this database is demonstrated by performing a new autosomal genomic scan on apolipoprotein B (apoB), LDL-apoB, and apoA-I levels, measured in 679 subjects of 243 nuclear families. Linkage was tested using both allele-sharing and variance-component methods. Only two loci provided support for linkage with both methods: a LDL-apoB locus on 18q21.32 and an apoA-I locus on 3p25.2. Adding those findings to the database highlighted the fact that the former is reported as a lipid-related locus for the first time, whereas the latter has been observed before. However, concerns arise when displaying all data on the same map, because a large portion of the genome is now covered with loci supported by at least suggestive evidence of linkage.     

Multilocus and interaction-based genome scan for alcoholism risk factors in Caucasian Americans: the COGA study

In this paper, we applied the nonparametric linkage regression approach to the Caucasian genome scan data from the Collaborative Study on the Genetics of Alcoholism to search for regions of the genome that exhibit evidence for linkage to putative alcoholism-predisposing genes. The multipoint single-locus model identified four regions of the genome with LOD scores greater than one. These regions were on 7p near D7S1790 (LOD = 1.31), two regions on 7q near D7S1870 (LOD = 1.15) and D7S1799 (LOD = 1.13) and 21q near D21S1440 and D21S1446 (LOD = 1.78). Jointly modeling these loci provided stronger evidence for linkage in each of these regions (LOD = 1.58 on 7q11, LOD = 1.61 on 11q23, and LOD = 1.95 on 21q22). The evidence for linkage tended to increase among pedigrees with earlier mean age of onset at 8q23 (p = 0.0016), 14q21 (p = 0.0079), and 18p12 (p = 0.0021) and with later mean age of onset at 4q35 (p = 0.0067) and 9p22 (p = 0.0008).     

Classification and regression tree and spatial analyses reveal geographic heterogeneity in genome wide linkage study of Indian visceral leishmaniasis

Background

Genome wide linkage studies (GWLS) have provided evidence for loci controlling visceral leishmaniasis on Chromosomes 1p22, 6q27, 22q12 in Sudan and 6q27, 9p21, 17q11-q21 in Brazil. Genome wide studies from the major focus of disease in India have not previously been reported.

Methods and Findings

We undertook a GWLS in India in which a primary ∼10 cM (515 microsatellites) scan was carried out in 58 multicase pedigrees (74 nuclear families; 176 affected, 353 total individuals) and replication sought in 79 pedigrees (102 nuclear families; 218 affected, 473 total individuals). The primary scan provided evidence (≥2 adjacent markers allele-sharing LOD≥0.59; nominal P≤0.05) for linkage on Chromosomes 2, 5, 6, 7, 8, 10, 11, 20 and X, with peaks at 6p25.3-p24.3 and 8p23.1-p21.3 contributed to largely by 31 Hindu families and at Xq21.1-q26.1 by 27 Muslim families. Refined mapping confirmed linkage across all primary scan families at 2q12.2-q14.1 and 11q13.2-q23.3, but only 11q13.2-q23.3 replicated (combined LOD = 1.59; P = 0.0034). Linkage at 6p25.3-p24.3 and 8p23.1-p21.3, and at Xq21.1-q26.1, was confirmed by refined mapping for primary Hindu and Muslim families, respectively, but only Xq21.1-q26.1 replicated across all Muslim families (combined LOD 1.49; P = 0.0045). STRUCTURE and SMARTPCA did not identify population genetic substructure related to religious group. Classification and regression tree, and spatial interpolation, analyses confirm geographical heterogeneity for linkages at 6p25.3-p24.3, 8p23.1-p21.3 and Xq21.1-q26.1, with specific clusters of families contributing LOD scores of 2.13 (P = 0.0009), 1.75 (P = 0.002) and 1.84 (P = 0.001), respectively.

Conclusions

GWLS has identified novel loci that show geographical heterogeneity in their influence on susceptibility to VL in India.     

A systematic genomewide linkage study in 353 sib pairs with schizophrenia

We undertook a genomewide linkage study in a total of 353 affected sib pairs (ASPs) with schizophrenia. Our sample consisted of 179 ASPs from the United Kingdom, 134 from Sweden, and 40 from the United States. We typed 372 microsatellite markers at approximately 10-cM intervals. Our strongest finding was a LOD score of 3.87 on chromosome 10q25.3-q26.3, with positive results being contributed by all three samples and a LOD-1 interval of 15 cM. This finding achieved genomewide significance (P<.05), on the basis of simulation studies. We also found two regions, 17p11.2-q25.1 (maximum LOD score [MLS] = 3.35) and 22q11 (MLS = 2.29), in which the evidence for linkage was highly suggestive. Linkage to all of these regions has been supported by other studies. Moreover, we found strong evidence for linkage (genomewide P<.02) to 17p11.2-q25.1 in a single pedigree with schizophrenia. In our view, the evidence is now sufficiently compelling to undertake detailed mapping studies of these three regions.     

A genomewide scan for loci predisposing to type 2 diabetes in a U.K. population (the Diabetes UK Warren 2 Repository): analysis of 573 pedigrees provides independent replication of a susceptibility locus on chromosome 1q

Improved molecular understanding of the pathogenesis of type 2 diabetes is essential if current therapeutic and preventative options are to be extended. To identify diabetes-susceptibility genes, we have completed a primary (418-marker, 9-cM) autosomal-genome scan of 743 sib pairs (573 pedigrees) with type 2 diabetes who are from the Diabetes UK Warren 2 repository. Nonparametric linkage analysis of the entire data set identified seven regions showing evidence for linkage, with allele-sharing LOD scores > or =1.18 (P< or =.01). The strongest evidence was seen on chromosomes 8p21-22 (near D8S258 [LOD score 2.55]) and 10q23.3 (near D10S1765 [LOD score 1.99]), both coinciding with regions identified in previous scans in European subjects. This was also true of two lesser regions identified, on chromosomes 5q13 (D5S647 [LOD score 1.22] and 5q32 (D5S436 [LOD score 1.22]). Loci on 7p15.3 (LOD score 1.31) and 8q24.2 (LOD score 1.41) are novel. The final region showing evidence for linkage, on chromosome 1q24-25 (near D1S218 [LOD score 1.50]), colocalizes with evidence for linkage to diabetes found in Utah, French, and Pima families and in the GK rat. After dense-map genotyping (mean marker spacing 4.4 cM), evidence for linkage to this region increased to a LOD score of 1.98. Conditional analyses revealed nominally significant interactions between this locus and the regions on chromosomes 10q23.3 (P=.01) and 5q32 (P=.02). These data, derived from one of the largest genome scans undertaken in this condition, confirm that individual susceptibility-gene effects for type 2 diabetes are likely to be modest in size. Taken with genome scans in other populations, they provide both replication of previous evidence indicating the presence of a diabetes-susceptibility locus on chromosome 1q24-25 and support for the existence of additional loci on chromosomes 5, 8, and 10. These data should accelerate positional cloning efforts in these regions of interest.     

Pleiotropic QTL on chromosome 12q23-q24 influences triglyceride and high-density lipoprotein cholesterol levels: the HERITAGE family study

To determine whether a common quantitative trait locus (QTL) influences the variation of fasting triglyceride (TG) and high-density lipoprotein cholesterol (HDL-C) levels, we used a bivariate multipoint linkage analysis with 654 polymorphic markers in 99 white and 101 black families. The phenotypes were investigated under two conditions: at baseline and after a 20-week exercise training intervention. A maximum genome-wide bivariate LOD score of 3.0 (p = 0.00010) was found on chromosome 12q23-q24, located within the IGF1 gene (insulin-like growth factor 1, at 107 cM) for TG and HDL-C at baseline in whites. This bivariate linkage peak is considerably higher than the univariate linkage results at the same chromosome location for either trait (for TG, LOD = 2.07, p = 0.00108; for HDL-C, LOD = 2.04, p = 0.00101). The genetic correlations between baseline TG and HDL-C levels were -0.14 for the residual and -0.33 for the QTL components. Moreover, association analysis showed that TG, HDL-C, and IGF1 are significantly associated (p = 0.04). In conclusion, these results suggest that a QTL on chromosome 12q23-q24 influences the variation of plasma TG and HDL-C levels. Further investigation should confirm whether IGF1 or another nearby gene is responsible for the concomitant variation in TG and HDL-C levels.     

Genotype-by-diet effects on co-variation in Lp-PLA2 activity and LDL-cholesterol concentration in baboons fed an atherogenic diet

Both lipoprotein-associated phospholipase A(2) (Lp-PLA(2)) activity, a biomarker of inflammation, and concentration of its primary associated lipoprotein, LDL, are correlated with adverse coronary outcomes. We previously reported a quantitative trait locus (QTL) corresponding to HSA2p24.3-p23.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-cholesterol (LDL-C) concentration in baboons fed a basal diet. Here, our goal was to locate pleiotropic QTLs influencing both traits in the same baboons fed a high-cholesterol, high-fat (HCHF) diet, and to assess whether shared genetic effects on these traits differ between diets. We assayed Lp-PLA(2) activity and LDL-C concentration in 683 baboons fed the HCHF diet. We used a bivariate maximum likelihood-based variance components approach in whole-genome linkage screens to locate a QTL [logarithm of odds (LOD) = 3.13, genome-wide P = 0.019] corresponding to HSA19q12-q13.2 with pleiotropic effects on Lp-PLA(2) activity and LDL-C levels in the HCHF diet. We additionally found significant evidence of genetic variance in response to diet for Lp-PLA(2) activity (P = 0.0017) and for LDL-C concentration (P = 0.00001), revealing a contribution of genotype-by-diet interaction to covariation in these two traits. We conclude that the pleiotropic QTLs detected at 2p24.3-p23.2 and 19q12-q13.2 on the basal and HCHF diets, respectively, exert diet-specific effects on covariation in Lp-PLA(2) activity and LDL-C concentration.     

Genome-wide linkage scan to identify loci associated with type 2 diabetes and blood lipid phenotypes in the Sikh Diabetes Study

In this investigation, we have carried out an autosomal genome-wide linkage analysis to map genes associated with type 2 diabetes (T2D) and five quantitative traits of blood lipids including total cholesterol, high-density lipoprotein (HDL) cholesterol, low-density lipoprotein (LDL) cholesterol, very low-density lipoprotein (VLDL) cholesterol, and triglycerides in a unique family-based cohort from the Sikh Diabetes Study (SDS). A total of 870 individuals (526 male/344 female) from 321 families were successfully genotyped using 398 polymorphic microsatellite markers with an average spacing of 9.26 cM on the autosomes. Results of non-parametric multipoint linkage analysis using S_all statistics (implemented in Merlin) did not reveal any chromosomal region to be significantly associated with T2D in this Sikh cohort. However, linkage analysis for lipid traits using QTL-ALL analysis revealed promising linkage signals with p≤0.005 for total cholesterol, LDL cholesterol, and HDL cholesterol at chromosomes 5p15, 9q21, 10p11, 10q21, and 22q13. The most significant signal (p = 0.0011) occurred at 10q21.2 for HDL cholesterol. We also observed linkage signals for total cholesterol at 22q13.32 (p = 0.0016) and 5p15.33 (p = 0.0031) and for LDL cholesterol at 10p11.23 (p = 0.0045). Interestingly, some of linkage regions identified in this Sikh population coincide with plausible candidate genes reported in recent genome-wide association and meta-analysis studies for lipid traits. Our study provides the first evidence of linkage for loci associated with quantitative lipid traits at four chromosomal regions in this Asian Indian population from Punjab. More detailed examination of these regions with more informative genotyping, sequencing, and functional studies should lead to rapid detection of novel targets of therapeutic importance.     

Locus for quantitative HDL-cholesterol on chromosome 10q in Finnish families with dyslipidemia

Decreased HDL-cholesterol (HDL-C) and familial combined hyperlipidemia (FCHL) are the two most common familial dyslipidemias predisposing to premature coronary heart disease (CHD). These dyslipidemias share many phenotypic features, suggesting a partially overlapping molecular pathogenesis. This was supported by our previous pooled data analysis of the genome scans for low HDL-C and FCHL, which identified three shared chromosomal regions for a qualitative HDL-C trait on 8q23.1, 16q23.3, and 20q13.32. This study further investigates these regions as well as two other loci we identified earlier for premature CHD on 2q31 and Xq24 and a locus for high serum triglycerides (TGs) on 10q11. We analyzed 67 microsatellite markers in an extended study sample of 1,109 individuals from 92 low HDL-C or FCHL families using both qualitative and quantitative lipid phenotypes. These analyses provided evidence for linkage (a logarithm of odds score of 3.2) on 10q11 using a quantitative HDL-C trait. Importantly, this region, previously linked to TGs, body mass index, and obesity, provided evidence for association for quantitative TGs (P = 0.0006) and for a combined trait of HDL-C and TGs (P = 0.008) with marker D10S546. Suggestive evidence for linkage also emerged for HDL-C on 2q31 and for TGs on 20q13.32. Finnish families ascertained for dyslipidemias thus suggest that 10q11, 2q31, and 20q13.32 harbor loci for HDL-C and TGs.     

Aggressive lipid management for cardiovascular prevention: evidence from clinical trials

Epidemiologic evidence shows that elevated serum cholesterol, specifically low-density lipoprotein cholesterol (LDL-C), increases the risk of coronary heart disease (CHD). Moreover, large-scale intervention trials demonstrate that treatment with HMG-CoA reductase inhibitors (statins), the most effective drug class for lowering LDL-C, significantly reduces the risk of CHD events. Unfortunately, only a moderate percentage of hypercholesterolemic patients are achieving LDL-C targets specified by the National Cholesterol Education Program (NCEP), in part because clinicians are not effectively titrating medications as needed to achieve LDL-C goals. Recent evidence suggests that more aggressive LDL-C lowering may provide greater clinical benefit, even in individuals with moderately elevated serum cholesterol levels. Furthermore, recent studies suggest that statins have cardioprotective effects in many high-risk individuals, including those with baseline LDL-C <100 mg/dl. High-density lipoprotein cholesterol (HDL-C) was recognized by the NCEP-Adult Treatment Panel II (ATP II) as a negative risk factor for CHD. The NCEP-ATP III guidelines have also reaffirmed the importance of HDL-C by increasing the low HDL-C designation from <35 to <40 mg/dl as a major risk factor for CHD. Similarly, triglyceride control will play a larger role in dyslipidemia management. As more clinicians effectively treat adverse lipid and lipoprotein cardiovascular risk factors, patients will likely benefit from reductions in cardiovascular events.