Novel genomic loci influencing plasma homocysteine levels.
OBJECTIVE
Genetic factors that influence interindividual variation in levels of plasma homocysteine, a risk factor for vascular disease, are not fully understood. We performed linkage analyses to identify genomic regions that influence homocysteine levels in blacks and non-Hispanic whites.


METHODS
Subjects (n=2283) belonged to hypertensive sibships and included 1319 blacks (63+/-10 years, 70% women) and 964 non-Hispanic whites (61+/-7 years, 57% women). Fasting plasma homocysteine was measured by high-pressure liquid chromatography. Genotypes were measured at 366 microsatellite marker loci distributed across the 22 autosomes. Plasma homocysteine adjusted for age, sex, body mass index, serum creatinine, and estrogen use (in women) was used in the genetic analyses. Heritability and linkage analyses were performed using a variance components approach.


RESULTS
Mean (+/-SD) homocysteine levels were 10.4+/-5.27 mumol/L in blacks and 10.0+/-2.84 micromol/L in non-Hispanic whites (P=0.58 for difference). Homocysteine levels were significantly (P<0.0001) heritable in blacks (h2=0.70) and in non-Hispanic whites (h2=0.49). Linkage analyses demonstrated significant evidence of linkage (multipoint logarithm of odds> or =3.0) for homocysteine on chromosomes 1q42, 14q32, and 19p13 in blacks and on chromosomes 9q34 and 12q24 in non-Hispanic whites. Tentative evidence of linkage (logarithm of odds 1.3 to 2.0) was present on chromosomes 2q32, 7p15, 8q24, 18q21, and 20p12 in blacks and chromosomes 6q26 and 18q21 in non-Hispanic whites. Four genes in the homocysteine metabolism pathway (MTR, DNMT1, GAMT, and CARM1) were present under 2 of the significant linkage signals in blacks (chromosomes 1q42 and 19p13).


CONCLUSIONS
Plasma homocysteine is a significantly heritable trait. Linkage analyses reveal several unique genomic loci that may influence circulating levels of homocysteine and therefore susceptibility to vascular diseases including stroke.
Kullo
Iftikhar J
IJ
Division of Cardiovascular Diseases, Mayo Clinic, Rochester, Minn 55905, USA. kullo.iftikhar@mayo.edu
Ding
Keyue
K
Boerwinkle
Eric
E
Turner
Stephen T
ST
Mosley
Thomas H
TH
Kardia
Sharon L R
SL
de Andrade
Mariza
M
D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase / Q000235:genetics; D001741:Black or African American / Q000235:genetics*; D000367:Age Factors; D000368:Aged; D015992:Body Mass Index; D002874:Chromosome Mapping; D002877:Chromosomes, Human / Q000235:genetics; D015331:Cohort Studies; D003404:Creatinine / Q000097:blood; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases / Q000235:genetics; D004967:Estrogens / Q000008:administration & dosage; D005260:Female; D005838:Genotype; D050937:Guanidinoacetate N-Methyltransferase / Q000235:genetics; D006710:Homocysteine / Q000097:blood*; D006801:Humans; D020138:Hyperhomocysteinemia / Q000208:ethnology / Q000235:genetics*; D008126:Lod Score; D008297:Male; D008875:Middle Aged; D011484:Protein-Arginine N-Methyltransferases / Q000235:genetics; D012307:Risk Factors; D012737:Sex Factors; D014481:United States / Q000453:epidemiology; D044465:White People / Q000235:genetics*
D004967:Estrogens; D006710:Homocysteine; D003404:Creatinine; D013766:5-Methyltetrahydrofolate-Homocysteine S-Methyltransferase; C494506:GAMT protein, human; D050937:Guanidinoacetate N-Methyltransferase; D011484:Protein-Arginine N-Methyltransferases; C119966:coactivator-associated arginine methyltransferase 1; D000076123:DNA (Cytosine-5-)-Methyltransferase 1; D004248:DNA (Cytosine-5-)-Methyltransferases; C000619380:DNMT1 protein, human