From the Departments of Biochemistry (H.Y., D.W.B.), Internal
Medicine/Section on Nephrology (B.I.F.), and Public Health Sciences (B.J.S.,
S.S.R.), Wake Forest University Baptist Medical Center, Winston-Salem, NC.
Correspondence to Barry I. Freedman, MD, Section on Nephrology, Wake Forest University Baptist Medical Center, Medical Center Blvd, Winston-Salem, NC 27157-1053.
Abstract—Kallikreins are serine
proteases that release kinins from kininogens. Kinins, via their
effects on cardiovascular and renal function, may be
involved in the pathogenesis of hypertension and renal failure. Two
groups of kallikreins exist, glandular or tissue kallikrein and plasma
kallikrein. In this study, we examined the human plasma kallikrein gene
KLK3 to determine whether it contributed to end-stage renal disease
(ESRD) susceptibility. We identified two novel polymorphic
sequences closely linked to the KLK3 gene, designated KLK3b and KLK3c
(heterozygosities: 0.64 to 0.68 and 0.48 to 0.52, respectively). We
mapped the KLK3 gene and the marker KLK3c to the long arm of human
chromosome 4 between F11 and D4S426 using a radiation hybrid panel. The
study population consisted of 142 sibling pairs concordant for ESRD
from 121 African American families. The 142 sibling pairs were
stratified into 78 pairs with hypertension- and chronic
glomerulonephritis–associated ESRD and 64 with non–insulin-dependent
diabetes mellitus–associated ESRD. Linkage analyses, using
SIBPAL of SAGE, and exclusion analysis, using MAPMAKERS/SIBS,
were performed. Linkage analysis of affected sibling pairs did
not reveal any evidence of linkage of KLK3 to ESRD in all 142 sib-pairs
or in the two stratified subsets. Exclusion analysis indicated
that the KLK3 gene could be excluded from contributing to ESRD at a
relative risk of 3 when the maximum log of the odds score of -2 was
used as the criterion for exclusion. However, an association
analysis using the relative predispositional effect technique
showed that alleles 7 and 9 of KLK3b were consistently
associated with ESRD. Alleles 7 and 9 were present in 11.2%
and 10.8% of the 113 unrelated ESRD probands and in 6.6% and 6.6% of
the 204 race-matched control subjects without renal disease (allele
P=.0041 and .0016, respectively). Alleles 7 and 9
were also present in 13% and 10.4% of the proband's first
siblings (allele P=.00014 and .0087, respectively).
The association of KLK3b alleles with ESRD raises the possibility
that polymorphisms in KLK3 may play a role in ESRD susceptibility.
The lack of linkage might reflect our relatively small family set.
© 1998 American Heart Association, Inc.
Scientific Contributions
Identification of Human Plasma Kallikrein Gene Polymorphisms and Evaluation of Their Role in End-Stage Renal Disease
Key Words: kallikrein • renal disease • African Americans • genetics • diabetes mellitus
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