Familial hypercholesterolemia in Brazil (original) (raw)
The Lebanese mutation as an important cause of familial hypercholesterolemia in Brazil
Brazilian Journal of Medical and Biological Research, 1999
Familial hypercholesterolemia (FH) is a common autosomal disorder that affects about one in 500 individuals in most Western populations and is caused by a defect in the low-density-lipoprotein receptor (LDLr) gene. In this report we determined the molecular basis of FH in 59 patients from 31 unrelated Brazilian families. All patients were screened for the Lebanese mutation, gross abnormalities of the LDLr gene, and the point mutation in the codon 3500 of the apolipoprotein B-100 gene. None of the 59 patients presented the apoB-3500 mutation, suggesting that familial defective ApoB-100 (FDB) is not a major cause of inherited hypercholesterolemia in Brazil. A novel 4-kb deletion in the LDLr gene, spanning from intron 12 to intron 14, was characterized in one family. Both 5' and 3' breakpoint regions were located within Alu repetitive sequences, which are probably involved in the crossing over that generated this rearrangement. The Lebanese mutation was detected in 9 of the 31 families, always associated with Arab ancestry. Two different LDLr gene haplotypes were demonstrated in association with the Lebanese mutation. Our results suggest the importance of the Lebanese mutation as a cause of FH in Brazil and by analogy the same feature may be expected in other countries with a large Arab population, such as North American and Western European countries.
Familial hypercholesterolemia in Brazil: Cascade screening program, clinical and genetic aspects
Atherosclerosis, 2015
Background: There is little knowledge about familial hypercholesterolemia in Brazil. This study presents the first results of genetic cascade screening performed in the city of Sao Paulo. Material and methods: Two-hundred and forty-eight suspected index cases were initially included. DNA was extracted from peripheral blood and the complete coding sequence of low-density lipoprotein receptor, exon 7 of proprotein convertase subtilisin/kexin type 9 gene and part of exon 26 of apolipoprotein B genes were sequenced. Multiplex Ligation-dependent Probe Amplification was performed on cases where a causal mutation was not identified through sequencing. After the identification of a causal mutation screening in first-degree relatives was pursued. Results: From 248 index cases, a mutation was found in 125 individuals (50.4%). 394 relatives were included in the cascade screening program and a mutation was identified in 59.4%. Seventy different causal mutations in the low-density lipoprotein receptor gene (97.2%) and 2 in the apolipoprotein B gene (2.8%) were found. No mutations were encountered in the proprotein convertase subtilisin/kexin type 9 gene. Mutations in exons 14 and 4 were the most prevalent and, 10 cases of true homozygotes (8 index cases and 2 relatives) and 1 compound heterozygote were identified. The most frequent mutation found was of Lebanese origin, the p.(Cys681*) mutation in exon 14 (8.5%). Conclusion: Genetic familial hypercholesterolemia cascade screening is feasible in Brazil and leads to identification of a mutation in approximately half of the index cases with higher rates of success in their relatives.
Familial hypercholesterolemia (FH) is an autosomal dominant disorder of the cholesterol metabolism, which constitutes a risk factor for coronary arterial disease (CAD). In the Azores Islands (Portugal), where mortality from CAD doubles its rate comparatively to the rest of the country and where a high frequency of dyslipidemia has been reported, the prevalence and distribution of FH remain unknown. The molecular characterization of a group of 33 possible cases of FH of Azorean background was undertaken in this study. A DNA array was initially used to search mutations in the LDLR, APOB and PCSK9 loci in 10 unrelated possible cases of FH. No mutations were detected in the array; after sequencing the full LDLR gene, 18 variants were identified, corresponding to two missense (c.806G > A; c.1171G > A) and sixteen synonymous alterations. Six of the synonymous variants which are consistently described in the literature as associated with altered cholesterol levels were used to build haplotypes. The most frequent haplotype corresponded to TTCGCC (45%), a “risk” haplotype, formed exclusively by alleles that were reported to increase cholesterol levels. Some of the variants detected in the full sequencing of the LDLR gene fell within the ligand-binding domain of this gene, defined by exons 2 to 6. To add information as to the role of such variants, these exons were sequenced in the remaining 23 possible FH cases. Two missense alterations (c.185C > T; c.806G > A) were found in this subset of possible FH cases. The missense alteration c.185C > T, identified in one individual, is novel for the Portuguese population. In silico analysis was not conclusive for this alteration, whose role will have to be further investigated. This study represents the first approach to the establishment of the mutational profile of FH in the Azores Islands.
Homozygous familial hypercholesterolemia in Lebanon: A genotype/ phenotype correlation
Familial hypercholesterolemia (FH) is an inherited disease characterized by the deposition of LDL in tissues causing premature atherosclerosis. Many genes are implicated in FH resulting in a large variability in the phenotype. DNA sequencing of the LDLR gene was done for forty patients clinically diagnosed with homozygous FH and forty family members variably affected. Patients underwent noninvasive heart and vascular studies. Statistical and pedigree analyses were used to correlate the different genotypes with the phenotypes. The prevalence of homozygosity at the Lebanese allele (2043 CNA) is 45%. However, 27.5% of the patients have no mutations at all in the LDLR gene, and 27.5% are either heterozygous for the 2043 CNA mutation, heterozygous for a mutation in another exon of the LDLR gene, or combined heterozygous for two different mutations. We confirm previous reports on the higher prevalence of FH in Lebanon. Our results do, however contradict previous reports on an assumed higher prevalence among the Christian Lebanese. Mutations in the LDLR especially combined heterozygosity can cause a severe phenotype similar to the homozygous mutation in the Lebanese allele. This information is particularly important in targeting the more prevalent heterozygotes in the general population with early diagnosis and intervention.
Clinical and molecular aspects of familial hypercholesterolemia in Ibero-American countries
Journal of Clinical Lipidology, 2017
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Preliminary spectrum of genetic variants in familial hypercholesterolemia in Argentina
Journal of Clinical Lipidology, 2017
Background Familial hypercholesterolemia (FH) is a genetic disorder characterized by elevated low density lipoprotein cholesterol (LDL-c) and early cardiovascular disease (CVD). As CVD is a leading cause of mortality in Argentina, early identification of patients with FH is of great public health importance. Objective The aim of our study was to identify families with FH and, to approximate to the characterization of the genetic spectrum mutations of FH in Argentina. Methods Thirty-three not related index cases were selected with clinical diagnosis of FH. Genetic analysis was performed by sequencing, MLPA and bioinformatics tools. Results Twenty genetic variants were identified among 24 cases (73%), 95% on the LDLR gene. The only variant on APOB was the R3527Q. Four were novel variants: c.-135C>A; c.170A>C, p.(Asp57Ala); c.684G>C, p.(Glu228Asp) and c.1895A>T, p.(Asn632Ile), the bioinformatics' analysis revealed clear destabilizing effects for two of them. The exon 14 presented the highest number of variants (32%). Four variants were observed in more than one case and the c.2043C>A p.(Cys681*) was carried by 18% of index cases. Two true homozygotes, three compound heterozygotes and one double heterozygote were identified. Conclusion This study characterizes for the first time in Argentina genetic variants associated to FH and suggest that the allelic heterogeneity of the FH in the country could have one relative common LDLR mutation. This knowledge is important for the genotype-phenotype correlation and for optimizing both cholesterol lowering therapies and mutational analysis protocols. In addition, these data contribute to the understanding of the molecular basis of FH in Argentina.
Molecular characterization of familial hypercholesterolemia in Spain
Atherosclerosis, 2012
We used the denaturing gradient gel electrophoresis (DGGE) method to define mutations in the promoter region, the 18 exons, and their flanking intronic sequences of the low-density lipoprotein (LDL) receptor gene LDLR, causing familial hypercholesterolemia (FH) phenotype in 100 German and in 100 Greek hypercholesterolemic individuals. In addition, we tested all patients for the presence of mutations in codons 3456-3553 of the gene encoding apolipoprotein B-100 (APOB). Twenty-six aberrant DGGE patterns were identified and subsequently directly sequenced. In LDLR, two novel missense mutations (c.1957G>T/p.V653F, c.647 G>A/p.C216Y) and one novel homozygous base substitution c.1-156 C>T in the repeat 2 of the promoter region were identified among German FH patients; one novel splice site c.1060+10C>G was identified among Greek FH patients. One of the German FH patients was a carrier for the mutations c.1171G>A/p.A391T and p.V653F, and two of the Greek FH patients were compound heterozygotes for the mutations c.1150C>T/p.Q384X and c.1158C>G/p.D386E. Two German FH patients carried the mutation p.R3500Q within APOB. Comparing the mutations within the LDLR gene of the two European FH populations, the German population seems to be more heterogeneous than the Greek cohort. Further studies in progress are trying to elucidate the responsiveness to drug therapy in association with LDLR genotype and the nutritional habits of the two FH populations.
The panorama of familial hypercholesterolemia in Latin America: a systematic review
Journal of Lipid Research, 2016
penetrance. Autosomal dominant FH is attributed to mutations in three different genes: LDL receptor (LDLR), APOB, and proprotein convertase subtilisin/kexin type 9 (PCSK9) (1, 3-5). Other FH genes have been searched for using exome sequencing without success (2). FH caused by mutations in LDLR adaptor protein (LDLRAP) is known as autosomal recessive FH (2). FH is the most common monogenic disorder leading to premature CHD; despite this fact, it is notoriously underdiagnosed and undertreated worldwide (6). Homozygous FH (HoFH) is characterized by extremely high levels of LDL-C (460-1,160 mg/dl) and early onset coronary artery disease (typically by the second decade of life) (7). Mean LDL-C concentration in untreated patients is close to 615 mg/dl (7, 8). Patients are classified into two groups based on the level of LDLR activity, either <2% (receptor negative) or 2-25% (receptor defective). Receptor defective patients have a better prognosis than receptor negative cases (9-11). Heterozygous FH (HeFH) is caused by a single inherited copy of a mutation. The frequency of a heterozygous mutation is >90, 5, and <1% in the LDLR, APOB, and PCSK9 genes, respectively (5). A causal mutation in one of these genes is identified in 60-80% of cases. Affected individuals are characterized by LDL-C levels two to three times greater than normal (190-400 mg/dl). The mean untreated LDL-C concentration is 199.9 mg/dl (12). HeFH is suspected Abstract The burden caused by familial hypercholesterolemia (FH) varies among countries and ethnic groups. The prevalence and characteristics of FH in Latin American (LA) countries is largely unknown. We present a systematic review (following the PRISMA statement) of FH in LA countries. The epidemiology, genetics, screening, management, and unique challenges encountered in these countries are discussed. Published reports discussing FH in Hispanic or LA groups was considered for analysis. Thirty studies were included representing 10 countries. The bulk of the data was generated in Brazil and Mexico. Few countries have registries and there was little commonality in FH mutations between LA countries. LDL receptor mutations predominate; APOB and PCSK9 mutations are rare. No mutation was found in an FH gene in nearly 50% of cases. In addition, some country-specific mutations have been reported. Scant information exists regarding models of care, cascade screening, cost, treatment effectiveness, morbidity, and mortality. In conclusion, FH is largely underdiagnosed and undertreated in the LA region. The genetic admixture with indigenous populations, producing mestizo's groups, may influence the mutational findings in Latin America. Potential opportunities to close gaps in knowledge and health care are identified.