The 1a-Hydroxylase Locus Is Not Linked to Calcium Stone Formation ...

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risk for first-degree relatives. From such .... Orlando,. FL) and with a family history of nephrolithiasis. (at least one affected sibling) ... ultrasound or plain x-ray film.
The 1 a-Hydroxylase Locus Is Not Linked to Calcium Formation or Calciuric Phenotypes in French-Canadian PATRICK SCOTT, DENIS OUIMET, YANICK GERALD GUAY, BERNARD GAGNON, LUC ALAIN BONNARDEAUX Service

de N#{233}phrologie and

Quebec,

Abstract. creased and

Calcium

production.

The

role

sibs,

using

analyses.

Sibs

with

1 17) had higher

a verified

24-h

interval

vitamin sibs

The

passage

from

a combination

a kidney

origin.

relatives

the

and

(

and

(n

urinary

serum

l,25(OH),

shows

absence

calcium idiopathic

non-

factors

urinary factors

potassium

as well

intake

Ncphrol

recurrent and has

have

between

of an affected

clustering,

It is usually in the

may

loss

of

and

predispose

the

as increased

demonstrated

proband

prevalence.

prevalence (parent,

For

stone

profamilial

for male

siblings

a value

higher

4,

insulin-dependent insulin-dependent

of the sibling,

analyses oxaluria,

calciuria

Ca/cr

formcrs)

ratios.

This

I a-hydnoxyla.se traits there

with

study locus

associated

to

with

is coaggregation

of

(I Am

stone

formation.

be estimated

to vary

1998)

model

of inheritance

younger

(7), disease

offspring)

the

lifetime

by

than about

stone

formation

mental

and

in and

when the

from

inactivating

termed

genetic

CLC-5;

factors

arc

stone

served

formation.

in monogenic

Nyhan

syndrome

ferase

deficiency)

et al. based

proportion

of affected

one of two oldest

relative

contribution

of environ-

of the with

to play

hyperoxalunia

in a renal 10),

In

addition,

such

chloride

also

that

in common

formation

as cystinunia

(hypoxanthine-guaninc

and

chan-

indicates role

stone

of

(8)

nephnopathy

a significant

disorders

molecular

the formation

hypcrcalciunic 9 and

is

to calcium

as primary

mutations

little

predisposing

elucidation

X-linked

siblings

However,

(5).

associated

references likely

lower than A polygenic

by Resnick

The

such

but 15).

=

2.5 non-

proposed

disorders (a rare

resulting

the

factors.

and

is a higher

of genes

or about

disease

=2),

are unaffected

number

genetic

(As (As

in which

both

nephrolithiasis,

calcium

A

there

from

hypertension

mellitus mellitus

in sibships

of monogenic

Dent’s

essential

has been that

siblings

known

nd

(As) can than

diabetes diabetes

on the observation

calcium

with an instudies, one

A factors

passage,

be excluded,

and

In addition,

to

is affected

excretion of calinclude decreased

termed

could

trait

or to quantitative

factor

bases surveys

locus.

locus

stone

formation

9: 425-432,

reveal

VDDJ

at the

and

phenotypes

not

recurrent

of the putative

oxaluric

stone-

did

Quantitative

of linkage

hypcrcalciuria. and

in

episodes)

sibs

to 24-h

D levels,

and

in 28 sib-

and

that

linkage

vitamin

stone

and

fonmens).

for

formcrs

(3

VDDI

to the

stone

evidence

stone

analyses

affected

a Ad of 2.0 (single

(recurrent no

recurrent

multipoint

among

formation

with

3.25

and

and

shared

of stone

(Cal serum

of environmental

include increased 1 ,2). Dietary risk

of family

ratios

Montreal,

with recurrent-only

Two-point

respectively,

Soc

result

factors

in alleles

revealed

=

chromosome

population,

can

excess

on

consequences. and

sibs.

Linkage

of single

(65 sib pains)

forming

calciuric

analyzed

sib pains)

0.02),

=

with

for kidney stone formation (4-6) for first-degree relatives. From such the

TROUVE,

H#{244}pitalMaisonneuve-Rosemoni,

(146

a 9-centiMorgan

is a common

medical

of metabolic

indices

population

locus

ships

and

linkage

(P

compared from

were

pain

intake (3). Large epidemiologic

extracting

oxalunia

0.02)

stone

Recognized

calcium,

derive

passage

in of

and/or infection. Calcium stones constitute the type of nephrolithiasis and are thought to result

to stone formation cium and oxalate

can

urobithiasis

VDDJ

intolerable

function prevalent

aggregation creased risk

trait

Markers

the

economic

renal most

fluid,

quantitative

I to 5% of the Caucasian

with

genetic

(P

120).

=

rate-

was evaluated at beast a pair

0.03),

=

la-hydroxylase)

of

associated

tein

D levels

affecting

important

(P

D

the

loading urine calcium/creatininc and P = 0.002, respectively), and

(ii

(putative

disorder

calcium

calciunia

encompassing

l2ql3-14

Guv-Bernier,

14 sibships

vitamin

I a-hydroxybasc,

and

in-

of calcium,

increased

vitamin D production, 28 sibships with qualitative

with

excretion

from

of the enzyme

fasting and postcalciuru en) ratios (P = 0.008 l,25(OH), stone-forming

associated

urine

to result

in active including

affected

often

and

suggested

limiting step 36 families,

is

absorption

been

de Recherche

PROULX, MARIE-LUCIE VALIQUETFE, and

Canada.

urolithiasis

intestinal has

Centre

Stone Families

(11

is ob),

Lcsch-

phosphonibosyltrans-

( 1 2), and adeninc

phosphonibosyltransferasc

Received July 9, 1997. Accepted September 22, 1997. deficiency ( I 3). Correspondence to Dr. Alain Bonnardeaux, Centre de Recherche Guy Bernier. Numerous studies have attempted to define the causes of H#{244}pital Maisonneuve-Roseniont, 5415 boul l’Assomption, Montr#{233}al, Qu#{233}bec, calcium stone formation by analyzing in vito and in vitro Canada HIT 2M4. biochemical markers related to calcium and oxalate ructaboI 046-6673/0903-0425$03.(X)/() bisru, and to inhibition of crystallization. Perhaps the most Journal of the American Society of Nephrology Copyright

U 1998 by the American

Society

of Nephrobogy

consistently

reported

anomaly

is

increased

urinary

calcium

426

Journal

excretion

of the American

(>0.

known

1 ruruollkg

per

cause,

i.e.

systemic

present

in approximately

only

5%

with

increased

in

the

Society

24 h). Hypercalciuria

population,

intestinal

that

idiopathic intestinal

(beading leak

idiopathic but rather

hypcrcalciunia the extremes by

hypercalciuric and

hyperabsonption,

hypercalciunia).

suggested

renal

with

However,

the

fact

that

are

various

now

deemed

degrees

event(s)

responsible

D pathway, intestinal explain

which

calcium this trait.

tribute

for

idiopathic

is the

only

hypencalciunia

hypercalciuria,

known

the

hormonal

and hence

D3 is the rate-limiting

vitamin

D3

(l,25(OH),D3).

percalciuria

maintain

similar

to

increased

urinary

percalciuric l,25(OH)2D3 infusion

given

of tnitium-labeled

changes inhibitor intestinal

calcium

is very

l,25(OH),D3,

absorption

and

subjects

renal

excretion

was

status.

and

an in

admin-

leukocytunia,

single,

and

urinary

Calcium

and

1 wk before

written)

to avoid

dairy

hydroxylase

locus

stone

formation

cium

metabolism

Materials Family

and

vitamin

putative

1 2q is not linked

or to intermediate and

the

phenotypes

to calcium

relevant

to cab-

D homeostasis.

the

first

Methods

informed

by institutional consent.

Probands

review with

comat least

ending

test was

two

Lunch gave

(i.e.

diarrhea, or small

Urine

elemental breakfast

glasses

(300

was delayed

yogurt,

samples

biochemical

were analyses

ml)

were

were

(verbal

and cheese)

and for 5 d

in 4-L disposable were instructed

verbally, a void, until

to initiate and

the

collect

the next

the morn-

void).

student

members

nurse

with

responsible urine

according

were

ascertained

a nephrologist

for the project

collection.

of water

were

calcium

protocol:

a 2-h

followed of 1 g of

Montreal, Quebec, Canablack coffee) was allowed, given

urine

to our institution performed

(Dr.

(P. Scott)

A supervised

to the following

after the final

transported

a

calcium

as diuretics,

defecation)

calcium (Novartis, (two pieces of toast,

until

hyper-

entailed

instructed

and

research

the 24-h

a

resection

restricted

as well

All family

performed

with (fever,

bowel

protocol

following

morning

radiologic Siblings primary

were collected Family members

during

ultrasound (renal colic,

status.

were

milk,

no

noted.

of infection

disease,

in writing

Test.

the trait.

a moderately

,

when

were

fasting urine collection (from 7 am. to 9 a.ru.) was obtained, by a 4-h collection (9 am. to 1 p.m.) after the ingestion

and

This study was approved

and all subjects

loading

Loading

effervescent da). A light

Ascertainment

Pedigrees. mittccs,

on chromosome

that

de-

resolution).

status

chronic

Patients

voided

on the morning

suggest

patient’s

from unaffected possible, to con-

evidence

supplements,

nurse,

1a-

results

(ra-

of pasthe total

no concomitant

phenotyping

immediately

urine

records when

for

under

products

or a Ph.D.

Our

to the

affection

The

sampling.

Bonnardeaux)

members.

bowel

vitamin

research

(including

stone

pyelogram

symptoms

but

culture),

collection

at 7 am.,

Calcium

definite

the unaffected

clinical

before the collection. Urine samples collection bags containing thymol.

ing

and

records

assessments

one

spontaneous

suggestive

an undetermined

24-h

(including

with

the hospital and x-rays),

with

Collection.

stopped

urine

sibs

the

clinical

according colic

of stone)

urine

assigned

by a clinical

for

of all

of a stone on an abdominal with suggestive symptoms

inflammatory

Urine

height,

passage

intravenous

as unknown

passage positive

also

24-h

weight,

symptoms when absence episode could be verified,

renal

no passage

af-

multiple

passage,

and/or

considered

large fected

that

participating

at least

We assigned

of stone

of stone

diet.

I a-hydroxylase formation, renal

with

After

analysis was performed on all stones available from biochemical analyses of stones from hospital records

and

by a clinical

descent

urology

we noted

sex,

where

determined and

concomitantly

of French-Canadian

or 36

relative

review

had

stone

calcium excretion, intestinal calcium absorption, and plasma 1,25(OH)2D3 bevels, we performed genetic linkage studies in families

records,

of stone

hospitals siblings

passage

were

collection

at the stone

at several

Age,

age

with suggestive If at least one

passage

were

(27).

To test whether genetic variation locus might be associated with calcium

respective

an unaffected

previous

Hy-

without

when

one and

city regions.

in each

a detailed

were retrieved. We also reviewed siblings (abdominal ultrasounds

parathyroidism,

(26). (4) Ketoconazole, induces a reduction

onset

by either

(stone

and

levels of Moreover,

increased

hospital

obtained

by

affected

of episodes

history a

(3)

and

the

verified

evidence

by the equilibrium are

recruited

and Quebec

Stones.

were

confirmed All

hematuria,

much

showing

( 19-22).

as measured

1 ,25(OH),D3,

to hypcrcalciuric

made.

episode

Renal

Episodes

from

were

for

Unaffected sibs with evidence or plain x-ray film and sibs

hy-

of calcium

excretion

in metabolic clearance rates of b,25(OH),D3 synthesis,

the

of active

that

probands

reviewing

pressure

were

available

firm

of calcium

idiopathic

absorption

calcium

rates,

study.

probands

Crystallographic the siblings,

to con-

may have increased plasma a free diet (17,23-25).

production

in the

blood

vitamin

hypothesis that could

with

balance

intestinal

fasting

subjects under

1,25(OH),D3

istered

subjects

of increased

sitting

scniption

for

in the formation

Subjects

a calcium

control

combination

step (2)

as

& Co.,

Traits

primary

stimulus

to the formation

from and

Status

dio-opaque stone) sage, or surgery.

and

stones, a disordered 1a-hydroxylasc activity is perhaps most attractive for the following reasons. (1) 1 a-Hydroxylation of vitamin

and

number

absorption, is a preeminent Among the candidate genes

to hypercalciuria,

of (18)

the

content Herring

and unaffected siblings and parents, parents were deceased. We ascertained

in the Montreal

interviews

Affection

of

proportion

regarding

C.

a family history of nephrolithiasis (at least interviewed by a clinical research nurse

clinics

Phenotvpic

D

“unclassifiable”

of fasting

intestinal calcium hyperabsorption. Although controversy persists

(Louis

26 of 36 families (28 sibships) comprised at least one pair of affected siblings with one or more verified episodes of nephrolithiasis.

beak

categories

a significant

calcium-oxalate

analysis

sibships

conducting

phos-

vitamin

these

of predominant

idio-

renal

increased

FL) and with sibling) were

French-Canadian

from

calcium

and

stone

crystallographic

and nephrobogy

might not represent specific entities of a continuous spectrum ( 17). This is

subjects

present

and results

to hypophosphatemia,

and

and this

of calcium,

of renal by

asked to contact affected intervening relatives when

reports

using standard seg(16) have proposed

excess

episode

Orlando, affected

associated

is heritable (14, 15), but

hypenparathyroidisru),

(leading

production,

also

calcium

dietary

one

determined

with

Sporadic

is heterogeneous

including

to secondary

phate

is usually

hypercalciunia dominant trait

hypercalciunia

of causes,

compared

absorption.

has not been rigorously tested analysis. Further investigations

a variety pathic

formcrs and

calcium

a is

without

hypercalciuria,

of stone

have suggested that idiopathic transmitted as an autosomal hypothesis negation

idiopathic

,

40%

general

of Nephrology

on the

at 9 am.

and

was collected on the same following

day.

I 1 am.

(I p.m.). day,

and

1a-Hydroxylase

Biochemical samples

Analyses.

was

determined

MO).

Biochemical

performed by

Serum

an

enzymatic

assay

l,25(OH),D3

Stillwater,

MN).

control

test

levels.

Serum

using

an RIA

levels

Interassay

sample

analysis

by an autoanalyzer.

and

intact

(Sigma

1 1.2%

Institute,

St.

was

with

levels

Juan

were

Capistrano,

three

Transmission

on

a

(+50%)

shown

assessed

genes

to be a powerful

heterozygous

CA).

Genotvping lymphoblastoid

from

cell

in linkage

lines.

disequilibrium

chromosome

l2q (VDDJ and telorueric

(D12S368)

amplified

well plates town, MA) (yP32)

We

used

with

the

established

marker

(D12S90)

a polymorphic putative

1 a-hydroxylase

a 9-centiMorgan

the dinucleotide

or from

region.

from

DNA

in 96-

under

standard

conditions.

gel electrophoresis ethylenediamine from reading were assigned

increasing

by

PCR

products

were

(6% polyacrylamide, tetra-acetic acid). the major bands starting at I for

1 for each

step

for the

to

and

1X were

each subject. Allele shortest allele, and

of I dinucleotide

repeat.

times

correct

for

a Sun ULTRA programs (29) distances ratio

I work were used

on our

at least with

to data

published

pairs

most

the next

likely

best

order)

for

Genetic

with

was

parameter-free shared

compared

(33).

Missing

mation rental

methods.

all pairs

number

of independent

available

were

two-affection

the proportion

(version

2.1)

from

estimated

status

i.e. from

in pairs

founders

in the

for at least one episode

(version

2.2) of SAGE.

available methods

to estimate

onset

in six different

status were

(affected, performed

with

24-h

Cockcroft-Gault

unaffected, using the

of alleles

creatinine

program

We

based

by each

unknown). Quantitative linkage squared sib-pair trait difference

shared (32)

identical-by-descent. within were

calcium

loading

used.

20%

of that

Regressions

were

X or

out of (X +

tests one should

that

have and

at least

five

P values

ratio-based

were

transmission

jointly

and

offspring but not in the TDTLIKE when

male

as well

their

sizes.

available that

test,

and

shown

index,

allows

the other program

genetic

infor-

reconstruct

pa-

of coru-

intervening

deceased

rela-

A total

of 237

of them.

and

unaffected)

a

serum

biochemical

24-h

underwent

urine

collection,

analyses.

2. There

or weight

sibs (not

number

pedignees

342

(affected

in Table

as the

The

included

height,

on female

for

were

shown).

There

a

Clinical

no differences

in affected

difference in unaffcctedlaffectcd ratios male siblings (P < 0.001) in complete

Table

1. Number sibships

of calcium according

No. of Affected Siblings per Sibship

of

bike-

of age

of

affection analyses regressed

unaf-

versus

was a significant

between sibships.

male Three

and fesets of

by the performed

stone-forming to disease

families

and

status No.

Status

of Sibships

I”

Status

2’

1

24

2

13

6

3

6

6

4

2

1

5

3

0

6

3

0

7

0

0

8

1

1

10

Total

no. of sibships

52

24

Total

no. of families

36

20

Affected b Affected

individuals individuals

Urine collections predicted

parents

completed

by

transmitted

all alleles

(including

was

are mass

on the infor-

maximum

parent’s

analysis

alleles

pedigrees,

siblings

evaluation

of stone passage.

uses

individuals DNA

clinical

used

severity

of the distribution

determined

excretions

formula

This

parameters

classes,

469 and

of stone passage). An subroutine program

was included,

in the pedigrees.

pro-

are computed

us to unequivocally

and

1 . Allele

families. to the

the

sibships

tives),

to the

minus

according

they

Siblings

and

multi-

according

of sibs

which In this

under

to calculate

weighted

number

,

of siblings,

(sibs concordant

on the number

expected

were

allowed

of with

with

considered,

considers

offspring

(34).

A likelihood

that

in detecting

children

of necessary

only

test been

the frequency

of heterozygous

genotypes

I describes

prised

likelihood scores) and allele all of the pair data available,

a sibship,

pairs,

(31)

and sibs concordant for at least three episodes age-of-onset covariate computed with the

lihood

qualitative in affected

TDTLIKE

Results

fected

markers

For

and

frequency

under

were

testing.

parental

analysis

distribution

the number way,

in the pedigree haplotypes.

characteristics

is similar

between

identical-by-descent

with

program

we used

mation

D/2S368-D12S90-

linkage

offspring

test (TDT)

same-generation

a likelihood

2.3 cM. This

the

affected

of the allele

multiple

disequilibrium

in body

point Lod scores (MLS, or maximum sharing with all three markers. To extract

AGEON

on

of independent segregation of marker and trait, using program (ANALYZE package) and SIBPAL programs from the SAGE. package (30). We also used the

MAPMAKERISIBS

the disease

(with

was and

compiled

and CRIMAP calculate genetic

order

of6.7

Method. of alleles

of a sibship

frequencies

programs

The MULTIMAP the markers and

intervals

analyzed

number

the hypothesis the SIBPAIR (version 2.6)

using

by G#{233}n#{233}thon.

was

the

The

over

Sib-Pair

traits

station. to order

sex-averaged

Affected traits.

performed

pedigrces.

1000:1

D12S83,

and

were

with

to be transmitted

corresponding

analyses

root,

the

all affected

comparing

a binomial

in an unbiased

Sibships

Analyses

All genetic

from

To reduce

opportunities

allele,

to their

to affected

Table Linkage

used

to sib-pair

that one allele be transmitted to affected alleles was also performed, as implemented

submitted

7 M urea, and genotypes

P values

Y) opportunities.

corrected

We enzyruat-

genomic

square

We

and evaluates

allele

allele

at the probability

more on

as well as centromeric to D12S90 from the

(cM)

repeats

gene

this

other

exact

alternative for a given

transmit

the

looking

using a thermal cycler (PTC-bOO; M. I. Research, Waterin 30 cycles of PCR with one of two primers end-labeled

denaturing Tris-borate determined numbers

leukocytes

locus; reference 28), (D12S83) markers

G#{233}n#{233}thon map spanning ically

peripheral

Test.

disequilibrium parents

they

gram, extracted

(untransformed,

Disequilibrium

in gametic

transmit was

of measurement

427

program ofthe ANALYZE package as an intrafamilial association on multiplex as well as simplex pedigrees (33). This test has

which

DNA

scales

Nephrolithiasis

log-transformed).

Louis,

24.4%

increased

(PTH)

San

were

by RIA (INCSTAR,

coefficient

hormone

bevels

Diagnostics,

on a sample

parathyroid

under

and serum

oxalate

were measured

variation

kit (Nicholls

of urine

Urine

in Calcium

a

with at least one episode with at least three episodes

of stone of stone

passage. passage.

428

Journal

of the American

Society

C

C C

-

C

C C

---C

+

+

r

C

+

ri C C

C

(I C C

twins

analyses).

C.’

stones

Q;; +

+

C

.

II

C1

II

II C

00

C

0

C

00

II

and

r-

stones).

C

Of

00

ammonium

II

+1

+1 rq

d

single

in

those,

d

C C

with

+1

Relatives

00

undetermined

r1 C

00

II

ri

C

0

-

5) 0

0 C,)

C N

O

+1

+1

CO

--CCC

+1 +1

+1 +1

-Cr

+1

r1t

5)

p

“C

‘i

“z1:

Q

0

C

+1 -

f2

0

the

latter

two

affection

with

three

one

uric

types

inflammatory for

and of

status,

was

acid

two

disease

acid

were

assigned

an

other

siblings

(af-

and

hyperparathyroidism,

were

uric

ncphrolithiasis).

of stones

as were

bowel

(18

one

calciuru-oxalate),

history

intermediate Phenotype

Phenotypes characteristics

previous

para-

respectively.

in Siblings are also included

this

difference

was

were

also

significant

increases

.C)

r1

00

00

-g

significant differences weight between affected

creatinine

ratios

The

urinary

24-h

forming

in

in Table

24-h calciunia and unaffected

only

significant

in

in fasting

and

2. There

corrected siblings.

for How-

women.

There

net

(z)

cabciuml

in affected

compared

with

unaffected

siblings.

oxalate

excretion

was

increased

in stone-

siblings

+1

+1

+1

+1

+1

+1

N

1 ,25(OH),D3

5)5)

compared

with

were

slightly

lings.

. .-

and

0 C

C

U

C

ri

C

C

(

C

C

C

r

---C

+1 +1 +1 +1

5)

\C

N

00 -

.0

C,)

C

Cr

II

II

non-stone

formers.

5)

C

cq

II

D12S368,

I C

‘i

-;

0 -.E

.

C

C

V 0

r1

C

z1

+1

+1

C

‘C C-.. C#{149}

C,)

+1 r’ C

+1

+1

L5

C

=

U

.e

.c

C,)

V

U 0

0_

ea

C)

E

a

shared

at

C)’,’ 5)

-c5) “0E

U ci

V0

.0

U

C-)

ei

C+_C._

0

E

ci

5)5)

Li

U

“CC)

5)0

._,

-c

.

sci

C

between

not

Serum

affected

sib-

calcium,

stone-forming

and

shown).

CO >

of the

]ct-Hydroxylase

1 3 alleles,

sibs,

shows

D12S90

(data

not

shown).

(LOD

score, locus

for

and

spectively. was in

also

4,

transmission ing

the

the

No

linkage

was

pairs

were

considered

on no

absence

present of linkage

that

allelic

not

associated

and

The

and for

simplex

in this

subset

to the

for

the

the

single-and-

phenotypes,

ne-

ANALYZE

package As

locus. putative

shown in

of pedigrees,

at the

allele

confirm-

Therefore,

the

1 a-hydrox-

-‘

eiead”

U Li

“1


10

ci0

U

and

ever,

0

0

(27

stones

-

“0

U

for all

sibships

calcium-phosphate,

phosphate,

CO

C

C)

-

ci

available 14

0

0

U

Crystalbo-

calcium

four

ci) C)

C

r-

ci 0

twin

from

predominantly

were body

Lt

5)

.-0

were

a known

with

fected)

0

5)

23

magnesium

+1

0

r

‘.co -;-

three

.c

f C

\

than

was

siblings

kidney

the affected

pregnancy.

of stones

affected

in the

of

(more

with

during

calcium-oxabate,

thynoidectomy 00

stone

included

presence

formers

analysis

22

the

discordant,

calcium-phosphate

C ,,:

+1

r’1

a

stone

was

one twin

for

C

predominantly

C

+1

pair

or biochemical

(spouse

00

recurrent

graphic

and

(only

concordant

one

passed

probands

I’

C

were

having

C

00

phenotyped

were

and

mixed 5)

were

Two

episodes),

c1

-

identical

ri

c

:

of Nephrology

susceptibility

to

calcium

Ia-Hydroxylase

Table

3.

Sib-pair

linkage

severity

of disease

Type

analysis

of calcium

and/or

No.

of Pairs

Affected

(

affected-affected

Affected (3 episodes) not affected-affected

a

Expected

ratios

LC

Expected

shared:nonshared

are 0.25,

:

Measurement

0.50.

of departure

from

1 Allele

IBDh

to

SignificanceC

2 Alleles

Shared

Not

Shared

x

P

43.6

0.01

NS

21.1

46.1

22.8

105.8

108.8

0.15

NS

1 1 .9

22.0

1 2.8

56.9

55.9

0.03

NS

1 8.6

42. 1

26.5

108.8

97.4

2.93

NS

4.3

6.8

8.4

26.8

19.7

2.60

NS

0.25

for sharing

is 50:50.

IBD,

expected

Status:

2 alleles,

respectively.

by descent.

shared:nonshared

(TDT)

At Least

0, 1 , and

identify

50:50

test

Transmitted

VDDJ

of the

(x

ratio

with

(D12S90)

1 dO.

locus

in 36

1 Episode

kidney

Affection

Not Transmitted

TDTi

Status:

Transmitted

ph

stone

pedigrees At Least

3 Episodes

Not Transmitted

TDT”

ph

2.78

0.43

1

14

8

1.64

0.60

7

2

2

37

44

0.60

1.00

18

24

5

21

20

0.02

0.98

11

6

6

24

31

0.89

1.00

11

17

1.29

1.00

7

55

40

2.37

0.37

28

23

0.49

0.87

8

14

19

0.76

1.00

0.91

1.00

Estimates h Corrected

for alleles that appear for multiple testing.

a

Genetic Linkage Analysis to Vitamin D Levels and Given

the

copies,

possibility

which

appropriate VDDI

locus

ularly

justified

strate

several

unia.

We

because

intestinal

oxalate

nine

before

ratios

complete

in Table

quantitative

5,

traits

sib-pain

no

square marginally but when group

genotypes are available values were noted (not lack

and

of

linkage

stringent

and

(and

for under

to scales

the analyses not

the

D12S90

definitions),

to

were

to

vitamin

in these

D physiology

and

hypercalciunia

We

have

with

barriers.

(since

tages

an

elevated defined

factors,

as well

to

disease,

susceptibility

any

with

the Mul-

noted

pairs

homogeneity

of the

the

of

the

decreased

with

detect

at close

1 (VDDI)

skeletal

in

25(OH)D3,

strongly

markers), suggests

no significant that, in addition

1a-hydroxybase dysfunction

activity (likely its p450 component) of a regulatory protein (35). Proof that

the

discrete

traits

(with

to quantitative

defect assay

involves on

decidual

suggests

that

I a-hydroxylation cells

from

of 1 a(OH)D3,

it is secondary

has patients

been with

The

but

not

to

to decreased

obtained the

and

changes.

group

which

is

phosphate,

smaller

doses

(VDDJ

gene type

specific

to physiologic

major

proximity

on to the

response

advan-

contributing

to

calcium,

severe

the

pool

power

rickets

located linguistic

to environmental

1 a-hydroxylase

plasma

and

have

markers

D deficiency

levels,

and of

due

of

popula-

because

obigogenic

used

putative

pedigrees

recently,

variability

have

locus

with

l,25(OH),D3

genetic

increasing We

putative

until area

size

thus

Pseudovitamin

associated

rate

of the large

homogeneous

geographic and

as the

studies from

a genetically

reducing

boci.

the

locus).

linkage

birth

Geographic of potentially

the

genetic in sibling

descent,

a well

As demonof

locus

French-Canadian

serum

of measure-

conducted

carried

no linkage

is

sibships.

1 a-hydroxylase

within

to calcium

load.

linkage

relevant

tion

calciumlcreati-

root, and log-transformed). significant P values were

for all three shown). This of

on

and

three

demon-

oxaluria

coupled

calcium

to

hypercabci-

analyses

evidence

obtained

0.66

Discussion

the

is partic-

pedigrees

linkage

an oral

it is

at

This

calciunia collections,

6

1.00

1.47

pheno-

study,

relevant

idiopathic

is indirectly

after

was

ment (untransformed, tiple test-corrected, oxalunia,

24-h urine

and

our

variation

in our to

traits present

phenotypes

sibs

genetic absorption

on

genetic

related

and

Locus

include

of

hypercalciuria.

affected

performed

absorption)

for 24-h

idiopathic

levels

might power

intermediate

characteristics

l,25(OH),D3

strated

to

and

the

5

0.86

times.

1 a-Hydroxvlase Phenotypes

whether

is linked

five

sibships

decrease

determine

handling

at least

of the Calciuric that

would

to

calcium

the

Alleles

according

37.4

Transmission/disequilibrium

Allele

relaxed

of Parental

locus

(D12S90)

5.0

and

ratio

Affection

to

No.

VDDI

17.9

affected-affected

entire

Sharing”

at the

I episode)

affected-affected

4.

disease

9.9

Unaffected

Table

stone

429

Nephrolithiasis

of Analysis 0 Alleles

not

radio-opaque

in Calcium

disease

the

or to basic

by direct (36).

In

430

Journal

Table

the American

of

5. Genetic

link age

significance

Trait

Society

analys

values

of Nephrology

is of quantitative

on

-

scales

Slope

of the Recression

Anal

per

rebated

pen

urine

the specific

kidneys

from

0.66

0.70

0.80

0.83

0.68 0.88

0.66 0.87

0.66 0.79

d

+0.01 +0.07 I .39

0.06

0.05

0.04

-

of calcium;

UOxV,

urine

oxalate

excretion.

with

deficiency

has been

analogous

disorder

the

Squared trait difference on the alleles IBD

confirmed (37).

in These

linkage is possible only when the value matrix, corrected for multiple testing.

multiplex

sib-pair

gathered

thus

far.

at

and

this

to

tionab

families,

would

be required

yses

presumably

linking

an effect from

through

disease

and

a gain

idiopathic

to VDDI

D12S90

isolated

population

of

of function,

is linked

hypercalciuria.

have

been

French

The

performed,

Canadians

linkage,

but also

linkage

in part,

with

disequilibrium.

that the genetic distance between the likely to be in the infra-centiMorgan

susceptibility

locus

formation (at least stone

fonmers)

This and

D12S90

range

predisposes

affection

that

mediate cluding

this

status.

locus

intestinal

absorption

as 24-h

allelic

phenotypes. dered posed

to calcium

urine

variation This

a major

These

results

any

VDDI boci is (38) and that

and

using

gene kidney

as a stone

we have

not found

variance

of inter-

an oral adding

calcium further

is not associated

load), evidence

with because

production to explain

has been proidiopathic hyper-

contributing apply

to calcium to the

stone

families

a disor-

formation

studied

here,

study

traits

allows

stone

conduct

segregation (penetrance

traditional

parametric

related

formed

scnibed

for

[39],

the

,

it is well

that and

status

trait,

and of

I

Addi-

linkage

analysis

effects.

in all

However,

it has

not

been

our

pedignees

to

would

indicate

genetic

pa-

gene

frequency)

For

stone

such

red

to use

intermediate

formation,

using

the

blood

inferred

no

in

quantitative data

are

available

the

the (42)

We and/or

that

Second,

cofactor

and

other

we

it is also still

frequencies

do

apply

not

only

abbe

possible

some

notes

to the

D12S90

investigate

this

locus

scientific

in

at

the

encodes

of the enzyme,

be of significant

of

are present

to

that

component

and

families.

provide

1a-hydroxylases

are

not the P-450

have

a

although

interest

even

if

case.

also

and

shown

oxaluric

radio-opaque

primary

purpose

sidening

that

published, homogeneous

findings

and

analyses

be performed to conbe valuable in demon-

across

we

[40],

linkage

(gene

could also

results

results,

that

countertnansport

parametric

]),

a segreeffect is been de-

enzyme

parameters

present

it is possible

moment.

[4 1

of the

these

First,

kidney

that gene have

sodium-lithium I-converting

genetic

homogeneity

region;

In the event

phenotype bevels) findings. This would

In publishing caution.

cell

E levels

corresponding roborate our strating

information.

angiotensin

immunogbobubin

calciuric

because

parents

analyses.

serum

calcium handling in certain individuals, hypothetical mutations of this gene must stone-forming population.

design

both

for

genetic

is a late-onset

for to the

of 0%).

parametric weaken

disease

available

consistent with that of a major well known major gene effects

the

the

sib-pair

fraction

function

to provide

gation pattern obtained (e.g.

would

an affected

respectively,

alternatively,

stone

boci contributing

3.25,

to calcium

were

used

kidney

on the proportion of phenotypic variability that would result from genetic effects. Segregation analyses on quantitative traits in nuclear families, as well as twin studies, should be per-

study

have

and

is negative.

of pairs

of major

analyses

rameters

calcium

at a necorubination

passage

that

We

exclusion

to detect

to phenotype

this

suited to situations in which inheritance of the trait is complex on unknown. To our knowledge, this is the largest collection of

the number

or,

and although they do not completely rule out the possibility that genetic variation at the 1a-hydroxylase locus has major effects on kidney stone formation or on intestinal and/or renal they do indicate that be uncommon in our

with

Presently, (Ad of 2.0

episodes,

possible

traits

pedigrees the

considered

3

kidney

relevant

important,

1 ,25(OH),D3 hypothesis

obviously

of the

after

excretion,

is particularly

trait

when

to 1 a-hydroxylase activity, inlevels, urinary calcium excretion,

at this locus

regulation of as a preeminent

calciunia,

Moreover,

(24-h oxalate

suggests

sibships by using a relaxed a more stringent (recurrent

explains

phenotypes relevant serum 1 ,25(OH),D3

as well

(22).

that

in our group of multiplex one stone passage) and

evidence

that

on

a founder

maximal power is achieved for linkage analyses this marker. We have excluded the putative 1 a-hydroxybase

and

anal-

dated 12 generations ago, and all affected individuals the same region carried the same allele (28), indicating

not only

Log

0.78

this

stone

nominal

Root

Square

its to

locus,

with

on Scalec

Untransformed

results strongly indicate that 1 a-hydroxybasc or one of cofactors is the defective protein, and that markers linked VDDI can be analyzed to evaluate whether genetic variation calcium

locus

0.65

enzyme

pigs

to the D12S90

-0.002

excretion

addition,

formation

P Values

Values for slopes are shown for untransformed phenotypes. p values for regression analyses of the squared differences

h

C

stone

.

sis

y

to calcium

measurement”

d

Ca/cr

UOxV/kg

UCaV,

a

of

+33.5

b,25(OH),D3 UCaV/kg

Fasting Calcr

traits

three

the

that

kidney

of the a number

there

phenotypes

study of

is familial with

stones.

and studies

use of family-based study design than

the

coaggregation passage

Although

this

is an expected on

the

of

of calcium was

not

the

finding

con-

have

been

subject

controls provides simple case-control

a more analysis.

Ia-Hydroxylase

Affected

sibs,

excretion

of

previous tion. excretion

be

intestinal

frequent our

and

of

excretion

calcium

loading

prevalent

in women,

trend

toward

excretion. affected

ble ages.

findings

reflect

factors

variance

This

with

findings,

the

This

study

A

with

case-control

the

vitamin

study,

production (from

hypercalciunia

and/or

encoding proteins and the intestine, zation

D receptor

inhibition will

calcium

of urine

be particularly

would

(syntenic)

human

boci

genetic

hypercalciunic

under through

way (45). subsequent

should

provide

weights

tion

As

estimation

idiopathic

hypencalciunia.

structure

and these

of calcium

stone

linkage studies

approaches

formation

and

4. 5.

cDNA cloned M,

Added

Since

for 25-hydroxyvitamin in the mouse (Takeyama Yanagisawa

hydnoxylase

1997), been

in Proof:

identified approaches

and

respective

stone be

6.

Parks

JH, Coe

Semiti

Nep/irol

and published

J,

Kato

and

vitamin

the

human (Monkawa

5:

faru-

cDNA

and

T, Yoshida

genomic

for calcium

Omdahl

used

with

recent IL,

rickets

(PDDR) 1997).

This

as a major

formation.

DNA

Kidney

Foundation

Dr. Bonnardeaux

du Qu#{233}bec.We

and

the

is a scholar

of

thank

Dr.

Kenneth

the

9.

Plenum,

atic kidney McGeown

of calcium

stones.

5, Shinki

10.

also T,

M,

Robertson

P1: The

in man:

main

Hypercal-

198 1 , pp 3-12 W, Rimm E, Stampfer M: A prospective study and other nutrients and the risk of symptom-

Pridgen

W,

N:

328: 833-838, stone disease.

D, Goodman oxalate

Peacock

1993 Cli,z

Sci

19:

M, Baker

strategies Am

C, Purdue

Molecular by

M,

for

J Hum of

predisposition N Engi

Marshall

1995,

Wrong

genetically

Genet

to

J Med

278:

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D, New

Ed., York,

pp 2385-2424 Fisher SE, Steinmeyer K, Schwappach B, Bolino A, Devoto M, Goodycr 0,

Ientsch

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common molecular basis for three eases. Nature 379: 445-449, 1996 Bonnardeaux A, Lapointe JY, Bichet An unturned Gaspanini

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stone

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Multilocus 8.

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D12S83

1552-1559,

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FL: Pathogenesis

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12:

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forma-

pathophysiology

this

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the

Speed R, Sergeant V. Smith epidemiology of urinary stone

hypercalciuria. submitting

site

determined

D-deficiency

supported

Council

McGraw-Hill,

Note

of

We

agreement

5,

kidney

formation of calcium 1313-1318, 1968

currently

are

to

were

465-471,

It

the optimal the

3.

excrc-

are

studies

ciuria or Research.

boci-

calcium

remain

elucidate

oxabate

Research

New

in

corresponding

oxabate

2.

D

candidates.

number

However,

should

ab-

1.

nor action Other

studies

to calcium

same

by the kidney on in crystalli-

to renal

of the

linked

of

is implicated

further candidate genes investigations, genome-wide

a first

lack

with

activity)

Such

calcium

tag

References

vitamin

at the

Medical

Combined

formation.

linked

map

in

Res

excluded

a

genes

the

(44).

be interesting

rat.

boci

Ultimately,

(on locus)

increased

to look

of genes

of genetic

and

ily

stone

important

tion

in the

locus

involved in calcium handling in the metabolism of oxabate,

have

on

Genet-

sequence

D12S90

> 15),

the Fonds de Recherche en Sante Morgan for helpful discussions.

linkage

a

expression)

we

the

1995).

Messerlian

Miner

gene

Research

STS-based

pseudovitaruin

J Bone

enzyruatically

Institute (Hudson TI, Stein Silva I, Slonim DK, Baptista

25-hydroxyvitamin

to the that

These at

nephrolithia-

1a-hydroxylase

vitamin

R,

Res

Acknowledgments

but

of candidate

neither

to

25-

Biophvs

of the

(BG4,

markers

score,

The

locus.

An

between

(Lod

FH:

for

panel

1945-1954,

(St-Arnaud

maps

gene

slightly

present

D12S90

study

confirms

compared

(23-25),

formation

that

increased

increased

receptor

stone

suggests

found

demonstrated

to the

and

this

(from

D

(43)

SH:

270:

we

3’ region

T: Mo-

human

on calciunic

calcium-oxabate study

centromenic

hypencalciunia

disease

is undetermined.

and

this

gene

the

results

in

menopause,

formers

of

is located

Gbonieux

stone

Xu

L,

gene

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