Genome Scans Provide Evidence for Low-HDL-C Loci on Chromosomes 8q23, 16q24.1-24.2, and 20q13.11 in Finnish Families
2002; Elsevier BV; Volume: 70; Issue: 5 Linguagem: Inglês
10.1086/339988
ISSN1537-6605
AutoresAino Soro, Päivi Pajukanta, Heidi E. Lilja, Kati Ylitalo, Tero Hiekkalinna, Markus Perola, Rita M. Cantor, Jorma Viikari, Marja‐Riitta Taskinen, Leena Peltonen,
Tópico(s)Cancer, Lipids, and Metabolism
ResumoWe performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL. We performed a genomewide scan for genes that predispose to low serum HDL cholesterol (HDL-C) in 25 well-defined Finnish families that were ascertained for familial low HDL-C and premature coronary heart disease. The potential loci for low HDL-C that were identified initially were tested in an independent sample group of 29 Finnish families that were ascertained for familial combined hyperlipidemia (FCHL), expressing low HDL-C as one component trait. The data from the previous genome scan were also reanalyzed for this trait. We found evidence for linkage between the low-HDL-C trait and three loci, in a pooled data analysis of families with low HDL-C and FCHL. The strongest statistical evidence was obtained at a locus on chromosome 8q23, with a two-point LOD score of 4.7 under a recessive mode of inheritance and a multipoint LOD score of 3.3. Evidence for linkage also emerged for loci on chromosomes 16q24.1-24.2 and 20q13.11, the latter representing a recently characterized region for type 2 diabetes. Besides these three loci, loci on chromosomes 2p and 3p showed linkage in the families with low HDL-C and a locus on 2ptel in the families with FCHL. Low serum HDL cholesterol (HDL-C), or hypo-α-lipoproteinemia, is the most frequently diagnosed dyslipidemia in patients with premature coronary heart disease (CHD) (Genest et al. Genest et al., 1992Genest Jr, JJ Martin-Munley SS McNamara JR Ordovas JM Jenner J Myers RH Silberman SR Wilson PW Salem DN Schaefer EJ Familial lipoprotein disorders in patients with premature coronary artery disease.Circulation. 1992; 85: 2025-2033Crossref PubMed Scopus (530) Google Scholar). The common form of low HDL-C that is associated with CHD is a typical complex disorder in which several genes and environmental factors affect the phenotype. Several candidate genes have been associated with low HDL-C in multiple sample groups (Davignon and Genest Davignon and Genest, 1998Davignon J Genest Jr, J Genetics of lipoprotein disorders.Endocrinol Metab Clin North Am. 1998; 27: 521-550Abstract Full Text Full Text PDF PubMed Scopus (30) Google Scholar). One of the most interesting findings indicated that allelic variants in the ATP-binding cassette transporter 1 gene (ABC1 [MIM 205400; MIM 600046]) contribute to low HDL-C in four French-Canadian families (Brooks-Wilson et al. Brooks-Wilson et al., 1999Brooks-Wilson A Marcil M Clee SM Zhang LH Roomp K van Dam M Yu L Brewer C Collins JA Molhuizen HO Loubser O Ouelette BF Fichter K Ashbourne-Excoffon KJ Sensen CW Scherer S Mott S Denis M Martindale D Frohlich J Morgan K Koop B Pimstone S Kastelein JJ Hayden MR Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat Genet. 1999; 22: 336-345Crossref PubMed Scopus (1439) Google Scholar; Rust et al. Rust et al., 1999Rust S Rosier M Funke H Real J Amoura Z Piette JC Deleuze JF Brewer HB Duverger N Denefle P Assmann G Tangier disease is caused by mutations in the gene encoding ATP-binding cassette transporter 1.Nat Genet. 1999; 22: 352-355Crossref PubMed Scopus (1210) Google Scholar). However, the significance of this or other candidate genes for the common form of low HDL-C has not been established. Here we report analyses of the first genome scan for low serum HDL-C performed in multiplex families from Finland. The sample group was selected to restrict both environmental and genetic heterogeneity. Finns descend from small founder populations that share a relatively homogeneous gene pool and environment (Peltonen et al. Peltonen et al., 1999Peltonen L Jalanko A Varilo T Molecular genetics of the Finnish disease heritage.Hum Mol Genet. 1999; 8: 1913-1923Crossref PubMed Scopus (309) Google Scholar). Excellent epidemiological data sets are an additional advantage, since these facilitate the adoption of age- and sex-specific population percentiles when defining affection status in family members (Porkka et al. Porkka et al., 1994Porkka KV Viikari JS Ronnemaa T Marniemi J Akerblom HK Age and gender specific serum lipid and apolipoprotein fractiles of Finnish children and young adults: the Cardiovascular Risk in Young Finns Study.Acta Paediatr. 1994; 83: 838-848Crossref PubMed Scopus (48) Google Scholar; Vartiainen et al. Vartiainen et al., 1994Vartiainen E Puska P Jousilahti P Korhonen HJ Tuomilehto J Nissinen A Twenty-year trends in coronary risk factors in north Karelia and in other areas of Finland.Int J Epidemiol. 1994; 23: 495-504Crossref PubMed Scopus (238) Google Scholar). The sample group with low HDL-C was collected in Helsinki and Turku University Central Hospitals in Finland. A total of 176 individuals, from 20 well-defined families with low HDL-C, were included in stage 1, and 5 additional families, with 43 individuals, were included in stage 2. Inclusion criteria for the probands with low HDL-C were an age of 30–60 years for both men and women, HDL-C levels 50% stenosis of one or more coronary arteries) or myocardial infarction. All of the three following criteria had to be fulfilled for the diagnosis of myocardial infarction: (1) typical clinical symptoms; (2) definite electrocardiographic findings, according to the Minnesota coding (World Health Organization criteria) (Rose et al. Rose et al., 1982Rose G Blackburn H Gillum R Cardiovascular survey methods. 2d ed. World Health Organization, Geneva1982Google Scholar); and (3) elevated levels of the creatine-kinase enzyme, CK, and its cardiac isoenzyme, CK-MB. In addition to the probands, seven siblings of the probands and two parents had CHD. Additional lipid criteria for the probands were total cholesterol (TC) <6.3 mmol/liter in men and <6.0 mmol/liter in women and triglycerides (TGs) 30 kg/m2 (table 1). The lipid profiles shown in table 1 are consistent with those described elsewhere (Brooks-Wilson et al. Brooks-Wilson et al., 1999Brooks-Wilson A Marcil M Clee SM Zhang LH Roomp K van Dam M Yu L Brewer C Collins JA Molhuizen HO Loubser O Ouelette BF Fichter K Ashbourne-Excoffon KJ Sensen CW Scherer S Mott S Denis M Martindale D Frohlich J Morgan K Koop B Pimstone S Kastelein JJ Hayden MR Mutations in ABC1 in Tangier disease and familial high-density lipoprotein deficiency.Nat Genet. 1999; 22: 336-345Crossref PubMed Scopus (1439) Google Scholar). The affected family members were identified as having low HDL-C, by use of the Finnish age- and sex-specific 10th population percentiles. Each study subject provided written informed consent prior to participating in the study. Any lipid-lowering medication was interrupted for 4 wk before the blood samples were taken. All samples were collected in accordance with the Helsinki declaration, and the ethics committees of the participating centers approved the study design. Serum TC, TGs, and HDL-C were measured as described elsewhere (Pajukanta et al. Pajukanta et al., 1998Pajukanta P Nuotio I Terwilliger JD Porkka KV Ylitalo K Pihlajamaki J Suomalainen AJ Syvanen AC Lehtimaki T Viikari JS Laakso M Taskinen MR Ehnholm C Peltonen L Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.Nat Genet. 1998; 18: 369-373Crossref PubMed Scopus (228) Google Scholar, Pajukanta et al., 1999Pajukanta P Terwilliger JD Perola M Hiekkalinna T Nuotio I Ellonen P Parkkonen M Hartiala J Ylitalo K Pihlajamaki J Porkka K Laakso M Viikari J Ehnholm C Taskinen MR Peltonen L Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol and apolipoprotein B levels.Am J Hum Genet. 1999; 64: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). Apolipoproteins A-I and A-II were measured by an immunoturbidimetric method with commercial kits (Boehringer-Mannheim).Table 1Clinical Characteristics of the Families with Low HDL-CAffectedaHDL-C levels <10th age- and sex-specific percentile. (n=104)Unaffected (n=115)Age (years)49.3 ± 15.743.7 ± 17.2Sex (% males)4750BMI (kg/m2)26.8 ± 4.124.7 ± 4.1HDL-C (mmol/liter).86 ± .161.37 ± .34TGs (mmol/liter)1.69 ± .811.22 ± .59TC (mmol/liter)5.27 ± .975.46 ± 1.11Apolipoproteins: A-I (mg/dl)120 ± 16147 ± 25 A-II (mg/dl)34 ± 638 ± 6Note.—All values except those for sex are expressed as mean ± SD. The affected group includes 25 probands with low HDL-C and 79 hypo-α-lipoproteinemic family members.a HDL-C levels 1.0 were obtained for markers on chromosomes 1–3, 6–9, and 16–20. Figure 1 shows these results under either a parametric recessive mode of inheritance or the ASP analysis. The highest LOD score, 2.9 (recombination fraction [θ]=0.10), was observed with the chromosome 3 marker D3S4545 by use of a dominant mode of inheritance. On chromosomes 1 and 9, two separate regions produced LOD scores >1.0. These two regions were located 72 cM and 10.7 cM apart, respectively. One of the regions on chromosome 1, located in the vicinity of the apolipoprotein A-II gene (APOA2 [MIM 107670]), produced a LOD score of 2.1 with D1S2844. No additional markers were genotyped in this particular region, since it was fine mapped in our previous studies (Pajukanta et al. Pajukanta et al., 1998Pajukanta P Nuotio I Terwilliger JD Porkka KV Ylitalo K Pihlajamaki J Suomalainen AJ Syvanen AC Lehtimaki T Viikari JS Laakso M Taskinen MR Ehnholm C Peltonen L Linkage of familial combined hyperlipidaemia to chromosome 1q21-q23.Nat Genet. 1998; 18: 369-373Crossref PubMed Scopus (228) Google Scholar; Lilja et al., Lilja et al., in pressLilja HE, Soro A, Ylitalo K, Nuotio I, Viikari JSA, Salomaa V, Vartiainen E, Taskinen M-R, Peltonen L, Pajukanta P. A candidate gene study in low HDL-cholesterol families provides evidence for the involvement of the apoA2 gene and the ApoA1C3A4 gene cluster. Atherosclerosis (in press).Google Scholar). In stage 2, the chromosomal regions that showed two-point LOD scores >1.0 in stage 1 were further studied by genotyping 67 additional markers and including five additional families with low HDL-C (fig. 2). The most significant linkage results on chromosomes 8, 16, 20, 2p, and 3 are given in tables 2–5. For the remaining chromosomal regions, no further evidence for linkage was obtained in stage 2.Table 2Two-Point and Multipoint Evidence for Linkage to Chromosome 8q23LOD ScorebThe first LOD score is that for sample group with low HDL-C and the second (i.e., after the slash mark) is that for the pooled sample group.LocationPositionaDistance (in cM) from the first marker.PairwisecMaximum LOD scores for the two-point linkage analysis. The recombination fractions are given in parentheses.ASPSimwalk Statistics AdResults of the nonparametric-linkage analysis from Simwalk, version 2.80, for the pooled sample group. Statistic A is most powerful at detecting linkage to a recessive trait, statistic B is most powerful at detecting linkage to a dominant trait, and statistic C is a more general statistic that indicates if a few founder-alleles are overly represented among affecteds.GAAT1A4.0.0 (.50)/.3 (.26).2/.51.3D8S11328.92.3 (.10)/4.7 (.06)1.4/3.13.3D8S59214.9.1 (.32)/1.0 (.18).2/.92.0Note.—For statistical analyses, see the legend for figure 1.a Distance (in cM) from the first marker.b The first LOD score is that for sample group with low HDL-C and the second (i.e., after the slash mark) is that for the pooled sample group.c Maximum LOD scores for the two-point linkage analysis. The recombination fractions are given in parentheses.d Results of the nonparametric-linkage analysis from Simwalk, version 2.80, for the pooled sample group. Statistic A is most powerful at detecting linkage to a recessive trait, statistic B is most powerful at detecting linkage to a dominant trait, and statistic C is a more general statistic that indicates if a few founder-alleles are overly represented among affecteds. Open table in a new tab Table 5Two-Point and Multipoint Evidence for Linkage to Chromosomes 2p and 3pLOD ScoreLocationPositionPairwiseASPSimwalk Statistics BChromosome 2p: D2S441aAlso genotyped in the sample group with FCHL..01.0 (.14)/1.2 (.16).6/.71.3 D2S1394aAlso genotyped in the sample group with FCHL.3.02.1 (.10)/1.1 (.20)1.8/1.11.5 D2S2866.2.4 (.20).41.2 D2S21147.9.1 (.28).01.0Chromosome 3p: D3S3050bGenotyped only in the sample group with FCHL..0.1 (.30).0.6 D3S1620.8.0 (.50).0.7 D3S1304aAlso genotyped in the sample group with FCHL.8.62.1 (.06)/1.9 (.12)1.0/1.21.1 D3S454512.5.5 (.22).71.1 D3S159716.2.0 (.50).0.5Note.—Linkage evidence was obtained mainly from the families with low HDL-C. The position and linkage results are as explained in table 2.a Also genotyped in the sample group with FCHL.b Genotyped only in the sample group with FCHL. Open table in a new tab Note.— For statistical analyses, see the legend for figure 1. Note.— Linkage evidence was obtained mainly from the families with low HDL-C. The position and linkage results are as explained in table 2. To further analyze the chromosomal regions on chromosomes 8, 16, 20, 2p, and 3, we performed linkage analyses, by use of low HDL-C as an affection status, in an independent sample group of 29 well-defined Finnish families with familial combined hyperlipidemia (FCHL) (table 6) (Pajukanta et al. Pajukanta et al., 1999Pajukanta P Terwilliger JD Perola M Hiekkalinna T Nuotio I Ellonen P Parkkonen M Hartiala J Ylitalo K Pihlajamaki J Porkka K Laakso M Viikari J Ehnholm C Taskinen MR Peltonen L Genomewide scan for familial combined hyperlipidemia genes in Finnish families, suggesting multiple susceptibility loci influencing triglyceride, cholesterol and apolipoprotein B levels.Am J Hum Genet. 1999; 64: 1453-1463Abstract Full Text Full Text PDF PubMed Scopus (131) Google Scholar). In addition to elevated TC and TGs, low HDL-C is one of the component traits of FCHL. When coding the family members of the families with FCHL as affected, we used the same 10th-percentile HDL-C trait as had been used in our HDL-C scan. The data collection, laboratory measurements, and phenotype determinations for the families with low HDL-C or FCHL were performed in the same center, thereby making clinical and biochemical data in these two sample groups fully compatible.Table 6Clinical Characteristics of the Families with FCHLAffectedaHDL-C levels <10th age- and sex-specific percentile. (n=64)Unaffected (n=75)Age (years)49.0 ± 14.145.0 ± 16.8Sex (% males)4839BMI (kg/m2)28.3 ± 4.125.5 ± 3.6HDL-C (mmol/liter).94 ± .251.57 ± .42TG (mmol/liter)3.24 ± 2.522.02 ± 1.24TC (mmol/liter)6.78 ± 1.326.85 ± 1.27Apolipoprotein: A-I (mg/dl)125 ± 21163 ± 25 A-II (mg/dl)38 ± 943 ± 7Note.—All values except those for sex are expressed as mean ± SD. The affected group includes 21 probands with FCHL and 43 hypo-α-lipoproteinemic family members.a HDL-C levels 3.0 (table 2). On chromosome 16, D16S3091 yielded a two-point LOD score of 2.2 (θ=0.12) in the pooled data analysis, yielding some additional evidence for this region (table 3). On chromosome 20, a LOD score of 1.9 (θ=0.14) was obtained with D20S171 (table 4). The chromosomal regions identified in only one of the sample groups (chromosomes 2p and 3p, in the families with low HDL-C, and 2ptel, in the families with FCHL) did not gain any further support in these pooled data analyses. The HOMOG program (Ott Ott, 1991Ott J Analysis of human genetic linkage. 2d ed. Johns Hopkins University Press, Baltimore1991Google Scholar) provided no statistical evidence for locus heterogeneity among families with low HDL-C or FCHL for any tested marker.Table 3Two-Point and Multipoint Evidence for Linkage to Chromosome 16q24.1-24.2LOD ScoreLocationPositionPairwiseASPSimwalk Statistics CD16S3040.0.1 (.32).11.1D16S505aAlso genotyped in the sample group with FCHL.4.51.5 (.12)/1.3 (.18)1.8/1.51.2D16S3091aAlso genotyped in the sample group with FCHL.6.71.9 (.08)/2.2 (.12)1.8/1.91.2D16S4029.1.2 (.34).6.9D16S306117.0.0 (.50).0.5Note.—The position and linkage results are as explained in table 2.a Also genotyped in the sample group with FCHL. Open table in a new tab Table 4Two-Point and Multipoint Evidence for Linkage to Chromosome 20q13.11LOD ScoreLocationPositionPairwiseASPSimwalk Statistics AD20S120.0.8 (.20).91.2D20S1023.5.4 (.20).41.1D20S171aAlso genotyped in the sample group with FCHL.8.71.3 (.16)/1.9 (.14)1.3/1.41.7D20S9411.0.4 (.26).31.4D20S17311.1.6 (.20).21.4Note.—The position and linkage results are as explained in table 2.a Also genotyped in the sample group with FCHL. Open table in a new tab Note.— The position and linkage results are as explained in table 2. Note.— The position and linkage results are as explained in table 2. Although our study design of the genomewide scan was selected to identify linked regions for a qualitative trait, we also analyzed the quantitative measures, HDL-C and TGs, by variance-component methods that utilized SOLAR version 1.6.7 (Almasy and Blangero Almasy and Blangero, 1998Almasy L Blangero J Multipoint quantitative trait linkage analysis in general pedigrees.Am J Hum Genet. 1998; 62: 1198-1211Abstract Full Text Full Text PDF PubMed Scopus (2512) Google Scholar). Additional covariates in the model were sex, age, BMI, ascertainment status (i.e., family with HDL-C or FCHL), and proband status. A logarithmic transformation of the variable was used if needed. No significant linkage results emerged from these analyses. For HDL-C, the highest LOD score, 1.94, was obtained on chromosome 13 with D13S1493 in a two-point analysis. (The qualitative analysis for this marker resulted in a LOD score of 1.32 in the pooled sample group.) For TGs, the highest LOD score, 1.52, was obtained on chromosome 8 in a multipoint analysis, 50 cM from the p-telomere. (The qualitative analysis for this region did not show positive results.) This TG region is located ∼70 cM from the peak linkage markers on chromosome 8q23, which were obtained using the qualitative analysis. All results for the variance-component analyses are available from our Web site (UCLA Human Genetics). The genotyping strategy was designed to maximize the information obtained from the affected individuals in the large pedigrees. The variance-component analyses can therefore use only the variation within this group, thus reducing our power to detect loci with this method. We also investigated the contribution of the ABC1 gene to low HDL-C in the families with low HDL-C. Two markers, D9S257 and D9S938, that flank the ABC1 region yielded LOD scores of 1.8 (θ=0.06) and 1.3 (θ=0.06). Results of the family-based association analyses—haplotype-based haplotype relative risk and transmission/disequilibrium tests (Terwilliger and Ott Terwilliger and Ott, 1992Terwilliger JD Ott J A haplotype-based "haplotype relative risk" approach to detecting allelic associations.Hum Hered. 1992; 42: 337-346Crossref PubMed Scopus (423) Google Scholar)—were nonsignificant. Next, we constructed haplotypes (D9S53-ABC1-D9S306-D9S1866-D9S938-D9S1784-D9S1677) that spanned a 21.8-cM region, and we monitored for shared haplotypes among the affected family members. Only five families revealed potential cosegregation, and, consequently, genomic DNA from the five probands was subjected to sequencing of the coding region of ABC1. Sequence analyses identified four polymorphisms that have previously been characterized: the sequence variants corresponding to R219K, in exon 7; V825I, in exon 17; I883M, in exon 18; and R1587K, in exon 35 (Clee et al. Clee et al., 2001Clee SM Zwinderman AH Engert JC Zwarts KY Molhuizen HO Roomp K Jukema JW van Wijland M van Dam M Hudson TJ Brooks-Wilson A Genest Jr, J Kastelein JJ Hayden MR Common genetic variation in ABCA1 is associated with altered lipoprotein levels and a modified risk for coronary artery disease.Circulation. 2001; 103: 1198-1205Crossref PubMed Scopus (264) Google Scholar). None of the nucleotide changes showed cosegregation with low HDL-C in these families. Our analyses of well-defined Finnish families with low HDL-C or FCHL revealed six loci that are potentially important for the regulation of the HDL-C levels, on chromosomes 2ptel, 2p, 3p, 8q23, 16q24.1-24.2, and 20q13.11. Three of these loci were supported by pooled data analyses of the families with low HDL-C and FCHL, whereas loci on chromosomes 2p and 3p appeared to be specific to the families with low HDL-C and another locus on chromosome 2ptel was seen only in the analysis of the families with FCHL. The most statistically significant result was observed on chromosome 8q23, with a two-point LOD score of 4.7 in the pooled data analysis under a recessive mode of inheritance. This chromosomal region has previously been linked to the regulation of serum-HDL-C levels in a genome scan of a population cohort of Mexican American families, who were not ascertained for the low-HDL-C trait (Almasy et al. Almasy et al., 1999Almasy L Hixson JE Rainwater DL Cole S Williams JT Mahaney MC VandeBerg JL Stern MP MacCluer JW Blangero J Human pedigree-based quantitative-trait-locus mapping: localization of two genes influencing HDL-cholesterol metabolism.Am J Hum Genet. 1999; 64: 1686-1693Abstract Full Text Full Text PDF PubMed Scopus (90) Google Scholar). Our most significant markers are located 20 cM centromeric from their peak markers. These results, obtained independently both in a population-based sample group and in well-defined families with low HDL-C, implicate the involvement of one or more genes in this region in the regulation of HDL-C. On chromosome 16q, markers on an 18-cM region showed suggestive evidence for linkage in the pooled data analysis. Some evidence for linkage to this region has also been reported in Dutch families with FCHL (Aouizerat et al. Aouizerat et al., 1999Aouizerat BE Allayee H Cantor RM Davis RC Lanning CD Wen PZ Dallinga-Thie GM de Bruin TW Rotter JI Lusis AJ A genome scan for familial combined hyperlipidemia reveals evidence of linkage with a locus on chromosome 11.Am J Hum Genet. 1999; 65: 397-412Abstract Full Text Full Text PDF PubMed Scopus (105) Google Scholar). Finally, on chromosome 20q, markers spanning a 33-cM region produced suggestive LOD scores. Previous analyses in both mouse studies and human studies have indicated that chromosome 20q harbors multiple loci that contribute to body adiposity, fasting insulin levels, and type 2 DM (Bowden et al. Bowden et al., 1997Bowden DW Sale M Howard TD Qadri A Spray BJ Rothschild CB Akots G Rich SS Freedman BI Linkage of genetic markers on human chromosomes 20 and 12 to NIDDM in Caucasian sib pairs with a history of diabetic nephropathy.Diabetes. 1997; 46: 882-886Crossref PubMed Google Scholar; Lembertas et al. Lembertas et al., 1997Lembertas AV Perusse L Chagnon YC Fisler JS Warden CH Purcell-Huynh DA Dionne FT Gagnon J Nadeau A Lusis AJ Bouchard C Identification of an obesity quantitative trait locus on mouse chromosome 2 and evidence of linkage to body fat and insulin on the human homologous region 20q.J Clin Invest. 1997; 100: 1240-1247Crossref PubMed Scopus (194) Google Scholar; Ghosh et al. Ghosh et al., 2000Ghosh S Watanabe RM Valle TT Hauser ER Magnuson VL Langefeld CD Ally DS et al.The Finland–United States investigation of non–insulin-dependent diabetes mellitus genetics (FUSION) study. I. An autosomal genome scan for genes that predispose to type 2 diabetes.Am J Hum Genet. 2000; 67: 1174-1185Abstract Full Text Full Text PDF PubMed Scopus (216) Google Scholar). Low HDL-C is a common feature in type 2 DM, and these findings may suggest the presence of one or more loci on 20q12-13 that are involved in HDL-C metabolism. Our results (1) have identified loci for low HDL-C in the pooled data analysis of two Finnish sample groups that were ascertained for overlapping traits and (2) have suggested a partially shared genetic background for the low-HDL-C and FCHL traits. We thank the family members, for their participation in this study; Michael Hayden, Angela Brooks-Wilson, Kirsten Roomp, and Suzanne Clee, for good collaboration; Ilpo Nuotio, Sirpa Koskela, Tiina Kuivanen, and Juha Vakkilainen, for their help in the sample collection; and Hannele Hilden, Leena Lehikoinen, Ritva Marjanen, Helinä Perttunen-Nio, Virve Vesterinen, Tomi Silvennoinen, Ann Kromsky, Geoff Josslyn, Maija Parkkonen, Jaana Hartiala, Jovita Sains, Oliver Cantada, and Petra Broas, for their excellent technical assistance. This work was supported by special state grants for health science research; grants from the Clinical Research Institute, Helsinki University Central Hospital, Finnish Cardiovascular Research Foundation, Finnish Cultural Foundation, and Duodecim Foundation; and a grant, to T.J. and M.P., from Helsingin Sanomat Centennial Foundation.
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