Mapping a novel locus for familial atrial fibrillation on chromosome 10p11-q21.

BACKGROUND: Atrial Fibrillation (AF), the most common cardiac arrhythmia, is a significant public health problem in the United States, affecting approximately 2.2 million Americans. Recently, several chromosomal loci and genes have been found to be associated with familial AF. However, in most other AF cases, the genetic basis is still poorly understood. OBJECTIVE: The purpose of this study was to investigate the molecular basis of familial AF in a Dutch kindred group. METHODS: We analyzed a four-generation Dutch family in which AF segregated as an autosomal dominant trait. After the exclusion of linkage to 10q22-24, 6q14-16, 5p13, KCNQ1, KCNE2, KCNJ2 and some ion-channel-associated candidate genes, a genome-wide linkage scan using 398 microsatellite markers was performed. RESULTS: Two-point logarithms of odds (LOD) scores >1 at recombination fraction [theta] = 0.00 and a haplotype segregating with the disorder were demonstrated only across regions of chromosome 10. Subsequent fine mapping gave a maximum two-point LOD score of 4.1982 at D10S568 at [theta] = 0.00. Distinct recombination in several individuals narrowed the shared region among all affected individuals to 16.4 cM on the Genethon map (flanking markers: D10S578 and D10S1652), which corresponds to chromosome 10p11-q21. Thirteen candidate genes residing in this region, which could be associated with AF, were screened. No mutation has been found in their coding regions including the intron splice regions. CONCLUSION: We identify a novel locus for AF on chromosome 10p11-q21, which provides further evidence of genetic heterogeneity in this arrhythmia.     

Further evidence for linkage of familial hyperaldosteronism type II at chromosome 7p22 in Italian as well as Australian and South American families

BACKGROUND: Familial hyperaldosteronism type II is a hereditary form of primary aldosteronism not attributable to the hybrid CYP11B1/CYP11B2 mutation that causes glucocorticoid remediable aldosteronism (or familial hyperaldosteronism type I). Although genetic defect(s) underlying familial hyperaldosteronism type II have not yet been elucidated, linkage to chromosome 7p22 was previously reported in two Australian families and a South American family with familial hyperaldosteronism type II. OBJECTIVE: To seek evidence of linkage to chromosome 7p22 in two Italian families with familial hyperaldosteronism type II based on markers that have already yielded evidence of linkage in one South American and two Australian familial hyperaldosteronism type II families and to assess the combined multipoint logarithm of odds score in these five families (two Australian, two Italian, and one South American). METHODS: Primary aldosteronism was diagnosed or excluded using widely accepted clinical and biochemical criteria. Genotypes of affected and unaffected Italian patients from two families were analysed using seven closely spaced microsatellite markers at 7p22, and multipoint logarithm of odds scores were calculated to assess linkage with familial hyperaldosteronism type II. RESULTS: All known affected individuals (four and two, respectively) from each of two Italian families shared identical haplotypes for the seven markers, consistent with linkage of the disease locus with the 7p22 region. The combined multipoint logarithm of odds score for five families showing linkage at 7p22 was highly significant at 5.22 (theta = 0) for markers D7S462 and D7S517. CONCLUSION: Linkage in two Italian families makes this the third geographical area to show linkage of familial hyperaldosteronism type II at 7p22, emphasizing the likely importance of this locus in identifying the causative mutation.     

Evidence for a Graves' disease susceptibility locus at chromosome Xp11 in a United Kingdom population

Graves' disease (GD), which has a strong female preponderance (female/male ratio, >5:1), is inherited as a complex genetic trait. Loci for GD have started to be defined using genome-wide approaches for genetic linkage. To date, 3 loci have been confirmed in at least 2 cohorts of GD patients, the strongest effect being at the cytotoxic T lymphocyte antigen-4 (CTLA-4) locus on chromosome 2q33 in our population. Two other loci for GD have recently been proposed, but not confirmed, on chromosomes Xq21 (GD3) and 14q31 (GD1). We studied a cohort of 75 sibling pairs with GD from the United Kingdom for linkage to 12 markers over a 83-cM region of the X chromosome and for 8 markers over a 36-cM region of 14q31-q33. A peak multipoint nonparametric linkage score of 2.21 (P = 0.014) was found at marker DXS8083 on Xp11, which increased to a nonparametric linkage score of 3.18 (P = 0.001) in data that had been conditioned for allele sharing at the CTLA-4 locus under an epistatic model. There was no evidence to support linkage of GD to Xq21.33-q22 (GD3) or at the 14q31-q33 (GD1) region in our population. A locus with a moderate contribution to GD susceptibility (lambda(s) = 1.4) is likely to exist in the Xp11 region, but we are unable to confirm that the GD1 or the GD3 regions contain major susceptibility loci in our United Kingdom GD population.     

Genetic studies of a family with hereditary hyperparathyroidism–jaw tumour syndrome

BACKGROUND AND OBJECTIVES: Familial hyperparathyroidism may occur as familial isolated hyperparathyroidism (FIHP) or as part of an inherited syndrome, in particular multiple endocrine neoplasia types 1 and 2A (MEN1, MEN2A) and hyperparathyroidism-jaw tumour (HPT-JT) syndrome. The localization of the genes responsible for these syndromes has enabled genetic screening of families with primary hyperparathyroidism (PHPT) to be carried out. This has important clinical implications in terms of individual follow-up and management. We previously reported a large FIHP family with an increased risk of parathyroid cancer and excluded its linkage to MEN1, MEN2 and PTH genes. Here we re-analysed this family and performed genetic linkage to the HPT-JT locus in chromosome 1q21-q32. Loss of heterozygosity studies of 1q21-q32, 11q13 and X chromosome were also performed. PATIENTS AND DESIGN: We studied 19 family members, aged 6-63 years. High molecular weight DNA was isolated from peripheral blood samples from 17 family members. For the two deceased individuals, DNA was extracted from normal paraffin embedded tissues. MEASUREMENTS: All individuals (except two deceased patients) had serum corrected calcium, inorganic phosphate, intact PTH, prolactin and various pancreatic hormones, measured on fasting blood samples. Twenty microsatellite markers were examined for the 1q21-q32 region, the locus for the HPT-JT gene. Genetic polymorphisms were determined by polymerase chain reaction amplification of genomic DNA and genetic linkage analysis was performed. Loss of heterozygosity studies were performed using paraffin-embedded parathyroid tissues from four affected members. RESULTS: Seven of the eight affected family members included in this study had biochemical evidence of PHPT and surgically proven parathyroid tumours. Indication of linkage of the disease to the HPT-JT locus was demonstrated with a maximum lod score of 2.32 by two-points linkage analysis. Linkage data were supported by multi-point analysis which gave a maximum lod score of 2.7. Meiotic recombinations detected in one affected individual narrowed the region to 26 cM. As a result of the genetic findings, we re-screened the living family members by orthopantomograph and renal ultrasound, and identified two jaw lesions in two gene carriers. One affected family member demonstrated polycystic kidney disease, thus establishing the association between the two conditions. A reduced penetrance of HPT in females was evident, in agreement with our previous study. No allelic deletion was detected in any tumour at 1q21-q32, 11q13 or X chromosome. CONCLUSIONS: This study illustrates the usefulness and importance of genetic studies in familial isolated hyperparathyroidism families. Our clinical and genetic findings indicate that this previously reported familial isolated hyperparathyroidism family has hyperparathyroidism-jaw tumour syndrome.     

Localization of gene for familial hypertrophic cardiomyopathy to chromosome 14q1 in a diverse US population

BACKGROUND. Familial hypertrophic cardiomyopathy, an inherited primary cardiac abnormality characterized by ventricular hypertrophy, is the leading cause of sudden death in the young. Recent application of restriction fragment length polymorphism markers has provided provocative results, with localization to chromosome 18 (Japanese studies), 16 (Italian studies), 14 (US and French-Canadian studies), and two (National Institutes of Health studies) indicating genetic heterogeneity. Interpretation remains speculative until at least one of these loci is confirmed in unrelated pedigrees by independent investigators. METHODS AND RESULTS. We studied eight unrelated families of varied ethnic origins across the United States. DNA from each individual was digested with restriction enzymes TaqI or BamHI and analyzed by Southern blots followed by hybridization with probes T cell receptor alpha (TCRA), myosin heavy chain beta, D14S25, and D14S26. Multipoint linkage analysis showed a maximum lod score of 4.3, placing the locus 10 cM from D14S26 between D14S26 and TCRA, with an odds ratio of 20,000:1 and 90% confidence limits of 12 cM proximal to D14S25 to 4 cM distal to TCRA. The probability of linkage to 14q1 was more than 99%. CONCLUSIONS. These results indicate that the loci for familial hypertrophic cardiomyopathy in our families is primarily 14q1 but does not exclude other loci in a small proportion of the families. Thus, 14q1 appears to be the locus for familial hypertrophic cardiomyopathy in a significant proportion of the US population.     

Reduced apelin levels in lone atrial fibrillation.

AIMS: Apelin is an endogenous peptide hormone that appears to have a physiological role in counter-regulation of the angiotensin and vasopressin systems. This peptide has been reported to be down-regulated in subjects with acute heart failure, but has not been studied in other cardiovascular conditions. We studied apelin levels in 73 subjects with lone atrial fibrillation (AF). METHODS AND RESULTS: Study subjects had electrocardiographic evidence of paroxysmal or chronic AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of coronary artery disease, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or antecedent hypertension. Controls were recruited from a healthy outpatient population. Plasma apelin levels were determined using a commercially available immunoassay. Seventy-three subjects with lone AF and 73 healthy controls were enrolled and studied. Mean levels of apelin were significantly lower in subjects with lone AF when compared with controls (307 vs. 648 pg/mL, P<0.00005). CONCLUSION: Reduced apelin levels were observed in this homogenous population of lone AF subjects and may represent an underlying diathesis predisposing to this common arrhythmia.     

Familial clustering of lone atrial fibrillation in patients with saddleback-type ST-segment elevation in right precordial leads.

AIMS: We recently identified a large family with a high prevalence of lone atrial fibrillation (AF) and saddleback-type ST-segment elevation in leads V(1-3), without a history of ventricular arrhythmias or syncope. On the basis of this finding, we studied whether there is a relationship between saddleback ST-elevation and lone AF. METHODS AND RESULTS: We examined 168 (mean age 50+/-8 years, 130 males) lone AF patients and 541 (mean age 50+/-6 years, 274 males) healthy subjects. The prevalence of saddleback ST-elevation was higher in the lone AF group than the control group (10 vs. 0.4%, P<0.001). None had a coved-type ST-elevation in baseline ECG or during drug challenge with ajmaline or flecainide (n=13), a family history of sudden cardiac death, ventricular tachyarrhythmias, syncope, or any other features diagnostic to the Brugada syndrome. Familial clustering of lone AF (i.e. AF in >30% of first-degree relatives) was more common among the subjects with saddleback ST-elevation (24 vs. 7%, P=0.03). CONCLUSION: Saddleback-type ST-segment elevation is a relatively common finding among patients with lone AF. The familial clustering of the disorder indicates that genetic factors may be involved in the pathogenesis of the ECG abnormality and lone AF in these patients.     

A novel titin mutation in adult-onset familial dilated cardiomyopathy

Familial dilated cardiomyopathy is a major cause of advanced heart failure and heart transplantation. In most families, the disease-causing mutation is unknown, and relatives should therefore undergo periodic screening to facilitate early diagnosis and therapy. In the present study, we describe a novel titin truncation mutation causing adult-onset familial dilated cardiomyopathy in an Israeli Arab family. The family members underwent physical examination, electrocardiography, and Doppler echocardiography. Linkage to candidate loci was performed, followed by gene sequencing. We identified 13 clinically affected family members (8 men and 5 women, mean age 47 ± 12 years). Compared with their healthy first-degree relatives, the affected relatives had a larger end-diastolic left ventricular dimension (60 ± 10 vs 49 ± 4 mm, p <0.001), lower ejection fraction (43 ± 11% vs 60 ± 6%, p <0.001), and markedly higher end-systolic volume indexes but no difference in wall thickness or diastolic function. The linkage studies or direct sequencing excluded LMNA, MYH7, TNNT2, TNNI3, SCN5A, DES, SGCD, ACTC, PLN, and MYH6 but established linkage to the TTN locus at chromosome 2q31, yielding a maximum (2-point) LOD score of 3.44. Sequence analysis identified an insertion (c.58880insA), causing protein truncation after 19,628 amino acids (p.S19628IfsX1). No founder effect was found among the Israeli Arabs. In conclusion, titin is a giant protein with a key role in sarcomere assembly, force transmission, and maintenance of resting tension. Although some mutations result in skeletal myopathy, others cause isolated, maturity-onset cardiomyopathy.     

Familial Adenomatous Polyposis and Mental Retardation Caused by a de novo Chromosomal Deletion at 5q15-q22: Report of a Case

Familial adenomatous polyposis, caused by mutations in the adenomatous polyposis coli gene located at chromosome 5q21, is an autosomal dominant syndrome characterized by polyposis of the colon and rectum and nearly 100 percent progression to colorectal cancer. We report a case of familial adenomatous polyposis and mental retardation caused by a chromosomal deletion at 5q15-q22. Chromosomal analysis is considered part of the evaluation of children with mental retardation and developmental delay. The resulting karyotypes from high-resolution chromosomal analysis can help characterize large deletions, some of which involve known tumor suppressor genes. Because familial adenomatous polyposis may arise from de novo chromosomal deletions involving the adenomatous polyposis coli gene locus, individuals with chromosomal deletions involving 5q21 should be considered at-risk for familial adenomatous polyposis and offered standard screening with flexible sigmoidoscopy by 10 to 12 years of age. Supported, in part, by the Grace J. Fippinger Foundation, the William Bianco Trust, and the Ferdinand Koch Fund. Presented at the meeting of the Collaborative Groups of the Americas on Inherited Colorectal Cancer, Baltimore, Maryland, October 13 to 14, 2002.     

细胞毒性T淋巴细胞相关抗原-4基因与中国北方汉族Graves病连锁关系研究

目的　确定位于染色体 2q3 1 q3 3区的细胞毒性T淋巴细胞相关抗原 4(CTLA 4)基因是否是中国北方汉族Graves病 (GD)的主要易感基因。方法　采用 5个高度多态且覆盖整个染色体2q3 1 q3 3区的微卫星标记筛查 5 4个 (3 2 2人 )中国北方汉族GD多发家系。分别计算疾病在呈显性及隐性遗传的各外显率下 ,各微卫星的两点及多点Lod值 ,并计算多点非参数连锁值。结果　在每种遗传模式下 ,各微卫星的两点Lod值 (与疾病基因位点的重组率为 0时 )及多点Lod值均小于 - 2。非参数连锁值均无显著的统计学意义 (P >0 0 5 )。结论　染色体 2q3 1 q3 3区不存在与中国北方汉族GD相连锁的基因位点。CTLA 4基因不是中国北方汉族GD的主要易感基因     

Discordant atrial natriuretic peptide and brain natriuretic peptide levels in lone atrial fibrillation

OBJECTIVES: We sought to characterize natriuretic peptide levels in a cohort of rigorously characterized subjects with lone atrial fibrillation (AF). BACKGROUND: Atrial natriuretic peptide (ANP) and brain natriuretic peptide (BNP) are sensitive biomarkers of cardiac contractile dysfunction. Both peptides have been reported to be elevated in cohorts with AF, but previous studies have included subjects with underlying structural heart disease. We studied these hormones in 150 subjects with lone AF. METHODS: Study subjects had electrocardiographic evidence of at least one episode of AF and a structurally normal heart on echocardiography. Subjects were excluded if they had a history of a myocardial infarction, rheumatic heart disease, cardiomyopathy, significant valvular disease, hyperthyroidism, or hypertension that preceded the onset of AF. Control subjects were obtained from a healthy outpatient primary care population. Plasma pro-ANP and N-terminal pro-BNP (nt-pro-BNP) levels were determined using commercially available immunoassays. RESULTS: A total of 150 serial subjects with lone AF were enrolled and studied, the majority during normal sinus rhythm. Median levels of nt-pro-BNP were significantly elevated in subjects with lone AF as compared with control subjects (166 vs. 133 fmol/ml, p=0.0003). There was no significant difference in pro-ANP levels between subjects with lone AF and control subjects (1,730 vs. 1,625 fmol/ml, p=0.90). CONCLUSIONS: Discordant natriuretic peptide levels were observed in this homogeneous population of subjects with lone AF. This biomarker pattern, which is present even in sinus rhythm, may represent an underlying subclinical predisposition to this common arrhythmia.     

A genome-wide search identifies potential new susceptibility loci for Crohn's disease

Chronic inflammatory bowel disease (IBD) presents as two major clinical forms, Crohn's disease (CD) and ulcerative colitis (UC). Genetic epidemiological studies and animal models suggest that inherited factors play significant roles in the susceptibility to both forms of IBD. From four genome-wide scans, putative susceptibility loci on chromosome 16 (IBD1 for CD), and on chromosomes 1, 3, 4, 6, 7, 10, and 12 for IBD, have been identified. Several other groups, including ours, have confirmed linkage to the loci on chromosomes 12 and 16. The aim of this study is to identify other potential susceptibility loci for CD with a genome-wide search approach. In our sample of 222 individuals from 46 families (20 Jewish and 26 non-Jewish), with a total of 65 sibpairs diagnosed with CD, we observed a novel locus with suggestive linkage [multipoint logarithm of the odds score (Mlod) > 2] at chromosome 14q11.2 (Mlod = 2.8, p = 0.0002). In addition, suggestive linkage was observed in our Jewish families at chromosome 17q21-q23 (Mlod = 2.1, p = 0.01) and chromosome 5q33-q35 (Mlod = 2.2, p = 0.0003). The syntenic regions of the latter locus are mapped within two putative loci on mouse chromosomes 11 and 18, which were identified in a mouse IBD model induced by dextran sulfate sodium (29). Our preliminary results provide potential evidence for several susceptibility loci contributing to the risk of CD. The observation of man-mouse synteny may accelerate the identification of CD susceptibility gene(s) on human chromosome 5.     

A familial hypertrophic cardiomyopathy locus maps to chromosome 15q2.

We report that a gene responsible for familial hypertrophic cardiomyopathy (FHC) in a kindred with a mild degree of cardiac hypertrophy maps to chromosome 15q2. The gene encoding cardiac actin, located on chromosome 15q, was analyzed and excluded as a candidate for FHC at this locus. Two additional families with typical FHC were studied and the disorder in one also maps to the chromosome 15q2 locus. The maximum combined multipoint logarithm of odds score in the two linked families is 6.02. Although these two kindreds reside in the same country, we believe that their disorder is caused by independent mutations in the 15q2 locus because of the clinical and genotypic differences between affected individuals. Mutations in at least four loci can cause FHC: chromosomes 14q1 (beta cardiac myosin heavy chain gene), 1q3, and 15q2 and another unidentified locus, suggesting substantial genetic heterogeneity.     

孤立性房颤的临床特征及亚型分析

目的通过病例分析研究，总结孤立性房颤的临床亚型。方法对69例孤立性房颤进行询问病史，全面体格检查以及心电图、动态心电图、超声心动图等严格检出和控制人选研究对象，对所获临床资料进行统计分析。结果研究对象91．3％为阵发房颤，15．9％为永久性房颤；房颤睡眠中发作占43．2％，运动后发作47．5％，餐后发作28．6％等。有房颤家族史27．5％。结论孤立性房颤的临床亚型可分为睡眠发作型、运动诱发型和餐后发作型，部分孤立性房颤患者具有家族遗传性     

Familial isolated primary hyperparathyroidism

Familial primary hyperparathyroidism (PHPT) Is usually encountered in the context of multiple endocrine neoplasia (MEN) syndromes. Few families have been reported in the literature where PHPT was the only abnormality. However, in these families no long-term follow-up data were reported and no genetic linkage studies were performed. OBJECTIVE We investigated a large family with a familial primary hyperparathyroidism for biochemical and genetic markers of multiple endocrine neoplasia syndromes. DESIGN A family screening study. PATIENTS Thirty-seven family members participated in this study including 7 patients who had been previously operated upon for PHPT. MEASUREMENTS Serum calcium (albumin adjusted), was measured in all family members. Hypercalcaemic subjects and patients who had been operated upon for PHPT were assessed for biochemical markers of MEN syndromes (serum gastrin, prolactin, calcitonin, fasting plasma glucose and 24-hours urinary excretion of adrenaline, noradrenaline and vanillylmandelic acid (VMA). Genetic linkage analysis was performed using DNA markers linked to chromosome 11q13, the presumed MEN type 1 (MEN-1) locus. RESULTS Four new patients with PHPT and two with probable PHPT were discovered. No clinical or biochemical evidence of MEN syndromes could be detected. DNA marker pMS5l(D11S97) was Informative, maximum two-point lodscore of 2·12 at a recombination fraction of 0·05 confirming linkage to chromosome 11q13. CONCLUSIONS Familial PHPT can exist as a separate clinical entity. Isolated familial PHPT is caused by mutation in a gene located in the MEN-1 region on chromosome 11q13, possibly the MEN-1 locus.     

Genetic heterogeneity underlies juvenile hemochromatosis phenotype: analysis of three families of northern Greek origin

Hereditary hemochromatosis is a genetically heterogeneous disease. Common HFE mutations (C282Y and H63D) are related to the majority of hereditary hemochromatosis cases in populations of Northern European ancestry (HFE1). Juvenile hemochromatosis (JH) is a more severe iron overload disorder, usually presenting at the second decade of life. The gene responsible for JH lies on a genetic locus at chromosome 1q. We have performed a genetic linkage study in three families of Northern Greek origin with typical clinical features of JH. In two families results were in accordance with linkage to chromosome 1q. In one family linkage of the disease to the genetic loci at 1q21, 7q22, and 6p22 was excluded. We suggest that more than one gene may underlie the JH phenotype. This genetic type of hemochromatosis may be designated 1q unlinked juvenile hemochromatosis. Family studies are necessary to establish the genetic diagnosis of JH.     

Exclusion of cardiac myosin heavy chain and actin gene involvement in hypertrophic cardiomyopathy of several French families.

Familial hypertrophic cardiomyopathy (FHC) is characterized by idiopathic myocardial hypertrophy, which often and predominantly involves the interventricular septum. The disease is transmitted as an autosomal dominant trait, and its major risk is sudden death. It was recently demonstrated that this disease is genetically heterogeneous and that in 13 of 18 unrelated families the morbid locus, termed FHC-1, maps to chromosome 14q11-12 in and/or very near the cardiac beta-myosin heavy chain gene. We have performed linkage analysis with five chromosomal markers detecting polymorphisms in either the cardiac beta-myosin heavy chain gene or the cardiac actin gene (located on chromosome 15q) on eight families from different regions of France. We show that 1) it is possible to analyze medium-sized families by using highly informative microsatellite markers located in these genes and 2) the disease is not linked to the two contractile protein genes in any of these families. Moreover, 10-20% of chromosome 14 and 20-40% of chromosome 15 in the vicinity of the respective markers were excluded as possible locations for the morbid locus. These results provide new insights into the identification of the genes responsible for FHC.     

Molecular genetic studies in atrial fibrillation

Atrial fibrillation is a complex disease. Its etiologies are diverse and genetic factors may also contribute to this disease. With the advent of modern molecular biology technology, it is now possible to explore the genetic components in the pathogenesis of atrial fibrillation. Past molecular genetic studies on atrial fibrillation in the literature can be divided into linkage analysis studies and association studies. The subjects for linkage analysis studies are pedigrees of probands with Mendelian hereditary atrial fibrillation. The first locus identified for autosomal dominant atrial fibrillation locates at 10q22-q24. However, the exact gene is still unknown. Another linkage analysis study in Chinese revealed that LQT1 gene (I(Ks) alpha-subunit) was the responsible gene. A missense mutation in the I(Ks) alpha-subunit results in a gain of function, which is important in causing atrial fibrillation. The third known locus for familial atrial fibrillation locates at 6q14-16. The responsible gene remains still unknown. The other type of studies takes the case-control design (association studies) and the subjects have multigenic atrial fibrillation. In a study in a Japanese population, it was reported that the angiotensin-converting enzyme insertion/deletion polymorphism was not associated with atrial fibrillation. On the other hand, researchers in Taiwan reported that a nonsynonymous single nucleotide polymorphism of the LQT5 gene (I(Ks) beta-subunit) is associated with atrial fibrillation. In summary, there is growing evidence showing that genetic factors are important in the pathogenesis of atrial fibrillation. We expect that more genes responsible for or contributing to atrial fibrillation will be identified in the future and these will elucidate the molecular mechanisms of atrial fibrillation.     

Atrial fibrillation: molecular biology bases

BACKGROUND: Atrial fibrillation is the most frequent form of sustained arrhythmia. In most cases the arrhythmia is acquired, in rarer cases it may occur as a familial disease with a autosomal dominant pattern of inheritance. Recent advances in molecular biology and genetics have had a major impact on our understanding of the mechanisms responsible for the initiation, maintenance and chronification of the arrhythmia. Recently, the chromosomal locus for familial atrial fibrillation has been mapped to chromosome 10q22-q23, however, so far the causative gene has not been identified. ATRIAL REMODELING: Atrial fibrillation itself modifies atrial electrical properties in a way that promotes the occurrence and maintenance of the arrhythmia, in other words "atrial fibrillation begets atrial fibrillation". The principle stimulus for atrial remodeling is the rapid atrial rate. PERSPECTIVES: It is hoped that the results of future studies will not only further improve our understanding of the mechanisms underlying atrial fibrillation but may also help to develop new therapeutic strategies.     

Molecular genetics of atrial fibrillation

Atrial fibrillation (AF) is the most common sustained cardiac arrhythmia. There is genetic predisposition for the development of AF. Recently, by linkage analysis, several loci have been mapped for monogenetic AF, including 11p15.5, 21q22, 17q, 7q35-36, 5p13, 6q14-16, and 10q22. Some of these loci encode for subunits of potassium channels (KCNQ1, KCNE2, KCNJ2, and KCNH2 genes), and the remaining are yet unidentified. All of the known mutations are associated with a gain of function of repolarization potassium currents, resulting in a shortening of action potential duration and atrial refractory period, which facilitate multiple re-entrant circuits in AF. In addition to familial AF, common AF often occurs in association with acquired diseases such as hypertension, valvular heart disease, and heart failure. By genetic association study, some genetic variants or polymorphisms related to the mechanism of AF have been found to be associated with common AF, including genes encoding for subunits of potassium or sodium channels, sarcolipin gene, renin-angiotensin system gene, connexin-40 gene, endothelial nitric oxide synthase gene, and interleukin-10 gene. These observations suggest that genes related to ionic channels, calcium handling protein, fibrosis, conduction and inflammation play important roles in the pathogenesis of common AF. The complete elucidation of genetic loci for common AF is still in its infancy. However, the availability of genomewide scans with hundreds or thousands of polymorphisms has made it possible. However, challenges and pitfalls exist in association studies, and consideration of particular features of study design is necessary before making definite conclusions from these studies.