A common polymorphism in KCNH2 (HERG) hastens cardiac repolarization
Bezzina CR, Verkerk AO, Busjahn A, Jeron A, Erdmann J, Koopmann TT, Bhuiyan ZA, Wilders R, Mannens MM, Tan HL, Luft FC, Schunkert H, Wilde AA.
Cardiovasc Res. 2003 Jul 1;59(1):27-36.

OBJECTIVE: Genetic variants of cardiac ion channels may influence cardiac repolarization. Thereby such variants may modulate the penetrance of primary electrical disorders, contribute to differences in susceptibility to drug-induced QT-prolongation between individuals, or contribute to rhythm disturbances in the context of structural heart disease. Since the current encoded by KCNH2 (HERG; I(Kr)) is a primary determinant of repolarization, we conducted association studies between the respective alleles of the common amino acid-changing polymorphism at codon 897 (2690A>C; K897T) within HERG and rate-corrected QT interval (QTc).
METHODS AND RESULTS: Association analysis in Caucasian subjects (n=1030) revealed a significant association of this polymorphism with QTc (P=0.0025) with CC homozygotes having a significantly shorter QTc (388.5+/-2.9 ms) compared to AA homozygotes (398.5+/-0.9) and heterozygotes (AC, 397.2+/-1.2). The latter two genotypes were associated with comparable mean QTc's, suggesting that the 2690C-allele is recessive. After stratification by sex, the polymorphism was more predictive of QTc in females (P=0.0021), a finding that was replicated in a second population sample (n=352) from the same ethnic background (P=0.044). To assess whether this polymorphism could represent a 'functional' polymorphism, we compared the biophysical properties of K897- and T897-HERG channels by whole-cell voltage clamp. Compared to the K897 channel, the T897 channel displayed a shift of -7 mV in voltage dependence of activation and increased rates of current activation and deactivation.
CONCLUSION: As confirmed in modeling studies, these changes are expected to shorten action potential duration by an increase in I(Kr). This recapitulates the shorter QTc in females homozygous for the 2690C-allele.

Membrane expression of proteinase 3 is genetically determined
Schreiber A, Busjahn A, Luft FC, Kettritz R.
J Am Soc Nephrol 2003 Jan;14(1):68-75

Isolated human neutrophils exhibit a bimodal membrane proteinase 3 (PR3) expression. PR3 is the main target antigen in Wegener granulomatosis (WG). Cells with low expression can be easily distinguished from cell subsets with high expression. In a recent study, a large neutrophil subset expressing membrane PR3 (mPR3(+)) was a risk factor for systemic ANCA-associated vasculitis. PR3 membrane expression patterns are quite stable in a given individual, raising the possibility of genetic variance. The aims of this study were: (1) to investigate the association of mPR3 expression and the risk of WG in an independent German cohort; (2) to test the hypothesis that mPR3 expression on neutrophils is genetically influenced; and (3) to investigate whether or not mPR3 expression is a function of intracellular PR3 content. mPR3 expression was assessed by FACS analysis in isolated human neutrophils. Neutrophil mPR3 expression was studied in 35 patients with WG, 15 patients with other inflammatory diseases, 125 healthy volunteers, and 27 (15 monozygotic and 12 dizygotic) pairs of twins. The intracellular PR3 content was assessed by intracellular flow cytometry and by Western blotting after separating mPR3 low and high expressing cells by FACSort. FACS analysis in a subset of 16 healthy subjects showed a highly conserved PR3 phenotype in two independent investigations >12 mo apart (r = 0.937). Patients with WG demonstrated a significantly higher percentage of mPR3(+) neutrophils than healthy controls and patients with other inflammatory diseases. The mPR3(+) percentage was highly correlated in MZ twins (r = 0.99) compared with DZ twins (r = 0.06). The intracellular PR3 content was not different in persons with low or high mPR3 expression, nor was the PR3 content different in cells with low or high mPR3 expression within a given individual. These data indicate that WG patients have a higher percentage of mPR3-expressing neutrophils. Furthermore, mPR3 expression is influenced by genetic variance. Finally, mPR3 expression is independent of intracellular PR3 content.

Twin studies in the analysis of minor physiological differences between individuals
Busjahn A, Luft FC
Cell Physiol Biochem 2003;13(1):51-8
no abstract available