Unto the third generation: evidence for strong familial aggregation of physicians, psychologists, and psychotherapists among first-year medical and psychology students in a nationwide Austrian cohort census.

BACKGROUND: Medical students present higher numbers of physician relatives than expectable from the total population prevalence of physicians. Evidence for such a familial aggregation effect of physicians has emerged in investigations from the Anglo-American, Scandinavian, and German-speaking areas. In particular, past data from Austria suggest a familial aggregation of the medical, as well as of the psychological and psychotherapeutic, professions among medical and psychology undergraduates alike. Here, we extend prior related studies by examining (1) the extent to which familial aggregation effects apply to the whole nation-wide student census of all relevant (eight) public universities in Austria; (2) whether effects are comparable for medical and psychology students; (3) and whether these effects generalize to relatives of three interrelated health professions (medicine, psychology, and psychotherapy). METHODS: We investigated the familial aggregation of physicians, psychologists, and psychotherapists, based on an entire cohort census of first-year medical and psychology students (n = 881 and 920) in Austria with generalized linear mixed models. RESULTS: For both disciplines, we found strong familial aggregation of physicians, psychologists, and psychotherapists. As compared with previous results, directionally opposite time trends within disciplines emerged: familial aggregation of physicians among medical students has decreased, whilst familial aggregation of psychologists among psychology students has increased. Further, there were sex-of-relative effects (i.e., more male than female physician relatives), but no substantial sex-of-student effects (i.e., male and female students overall reported similar numbers of relatives for all three professions of interest). In addition, there were age-benefit effects, i.e., students with a relative in the medical or the psychotherapeutic profession were younger than students without, thus suggesting earlier career decisions. CONCLUSIONS: The familial aggregation of physicians, psychologists, and psychotherapists is high among medical and psychology undergraduates in Austria. Discussed are implications of these findings (e.g., gender equity, feminization of the medical field, ideas for curricular implementation and student counselling), study limitations, and avenues for future research.

Paradise lost or paradise regained? Changes in admission system affect academic performance and drop-out rates of medical students.

BACKGROUND: The Austrian State medical universities had to change their admission system in 2005. Until this year admission to medical studies was unrestricted. Innsbruck Medical University chose the Eignungstest für das Medizinstudium in der Schweiz (EMS) aptitude test for admission testing. AIMS AND OBJECTIVES: Did the implementation of a selection process affect the academic performance and drop-out rates of students according to gender? METHODS: Two groups of students were compared: 'open admission' (2002-2004), and 'selected' (2006-2009). Academic performance was tested according to results in the final exams after year 1 (SIP 1; SIP, summative integrierte Prüfung) and after year 3 (SIP 3). Drop-out rates were recorded using the registration system of the university. RESULTS: Both, male and female 'selected' students had a higher passing rate regarding SIP 1 and they passed SIP 1 in shorter time and using fewer attempts than the open admission group. The percentage in passing SIP 3 did not change due to change in admission. The drop-out rates were significantly reduced for male and female students. 'Unselected' female students had a significantly higher drop-out ratio than 'unselected' male counterparts. After EMS testing, the drop-out ratios of female and male students were not significantly different. CONCLUSION: Selected applicants were more able and better motivated to study medicine.

Genetics of the Lp(a)/apo(a) system in an autochthonous Black African population from the Gabon.

Plasma lipoprotein(a) (Lp(a)) is a quantitative trait associated with atherothrombotic disease in European and Asian populations. Lp(a) concentrations vary widely within and between populations, with Africans exhibiting on average two- to threefold higher Lp(a) levels and a different distribution compared to Europeans. The apo(a) gene locus on chromosome 6q26-27 (LPA, MIM 152200) has been identified as the major quantitative trait locus (QTL) for Lp(a) concentrations in Europeans and populations of African descent (North American and South African Blacks) but data on autochthonous Black Africans are lacking.Here, we have analysed Lp(a) plasma concentrations, apo(a) isoforms in plasma and four polymorphisms in the LPA gene in 31 African families with 54 children from Gabon. Weighted midparent-offspring regression estimated a heritability h2=0.76. The correlation of Lp(a) levels associated with LPA alleles identical by descent (IBD) resulted in a heritability estimate of 0.801. Our data demonstrate that Lp(a) concentrations are highly heritable in a Central African population without admixture and high Lp(a) (median 43 mg/dl). LPA is the major QTL, explaining most or all of the heritability of Lp(a) in this population.

Association of polymorphisms of the apolipoprotein(a) gene with lipoprotein(a) levels and myocardial infarction.

BACKGROUND: Serum lipoprotein(a) [Lp(a)] concentration is largely determined by variability at the apolipoprotein(a) gene locus. Most prominent effects relate to polymorphisms in the promoter (a pentanucleotide [PN] repeat) and coding regions (a kringle IV [K4] repeat), the latter of which also affects Lp(a) particle size. The impact of these polymorphisms on cardiovascular risk is poorly understood. METHODS AND RESULTS: We studied both polymorphisms and Lp(a) levels in 834 registry-based myocardial infarction (MI) patients (38% women) and 1548 population-based controls. Lp(a) concentrations were inversely related with the numbers of K4 and PN repeats. However, the effect of the PN polymorphism was restricted to subjects producing small Lp(a) particles (8 PN 8.7 mg/dL; P<0.0001). The odds to present with MI were elevated in individuals producing small Lp(a) particles (

A common nonsense mutation in the repetitive Kringle IV-2 domain of human apolipoprotein(a) results in a truncated protein and low plasma Lp(a).

LPA, the gene coding for apolipoprotein(a) [apo(a)], is the major determinant of lipoprotein(a) [Lp(a)] plasma levels, which are associated with risk for coronary heart disease (CHD) and stroke. It is not completely understood how variation in LPA relates to Lp(a) concentrations. One type of variation related to Lp(a) levels is the number of Kringle (K) IV-2 (g.61C>T; GenBank L14005.1) repeats in LPA, but sequence variation may also contribute. Human apo(a) contains from two to >40 nearly identical K IV-2 repeats of genomic size 5.5 kb, which makes it difficult to detect mutations. To elucidate the genetic variation of the apo(a) K IV-2 domain, we isolated a single "nonexpressing" apo(a) allele with 26 K IV-2 repeats, followed by PCR, cloning and sequencing of 96 clones, resulting in an average coverage of each K IV-2 repeat of approximately four-fold. The previously described K IV types 2A and 2B (K IV-2A and K IV-2B) were detected in 74% of the clones. In addition, a new type designated 2C (K IV-2C) was present. A nonsense mutation in the first exon of K IV-2 (g.61C>T) predicted to result in a truncated protein (p.R21X) was found in nine clones on a K IV-2A background. The presence of this mutation was confirmed by analysis of genomic DNA and was shown to represent the rare allele (frequency 0.02) of a SNP. Immunoblot analysis of apo(a) from plasma confirmed the presence of a truncated apo(a) isoform in the index individual and family members. Our data show that SNPs affecting Lp(a) plasma concentrations also exist in the apo(a) K IV-2 domain.

Analysis of the apo(a) size polymorphism in Asian Indian populations: association with Lp(a) concentration and coronary heart disease.

Most studies aiming to detect associations of genetic variation with common complex diseases, e.g. coronary heart disease (CHD) have been performed in populations with a western lifestyle but it is unclear whether associations detected in one geographic group exist also in others. We here have determined lipoprotein(a) levels and apo(a) K-IV-2 repeat genotypes in CHD patients (N=254) and controls (N=480) from two Asian Indian populations (Tamil Nadu and New Delhi). In both populations and also in the pooled dataset median Lp(a) levels were significantly elevated in the patients (27.4 mg/dl) compared with the controls (17.6 mg/dl). Apo(a) K-IV-2 allele frequencies were not different between the CHD patients and controls and thus did not explain the increased Lp(a) levels in CHD patients. Contrary to what has recently been observed in Black and White men short (K-IVor=30) apo(a) alleles were all associated with higher Lp(a) levels in the patients. Accordingly relative risk (estimated as odds ratio) for CHD rose continuously with increasing Lp(a) but was independent of apo(a) allele length. Together with previous studies our results indicate that the relation between apo(a) genotypes, Lp(a) levels, and CHD may be heterogeneous across ethnic groups and that it depends on the genetic architecture of the Lp(a) trait in a given population whether an association of K-IV-2 repeat length with CHD exists or not.

Clinical and genetic features in a family with CADASIL and high lipoprotein (a) values.

We present a family with cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL) and elevated lipoprotein(a) [Lp(a)] levels. In addition to neurological examinations, ultrasound of extra- and intracranial arteries, laboratory tests, and cerebral magnetic resonance imaging (MRI), a whole genome screening with mutation analyses was performed. Rather untypical for CADASIL, stenoses of large intracranial arteries were detected in the index patient. All affected subjects lacked a history of migraine, mood disturbances, and cognitive decline despite extensive white matter lesions in two individuals. Furthermore, evidence of early cerebral microangiopathy was demonstrated in three children (age 9, 11 and 13). We were able to explain the mechanism of elevated Lp(a) on the basis of the kringle IV type 2 repetition size. A mutation S118C located in exon 4 of Notch3 was responsible for CADASIL. Elevated Lp(a) might have contributed to the cerebrovascular phenotype in this family.

Plasma distribution of apoA-IV in patients with coronary artery disease and healthy controls.

Recent studies showed lower apolipoprotein A-IV (apoA-IV) plasma concentrations in patients with coronary artery disease (CAD). The actual distribution of the antiatherogenic apoA-IV in human plasma, however, is discussed controversially and it was never investigated in CAD patients. We therefore developed a gentle technique to separate the various apoA-IV-containing plasma fractions. Using a combination of precipitation of all lipoproteins with 40% phosphotungstic acid and 4 M MgCl2, as well as immunoprecipitation of all apoA-I-containing particles with an anti-apoA-I antibody, we obtained three fractions of apoA-IV: lipid-free apoA-IV (about 4% of total apoA-IV), apoA-IV associated with apoA-I (LpA-I:A-IV, 12%), and apoA-I-unbound but lipoprotein-containing apoA-IV (LpA-IV, 84%). We compared these three apoA-IV fractions between 52 patients with a history of CAD and 52 age- and sex-matched healthy controls. Patients had significantly lower apoA-IV levels when compared to controls (10.28 +/- 3.67 mg/dl vs. 11.85 +/- 2.82 mg/dl, P = 0.029), but no major differences for the three plasma apoA-IV fractions. We conclude that our gentle separation method reveals a different distribution of apoA-IV than in many earlier studies. No major differences exist in the apoA-IV plasma distribution pattern between CAD patients and controls. Therefore, the antiatherogenic effect of apoA-IV has to be explained by other functional properties of apoA-IV (e.g., the antioxidative characteristics).