Possible Association of MN Locus Haplotypes
with Essential Hypertension
EUGENE R. H E I S E , MICHAEL A. M O O R E , QUEEN B. R E I D , AND HAROLD O.
GOODMAN
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
SUMMARY Five multigenerational kindreds with familial hypertension were typed for human
leukocyte antigen (HLA) and blood group antigens to investigate genetic factors that influence variability in blood pressure. Pedigree analysis revealed that children of matings in which both parents
were hypertensive had a significantly greater risk of hypertension than children of matings in which
one parent or neither parent was hypertensive. Blood types N and MN were abnormally distributed
among hypertensive as compared with normotensive members of white but not black families. The
distribution of ABO and Rh types was not significantly different between hypertensive and normotensive siblings. When all possible pairings of siblings were examined for HLA haplotype sharing,
abnormal distributions were observed among hypertensive sib pairs whereas the expected mendelian
segregation was observed among hypertensive-normotensive sib pairs and normotensive-normotensive sib pairs. These results suggest the genetic factors controlling variation in blood pressure may
include loci in the region of the MN locus on chromosome 4 and, possibly, the major histocompatibility
complex on chromosome 6. (Hypertension 9: 634-640, 1987)
KEY WORDS • hypertension
HLA haplotypes
• family studies • genetic factors
• MN blood groups
male relatives of hypertensive persons as compared
with male relatives 3 ''' and by the similarity of blood
pressures of female relatives. l2 However, these results
do not establish an X-chromosome linkage with hypertension.
Proposed genetic markers of hypertension include
the Na + -K + cotransport system,13"15 alleles of the MNS
blood groups,16-17 and ABO blood group systems. 18 ' 19
Convincing evidence for associations with human leukocyte antigen (HLA)-ABC antigens from population
studies has not been obtained.20"26 However, genes in
the region of HLA that are not in linkage disequilibrium most likely would not have been detected in these
studies. Alleles of properdin factor B and C3 of the
complement system have been associated with ischemic heart disease27 and benign essential hypertension
(see Kristensen20 for references).
The purpose of the present study was to assess the
reported influence of particular blood group alleles on
the variability in blood pressure and to perform an
HLA haplotype segregation analysis in families with
hypertension. Since genetic association or linkage may
be dependent on both the group under study and its
environment, we included both black and white families in an effort to identify genetic components that are
either common or disparate to different ethnic groups
living in the same area. These results are consistent
A LTHOUGH it has been speculated that an inter/ \
action of environmental factors acting on parM. J L ticular genotypes is responsible for familial
(essential) hypertension, the genetic component is
poorly defined and the mode of inheritance has not
been determined. 1 The occurrence of hypertension and
coronary heart disease in multiple family members and
in successive generations does not distinguish between
inherited and acquired factors. Nevertheless, the role
of genetic factors is clear from the human studies2"4 and
from animal models of hypertension.5"7 Essential hypertension generally is regarded as a polygenic disorder,8- 9 although it has been suggested that a single gene
with complex expression over many years might be
responsible. 10
A sex-related pattern of inheritance is indicated by
the increased prevalence of hypertension among feFrom the Departments of Microbiology and Immunology, Pediatrics, and Medicine, Bowman Gray School of Medicine of Wake
Forest University, and the Department of Natural Science, Winston-Salem State University, Winston-Salem, North Carolina.
Supported in part by Minority Hypertension Research Development Grant HL 07304 from the National Heart, Lung, and Blood
Institute.
Address for reprints: Eugene R. Heise, Department of Microbiology and Immunology, Bowman Gray School of Medicine, Winston-Salem, NC 27104.
Received October 11, 1985; accepted January 21, 1987.
634
MN HAPLOTYPES IN HYPERTENSION///ei\se et al.
with a genetic relationship between the MN blood
group and essential hypertension. Evidence of a possible linkage of HLA haplotypes and essential hypertension in one family will be demonstrated.
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Materials and Methods
Pedigree Evaluation
Family histories were obtained from new patients
seen in one of four outpatient hypertension clinics at
the Bowman Gray School of Medicine, North Carolina
Baptist Hospital, and Reynolds Health Center (Winston-Salem, NC, USA). Patients who had living relatives with hypertension in multiple generations were
invited to participate. Informed consent was obtained
from all participants or their parents (in the case of
patients less than 21 years of age). All persons over 12
years of age were included. Blood pressure measurements were obtained by one of us (Q.B.R.) with a
mercury manometer while the subject was seated. First
and fifth Korotkoff sounds were used for the systolic
and diastolic blood pressures, respectively. Blood
pressure determinations were obtained on one to two
different occasions in each subject. Home visits were
required to obtain pedigree data, follow-up blood pressure measurements, and blood specimens from some
subjects. Family members were categorized as hypertensive, borderline hypertensive, or normotensive.
Persons under 18 years of age were considered hypertensive if their blood pressure was equal to or exceeded
the 95% percentile for their age. For those 18 to 40
years of age, hypertension was defined as a blood
pressure of 150/90 mm Hg or more. Subjects over 40
years of age were classified as hypertensive if their
blood pressure exceeded 160/90 mm Hg on more than
one occasion or if they had a history of hypertension
and were receiving treatment. Borderline hypertension
was considered to be present in those not taking hypertension medication, with normal blood pressure values
on more than one determination, an average systolic
pressure between 150 and 160 mm Hg, and no evidence of end-organ disease on the basis of physical or
laboratory examination.
Phenotyping
Commercial antisera for A, B, M, N, S, s, C, c, D,
E, e, Fy (a), Fy (b), K, k, and Xg were used for blood
grouping by a standard tube hemagglutination assay. A
local serum panel was used to type for 13 HLA-A, 14
HLA-B, and 6 HLA-C antigens by a two-stage microcytotoxicity assay.
Analytical Methods
HLA haplotypes were deduced from the segregation
patterns in two or three generations. The chi-square
statistic was used to test the statistical significance of
blood group phenotypes in hypertensive and normotensive subjects. Departure from expected mendelian
segregation was evaluated by a goodness-of-fit chisquare test. An a value of 0.05 was accepted as the
level of significance.
635
Results
Table 1 shows that of 195 subjects studied, 29%
were hypertensive, 3% were borderline hypertensive,
and 69% were normotensive. HLA typing was available for 63% of the subjects. To establish the familial
nature of hypertension, we compared the prevalence of
hypertension among the offspring for three types of
matings. Table 2 demonstrates that where 1) both parents were affected, 2) one parent was affected, and 3)
neither parent was affected, hypertension was found in
44.8%, 12.8%, and 0% of the offspring, respectively.
These differences were statistically significant. When
the data were analyzed by sex of the offspring, the
correlation with mating type was strongest in female
offspring whose parents were both hypertensive. We
could not analyze the backcross (i.e., hypertensive x
normotensive matings according to the sex of the hypertensive parent) because of the small numbers in the
cells.
Blood grouping was available for two white families
and two black families. Table 3 shows that there were
no significant differences in the distribution of four
ABO phenotypes in hypertensive subjects as compared
with normotensive subjects in either the black or white
families. In contrast, analysis of the MN antigen distribution revealed a statistically significant difference in
the distribution of the MN alleles in hypertensive white
subjects as compared with normotensive white subjects. This result was caused by an excess of the N
phenotype and a deficiency of the M phenotype among
hypertensive white subjects. Thus, 14 of 16 (88%)
hypertensive white subjects and 11 of 11 (100%) normotensive white subjects were either heterozygous or
homozygous for the N allele. In contrast, the M antigen was expressed in only seven of 16 (44%) hypertensive white subjects as compared with 27 of 34 (79%)
normotensive white subjects. In blacks, shifts in the
same direction were noted but did not reach statistical
significance.
Seven different Rh genotypes could be distinguished in the three families based on proven or probable haplotype assignments. Table 4 indicates that
there was no significant difference in the distribution
of Rh genotypes between hypertensive and normotensive subjects.
Population studies have yielded no consistent HLA
antigen associations with hypertension. We reasoned
TABLE 1.
Occurrence of Hypertension in Five Kindreds
Number tested
Family
Race
233
234
239
251
253
White
Total
Black
White
Black
White
Blood pressure status
Blood
pressure
HLA
type
Hypertensive
Borderline
Normotensive
43
79
15
37
21
195
40
39
10
19
16
124
14
27
4
5
7
57
0
1
2
0
0
3
29
51
9
32
14
135
HYPERTENSION
63§
VOL
9,
No
6,
JUNE
1987
TABLE 2. Occurrence of Hypertension in the Offspring of Matings in Which Both, One, or Neither Parent Was
Hypertensive
Number of Hypertensive Offspring/Total Number
Hypertensive
x
hypertensive
9/13 (69.2)
4/16 (25.0)
13/29 (44.8)
Hypertensive
x
normotensive
Gender
1/14(7.1)
Female
4/25 (16.0)
Male
5/39 (12.8)
Total
Percentage of total is shown in parentheses.
TABLE 3. Distribution of ABO and MN Blood Types Among Hy
pertensive and Normotensive Subjects
Normotensive
Variable
Hypertensive
P
*2
ABO
O
A
B AB
O
fi
S
0
•i
WJiitp
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Black
Total
MN
White
Black
Total
^
2 4 5 0
8 9 7 3
M MN N
2
5
9
3 10
9
5 15 18
2
13
M
11
11
22
A B AB
3
d
6 4 2
17 8 5
MN N
7
16
12 12
28 19
11
0 69
2.18
0.59
NS
NS
NS
6.62 <0.05
2.34
NS
6.20 <0.05
that a haplotype analysis could be informative, asgaor geographic groups and between population and family studies. Haplotype segregation in three kindreds is
shown in Figures 1 through 3. We used a sib-sib pair
analysis to determine the number of HLA haplotypes
that were shared between sibling pairs in which both
members of the pair were either hypertensive or normotensive. All possible pairwise combinations of haplotyped siblings were included. Table 5 reveals that
FIOURE 1.
Pedigree of Family 233 (white).
Normotensive
x
normotensive
0/8(0)
0/11 (0)
0/19 (0)
8.83
2.47
10.6
<O.O25
>0.10
<0.005
TABLE 4. Distribution ofRh Genotypes Among Hypertensive and
Normotensive Subjects
Total
White
Black
Hyper- Normo- Hyper- Normo- Hyper- NormoProbable
tensive tensive tensive tensive tensive tensive
genotype
4
4
4
4
0
cde/cde
0
11
12
6
3
CDe/cde
8
6
0
4
0
0
4
CDe/Cde
0
1
1
1
4
3
cDE/cde
n
CDe/cde
CDE/CDe
CDe/cdE
i
l
0
4
5
1
5.37
X2
NS
P
Degrees of freedom = 6.
7
0
0
2
0
0
3.61
NS
11
5
1
4
1
0
8.25
NS
hypertensive pairs departed from mendelian segregation, but that the departure was of borderline statistical
significance. Thus, an excess of hypertensive sib pairs
were found to share one or two HLA haplotypes. In
contrast, hypertensive-normotensive pairs and normo-
MN HAPLOTYPES IN HYPERTENSION///me et al.
A2S| 42
12
BIB B7
BI7 B37
O
Femole
•
Mole
B
Hypertensive
haplotype was present in only one of the kindreds. To
increase the numbers in each of the cells of the 2 X 2
tables, we then analyzed each of the HLA-A,B antigens separately. Table 6 shows that HLA-B18 was
more frequent and HLA-B5 was less frequent as compared with the frequency in normotensive subjects.
The pronounced effect of this one family is evident in
both the HLA haplotype and the phenotype analyses.
41
9
5I
6
•JTi
Discussion
Essential hypertension is probably a complex of
multifactorial diseases involving combinations of genetic and environmental influences. Wright28 suggested that the number of leading genes (i.e., those accounting for most of the variability in those who are or
are not affected) is probably low in any particular family. His conjecture is supported in hypertension by the
relatively large risk for recurrence in siblings, which
would not be compatible with segregation at a large
number of loci unless the responsible alleles were near
fixation in the general population. The results of the
present study are consistent with the possibility that at
least two marker loci are important factors in blood
pressure variability.
The most striking finding concerns the MN locus.
Overall, 33 of 38 (87%) hypertensive subjects carried
the N allele, whereas 47 of 69 (68%) of normotensive
subjects carried this allele. The distribution of the M,
MN, and N types among affected and unaffected subjects differed significantly in the white families only
(see Table 3). These data may be compared with those
of Miller et al., l7 who reported on a population study of
U.S. whites and blacks. They found a significantly
different distribution of MNSs phenotypes only between white hypertensive and normotensive subjects.
When their data were analyzed according to the MN
locus alone, as in the present study, no significant
differences were found in the distribution of MM, MN,
MN
Al |A2
B37 B7
I B Borderline
0
637
Normotensive
rf Indei Cose
FIGURE 2. Pedigree of Family 239 (white).
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
tensive pairs gave the expected mendelian pattern of
1:2:1 for two, one, and no shared haplotypes. Further
inspection of the data revealed that excess haplotype
sharing occurred chiefly in one white family (No.
233). In this family, all nine siblings (5 women and 4
men) of the first generation were hypertensive. HLA
typing was available from eight of the nine siblings.
Five of these eight hypertensive siblings inherited
haplotypes ac, two inherited haplotypes be, and one
inherited haplotypes cd (where a = A23,B18; b =
A29.B12; c = A2.B12; and d = A26.B27).
To determine whether particular haplotypes were
associated with hypertension we examined the distribution of the 61 defined HLA haplotypes among hypertensive and normotensive subjects in the five
kindreds using the chi-square statistic for each 2 x 2
comparison. The only statistically significant finding
was a decreased frequency of the HLA-A2,B5 haplotype among hypertensive subjects (x2 = 3.95), but this
L
1,
[A,
c
B17
J
A23
C2 C3
B - B40
Al Al |A23
C - C - C2
B13 B17| B —
FIGURE 3. Pedigree of Family 253 (white). See Figure 2 for key to symbols.
HYPERTENSION
638
VOL 9, No 6, JUNE 1987
TABLE 5. Departure of HLA Haplotype Segregation from Hardy-Weinberg Equilibrium
No. of concordant haplotypes
Hypertensive-normo tensive
sib pairs
(n = 69)
Hypertensive sib pairs
(i=42)
Normotensive sib pairs
(n = 46)
Observed
Expected
Observed
Expected
Observed
Expected
14 (33)
24(57)
4 (10)
10.5 (25)
21.0(50)
10.5 (25)
19 (28)
32 (46)
18(26)
17.3 (25)
34.5 (50)
17.3(25)
11(24)
25 (54)
10(22)
11.5(25)
23.0 (50)
11.5(25)
5.62
<0.06
0.38
NS
0.35
NS
Percentages are shown in parentheses. Degrees of freedom = 2.
TABLE 6.
Distribution of HLA Phenotypes in Hypertensive
Normotensive Subjects
Hypertensive Normotensive
HLA antigen
(" = 79)
(n = 37)
Al
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
A2
A3
A9 (23, 24)
A10 (25, 26)
All
A28
A29
A30
A31
A32
Aw33
Aw34
7
10
5
18
6
0
4
10
3
1
0
0
2
(18.9)
(27.0)
(13.5)
(48.7)
(16.2)
(0.0)
(10.8)
(27.0)
(8.1)
(2.7)
(0.0)
(0.0)
(5.4)
23
25
16
27
12
6
7
17
7
1
6
1
2
(29.1)
(31.6)
(20.3)
(34.2)
(15.2)
(7.6)
(8.9)
(21.5)
(8.9)
(1.3)
(7.6)
(1.3)
(2.5)
13 (16.5)
B5 (51, 52)
1 (2.7)
B7
26 (32.9)
14 (37.8)
6 (7.6)
0 (0.0)
B8
17 (21.5)
11 (29.7)
B12 (44, 45)
2 (5.4)
B13
1 (1-3)
B14
10 (12.7)
1 (2.7)
B15
0 (0.0)
4 (5.0)
B17
7 (18.9)
13 (16.5)
B18
14 (37.8)
11 (13.9)
B21
0 (0.0)
1 (1.3)
Bw22
0 (0.0)
2 (2.5)
B27
2 (5.4)
2 (2.5)
B35
13
(16.5)
6 (16.2)
B37
2 (5.4)
3 (3.8)
B40
4 (10.8)
13 (16.5)
Bw47
0 (0.0)
1 (1.3)
4 (5.0)
Bw53
I (2.7)
Percentases are shown in D<irentheses.
and
X2
1.37
0.26
0.77
2.22
0.02
2.75
0.11
0.43
0.02
0.31
2.75
0.47
0.63
P
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
NS
4.49
0.27
2.75
0.93
1.71
2.45
1.94
0.05
8.54
0.47
1.90
0.63
0.00
0.15
0.73
0.47
0.34
<0.04
NS
NS
NS
NS
NS
NS
NS
<0.005
NS
NS
NS
NS
NS
NS
NS
NS
and NN types when hypertensive subjects were compared with normotensive subjects; however, they
found that hypertensive whites had a lower frequency
of the S gene and a higher frequency of the s gene than
did normotensive whites (p< 0.005).
In 1964, Cruz-Coke et a l . " observed a tendency for
the NN homozygotes to become hypertensive under
the influence of environmental factors, whereas the
MM homozygotes tended to be normotensive. In the
Israeli study reported by Medalie et al. ,18 the frequency
of NN homozygotes in hypertensive subjects was
35.5% compared with a frequency of approximately
20% in European white populations. A connection
with hypertension also is suggested by the association
of the MN locus with variances of serum cholesterol,
high density lipoprotein cholesterol, non-high density
lipoprotein cholesterol, and triglyceride levels. 2930
The M and N genes are known to encode for the amino
terminal sequences of glycophorin A, whereas the S
and s genes are associated with glycophorin B. Additional studies on other polymorphisms in the MNSs
gene region were indicated by Martin et al., 29 who
reported that the variance of triglyceride levels was
larger in M~ (N phenotype) subjects than in M + (M
and MN) subjects. We did not type for the closely
linked Ss or Gc loci. Recently, we observed a statistically significant increase in the frequency of the Gc 2-2
type of the vitamin D binding protein in a group of
white female patients with fibromuscular dysplasia, all
of whom were being treated for hypertension (E. R.
Heise, unpublished data, 1986).
With respect to the ABO blood group (chromosome
9) our material did not support the weak association
(relative risk, 1.5) between the group A phenotype and
hypertension reported by others based on population
studies.18 The A allele also has been associated with
ischemic heart disease. 1 9 3 1 3 2 The dopamine-/3-hydroxylase locus has been linked to the ABO locus on
chromosome 9 and might provide a plausible hypothesis for the reported association at the population level.
To our knowledge, the Rhesus system (chromosome 1)
has not been associated with hypertension, and the
present study makes it unlikely that marker loci will be
found in the region of the Rh locus.
Garay et al. 13 reported a decreased net Na + K + flux
ratio in patients with essential hypertension and in
some normotensive offspring of hypertensive patients.
Several investigators have suggested that an abnormality of sodium metabolism plays a role in essential hypertension. 1314 The considerable overlap in cotransport values between hypertensive and normotensive
subjects has led to conflicting results. Race may ac-
MN HAPLOTYPES IN HYPERTENSION/Z/cue et al.
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
count for part of the variability. Thus far, blood groups
apparently have not been considered as a covariable in
membrane flux studies.
Analysis of the HLA data revealed that significant
deviations in expected mendelian segregation occurred
in hypertensive-normotensive pairs and in normotensive-normotensive pairs. In the overall analysis, we
observed an excess of hypertensive sib pairs sharing
one or two haplotypes. When the data were analyzed
by family, most of die deviation was found to originate
from one family (see Figure 1). In diis white family, all
nine siblings (five women, four men) of the first generation were hypertensive, and six of the nine were
under treatment for hypertension. HLA typing was
available for eight of these siblings. Of these eight
hypertensive subjects, five were HLA-haploidentical
and the remaining three shared one haplotype with the
other five. The predominance of this one family in the
overall HLA analysis was alsoreflectedin the frequency distribution of HLA-A.B antigens, where 18 occurred significantly more often in hypertensive subjects as compared withtiieirnormotensive cohorts. We
do not attribute biological significance to this observation because of the nonrandom nature of the sample.
The only other significant result of HLA antigen analysis was a significant decrease of B5 in the hypertensive
subjects. HLA-B5 was present in Family 233, but not
in the other four families, again showing the predominant effect of this family on the overall HLA analysis.
It was of interest to examine the blood group distribution in the same kindred (No. 233). Ten of 11 hypertensive members (91%) carried the N allele, whereas
25 of 27 normotensive members (93%) carried the M
allele. The NN genotype was 5.3 times more frequent
in the hypertensive members as compared with normotensive members of this family. In contrast, MM homozygotes were 4.1 times more frequent in the normotensive members than in the hypertensive members. In
this kindred, blood group N allele and HLA-B18 were
correlated widi hypertension, whereas the M allele and
HLA-B5 were correlated witii normotension.
These data suggest that the MNSs regions and, possibly, the HLA region may contain genes that contribute to hypertension through either pleiotropic effects of
the loci themselves or the action of other neighboring
loci on chromosome 4 and chromosome 6, respectively. Further studies will be needed to distinguish between these possibilities.
Acknowledgments
We thank Robin Burgess, R.N., for coordinating the studies in
the research unit. Kent Volosin assisted in data collection and
preparation of the pedigrees, and Robert C. Elston provided guidance in the study. The staff of the Medical Immunology Laboratory
performed the HLA typing. Blood grouping was provided by the
Medical Genetics Laboratory.
References
1. Johnson BC, Epstein FH, Khelsburg MO. Distribution and
familial studies of blood pressure and serum cholesterol levels
in a total community: Tecumseh, Michigan. J Chronic Dis
1965;18:147-160
639
2. Ayman D, Heredity in arteriolar (essential) hypertension. Arch
Intern Med 1934^3:792-802
3. Thomas CB. Familial patterns in hypertension and coronary
heart disease. Circulation 1959;2O;25-29
4. Grim CE, Luft FC, Miller JZ, Rose RJ, Christian JC, Weinberger MH. An approach to the evaluation of genetic influences on factors that regulate arterial blood pressure in man.
Hypertension 1980;2(suppl I):I-34-I-42
5. Alexander M, Hinshaw LB, Drury DR. Development of a
strain of hypertensive rabbits. Proc Soc Exp Biol 1954;
85:855-858
6. Iwai J, Knudsen KD, Dahl LK, Heine M, Leitl G. Genetic
influence on the development of renal hypertension in parabiotic rats. J Exp Med 1969;129:5O7-522
7. Schlager G. Genetic control of blood pressure by more than
one pair of alleles. Proc Soc Exp Biol 1971;136:863-866
8. Morrison SI, Morris JN. Epidemiological observations on high
blood pressure without evident cause. Lancet 1959;2:864-887
9. McKusick V. Genetics and the nature of essential hypertension. Circulation 1960;22:857-863
10. McDonoughJR, Garrison CE, HarocsCG. Blood pressure and
hypertensive disease among negroes and whites. Ann Intern
Med 1964;61:208-228
11. Thomas CG, Cohen BH. The familial occurrence of hypertension and coronary artery disease with observations concerning
obesity and diabetes. Ann Intern Med 1955;42:9O-125
12. Miall WE, Oldham PD. The hereditary factor in arterial blood
pressure. Br Med J 1963; 1:75-80
13. Garay RP, Hannaert P, Dagher G, Nazaret C, Mariadonneau I,
MeyerP. AbnormalerythrocyteNa+,K+ cotransportsystem, a
proposed marker of essential hypertension. Clin Exp Hypertens 1981;3:851-859
14. Losse H, Zidek W, Zumkley H, Wessels S, Vetter H. Intracellular Na+ as a genetic marker of essential hypertension. Clin
Exp Hypertens 1981;3:627-640
15. Tuck ML, Gross C, Maxwell MH, Brickman AS, KrasnoshteinG, Mayes D. Erythrocyte Na + , K + cotransport and Na + ,
K + pump in black and Caucasian hypertensive patients. Hypertension 1984;6:536-544
16. Cruz-Coke R, Nagel R, Etcheverry R. Effects of locus MN on
diastolic blood pressure in a human population. Ann Hum
Genet 1964;28:39-48
17. Miiler JZ, Grim CE, Conneally PM, Weinberger MH. Association of blood groups with essential and secondary hypertension: a possible association of the MNS system. Hypertension
1979; 1:493-497
18. Medalie JH, Papier C, Goldbourt U, et al. Blood groups and
hypertension. Isr J Med Sci 1973;9:989-997
19. Allan TM, Dawson AA. ABO blood groups and ischemic heart
disease in men. Br Heart J 1968;30:377-382
20. Kristcnsen BO. Aspects of immunology and immunogenetics
in human essential hypertension with special reference to vascular events. J Hypertens 1984;2:571-579
21. Patel R, Johnson J, Ansari A. Immunogenetic studies in essential hypertension among black patients: I. Correlative studies of
serum autoantibody formation. Int Arch Allergy Appl Immunol 1982;67:145-148
22. Low B, Schersten B, Sartor G, Thulin T, Mitelman F. HL-A8
and wl5 in diabetes mellitus and essential hypertension [Letter]. Lancet 1975^2:695
23. Gelsthaorpe K, Doughty RW, Sartor G, Thulin T, Mitelman F.
HL-A antigens in essential hypertension. Lancet 1975;1:
1039-1040
24. Fernandez-Cruz A Jr, Otero ML, Perez LL, Femandez-Pinilla
C, Martell-Claros N. HLA antigens in Spanish patients with
essential hypertension. Clin Sci 1981;61:367s-368s
25. Otero ML, Claros NM, Perez LL, Fernandez-Pinilla C, Fernandez-Cruz A. Severe hypertension in the Spanish population: association with specific HLA antigens. Hypertension
1983;5(suppl V):V-149-V-153
26. Gudbrandsson T, Herlitz H, Hansson L, Rydberg L. Human
leucocyte antigens in patients with previous essential malignant hypertension. Clin Sci 1980,59:43 ls-434s
27. Go RCP, Olson G, Acton RT, et al. Association of factor B
with ischemic heart disease (IHD). In: Rao C, Dabaeeru C,
640
HYPERTENSION
eds. Genetic epidemiology of coronary heart disease: past,
present and future. New York: Alan R. Liss, 1984:479-480
28. Wright S. Evolution and the genetics of populations. Chicago:
University of Chicago Press, 1968:373-440
29. Martin NG, Rowell DM, Whitfield JB. Do the MN and JK
systems influence environmental variability in serum lipid levels? Clin Genet 1983;24:1-14
30. Magnus P, Berg K, Boarresen AL, Nance WE. Apparent influ-
VOL. 9, No
6, JUNE
1987
ence of marker genotypes on variation in serum cholesterol in
monozygotic twins. Clin Genet 1981; 19:67-70
31. Mitchell JRA. An association between ABO blood group distribution and geographical differences in death-rates. Lancet
1977;l:295-297
32. Talbot S, Wakley EJ, Ryrie D, Langman MJS. ABO bloodgroups and venous thromboembolic disease. Lancet 1970;
1:1257-1259
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Possible association of MN locus haplotypes with essential hypertension.
E R Heise, M A Moore, Q B Reid and H O Goodman
Downloaded from http://hyper.ahajournals.org/ by guest on June 15, 2017
Hypertension. 1987;9:634-640
doi: 10.1161/01.HYP.9.6.634
Hypertension is published by the American Heart Association, 7272 Greenville Avenue, Dallas, TX 75231
Copyright © 1987 American Heart Association, Inc. All rights reserved.
Print ISSN: 0194-911X. Online ISSN: 1524-4563
The online version of this article, along with updated information and services, is located on
the World Wide Web at:
http://hyper.ahajournals.org/content/9/6/634
Permissions: Requests for permissions to reproduce figures, tables, or portions of articles originally
published in Hypertension can be obtained via RightsLink, a service of the Copyright Clearance Center, not
the Editorial Office. Once the online version of the published article for which permission is being
requested is located, click Request Permissions in the middle column of the Web page under Services.
Further information about this process is available in the Permissions and Rights Question and Answer
document.
Reprints: Information about reprints can be found online at:
http://www.lww.com/reprints
Subscriptions: Information about subscribing to Hypertension is online at:
http://hyper.ahajournals.org//subscriptions/